MX2008006162A - Combination vaccine comprising an attenuated bovine viral diarrhea virus - Google Patents

Abstract

The present invention relates to combination vaccines for the prophylaxis and treatment of microbiological infections in cattle which comprise an attenuated bovine viral diarrhea virus (BVDV) for the the prophylaxis and treatment of BVDV caused infections, and a further immunological active component for the prophylaxis and treatment of microbiological infections other than BVDV.

Description

COMBINED VACCINE COMPRISING A DIVERED VIRUS OF BOVINE VIRAL DIARRHEA FIELD OF THE INVENTION The present invention relates to the field of animal health and, in particular, to combination vaccines comprising an attenuated bovine viral diarrhea virus (BVDV) and by at least one additional immunological active component for treating or preventing diseases or disorders in cattle, caused by infectious agents. BACKGROUND OF THE INVENTION Bovine viral diarrhea virus (BVDV) type 1 (BVDV-1) and type 2 (BVDV-2) produce bovine viral diarrhea (BVD) and mucosal disease (MS) in the cattle (Baker, 1987, Moennig and Plagemann, 1992, Thiel et al., 1996). The division of VDVB into 2 species is based on significant differences at the level of genomic sequences (summarized in Heinz et al., 2000) that are also obvious from limited neutralizing antibody cross-reactions (Ridpath et al.1994 Viral proteins of BVDV, and any other virus of the pestivirus family, are arranged in the polyprotein in the order NH2-Npro-C-Erns-El-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH (Lindenbach and Rice, 2001.) Protein C (= core- or capsidprotein) and Erns, El and E2 glycoproteins represent the structural components of BVDV, and Erns and E2 were found to be targets for REF. : 191823 neutralization of the antibody (Donis et al., 1988; Patón et al., 1992. van Rijn et al., 1993; eiland et al., 1990, 1992). Erns lacks a typical membrane anchor and is secreted in considerable amounts from infected cells; it has been reported that this protein exhibits an RNase activity (Hulst et al., 1994; Schneider et al., 1993; indisch et al., 1996). The function of this enzymatic activity for the viral life cycle is unknown at present. The enzymatic activity depends on the presence of two stretches of amino acids conserved between the Erns pestivirus and different known RNases of plant and fungic origin. These two conserved sequences contain a histidine residue (Schneider et al., 1993). The exchange of each of these residues by lysine in the Erns protein of a vaccine strain against the Classical Swine Fever Virus (VFPC) caused the destruction of the RNase activity (Hulst et al., 1998). The introduction of these mutations into the genome of the VFPC vaccine strain did not influence viral viability or growth properties, but led to a virus exhibiting a cytopathogenic phenotype (Hulst et al., 1998). Similarly, Meyers et al. showed that a negative RNase variant of the virulent strain of the VFPC Alfort / Tubingen was fully viable. However, the respective virus mutant did not show a cytopathic phenotype (Meyers et al., 1999).

Npro represents the first protein encoded by the long open reading frame in pestivirus RNA. Npr0 represents a non-structural protein that has a protease activity and that cleaves itself from the nascent polyprotein (Stark et al., 1993; Wiskerchen et al., 1991), presumably already during translation. Npro is a cysteine protease (Rumenapf et al., 1998), which is not essential for virus replication (Tratschin et al., 1998). Recently, it has been shown that Npr0 interferes in some way with the antiviral cellular defense, so that the hypothesis of modulating the immune system inside an infected host can be made (Ruggli et al., 2003). Mayer and colleagues showed evidence of an attenuation of VFPC as a consequence of a deletion of the Npro gene (Mayer et al., 2004). The present vaccines against BVDV for the prevention and treatment of BVDV infections continue to have drawbacks (Oirschot et al., 1999) Vaccines against BVDV-1 provide only partial protection against BVDV-2 infection, and mothers Vaccinated animals can produce calves that are persistently infected with virulent VDVB-2 (Bolin et al., 1991, Ridpath et al., 1994). This problem is probably due to the great antigenic diversity between type 1 and type 2 strains, which is the most marked in glycoprotein E2, the main antigen for virus neutralization (Tijssen et al., 1996). Most monoclonal antibodies against type 1 strains can not bind to type 2 viruses (Ridpath et al., 1994). Currently, authorized VVV vaccines of BVDV are produced using attenuated viruses obtained by repeated passage in bovine or porcine cells (Coggins et al., Cornell Vet. 51: 539-, 1961; Philips et al., Am. J. Vet. Res. 36: 135-, 1975), or using chemically modified viruses that exhibit a temperature-sensitive phenotype (Lobmann et al., Am. J. Vet. Res. 45: 2498-, 1984; 47: 557-561,1986 ). A single dose of the vaccine with the VVM is sufficient for immunization, and the duration of immunity can last for years in vaccinated cattle. However, since these vaccines have been developed using VDVB type I virus strains, protection is against type I virus only. In addition, these vaccines, although attenuated, are very often associated with safety problems. Vaccine viruses can cross the placenta of pregnant animals, p. ex. cows, and can lead to clinical manifestations in the fetus and / or induction of persistently infested calves. Therefore, they can not be applied to breeding flocks containing pregnant cows. Pregnant cows have to stay away from vaccinated cattle to protect the fetuses and should not be vaccinated themselves. Parainfluenza virus 3 (PI-3) is an RNA virus classified within the paramyxovirus family. Infections caused by PI-3 are common in cattle. Although PI-3 is capable of causing disease, it is usually associated with mild to asymptomatic infections. The most important function of PI-3 is to act as an initiator that can lead to the development of secondary bacterial pneumonia. Clinical signs include pyrexia, cough, nasal and lacrimal serous secretion, increased respiratory rate and increased breath sounds. The intensity of the signs worsens with the onset of bacterial pneumonia. Pneumonia victims without complications from PI-3 are rare. The lesions include cranioventral lung consolidation, bronchiolitis and alveolitis with severe congestion and hemorrhage. Inclusion bodies can be identified. Most fatal cases will also have a bacterial bronchopneumonia. The Bovine Syncytial Respiratory Virus (VRSB) is an RNA virus classified as a pneumovirus of the paramyxovirus family. In addition to cattle, sheep and goats can also be infected with respiratory syncytial viruses. This virus owes its name to its characteristic cytopathic effect, the formation of syncytial cells. It is known that there are antigenic subtypes for RSVB, and preliminary data suggest that there may be antigenic subtypes of RSVB. VRSB is distributed throughout the world and is indigenous to the cattle population. RSV infections associated with respiratory disease occur predominantly in young cattle and dairy cows. Passively derived immunity does not appear to prevent RSV infection but will reduce the severity of the disease. Initial exposures to the virus are associated with severe respiratory disease; Subsequent exposures produce mild or asymptomatic disease. VRSB appears to be a major virus in the bovine respiratory disease complex due to its frequency of occurrence, its predilection for the lower respiratory tract and its ability to predispose the respiratory tract to secondary bacterial infections. In epidemic outbreaks, the morbidity tends to be high, the lethality can be 0-20%. Signs include increased rectal temperature to 40-42 ° C, depression, decreased food intake, increased respiratory rate, cough, and runny and lacrimal discharge. In general, respiratory signs predominate. Dyspnea may become pronounced in later stages of the disease. Sometimes subcutaneous emphysema manifests. Secondary bacterial pneumonia is a frequent manifestation. A biphasic disease pattern has been described but it is not consistent. Macroscopic lesions include diffuse interstitial pneumonia with subpleural and interstitial emphysema along with interstitial edema. These lesions resemble other causes of interstitial pneumonia and must be differentiated. See also atypical interstitial pneumonia. Histological examination reveals syncytial cells in the bronchiolar epithelium and lung parenchyma, intracytoplasmic inclusion bodies, proliferation and / or degeneration of the bronchiolar epithelium, alveolar epithelialization, edema and formation of the hyaline membrane. The bovine herpes virus (HBV-1) is associated with several diseases and symptoms in cattle: infectious bovine rhinotracheitis (IBR), pustular infectious vulvovaginitis (VIP), balanoposthitis, conjunctivitis, abortion, encephalomyelitis and mastitis. Only one serotype of HBV-1 is recognized; however, three subtypes of HBV-1 have been described based on viral DNA endonuclease cleavage patterns. These types are called HBV-1.1 (respiratory subtype), HBV-1.2 (genital subtype) and HBV-1.3 (encephalic subtype). Recently, VHB-1.3 has been reclassified as a different herpes virus called HBV-5. HBV-1 infections spread in the cattle population. In cattle of closed corrals. { feedlot), the respiratory form is the most common. Viral infection alone is not life threatening but predisposes cattle to secondary bacterial pneumonia, which can lead to death. In breeding cattle, genital infections or abortion are the most common. Genital infections can occur in bulls (pustular infectious balanoposthitis) and cows (VIP) within 1-3 days of mating or close contact with an infected animal. Transmission can occur in the absence of visible injuries and through artificial insemination with semen of asymptomatic infected bulls. Cattle with HBV-1 infections generally do not show clinical signs when the virus is reactivated, but definitely act as a source of infection for other susceptible animals and perpetuate the disease. The incubation period for respiratory and genital forms is 2-6 days. In the respiratory form, clinical signs vary from mild to severe, depending on the presence of secondary bacterial pneumonia. Clinical signs include pyrexia, anorexia, cough, excessive salivation, nasal discharge that progresses from serosa to mucopurulent, conjunctivitis with lacrimal discharge, inflamed nasal orifices (this is why the common name "red nose"), and dyspnea if the larynx is occluded with purulent material. Pustules can develop in the nasal mucosa and later form diphtheritic plaques. Conjunctivitis with corneal opacity may occur as the only manifestation of HBV-1 infection. In the absence of bacterial pneumonia, recovery generally occurs 4-5 days after the onset of clinical signs. Abortions can occur concurrently with the respiratory disease, but they can also occur up to 100 days after infection. Abortions can occur regardless of the severity of the disease in the mother. Abortions generally occur during the second half of pregnancy, but premature embryonic death may also occur. The first signs of genital infections in cows are frequent urination, elevation of the tail and light vaginal discharge. The vulva becomes inflamed and small papules appear, then erosions and ulcers on the mucosal surface. If secondary bacterial infections do not appear, the animals recover after 10-14 days. If bacterial infections appear, there may be an inflammation of the uterus and transient infertility, with purulent vaginal discharge for several weeks. In the bulls similar lesions appear in the penis and the foreskin. Infection with HBV-1 can be severe in young calves and cause widespread disease. Pyrexia, ocular and nasal secretions, dyspnea, diarrhea, incoordination and possibly seizures and death in a short period after the generalized viral infection can occur. IBR is rarely fatal in cattle, unless it is complicated by bacterial pneumonia. In IBR infections without complications, most injuries are limited to the upper respiratory tract and the trachea. Petechial to ecchymotic hemorrhages can be observed in the mucous membranes of the nasal cavity and paranasal sinuses. Focal areas of necrosis may develop in the nose, pharynx, larynx and trachea. The lesions can be allied to form plaques. The breasts are often filled with a serous or serofibrinous exudate. As the disease progresses, the pharynx is covered with a serofibrinous exudate, and fluid dyed with blood can be found in the trachea. The pharyngeal and pulmonary lymph nodes can become very inflamed and hemorrhage. Tracheitis can spread to the bronchi and bronchioles; When this happens, the epithelium breaks off in the airways. Viral lesions are usually masked by secondary bacterial infections. In young animals with generalized HBV-1 infection, erosions and ulcers superimposed with particles in the nose, esophagus and anterior stomach can be found. In addition, white foci can be found in the liver, kidneys, spleen and lymph nodes. Aborted fetuses may have pale, focal, necrotic lesions in all tissues, but they are especially visible in the liver. It has been identified that a large number of other Bovine Respiratory Viruses are involved in bovine respiratory disease. The bovine herpes virus 4 has been implicated in various diseases, including bovine respiratory disease. Bovine adenovirus has been associated with a broad spectrum of diseases, with bovine adenovirus type 3 being the serotype most commonly associated with bovine respiratory disease. It has been recognized that two serotypes of bovine rhinovirus cause respiratory tract infections in cattle. Other viruses that are described have been associated with bovine respiratory disease include reovirus, enterovirus and bovine coronavirus. These viruses have a similar function to the other viruses previously analyzed in the sense that, in combination with other stressors, they can act as initiators of bacterial pneumonia. In calves, the bovine coronavirus is also commonly associated with diarrhea. It replicates in the epithelium of the upper respiratory tract and in the enterocytes of the intestine, where it produces lesions similar to rotavirus, but it also infects the epithelial cells of the large intestine until it produces the atrophy of the colonic rims. There are no vaccines available for the prevention of these viral respiratory diseases. Bovine rotavirus is the most common viral cause of diarrhea in calves. Rotavirus of groups A and B are involved, but group A is the most prevalent and clinically important, and contains several serotypes of different virulence. Rotavirus replicates in the mature absorbent and enzyme-producing enterocytes in the villi of the small intestine, leading to rupture and detachment of the enterocytes with release of the virus until infecting adjacent cells. Rotavirus does not infect the immature cells of the crypts. With virulent rotavirus strains, the loss of enterocytes exceeds the ability of intestinal crypts to replace them; consequently, the height of the villi is reduced, with a consequent decrease in the surface area of intestinal absorption and digestive intestinal enzymatic activity.

Other viruses, including Breda virus, a calici virus, Adenovirus, Astrovirus and Parvovirus, have been demonstrated in the feces of calves with diarrhea, and can cause diarrhea in experimental calves. However, these agents can also be demonstrated in the feces of healthy calves. The importance of these agents in neonatal diarrhea syndrome should still be determined. Manheimia haezaolytica (formerly Pasteurella has emolytica) biotype A, serotype 1, is the bacteria most frequently isolated from the lungs of cattle with bovine respiratory disease. Although it is cultivated less frequently than M. ha emolyti ca, Pasteurella multocida. It is also an important cause of bacterial pneumonia. When a lung abscess occurs, usually in association with chronic pneumonia, Actinoxpyces pyogenes is frequently isolated. Under normal conditions, M. haemolyti ca remains limited to the upper respiratory tract, in particular to the tonsillar crypts, and it is difficult to obtain a healthy bovine cattle culture. After a viral infection or stress, the replication rate of M. haemolyti ca in the respiratory tract increases rapidly, as does the probability of culturing the bacterium. The rate of bacterial proliferation and colonization of the lungs may be due to the suppression of the host defense mechanism related to stressors or viral infections. It is during this phase of logarithmic growth when the virulence factors are elaborated by M. haemolyti ca, such as an exotoxin that has been called leukotoxin. The interaction between the virulence factors of the bacteria and the host defenses produces tissue damage and the development of pneumonia. The clinical signs of bacterial pneumonia are often preceded by signs of viral infection of the respiratory tract. With the onset of bacterial pneumonia, the intensity of clinical signs increases, and they are characterized by depression and toxemia. There will be pyrexia (40-41 ° C); serous to mucopurulent nasal discharge; wet cough; and a rapid and superficial respiratory rate. The auscultation of the cranioventral lung field reveals an increase in bronchial noises, crackles and dry rales. In severe cases, pleurisy may occur, characterized by a pattern of irregular breathing and grunting at expiration. The animal will look unprofitable if the pneumonia becomes chronic, which is usually associated with the formation of lung abscesses. M. haemolyti ca causes severe acute fibrinous pneumonia or fibrinonecrotic pneumonia. Pneumonia has a bronchopneumonic pattern. In general terms, there are extensive cranioventric regions of a reddish-black to grayish-brown color of consolidation with gelatinous thickening of the interlobular septa and fibrinous pleuritis. Extensive thrombosis, foci of pulmonary necrosis and limited evidence of bronchitis and bronchiolitis occur. P. mulcidae is associated with less fulminant fibrinose to fibrinopurulent bronchopneumonia. Unlike M. haemolytica, P. multocida is associated only with small amounts of fibrin exudation, certain thrombosis, limited pulmonary necrosis, and suppurative bronchitis and bronchiolitis. Haemophilus somnus is increasingly recognized as a major pathogen in bovine respiratory disease; These bacteria are normal inhabitants of the nasopharynx of cattle. The pulmonary infection by H. somnus produces purulent bronchopneumonia that can be followed by septicemia and multiorgan infection. Occasionally, H. somnus is associated with extensive pleuritis. H. somnus can cause an acute, usually fatal, septicemic disease, which may involve the nervous, musculoskeletal, circulatory and respiratory systems and apparatus, either individually or together. The reproductive system is frequently affected, but usually without clinical involvement of the other systems or devices. The disease can be characterized by fever, intense depression, ataxia, weakness, blindness, coma and death after a few hours or a few days. Occurs sporadically in cattle and dairy cows, and is found almost everywhere in the world. H. somnus is a gram-negative, mobile, pleomorphic coccobacillus that does not form spores, which requires an enriched medium and a microaerophilic atmosphere for cultivation. It seems to be identical to Histophilus ovis and Haemophilus agni, etiological agents of septicemia, mastitis and ovine epididymitis; however, the transmission of H. somnus between sheep and cattle has not been demonstrated. The pathogenic and non-pathogenic strains have been differentiated by intracisternal inoculation of young calves with organisms from different sources. The pathogenic and nonpathogenic strains of H. somnus are carried in the sheath and the prepuce of the males, the vagina of bovine females and the nostrils of both sexes. The organism can colonize the airways, probably after inhalation, and is often found in the urine. The prevalence of the organism in cattle is probably high since high titers of specific antibodies are found in a large proportion of bovine animals ed. Various syndromes caused by H. somnus have been recognized, including thrombomeningoencephalitis, fibrinopurulent bronchopneumonia, fibrinous pleuritis, and polyarthritis. Muscular necrosis of the myocardium and skeleton occurs. Suppurative vaginitis, cervicitis and endometritis have been documented in experimentally and naturally infected cows after crossing, and the organism is a cause of sporadic abortion. The strains of H. somnus that cause the disease adhere to the endothelium of the vessels, producing contraction, collagen exposure, platelet adhesion and thrombosis. TME occurs when this occurs in the brain and associated membranes, after invasion of the organism into the bloodstream of susceptible cattle. Strains may attach to the endothelium of the pleura, myocardium, synovium, or a variety of other tissues, and cause inflammation at these si(eg, infections of the larynx and middle ear have been reported). The susceptibility of individual animals and variations in the preference of strains of the organism by vessels in different tissues may be important in the development of the disease form, but the mechanisms involved are not fully understood. Reproduction problems may not necessarily be preceded by bacteremia, but the pathogenesis has not been well defined. In general, fever of 42 ° C is the first sign of the disease; however, the temperature usually decreases to normal or subnormal levels after a few hours. Other findings are determined by the system or systems involved and can include rapid breathing, stiffness, knuckle formation in the giblets, intense depression, ataxia, paralysis and opisthotonos, followed by coma and death after several hours. Affected animals may suffer from blindness and retinal hemorrhages are sometimes observed with gray spots of retinal necrosis. Discordant signs such as hypersensitivity, convulsions, excitement, nystagmus, and circular turns are manifested, and may be related to the affected CNS regions during the course of the disease. Occasionally, animals are found dead, suggesting a rapidly fatal course. It is common for there to be a marked change in the total and differential leukocyte count; leukopenia and neutropenia occur in severe, usually acute and fatal disease, while neutrophilia can occur in less severe disease. In TME, the total cell count of CSF increases markedly, and neutrophils predominate. During septicemia, the organism can recover from blood, synovial fluid, CSF, brain, kidneys, urine and a variety of other organs. The lesions are characterized by vascular thrombosis and infarction of the surrounding tissue. The red-brown necrosis foci randomly distributed with surface haemorrhage and sections of the brain and spinal cord, retina, skeletal muscle, myocardium, kidney, inine and spleen are characteristic. Fibrinopurulent meningitis with cloudy CSF may sometimes be seen on the surface of the brain and spinal cord, and polyserositis may occur, especially of the joints and pleura. Acute fibrinous bronchopneumonia with tissue necrosis may develop after airborne infections. The exact function of mycoplasmas and ureaplasmas in bovine respiratory disease requires a better definition. Mycoplasmas can be recovered from the respiratory tract of non-pneumonic calves, but the frequency of isolation is higher in those with respiratory disease. Mycoplasmas commonly recovered from the lungs of pulmonary calves include Mycoplasma dispar, Mycoplasma bovis and Ureaplasma spp. Experimental infections usually produce latent or mild signs of respiratory disease. This does not prevent a synergistic function of mycoplasmas together with viruses and bacteria in bovine respiratory disease. The lesions described include peribronchial and peribronchial perivascular lymphoid infiltrate and alveolitis. The cultivation of these organisms requires special means and conditions, and the proliferation of organisms can take up to a week. Chlamydia has been identified in different parts of the world as a cause of enzootic pneumonia in calves. The causative agent is Chlamydia psittaci. Some respiratory isolates of calves have the properties of immunotypes 1 and 6 and are similar to strains recovered from intestinal infections and abortions of cattle and sheep. Immunotype 6 has been recovered from pneumonic lungs of calves and pigs. Therefore, the gastrointestinal tract should be considered an important site in the pathogenesis of chlamydial infections and as a natural reservoir and source of organisms. Chlamydia pneumonia has affected calves under a full range of conditions as well as dairy farms. A synergy between Chlamydia and P. haemolyti ca has been experimentally demonstrated. Calves with chlamydia pneumonia usually have fever, lethargy, and dyspnea, and have a serous, mucopurulent nasal discharge and a dry cough. Weaned calves are the most frequently affected, but older cattle can also show signs. Acute lung injury is a bronchointerstitial pneumonia. The anteroventral parts of the lungs are affected but, in severe cases, the lobes may be involved. Dry cough is attributed to tracheitis. Microscopic changes in the lungs include suppurative bronchitis and alveolitis that progress to type II pneumocyte hyperplasia and interstitial thickening. Bovine genital campylobacteriosis is a venereal disease of cattle characterized mainly by premature embryonic death, infertility, prolonged calving and, occasionally, miscarriages. It is probably distributed all over the world. The cause is the bacterium Campylobacter fetus venerealis or mobile Campylobacter fetus fetus, gram-negative, curved or spiral, polar and flagellated. For many years it was believed that C. fetus fetus (formerly C. fetus in tes tinalis) was generally an intestinal organism that caused abortions in cattle only occasionally and was not a cause of infertility. However, it has been shown that C. fetus fetus can also be an important cause of classical infertility syndrome usually attributed to Campyl oba cter fetus venerealis. There are several strains of C. fetus fetus, and the only way to determine if a strain is a cause of infertility is to test that possibility in a group of heifers. Campyloba cter spp are very labile and are rapidly destroyed by heat, drying and exposure to the atmosphere. Unless they are cultured rapidly after they are harvested from the animal and are grown under microaerophilic or anaerobic conditions, campylobacters will not proliferate. LaCampyloba cter fetus is transmitted in venereal form and also by contaminated instruments, straw bedding or by artificial insemination using contaminated semen. Susceptibility to infection varies in each bull as some become permanent carriers, while others appear to be resistant to infection. The bulls can also transmit the infection mechanically for several hours after copulating with an infected cow. In cows, the duration of the carrier state is also variable; some eliminate the infection quickly, while others can carry C. fetus for = 2 years. IgA antibodies are spread in cervical mucus in significant amounts in -50% of cows for several months after infection and are useful from a diagnostic point of view. While most of the genital tract may be free of infection when a cow eventually conceives, the vagina may remain chronically infected, even during pregnancy. Cows are systemically normal, but there is a variable degree of mucopurulent endometritis that causes premature embryonic death, prolonged luteal phases, irregular stromal cycles, repeated crossover and, as a consequence, prolonged calving. Observed abortions are not common. In herds not intensively controlled, the disease can only be observed when pregnancy tests reveal low or marginally low pregnancy rates but, more importantly, due to large variations in gestation periods, especially when the disease is recent in the herd. In subsequent years, infertility will usually be limited to replacement heifers and some susceptible cows. The bulls are asymptomatic and produce normal semen. Leptospirosis is a contagious disease of animals, including man, caused by various immunologically distinct leptospiral serovars, most of which are considered subgroups of Leptospira interrogans. Infections may be asymptomatic or cause various signs including fever, jaundice, haemoglobinuria, renal failure, infertility, miscarriage and death. After acute infection, leptospires are often located in the kidneys or reproductive organs and spread in the urine, sometimes in large amounts for months or years. Since organisms survive in shallow waters for extended periods, the disease is waterborne. In the United States, the disease is mainly due to the serovars Leptospira hardjo, Leptospira pomona and Leptospira grippotyphosa. However, the serovars Leptospira canicola and Leptospira icterohaemorrhagiae have also been isolated. The calves may suffer from fever, anorexia and dyspnea and, in infections by Leptospira pomona, jaundice, hemoglobinuria and anemia. The body temperature can suddenly rise to 40.5-41 ° C. Hemoglobinuria occasionally lasts more than 48-72 hours. Jaundice quickly subsides and anemia follows. The number of erythrocytes begins to increase after 4-5 days and returns to normal values 7-10 days later. However, Leptospira hardj infections usually do not cause hemolytic anemia, which makes diagnosis difficult. Morbidity and mortality is higher in calves than in adult cattle. In older cattle, the signs vary widely and the diagnosis becomes more difficult. Leptospira hardj or enzootic infections, which usually produce abnormal milk, are more evident in dairy cows than in cattle. Signs are usually limited to less milk and calf production; there is no hemolytic crisis. The milk is thick, yellow and tinged with blood; It may contain clots, although there are few signs of breast inflammation. Milk production returns to normal at 10-14 days, even in the absence of a treatment. Abortions and stillbirths, which are common in Leptospira pomona and sporadic infections in Leptospira hardj infections, generally occur 3-10 weeks after the initial infection. Abortions are more common during the third trimester. A simultaneous series of abortions in a breeding flock is usually the first sign of leptospirosis, since the initial mild signs often go unnoticed. In flocks enzootic infected, abortions occur mostly in younger animals and are sporadic, rather than manifested in series. Calves raised by previously infected cows are protected with antibodies from colostrum for up to 6 months. The calves in general have an antibody titre similar to that of their mothers. In the acute form, anemia, jaundice, hemoglobinuria and submucosal hemorrhages are prominent. The kidneys become inflamed, with multifocal petechia and ecchymotic hemorrhages that turn pale with time. The liver can swell, with tiny areas of focal necrosis. Petechiae are observed in other organs in fulminating cases; However, in Leptospira hardj or more prevalent infections, the lesions are mainly limited to the kidneys. Brucellosis is caused by bacteria of the genus Brucella and is characterized by abortion, retention of placenta and, to a lesser degree, orchitis and infection of accessory sex glands in males. The disease in cattle, buffalo from India and bison is caused almost exclusively by Brucella abortus; however, Brucella suis or Brucella melitensis is occasionally implicated in some herds of cattle. The Brucella sui s does not seem to spread from one cow to another. The infection spreads rapidly and causes many miscarriages in unvaccinated herds. Typically, in a herd in which the disease is enzootic, the infected cow aborts only once after exposure; the subsequent pregnancies and lactations appear to be normal. After exposure, many cattle become bacteremic for a short period and develop agglutinins and other antibodies; others resist infection, and a small percentage of infected cows recover. A positive serum agglutination test usually precedes abortion or a normal delivery but can be delayed by -15% of the animals. The incubation period can be variable and is related to the stage of gestation at the time of exposure. The organisms are spread in the milk and vaginal secretions, and the roof can suffer temporary sterility. Bacteria can be found in the uterus during pregnancy, uterine involution and, infrequently, for a long time in the uterus without pregnancy. The spread through the vagina disappears to a large extent with the reduction of fluids after delivery. Some infected cows that previously aborted disseminated brucellae through the uterus in subsequent normal deliveries. Organisms are spread in milk for a variable period of time in most cattle, and this happens for life. Natural transmission occurs by ingestion of organisms, which are present in large quantities in aborted fetuses, fetal membranes and uterine secretions. Cattle can eat contaminated food and water or lick contaminated genitalia from other animals. The venereal transmission of infected bulls to susceptible cows seems to be infrequent. Transmission can occur by artificial insemination when semen contaminated with Brucella is deposited in the uterus but, as has been reported, not when it is deposited on the cervix. Brucellae can enter the body through mucous membranes, conjunctivae, wounds or even intact skin. Mechanical vectors (eg, other animals, including man) can spread the infection. The Brucellae has been recovered from the fetuses and fertilizer that has remained in a cold environment during > 2 months. Direct exposure to sunlight destroys organisms after a few hours. Abortion is the most obvious manifestation. Infections can also lead to stillborn or weak calves, retention of placentas, and decreased milk production. Usually, general health is not impaired in uncomplicated abortions. Semen vesicles, blisters, testicles and epididymides may be infected in bulls; therefore, organisms are found in semen. The agglutinins can be demonstrated in the seminal plasma of infected bulls. Testicular abscesses can occur. Long-term infections can result in arthritic joints in some bovine animals. Actinomyces (Corynebacterium) pyogenes causes sporadic abortion in the last trimester. Infrequently, the incidence in a herd can reach enzootic levels (64%). Bacteria are present in the mucous membranes of many normal cows, as well as in uterine and abscess secretions. Access to the bloodstream and cause endometritis and placentitis, which is diffuse with a reddish brown to brown color. The fetus is self-limited, with the possibility of fibrinous pericarditis, pleuritis or peritonitis. Clostridia consists of relatively large organisms, anaerobes, spore-forming, rod-shaped organisms. The spores are oval, sometimes spherical, and are central, subterminal or terminal. The vegetative forms of clostridia in the interstitial fluid of infected animals occur individually, in pairs or infrequently in chains. The differentiation of the different pathogenic species and related species is based on the characteristics of culture, the shape and position of the spores, the biochemical reactions and the antigenic specificity of toxins or surface antigens. The natural habitats of organisms are the soil and the digestive tract of animals, including man. Pathogenic strains can be acquired from susceptible animals by contamination of wounds or by ingestion. The diseases thus produced are a constant threat to the successful production of all types of livestock in many parts of the world. Clostridium haemolyticum is an organism that is transmitted through the soil, which can be found naturally in the gastrointestinal tract of cattle. It can survive for long periods in contaminated soil or carcass bones of animals that have been infected. After ingestion, the latent spores eventually lodge in the liver. The incubation period is extremely variable, and the onset depends on the presence of a locus of anaerobiosis in the liver. The germination nest is very often caused by infection by a trematode, less frequently by a high nitrate content in the diet, accidental liver puncture, liver biopsy or any other cause of localized necrosis. When the conditions for anaerobiosis are favorable, the spores germinate, and the resulting vegetative cells multiply and produce β-toxin (phospholipase C), which causes intravascular hemolysis and its sequelae, including hemolytic anemia and hemoglobinuria. The cattle can be found dead without premonitory signs. Usually, there is a sudden onset of severe depression, fever, abdominal pain, dyspnea, dysentery, and hemoglobinuria. Anemia and jaundice are present in varying degrees. It can cause chest edema. The levels of Hgb and erythrocytes decrease a lot. The duration of clinical signs varies between -12 hours in pregnant cows and -3-4 days in the rest of the cattle. Mortality in untreated animals is -95%. Some bovine animals suffer asymptomatic attacks of the disease and from there act as immune carriers. Dehydration, anemia and, sometimes, subcutaneous edema occur. There is a bloody fluid in the abdominal and thoracic cavities. The lungs are not severely affected and the trachea contains bloody foam with mucosal hemorrhages. The small intestine and occasionally the large intestine have hemorrhages; its contents frequently contain free or coagulated blood. An anemic infarct in the liver is virtually pathognomonic; it is slightly elevated, lighter in color than the surrounding tissue and is highlighted by a bluish red congestion zone. The kidneys are dark, friable and usually splashed with petechiae. The bladder contains violet-red urine. After death, the cadaveric rigidity is established more quickly than usual. Clostridium chauvoei occurs naturally in the digestive tract of animals. It can probably remain viable in the soil for many years, although it does not actively develop there. Contaminated forage seems to be a source of organisms. Outbreaks of black mockingbirds have occurred in cattle on farms where there have been recent excavations, suggesting that soil disturbance could activate latent spores. The organisms are probably ingested, pass through the wall of the gastrointestinal tract and, after accessing the bloodstream, are deposited in muscle tissues and other tissues. In cattle, infection by black morriña is endogenous, unlike malignant edema. The lesions develop without any history of injuries, although bruising or excessive exercise can precipitate some cases. Commonly, the animals that contract black morriña are from cattle farms, have excellent health, gain weight and are usually the best animals in their group. Outbreaks occur in which several new cases are found every day for several days. Most cases occur in cattle from 6 months to 2 years of age, but can attack prosperous calves as young as 6 weeks and bovine cattle 10-12 years. The disease usually occurs in summer and fall, and is less common during the winter. In sheep, the disease is not limited to the young, and most cases follow some form of injury such as cuts, shearing or castration Usually, the onset is sudden and some dead animals can be found without premonitory signs. Acute lameness and pronounced depression are common. Initially, fever occurs but, by the time clinical signs are evident, the temperature may be normal or subnormal. Edematous inflammations and characteristic crackles can develop in the hip, shoulder, thorax, back, neck or elsewhere. At first, the inflammation is small, hot and painful. As the disease progresses rapidly, the inflammation enlarges, crepitus appears to the touch, and the skin becomes cold and insensitive, as it decreases blood flow. General signs include prostration and tremors. Death occurs in 12-48 hours. In some bovine animals, the lesions are limited to the myocardium and the diaphragm, without reliable indications in the localized lesion prior to death. It is suspected, although it has not been confirmed, that Clostridium novyi is a cause of sudden death in cattle and pigs fed high-grain diets, and in which no pre-existing lesions were detected in the liver. The lethal and necrotizing toxins (mainly toxin a) damage the liver parenchyma, thus allowing the bacteria to multiply and produce a lethal amount of the toxin. Usually, death is sudden without well-defined signs. Affected animals tend to lag behind the herd, assume sternal recumbency, and die within a few hours. Most cases occur in summer and early fall, when the liver infection caused by trematodes is at its peak. The disease is more prevalent in sheep from 1 to 4 years of age and is limited to animals infected with liver flukes. The differentiation of acute fascioliasis can be difficult, but the peracute deaths of the animals show typical lesions at necropsy that should raise suspicion of infectious necrotic hepatitis. The most characteristic lesions are grayish-yellow necrotic foci in the liver that often follow the migratory traces of young trematodes. Other common findings include enlarged pericardium filled with a straw-colored fluid, and excess fluid in the peritoneal and thoracic cavities. Usually, there is an extensive rupture of the capillaries in the subcutaneous tissue, which causes the adjacent skin to turn black (hence the common name black disease). Clostridium septicum is found in the soil and intestinal contents of animals (including man) around the world. The infection commonly occurs through contamination of wounds that contain devitalized tissue, dirt or some other debilitating tissue. Injuries caused by accident, castration, unhygienic vaccination and childbirth can be infected. The general signs, such as anorexia, intoxication and high fever, as well as local lesions, are manifested after a few hours or a few days of the predisposing lesion. Local lesions are soft prominences that sag when pressed and spread rapidly due to the formation of large amounts of exudate that infiltrate the subcutaneous and intramuscular connective tissue of the affected areas. The muscle in the areas is dark brown to black.

Gas accumulations are common. Extensive edema of the head of rams occurs after infection of wounds caused by fights. Malignant edema associated with lacerations of the vulva at delivery is characterized by significant edema of the vulva, severe toxemia and death in 24-48 hours. The similarity with the black morriña stands out, and the differentiation in the necropsy is not reliable; Laboratory confirmation is the only accurate procedure. Horses and pigs are susceptible to malignant edema but not to black morriña. j avascript: pop indo ('gencl03.htm', 'gencl03', '../ .. / img / bgraph / genc! 03.jpg'); Infectious diseases caused by Clostridium sordellii are also characterized by a non-gaseous and non-hemorrhagic edematous inflammation in the head, face and neck of young rams. This infection starts in young rams because of the continuous attacks on each other. The tissues with bruises and aggressions provide adequate conditions for the development of pathogenic clostridia, and breaks in the skin offer an opportunity for admission. Infection with types A, B and C of C. perfringens produces severe enteritis, dysentery, toxemia and high mortality in young calves. Types B and C both produce the highly necrotizing and lethal ß toxin that is responsible for extensive intestinal damage. This toxin is sensitive to proteolytic enzymes, and the disease is associated with the inhibition of proteolysis in the intestine. It has been suggested that colostrum from sows, which contains a trypsin inhibitor, is a factor in the susceptibility of young pigs. Type C also causes enterotoxemia in adult cattle. In calves, acute diarrhea, dysentery, abdominal pain, seizures and opisthotonos occur. Death can occur in a few hours, but less severe cases survive for a few days and recovery is possible over a period of several days. Hemorrhagic enteritis with ulceration of the mucosa is the most important lesion in all species. In general terms, the affected part of the intestine presents a deep blue-purple color and to the naked eye it seems to be an infarct associated with mesenteric torsion. Samples of intestinal contents can be analyzed for gram-positive, rod-shaped bacteria, and filtrations can be performed to detect toxins and then identified by neutralization with specific antiserum. This classical enterotoxemia caused by type D of C. perfringens occurs infrequently in cattle. It is distributed all over the world and can occur in animals of any age. The disease has been suspected in well-nourished cattle calves suckled by highly productive cows that graze leafy forage and in the syndrome of sudden death in cattle from enclosed pens (feedlot); however, there is a lack of supporting data for the latter case. Sharply affected calves that are not dead exhibit mania, seizures, blindness and die within a few hours. Subarely affected calves look stunning for a few days and can recover. Tetanus toxemia is caused by a specific neurotoxin produced by Clostridium tetani in the necrotic tissue. Virtually all mammals are susceptible to this disease. Although tetanus is distributed throughout the world, there are some areas, such as the Rocky Mountain section of the North of the United States, where the organism is very rare in the soil and where tetanus is practically unknown. In general, the appearance of tetani C in the soil and the incidence of tetanus in humans and horses is greater in warmer areas of different continents. Clostridium tetani, an anaerobe with terminal spherical spores, is found in the soil and in the digestive tract. In most cases, it is introduced into tissues through wounds, particularly deep-puncture wounds, which provide an adequate anaerobic environment. Infection with Salmonella spp can cause diarrhea in animals of all ages, especially those that are stressed, crowded or exposed to a heavily contaminated food or water supply. Salmonellosis is caused by many salmonella species and is clinically characterized by one or more of three major syndromes: septicemia, acute enteritis, and chronic enteritis. The incidence has increased with the intensification of the production of all types of livestock. Young calves develop the septicemic form. Adult cattle develop acute enteritis. Chronic enteritis may develop occasionally in cattle. Pregnant animals can abort. In older animals, the disease is manifested by dysentery and toxemia, and mortality can be significant. Although many other Salmonella spp can cause the disease, the most relevant in cattle are S. typhimurium, S. dublin and S. newport. Although the resulting clinical patterns are not clear, the different salmonella species tend to differ in their epidemiology. The plasmid profile and drug resistance patterns are sometimes useful markers for epidemiological studies. The feces of infected animals can contaminate food and water, milk, processed and fresh meats from slaughterhouses, plant and animal products used as fertilizers or feed, fodder and pasture, and many inert materials. Organisms can survive for months in humid areas such as pig pens or in underground shelters with water but survive less than 1 week in compost cattle. Rodents and wild birds are also sources of infection. The prevalence of infection varies between species and countries, and is much higher than the incidence of clinical disease, which is commonly precipitated by stressful situations such as sudden food deprivation, transportation, drought, stacking, childbirth and administration of some drugs. Other important gastrointestinal pathogens are Cryptosporidium parvum and Mycobacterium avium paratuberculosis. Paratuberculosis is a chronic contagious enteritis characterized by persistent and progressive diarrhea, thinning, weakening and finally death. It affects cattle, sheep, goats, llamas, camels, farm deer and other domestic, exotic and wild ruminants. It has also been recognized in wild rabbits; horses and pigs can be infected experimentally. It is distributed all over the world. There are contradictory data on the involvement of the organism in Crohn's disease, a chronic enteritis in humans. Animals with paratuberculosis should be considered potential zoonotic risks until the situation is clarified. The causative organism is MycoJbacterium avium paratuberculosis, formerly known as M. paratuberculosis or M. johnei. Occasionally, other subspecies of M. avi um are isolated from cases. The organism is quite resistant and can survive in forage for more than 1 year, but sunlight, alkaline soil and drought reduce its survival rate. It is eliminated in large quantities in the faeces of infected animals, and the infection is acquired by ingestion of contaminated food and water. The introduction of the disease to a clean herd is usually produced by asymptomatic infected carriers. Infection is acquired early in life, but clinical signs rarely develop in cattle <; 2 years old. Resistance increases with age, and cattle exposed for the first time in adulthood are unlikely to become infected. Most calves become infected shortly after birth, either through the udders of mothers contaminated with feces of infected animals or being housed in contaminated pens. The organism may also be present in colostrum and in the milk of infected cows, and intrauterine infections have also been described. After ingestion, the bacteria infect the macrophages of the mucosa of the small intestine and the associated lymph nodes. Most animals will eliminate infection by a cell-mediated early immune response that promotes microbicidal activity in macrophages. In susceptible animals, organisms multiply and cause chronic enteritis that leads to clinical disease. This may take months or years to develop and usually coincides with a decline in cell-mediated immunity and an ineffective elevation of the antibody in the serum. However, fecal elimination begins before the clinical signs appear. Mycobacterium tuberculosis can be isolated from faeces, mesenteric and ileocecal lymph nodes, thickened intestinal walls and, less frequently, the udder and reproductive systems of both sexes. Cryptosporidiosis is an enterocolitis of cosmopolitan distribution caused by the coccidial parasite Cryptosporidivaa parvum. It is not host specific and is common in young ruminants, particularly in calves; It is also found in man and pigs and is rare in dogs, cats and horses. Another cryptosporidia causes the disease in reptiles and birds. The disease in calves, characterized by thinning and watery diarrhea, is impossible to distinguish clinically from many other causes of diarrhea in calves. Cryptosporidium parvum is a tiny protozoon that is transmitted by the fecal-oral route. Oocytes sporulate (four sporovocytes) when they spread in the stool and, therefore, are immediately ineffective. The average incubation period is -4 days. Calves 1-3 weeks old seem to be the most susceptible. Signs such as anorexia, weight loss, diarrhea and tenesmus resemble those caused by many other intestinal pathogens; However, infections without signs also appear. Cryptosporidiosis without complications is rarely fatal. The disease can be severe in immunocompromised individuals. If severe disease is seen in calves, other disease agents or concurrent infections should be ruled out. Although C. parvum can infect virtually the entire digestive tract, the distal small intestine is usually the most affected. Infection in horses is limited to the small intestine. The macroscopic lesions may consist of hyperemic intestinal mucosa and yellowish intestinal contents. Microscopically, light to intense villous atrophy is observed with spherical organisms on the brush border. Unlike Eimeria and Isospora spp, which are intracellular parasites, C. parvum is intramembranous and resides within the brush border of intestinal epithelial cells. Chlamydia psittaci causes sporadic abortions after the fourth month of pregnancy, but usually in the last trimester. Chlamydia causes placentitis, fetal pneumonia and hepatitis. The samples stained with cotyledons can reveal the organisms; if not, the tissues can be grown in eggs of embryonated chickens. Abortion is usually sporadic in cows, but a vaccine against sheep chlamydia has been used in cattle. The inflammation of the mammary gland (mastitis) is almost always due to the effects of infection by bacterial or fungal pathogens. Mastitis can be associated with infections of many other organisms that include Streptococcus uberis, Streptococcus dysgalactiae, Klebsiella spp. Pseudomonas aeruginosa, Actinomyces pyogenes, Mycoplasma spp, Nocardia asteroides, Serratia, Mycobacterium spp, Clostridium perfringens, Pasteurella spp, yeasts and Proto theca spp. Dermatomycoses (Dermatophytosis) in animals are anthropozoonotic diseases of the skin and related tissue. Clinical symptoms are characterized by alopecia in the affected area, hyperemia, desquamation and asbestos-like scabs. Inflammation is often accompanied by suppuration. Dermatomycoses are often also characterized by localized infection in the skin. Dermatomycosis in animals has an important socioeconomic impact. Sick animals require prolonged treatment and can spread the infection to both animals and humans. Dermatophytosis is caused by infections caused by mycosis of Trichophyton spp. or Microsporum spp. The most relevant causes for cattle are Trichophyton verrucosum, Trichophyton mentagrophytes or Trichophyton sarkisovii. An infection of the lower respiratory tract, which usually results in bronchitis or pneumonia, can be caused by any of the various parasitic nematodes, including Dictyocaulus viviparus in cattle. This worm of the lungs belongs to the Tri chostrongyloidea family and has direct life cycles. The lungworm of cattle is common in northern Europe and is the cause of extensive "peel" or "skin" outbreaks in young grazing cattle. Since the infection by D. viviparus in cattle is the most important from the economic point of view, has been well researched and many observations can be applied to other species. Clinical disease usually develops on the first exposure to sufficient infective larvae. In cattle, this usually occurs during the first grazing season; however, an increase in the number of older bovine animals has been described. Signs of the lung worm vary from moderate cough with mild increases in frequencies to severe persistent cough and dyspnea, and even respiratory failure. A reduction in weight gain, reduced milk production and weight loss accompany many livestock infections. Mild, obvious infections can occur in all species. The most consistent signs in cattle are tachypnea and cough. Trichomoniasis is a venereal protozoan disease of cattle, characterized mainly by premature fetal death and infertility, which produces extensive calving intervals. It is probably distributed all over the world. The causative protozoan, Trichomonas (Tritrichomonas) fetus, is piriform and commonly 10-15 * 5-10 μm, but there is an important pleomorphism. It can become spherical when grown in artificial media. At its anterior end, there are three flagella of approximately the same length as the body of the parasite. An undulating membrane extends along the body and is bordered by a marginal filament that continues beyond the membrane as a posterior flagellum. Although T fetus can survive the procedure used to freeze semen, it is destroyed by drying or high temperatures. Trichomonas fetus is found in the genitalia of cattle. When cows naturally mate with an infected bull, 30-90% of them become infected, suggesting that there are differences between the strains. Variation in susceptibility by copulation to trichomoniasis may also exist. Bulls of all ages can remain infected indefinitely but this is less likely in younger males. In contrast, most cows are free from infection 3 months after copulation. However, immunity is not prolonged and reinfection appears. Transmission can also occur when semen from infected bulls is used for artificial insemination. The most common sign is infertility caused by embryonic death. This produces repeated copulations and prolonged births. Fetal death and abortions may also occur, but they are not as common as the most premature losses during pregnancy. Tri chomonas fetus has been found in vaginal cultures taken only at 8 months of gestation and, apparently, infected mothers can give birth to live calves. Sometimes, a pyometra develops after copulation. The Neospora caninum is a strict intracellular protozoan parasite that has previously been confused with Toxoplasma gondii. Only asexual stages are known and resemble T gondii. The complete life cycle of N caninum is unknown, but it can be transmitted transplacentally in dogs, cattle, goats, sheep and cats, and subsequently their offspring may be affected. The tachyzoites have a size of 5-7 x 1-5 μm, depending on the division stage. They are divided by endodiogenesis. Tachyzoites are found in myocytes, neural cells, skin cells, macrophages, and other cells. Tissue cysts up to 100 μm in diameter are found in neural cells; The wall of the cyst is amorphous and has a thickness of up to 4 μm. The cysts do not have septa and enclose bradyzoites of 7 * 1.5 μm. In dairy cows, N caninum is a leading cause of abortions in many countries, particularly in the United States. The calves can be aborted, be born dead, be born with low weight, weak or paralyzed, or they can be paralyzed to the 4 weeks of the birth. Nonsuppurative encephalitis is the main lesion in the tissues of aborted fetuses. Abortion can occur at any time during pregnancy, and some cows can abort again; The mothers of these calves are clinically normal. Babesiosis is caused by intraerythrocytic protozoan parasites of the genus Babesia. A wide range of domestic and wild animals is affected andSometimes, man can be affected by the disease, which is transmitted by ticks and has reached a worldwide distribution. The two important species in cattle - Babesia bigemina and Babesia bovis - are propagated in tropical and subtropical areas and are the focus of this analysis. In enzootic areas, there are two characteristics that are important in determining the risk of clinical disease: 1) the calves have a degree of immunity (related to both antibodies derived from colostrum and with age) that persists for -6 months, and 2 ) animals that recover from Babesia infections are immune for life. Therefore, with high levels of tick transmission, all neonatal calves will become infected with Babesia around 6 months of age, will exhibit few, if any, clinical signs and will subsequently be immunized. This situation of enzootic stability may be affected by a natural (eg, climatic) or artificial (eg, acaricide treatment) reduction in the amount of ticks to levels at which the transmission of Babesia by ticks to calves is insufficient to ensure that everyone becomes infected during this critical early period. Other circumstances that can lead to clinical epizootic outbreaks include the introduction of susceptible cattle to enzootic areas and the raid of ticks infected with Babesia to areas previously free of ticks. The variation of the strains in the immunity has been demonstrated but probably has no significance in the field. The acute illness generally lasts -1 week. The first sign is fever (often 41 ° C or higher), which persists throughout the disease and then is accompanied by inappetence, increased respiratory rate, muscle tremors, anemia, jaundice and thinning with hemoglobinemia and haemoglobinuria in the final stages . With the infection by B. bovis often affects the CNS due to parasitized erythrocytes in the capillaries of the brain. Constipation or diarrhea may appear. Pregnant cows often abort. With virulent strains of B. bovis, a hypotensive shock syndrome, combined with generalized non-specific inflammation, coagulation disorders and erythrocytic stasis in the capillaries, contributes to the pathogenesis. With most strains of B. bigemina, the pathogenic effects are more directly related to the destruction of erythrocytes. Animals that recover from acute disease are still infected with B. bovis for a number of years and, in the case of B. bigemina, for some months. No overt signs appear during this carrier stage. The lesions include a friable and enlarged spleen; an inflamed liver with an enlarged gallbladder that contains thick granular bile; congested kidneys of dark color; and generalized anemia and jaundice. Urine often, but not invariably, is red. Other organs, including the brain and the heart, may present congestion or petechial hemorrhages. The susceptibility of cattle breeds to Babesia infections varies; for example, Brahman cattle are more resistant to B infection. bovis that the British race. BRIEF DESCRIPTION OF THE FIGURES Fig. 1 Neutralization of serum against NY93 / C (VDVB type II) Fig.2 Assay of neutralization of serum against KE9 (VDVB type II) Fig. 3 Assay of neutralization of serum against NY93 / C (VDVB type II) DETAILED DESCRIPTION OF THE INVENTION All subsequent sequences show the suppressed regions indicated by dashes (-), which are also numbered, while the sequences in the sequence listing attached to this memory are numbered continuously without the suppressed regions or the amino acid codons. SEQ ID NO: 1 XIKE-A cDNA sequence SEQ ID NO: 2 XIKE-A-NdN cDNA sequence SEQ ID NO: 3 XIKE-B cDNA sequence SEQ ID NO: 4 XIKE-B cDNA sequence -NdN SEQ ID NO: 5 amino acid sequence of XIKE-A SEQ ID NO: 6 amino acid sequence of XIKE-A-NdN SEQ ID NO: 7 amino acid sequence of XIKE-B SEQ ID NO: 8 amino acid sequence of XIKE -B-NdN SEQ ID NO: 9 XIKE-C-NdN amino acid sequence SEQ ID NO: 10 XIKE-C-NdN cDNA sequence SEQ ID NO: 11 XIKE-C cDNA sequence SEQ ID NO: 12 sequence of amino acids of XIKE-C The present invention relates to combined vaccines for the treatment and / or prophylaxis of cattle against microbiological infections, in which one of the infections is produced by the BVDV. The combination vaccine as described herein comprises at least one attenuated VDBV, wherein the attenuated VDBV comprises at least one mutation in the Erns glycoprotein coding sequence and at least one other mutation in the Npro coding sequence. , which preferably leads to a combined inactivation of the RNase activity residing in the Erns glycoprotein, in addition to the inactivation of the immunomodulatory activity (hypothesized) residing in Npro. The invention also relates to methods for producing the combined vaccines. According to a preferred embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections of the respiratory and reproductive systems of cattle, where the combined vaccine comprises an attenuated VDBV as described herein and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by the Bovine Herpes Virus (VHP), the Bovine Syncytial Respiratory Virus (VRSB), the Parainfluenza Virus (PI- 3), Campylobacter fetus, Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira hardjo, Leptospira bovis, Leptospira interrogans and / or Leptospira ponoma. According to a more preferred embodiment, the combined vaccine comprises an attenuated VDVB, as described herein, and at least one HBV antigen, VRSB, PI-3, Campylobacter fetus, Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii. Leptospira prajitno, Leptospira hardjo (Leptospira hardjo prajitno and Leptospira hardjo-bovis), Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and / or Leptospira ponoma. According to a more preferred embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle produced by BVDV, PI-3, VRSB , RIB and / or HBV, wherein the vaccine comprises at least one attenuated VDVB, as described herein, and an additional active immunological component effective for the treatment and / or prophylaxis of infections caused by PI-3, VRSB, RIB and HBV. According to a more preferred embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle produced by BVDV, PI-3, RIB , VRSB, RIB and / or HBV, wherein the vaccine comprises at least one attenuated VDVB, as described herein, and at least one PI-3, RIB, VRSB and / or HBV antigen.

DEFINITIONS OF TERMS AND EXPRESSIONS USED IN THE DESCRIPTIVE MEMORY: Prior to the embodiments of the present invention, it should be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" , "la", include a plural reference, unless in the context it is clearly stated otherwise. Thus, for example, the reference to "a VDVB" includes a VDVB plurality of this type, the reference to the "cell" is a reference to one or more cells and their equivalents known to those skilled in the art, and so on. Unless defined otherwise, all technical and scientific terminologies used herein have the same meanings as those generally understood by one of ordinary skill in the art to which this invention pertains. Although it may be used in practice or tested in the present invention, any method and material similar or equivalent to those described herein will be methods, preferred devices and materials are described below. All publications mentioned herein are incorporated by reference in their totalities for the purpose of describing and exposing cell lines, vectors and methodologies as outlined in publications that could be used in connection with the invention. Nothing in this document should be construed as an admission that the invention is not entitled to be a precedent of such description by virtue of the prior invention. The term "BVDV", as used herein, refers to all viruses belonging to the bovine viral diarrhea virus type (BVDV) type 1 (BVDV-1) and to BVDV type 2 ( VDVB-2), including any sub-species such as the, lb, 2a, 2, b and the like in the genus Pestivirus within the family Flaviviridae (Heinz et al., 2000). The most classical type 1 VDVB strains and the most recently recognized type 2 VDVB strains exhibit some limited but distinctive differences in nucleotide and amino acid sequences. "Protein C", "Protein C" or "Protein-C", as used herein, refers to a structural component of the pestivirus virion (Thiel et al., 1991). "Protein C" is the capsid or protein of the pestivirus core. The term, depending on the context, may also refer to "Protein C" with one or several amino acid exchanges resulting from the mutation of the coding nucleotide sequence. The term "Npro", as understood herein, refers to the first protein encoded by the viral open reading frame and cleaves itself from the rest of the synthesized polyprotein (Stark, et al., J. Virol 67: 7088-7093 (1993); iskerchen, et al., Virol. 65: 4508-4514 (1991)). The term, depending on the context, may also refer to the remaining "Npro" amino acids after mutation of the coding nucleotide sequence or the nucleotide sequence coding for the protein itself.

"Protease activity residing in Npr0" refers to the cleavage activity of the "Npro" polypeptide. Inactivation of Npro, as used herein, means the prevention or a considerable reduction of the probable immunomodulatory activity of Npro by mutation. In a preferred embodiment, this mutation prevents or greatly reduces the interference of Npr ° with the induction of an interferon response by the infested cells, as described by Rüggli et al., (2003). In this case, inactivation of Npro would allow a normal interferon response to be mounted. "Treatment signal", as used herein, refers to a substance that ensures the generation of a functional N-terminus of pestivirus protein C, preferably of BVDV, in particular a substance selected from the ubiquitin group, LC3 , SUMO-1, NEDD8, GATE-16 and GABA (A) RAP. Also proteases selected from the group of intein, picornavirus 3C, caridovirus 2A and pl5 of the rabbit hemorrhagic disease virus are understood as "treatment signals", as used herein. Any other similar signal of treatment known to those skilled in the art that ensures the generation of a functional N-terminus of protein C must also be included in the expression "treatment signal". "Grns ,, ^ ^^" as used herein, refers to the Erns glycoprotein which represents a structural component of the pestivirus virion (Thiel et al., 1991). Erns lacks a typical membrane anchor and is secreted in considerable amounts from infected cells; it has been reported that this protein exhibits an RNase activity (Hulst et al., 1994; Schneider et al., 1993; indisch et al., 1996). It should be noted that the term EO glycoprotein is often used in a manner synonymous with Erns glycoprotein in publications. The term, depending on the context, may also refer to the protein "Ems mutated after the mutation of the coding nucleotide sequence or the nucleotide sequence coding for that protein itself." RNase activity residing in the Erns glycoprotein "refers to to the cleavage activity of the glycoprotein RNA, ie the ability of the Erns glycoprotein to hydrolyze RNA The expression "inactivation of the RNase activity residing in the glycoprotein" refers to the inability or reduced capacity of an Erns glycoprotein Modified to hydrolyze RNA compared to the unmodified wild type of the Erns glycoprotein The inactivation of Erns, as used herein, means an RNase activity not significantly above the level measured for non-infested control cells in an assay of RNase as described in Meyers et al., 1999. "Not significantly above the level measured for to uninfected control cells in an RNase assay, as described in Meyers et al., 1999", means, for example, that the RNase activity is less than 150%, compared to uninfested control cells. Attenuation: "A pestivirus or attenuated VDVB particle", as used herein, means that there is a statistically significant difference between the virulence of pestiviruses or attenuated VDVB particles of the present invention, wherein the attenuated viral particles have been attenuated by a method described herein, and wild-type pestiviruses or BVDV isolates that have been derived from pestiviruses or attenuated BVDV particles, for the predominant clinical parameters, in the case of BVDV for diarrhea, pyrexia and lethality in animals infested with the same dose, preferably 6xl06DICT50. Thus, attenuated VDVB particles do not cause diarrhea, pyrexia or lethality and, thus, can be used in a vaccine. "Bovine pathogen", as used herein, means a microorganism that has an impact on livestock health. "Active immune component" or "immunologically active component", as used herein, means a component that induces or stimulates the immune response in an animal to which the component is administered. According to a preferred embodiment, the immune response is directed to the component or to a microorganism comprising the component. According to another preferred embodiment, the immunological active component is an attenuated microorganism, including a modified live virus (VVM), an inactivated microorganism or at least an immunologically active part of a microorganism. "Immunological active part of a microorganism", as used herein, refers to a protein, sugar or glycoprotein containing a fraction of a microorganism comprising at least one antigen that induces or stimulates the immune response in an animal to which the component is administered. According to a preferred embodiment, the immune response is directed to the immunological active part of a microorganism or to a microorganism comprising the immunological active part. The term "vaccine", as used herein, refers to a pharmaceutical composition comprising at least one immunologically active component that induces an immune response in an animal and, possibly, but not necessarily, one or more additional components that they reinforce the immunological activity of the active component. A vaccine may additionally comprise additional components typical of the pharmaceutical compositions. The immunologically active component of a vaccine may comprise whole virus particles, either in their original form or as attenuated particles in a so-called modified live vaccine (VVM) or inactivated particles by appropriate methods in a so-called killed vaccine (VM). In another form, the immunologically active component of a vaccine may comprise appropriate elements of the organisms (subunit vaccines), wherein these elements are generated by destroying the whole particle or the developing cultures containing particles of this type and, optionally, subsequent steps of purification that provide the desired structure (s), or by synthetic methods that include appropriate handling by the use of a suitable system, based, for example, on bacteria, insects, mammals or other species, optionally, isolation processes and Subsequent purification, or by induction of synthetic procedures in the animal in need of a vaccine by direct incorporation of genetic material using suitable pharmaceutical compositions (vaccination with polynucleotides). A vaccine may comprise one or simultaneously more than one of the elements described above. The term "vaccine", as understood herein, is a vaccine for veterinary use that comprises antigenic substances and is administered in order to induce a specific and active immunity against a disease caused by a microbiological infection, preferably by a infection by BVDV. The VDVB described herein, confer an active immunity that can be transferred passively through maternal antibodies against the immunogens it contains and sometimes also against antigenically related organisms. A vaccine of the invention refers to a vaccine as defined above, wherein an immunologically active component is a BVDV or derived from a nucleotide sequence having a homology greater than 70% with any known BVDV sequence (sense or antisense) . The term "live vaccine" refers to a vaccine comprising a replication competent, in particular a competent viral active competent component of replication.

"Combination vaccine", as used herein, means a vaccine comprising an attenuated VDVB, as described herein, together with a monovalent, bivalent or multivalent combination of an immunologically active component or components. "Microbiological infection", as used herein, means an infection caused by a microorganism that is pathogenic to cattle. The microorganisms include, but are not limited to, bacteria, viruses, yeast or fungi, mycoplasmas and parasites. A "fragment" according to the invention is any subunit of a polynucleotide molecule according to the invention, ie any subset. For DNA, the fragment is characterized because it is shorter than the DNA that covers the full-length viral genome. A "functional variant" of the nucleotide molecule, as used herein, is a nucleotide molecule that possesses a biological activity (either functional or structural) that is essentially similar to the nucleotide molecule according to the invention . The term "functional variant" also includes "a fragment", "a functional variant", "a variant based on the degenerative code of the nucleic acids" or "a chemical derivative". A "functional variant" of this type can, e.g. ex. , carry one or more changes, deletions or insertions of nucleotides. The functional variant preserves, at least in part, its biological activity, e.g. ex. , the function as an infectious clone or a vaccine strain, or even exhibit improved biological activity.

"It possesses a biological activity that is essentially similar" means, in relation to the pestiviruses provided therewith, for example, that the pestivirus is attenuated in a manner as described herein and results in a non-pathogenic virus suitable for the production of live attenuated virus, which loses ability to cross the placenta, but which mediates an immune response after vaccination. A "variant based on the degenerative nature of the genetic code" is a variant that results from the fact that a certain amino acid can be encoded by several different triplets of nucleotides. The variant retains, at least in part, its biological activity, or even exhibits improved biological activity. A molecule is "essentially similar" to another molecule if both molecules have essentially similar nucleotide sequences or biological activity. Thus, with the proviso that two molecules have a similar activity are considered variants, since that term is used in this memory if the nucleotide sequence is not identical, and two molecules that have a similar sequence of nucleotides are considered variants, since that term is used in this memory even if the biological activity is not identical. A "mutation," as used herein, refers to modifications in the nucleic acid molecules encoding the proteins / amino acids according to the invention. Mutations refer, but are not limited to substitutions (replacement of one or several nucleotides / base pairs), deletions (separation of one or several nucleotides / base pairs), and / or insertions (addition of one or more nucleotides / Base pairs) . As used herein, the mutation can be a single mutation or several mutations, therefore, the term "mutation (s)" is often used and refers to both a single mutation and several mutations. Mutations include, but are not limited to point mutations (single nucleotide mutations) or major mutations, where, p. ex. , parts of the coding nucleic acid molecules are deleted, substituted and / or an additional coding nucleic acid is inserted. Mutations may result in a modified expressed polypeptide, due to the change in the coding sequence. Modified polypeptides of this type are desired, as set forth in the description of the invention as shown below. Additional components to enhance the immune response are constituents that are commonly referred to as "adjuvants," such as, eg, ex. , aluminum hydroxide, mineral oil or other oils or auxiliary molecules added to the vaccine or generated by the body after the respective induction by additional components of this type, such as, but not limited to interferons, interleukins or growth factors. A "pharmaceutical composition" consists essentially of one or more ingredients capable of modifying physiological functions, e.g. ex. immunological functions of the organism to which they are administered, or of organisms that come in or on the organism. The term includes, but is not limited to antibiotics or antiparasitics, as well as other constituents commonly used to achieve certain other objectives, but not limited to features of treatment, sterility, stability, ability to administer the composition by enteral or parenteral routes, such as oral, intranasal, intravenous, intramuscular, subcutaneous, intradermal or other suitable route, tolerance after administration and controlled release properties. A non-limiting example of a pharmaceutical composition of this type, only provided for demonstration purposes, could be prepared as follows: A supernatant of an infested cell culture is mixed with a stabilizer (eg, spermidine and / or ASB (bovine serum albumin). )) and the mixture is subsequently lyophilized or dehydrated by other methods. Prior to vaccination, the mixture is then rehydrated in aqueous saline solution (eg saline solution, STF (phosphate buffered saline)) or non-aqueous solutions (eg emulsion in oil, aluminum-based adjuvant). The solution to the above technical problem is achieved by the description and the embodiments characterized in the claims. The present invention relates to a combined vaccine for the treatment and / or prophylaxis of a microbiological infection in cattle, comprising a live attenuated VDVB, as described herein, and at least one additional immunological active component to treat or prevent diseases or disorders in cattle produced by infectious agents other than BVDV.

VDVB to tenuated In WO 99/64604 it was described that VDVB can be attenuated by introducing at least one mutation in the Erns glycoprotein coding sequence, wherein the mutation (s) result in an inactivation of the RNase activity that resides in the Erns gene region. Furthermore, it has surprisingly been found that VDVB can be attenuated more efficiently by introducing at least one mutation in the Erns glycoprotein coding sequence and at least one other mutation in the Npro coding sequence which, preferably, leads to the combined inactivation of the RNase activity residing in the Erns glycoprotein, in addition to the inactivation of the immunomodulatory activity residing in Npro (WO 2005/111201). An immunomodulatory effect in one aspect is indicated, but is not limited to the indicated function for a pestivirus in an exemplary manner by Rüggli et al. (2003). Thus, according to one aspect, the present invention provides a combination vaccine comprising at least one attenuated VDVB having at least one mutation in the Erns glycoprotein coding sequence and / or at least one mutation in the coding sequence of the Erns glycoprotein and / or at least one other mutation in the coding sequence of Npro. Preferably, in an attenuated VDVB of this type the mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns, and / or the mutation in the Npro coding sequence leads to the inactivation of the Npro. The attenuated VDVB, as described herein, can be advantageously used in combination vaccines for the treatment and / or prophylaxis of microbiological infections in cattle. Surprisingly, the BVDVs described herein, which comprise any of the modifications in the region in the genes Npr ° and Erns, are safe for use in pregnant animals, since they do not cross the placenta. This is exemplified in a non-limiting manner for BVDV in example 3. In turn, VDVB with defined mutations within Npro and Erns as the basis of the attenuation will allow to avoid the risk of reversion to a more pathogenic strain. An additional advantage of attenuating mutations lies in their molecular singularity that allows them to be used as distinctive markers for an attenuated VDVB and to distinguish them from the VDVB of the field. Therefore, in a further aspect, the present invention provides a combined vaccine comprising at least one attenuated VDVB having at least one mutation in the Erns glycoprotein coding sequence and at least one other mutation in the Npro coding sequence. Preferably, in the attenuated VDVB, the mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns and / or the mutation in the Npro coding sequence leads to the inactivation of the Npro. Inactivation can take place by any mutation known to the person skilled in the Erns coding sequence technique and the Npro coding sequence, wherein the mutations are any mutation as defined in the "definitions" section, such as deletions, insertion mutations and / or substitution mutations. Most preferably, the mutation (s) are deletions, such as the likelihood of reversion of the wild type is the lowest for the deletions. Taken together, the expression attenuated VDVB or attenuated pestivirus, as used herein, means, but is not limited to any VDVB or attenuated pestivirus having at least one modification in the Erns glycoprotein coding sequence and / or at least a modification in the coding sequence of Npro. In the following, specific embodiments of any such modification in Erns and / or Npro are described in more detail. According to a preferred aspect, the expression VDVB attenuated or pestivirus attenuated in general, as used herein, means but is not limited to any VDVB or attenuated pestivirus having at least one modification in the Erns glycoprotein coding sequence and at least one modification in the Npro coding sequence. However, it is to be understood thereby that the present invention should not be limited to the specific modifications described herein. A person skilled in the art with knowledge of the teachings provided herein is capable of generating and introducing additional modifications within the Erns and / or Npro glycoprotein having the attenuation effect as described herein. Modifications of the VDVB Erns The Erns glycoprotein has been shown to form a disulfide-linked homodimer of about 97 kD, wherein each monomer consists of 227 amino acids corresponding to amino acids 268 to 494 of the VFPC polyprotein, as described by Rumenapf et al. (1993) The genome sequence of the VFPC Alfort / Tubingen strain is available in the GenBank / EMBL database under accession number J04358; alternatively, the amino acid sequence for strain CP7 of VDVB can be accessed in the GenBank / EMBL data bank (accession number U63479); in the VDVB CP7 polyprotein, the Erns protein corresponds to residues 271 to 497. Two amino acid regions are highly conserved in the Erns glycoprotein, as well as in some active RNase proteins of plants and fungi (Schneider et al., 1993) . These two regions are of particular importance for the enzymatic activity of RNase. The first region consists of the amino acid region at positions 295 to 307 (298 to 310 for the vDVB strain cp7) and the second region consists of the amino acids at positions 338 to 357 (341 to 360 for the cp7 strain of VDVB) of the viral polyprotein, as exemplified for the Alfort strain of VFPC in Meyers et al., 1999 (numbering according to the published deduced amino acid sequence of the Alfort / Tubingen strain of VFPC (Meyers et al., 1989) The amino acids of particular importance to the RNase activity, as mentioned above, are by no means limited to the position as defined for the Alfort / Tubingen strain of VFPC, but are simply used in an exemplary manner to indicate that the preferred amino acids are in that position or correspond to that position in other strains, such as those found in VDVB, VEF and pestiviruses in general, since they are highly conserved For pestiviruses other than the Alfort / Tubingen strain of VFPC , the numbering of the positions of the preferred amino acids may be different, but an expert in the field of pestivirus molecular biology will easily identify these preferred amino acids by the high degree of conservation of this amino acid sequence and the position of these motifs in the context of the sequence. In a particular, non-limiting example, position 346 of Alfort / Tubingen of VFPC is identical to position 349 of strain cp7 of VDVB. As a consequence, the present invention preferably relates to a VDVB according to the invention, wherein the mutation (s) in the Erns glycoprotein coding sequence are located in the coding nucleotide sequence corresponding to the amino acids at positions 298 at 310 and / or at positions 341 to 360. Preferably, the mutation of this type is (the amino acids are indicated in the symbols of a letter, the amino acid before the position number indicates that the amino acid is substituted, the amino acid after position number indicates the substitute amino acid (of the indicated deletion) for example, H300L, which means that the histidine at position 300 was replaced with leucine: Suitable modifications of the Erns glycoprotein are, for example, simple substitutions / deletions: S298G, H300K, H300L, H300R, H300del, W303G, P304del, E305A, C308G, R343G, E345del, W346G, K348A, H349K, H349L, H349del, H349Q, H349SV (mut ation H349S and insertion of V), K348R, W351P, W351G, W351L, W351K, W351H; double substitutions / deletions: H300L / H349L, K348del / H349del, H349del / G350del, E345del / H349del, W303G / E305A, H300K / H349K, H300K / H349L and triple deletions: L299del / H300del / G301del, K348del / H349del / G350del. The numbering is according to the published amino acid sequence of BVDV CP7 for all the above listed mutants. All mutants listed above were tested at least as VDVB mutants without mutations in the Npro region. For example, suitable mutants of the pestivirus Erns glycoprotein, such as BVDV, are provided by WO 99/64604, which is incorporated herein in its entirety. However, it should be noted that, according to the present invention, at least one additional mutation must be present in the Npro region, as described in more detail below. Particularly, it was found that deletion or substitution of the histidine residue at position 349 (VDVB) leads to an efficient inactivation of Erns and, therefore, leads to particularly useful live VDVB vaccines. The present invention demonstrates that BVDVs are viable and encode an Erns protein without RNase activity when the histidine residue is deleted at position 349 (numbering according to the published sequence of VDVB CP7 (Meyers et al., 1996b)). Therefore, preferably, the BVDV as used in the combined vaccine carries a mutation in the Erns glycoprotein coding sequence that is a deletion or substitution of the histidine residue at position 349. Even more specifically, the putative active site of the RNase is represented by the conserved sequences of Erns SLHGIWPEKICTG (SEQ ID NO 13) and / or LQRHEWNKHGWCNWFHIEPW (SEQ ID NO 14) (sequence of the New York '93 protein of VDVB-2 shown here in an exemplary manner; they can possibly be found in other VDVB sequences, but the identity of the motif will always be obvious to an expert in the field). As an example, the corresponding amino acid sequences of VDVB-1 CP7 would be SLHGIWPEKICTG (SEQ ID NO 13) and / or LQRHEWNKHGWCNWYNIEPW (SEQ ID NO 15). Therefore, preferably, the VDVB of the combined vaccine carries mutation (s) in the Erns glycoprotein coding sequence located in the nucleotide sequence of the conserved Erns sequence SLHGIWPEKICTG (SEQ ID NO 13) and / or LQRHEWNKHGWCNWFHIEPW (SEQ ID NO 14). These sequences represent the putative active site of RNase. The sequences SLHGIWPEKIC (SEQ ID NO. 16) and RHEWNKHGWCNW (SEQ ID NO. 17) of the putative active site of Erns are even more conserved in pestiviruses. Thus, preferably, the BVDV used for the preparation of a combination vaccine, as described herein, has at least one mutation in the coding sequence of the protein Npr ° and / or the glycoprotein Erns, wherein the mutation (s) in the coding sequence of the Erns glycoprotein are located in the nucleotide sequence of the conserved Erns sequence SLHGIWPEKIC (SEQ ID NO 16) and / or RHEWNKHGWCNW (SEQ ID NO 15). Preferably, the mutation is located in only one of the sequences. Thus, preferably, the BVDV used for the preparation of a combined vaccine, as described herein, has at least one mutation in the coding sequence of the Npro protein and / or the Erns glycoprotein, wherein the mutations or the coding sequence of the Erns glycoprotein are located in the nucleotide sequence of the conserved Erns sequence SLHGIWPEKIC (SEQ ID NO 16) and / or RHEWNKHGWCNW (SEQ ID NO 17). Preferably, mutations of this type concern two different amino acids, ie they are double mutations. Thus, the mutations can be mutations of 1 to 3 nucleotides in two different triplets that encode two amino acids. Thus, the invention also relates to a combined vaccine comprising a live attenuated VDVB having at least one mutation in the coding sequence of the Npro protein and / or the Erns glycoprotein, wherein the mutation (s) in the coding sequence of the Erns glycoprotein are two mutations located in the nucleotide sequence of the conserved Erns sequence SLHGIWPEKIC (SEQ ID NO 16) and / or RHEWNKHGWCNW (SEQ ID NO 17). Preferably, mutations of this type concern a single amino acid. Thus, the mutation may consist of mutations of 1 to 3 nucleotides in a triplet that encode an amino acid. Thus, the invention also relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, comprising a live attenuated VDVB having at least one mutation in the coding sequence of the protein Npr0 and / or the Erns glycoprotein, wherein a single mutation is located in the conserved Erns sequence SLHGIWPEKIC (SEQ ID NO 16).

Modification of the lSPro gene of the VDVB As mentioned above, the attenuated VDVBs provided by the present invention, with at least one mutation in the Erns glycoprotein coding sequence and / or in the coding sequence of the NPro protein, where the mutation preferably results in the inactivation of the RNase activity residing in the glycoprotein ERNS and / or the immunomodulatory activity residing in Npro. Inactivation of Npro is achieved in the BVDV of the specified formula described more in detail below, where between 0 and all the amino acids of Npro are present; ubiquitin or LC3 or another sequence that served as a processing signal (eg, SUMO-1, NEDD8, GATE-16, GABA (A) RAP, or proteases, such as, eg, intein, picornavirus 3C, caridovirus 2A, or pl5 of the haemorrhagic disease of rabbits) are present or absent. In the case where a processing signal is present, the coding sequence of the processing signal is inserted at or near the C-terminal end of the Npro protein (remaining part thereof). Only in the case that a processing signal is present, any number of amino acids encoding Npr0 (= Npro amino acids) can be present. In the case that no processing signal is inserted, a maximum of 12 amino acids, preferably amino-terminal amino acids of Npro, may be present, and the remaining amino acids must be deleted. In addition, mutations other than those of Erns as described above (at least one of which must be present in the attenuated VDVB as described herein), the remaining attenuated VDVB sequences may remain unmodified, ie they are not mutated , or may also have mutations near the N-terminus of protein C. A number of more specific embodiments as described below, exemplify this. Therefore, the attenuated VDVB of the combined vaccine is modified in the coding regions of the Erns as described above and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded according to the invention. characterized in the following formula: [Npro] x- [PS] y- [C-term] and in which: [Npro] refers to the Npro portion of the polyprotein, where "x" represents the number of amino acids of Npro present in the polyprotein; [PS] refers to a processing signal selected from: ubiquitin, LC3, SUMO-1, NEDD8, GATE-16 or GABA (A) RAPo proteases such as, e.g. ex. , intein, picornavirus 3C, caridovirus 2A, or pl5 of the rabbit hemorrhagic disease virus, or any processing signal known to a skilled person that ensures the generation of a functional N-terminus of protein C. "Y" may be = 0, which means that a processing signal is not present (= PS is absent), or "Y" can be = 1, which means that a processing signal (= PS present) is present. [C-term] refers to the complete pestivirus, in particular to the complete BVDV polyprotein, except Npror but which includes the protein (C) with capsid and any other protein present in the pestivirus polyprotein, in particular in the VDVB polyprotein , including the carboxyl-terminal NS5B. Preferably, the Erns glycoprotein in [C-term] is mutated, so that the RNase activity residing in the Erns glycoprotein is inactivated. The term "any other protein present in the BVDV pestivirus / polyprotein polyprotein" refers to Erns, El, E2, p7, NS2, NS3, NS4A, NS4B and NS5A, wherein the Erns glycoprotein is mutated, preferably as described in this memory (see above), so that the RNase activity residing in the Erns glycoprotein is inactivated. Preferably, the pestivirus, in particular the BVDV according to the invention, has a protein C that is not mutated except for the amino acid in position 2 which is changed from D to N. Therefore, [C-term *] is the same as [C-term] but with a mutation at position 2 of protein C (N instead of D); if "y" is = 0 (means that [PS] is not present), then "x" is 0 to 12, (meaning that a specific Npro amino acid is not present, nor 1 to 12 amino acids of Npro, preferably from the N-terminus. from Npro); if "y" is = 1 (means that [PS] is present), then "x" is 0 to 168; (means that a specific amino acid of Npro or 1 is not present to all 168 amino acids of Npro, preferably of the N-terminus of Npro). Also more preferably, the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: [Npro]? - [PS] o- [C-term] and wherein the definitions are as they are defined before. A specific example is described below, in which the N-terminal methionine is followed by protein C and any other protein present in the polyprotein, including the carboxyterminal NS5B. Accordingly, more preferably, the attenuated VDVB as described herein, is encoded by a polyprotein as characterized by the following formula: M [C-term] and wherein the definitions are as defined above. Also more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: [Npro] 3- [PS] 0- [C-term] and wherein the definitions are as defined above. A specific example of BVDV is described below, wherein the N-terminal methionine is followed by the EL sequence of Npro and protein C and any other protein present in the polyprotein including the carboxyl-terminal NS5B. Accordingly, more preferably, the attenuated VDVB as described herein is encoded by a polyprotein as characterized by the following formula: MEL- [C-term] and wherein the definitions are as defined above. Also more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: [Npro] 4- [PS] 0- [C-term] and wherein the definitions are as defined above.

A specific example of BVDV is described below, wherein the N-terminal methionine is followed by the sequence of Npro ELN (SEQ ID NO 18) and protein C and any other protein present in the polyprotein including the carboxyl-terminal NS5B . Therefore, most preferably, the invention relates to a BVDV, wherein the mutation (s) in the Npro coding sequence leads to an encoded polyprotein, as characterized by the following formula: MELF- [C-term]. and where the definitions are as defined above. Also more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: [Npro] 6- [PS] 0- [C-term] and wherein the definitions are as defined above. A specific example of an attenuated VDVB is described below, wherein the N-terminal methionine is followed by the sequence of Npro ELFSN (SEQ ID NO 19) and protein C and any other protein present in the polyprotein including the carboxyl NS5B -terminal. Accordingly, more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: MELFSN- [C-term]. and where the definitions are as defined above. A specific example of an attenuated VDVB is described below, wherein the N-terminal methionine is followed by the Npro ELFSNE sequence (SEQ ID NO 20); ELFSNEL (SEQ ID NO 21); ELFSNELL (SEQ ID NO 22); ELFSNELLY (SEQ ID NO 23); ELFSNELLYK (SEQ ID NO 24); or ELFSNELLYKT (SEQ ID NO 25) and protein C and any other protein present in the polyprotein that includes the carboxyl-terminal NS5B. Accordingly, more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: MELFSN- [C-term]. MELFSNE- [C-term]; MELFSNEL-- [C-term]; MELFSNELL- [C-term]; MELFSNELLY- [C-term]; MELFSNELLYK- [C-TERM] MELFSNELLYKT- [C-TERM] and where definitions are as defined above. Also more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: [Npro] 4- [PS] 0- [C-term *] and wherein the definitions they are as defined above, except for the fact that the amino terminal part of protein C is changed, also as defined above. We describe below a specific example of a VDVB, where the N-terminal methionine is followed by the Npro ELF sequence and in the protein C sequence, the amino acid at position 2 is changed from D to N. Therefore, the amino-terminal protein C sequence is SNEGSK (SEQ ID NO 26), instead of SDEGSK (SEQ ID NO 27). In consecuense, more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: MELF- [C-term *] where in protein C, the amino acid in the 2-position it is changed from D to N, and where the definitions are as defined above. Also more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula: [Npro] x- [PS]? - [C-term] where the definitions are as are defined above, and wherein PS is any of the PSs described above, and more preferably selected from the ubiquitin or LC3 group. Another specific example of VDVB is described below, wherein the N-terminal methionine is followed by any of the 21 or 28 amino acids of Npro, ubiquitin or LC3 and protein C. Accordingly, more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or of the Npro, where the mutation (s) in the coding sequence of Npro they lead to a polyprotein encoded as characterized by the following formula: [Npro] 22- [PS] i- [C-term], wherein preferably, the PS is ubiquitin or LC3 or [Npro] 29 - [PS] i- [C-term], where preferably, PS is ubiquitin or LC3 or Ubiquitin is a well-preserved and well-known 76 amino acid cellular protein. Among other functions, ubiquitin is a key player in the catabolism of the protein, since conjugation with ubiquitin can mark a protein for degradation through the proteasome. Ubiquitin conjugated with or condensed to other proteins through the carboxy-terminal glycine can be separated by cleavage by cellular proteases specific for ubiquitin. Thus, fusion of a protein to the carboxy terminus of ubiquitin will usually result in a defined proteolytic cleavage of the fusion protein in its components when expressed in a cell. LC3 (light chain proteins 3 associated with microtubules) represents a cellular protein of 125 amino acids that fulfills a variety of functions (given length for bovine LC3). Recently, a fundamental role of the protein in autophagy has been defined. During this procedure, LC3 is activated by carboxy-terminal cleavage. With this, a new carboxy terminus consisting of glycine is generated. LC3 is then conjugated, through the carboxy-terminal glycine, to phosphatidylethanolamine present in the membranes of autophagic vesicles. Due to this procedure, a protein condensed to the carboxy terminus of LC3 will be cleaved off by a cellular protease in a defined position. Also more preferably, the invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises a modified attenuated VDVB in the coding regions of the Erns as described above, and / or in the Npro, where the mutation (s) in the Npro coding sequence leads to a polyprotein encoded as characterized by the following formula selected from the group of: [Npro] 2- [PS] y- [C-term] and, preferably, ME- [PS] and- [C- term]; [Npro] 5- [PS] y- [C-term] and, preferably, ME- [PS] y- [C-term]; [Npro] 7- [PS] y- [C-term] and, preferably, ME- [PS] y- [C-term]; [Npro] 8- [PS] y- [C-term] and, preferably, ME- [PS] y- [C-term]; [Npr0] 9- [PS] y- [C-term] and, preferably, ME- [PS] y- [C- term]; [Npro]? 0- [PS] y- [C-term] and, preferably, ME- [PS] y- [C-term]; [Npro] ?? - [PS] y- [C-term] and, preferably, ME- [PS] y- [C-term]; and [Npro] 12- [PS] y- [C-term] and, preferably, ME- [PS] and- [C-term]; and where the definitions are as defined above. The preferably described embodiments refer to BVDV. Most preferably, y is 0 (PS is not present). NDE ERP Npro mutants suitable for VDVB include those mentioned in the following table: Table: VDVB double Npro ERN mutants: Npro mutations are defined by the rest of their amino-terminal sequences. For example; MELF- mutant means that the coding region of Npro is completely suppressed except for the amino-terminal amino acids MELF. In accordance with one embodiment of the present invention, the attenuated VDVB of the combined vaccine as provided herein is a VDVB of type 1. Preferably, the attenuated VDVB is based on one of the following strains of the VDVB type 1: NADL, Osloss, SD-1, CP7 or KE9, wherein each of the strains comprises at least one of the ERNS and / or Npro mutations as described above, and preferably at least one of the double mutants within the ERN region? and Npro as listed in the previous table. According to another embodiment, the attenuated VDVB of the combined vaccine as provided herein is a VDVB of type 2. Preferably, the attenuated VDVB is based on one of the following strains of VDVB type 2: 890, C413, or New York '93C, wherein each of the strains comprises at least one of the ERNS and / or Npro mutations as described above, and preferably at least one of the double mutants within the ERNS and Npro region as listed in the previous table. VDVB-1 and VDVB-2 are differentiated according to features of their genomic sequences (Heinz et al., 2000 and references therein). VDVB-1, as described herein, can be used in the manufacture of a composition for use in the prevention and / or treatment of BVDV type 1 infections in breeds of cattle breeding, in pregnant cows and in Induction of fetal protection against type 1 BVDV infection in pregnant cows. Surprisingly, a BVDV-2, as described herein, can be used in the manufacture of a combined vaccine for use in the prevention and / or treatment of BVDV type 1 infections in livestock breeds. In particular, the invention relates to the use of a VDVB type 2 as described herein, in the manufacture of a combined vaccine for use in the prevention and / or treatment of type 1 BVDV infections in pregnant cows. Preferably, VDVB type 2, as provided herein, can be used in the manufacture of a combined vaccine for use in the induction of fetal protection against type 1 BVDV infections in pregnant cows. Surprisingly also, a BVDV-1, as described herein, can be used in the manufacture of a combined vaccine for use in the prevention and / or treatment of BVDV type 2 infections in livestock breeds. In particular, the invention relates to the use of a type 1 VDVB as described herein, in the manufacture of a combination vaccine for use in the prevention and / or treatment of type 2 BVDV infections in pregnant cows.

Preferably, the VDVB type 1 according to the invention can be used in the manufacture of a combined vaccine for use in the induction of a fetal protection against BVDV type 2 infections in pregnant cows. Most preferred is the use of type 1 and type 2 VDVB in combination for the manufacture of the combination vaccines described herein for use in the prevention and / or treatment of type 1 and / or type BVDV infections. 2 in breeds of cattle raising, in pregnant cows and in the induction of fetal protection against type 1 and / or type 2 BVDV infections in pregnant cows. Thus, preferably the combined vaccines provided herein comprise an attenuated VDVB of type 1 and type 2 as described above. For example, the combined vaccines provided herein comprise an attenuated VDVB of type 1 and type 2, which is based on the strains: NADL / 890; NADL / C413; NADL / NewYork '93 / C; CP7 / 890; CP7 / C413; CP7 / NewYork '93 / C; KE9 / 890; KE9 / C413; New York '93C, wherein each of the strains comprises at least one of the ERNS and / or Npr0 mutations as described above, and more preferably at least one of the double mutants within the ERNS and Npro region as listed in the previous table. More preferably, any of the combined vaccines provided herein may include one or more attenuated VDVB subtypes of type 1 and one or more attenuated VDVB-2 subtypes, e.g. ex. , one or more attenuated VDVBs of subtypes la, lb, lc, Id, le, lf, lg, lh and the like, and one or more attenuated VDVBs of subtypes 2a, 2b and the like. A combination vaccine comprising the attenuated VDVB of subtypes la, lb and 2a is more preferred. Thus, according to a preferred embodiment of the present invention, the phrase "attenuated VDVB (types 1 and / or 2)" includes, but is not limited to, combinations of DVB viruses comprising one or more attenuated VDVBs of type 1 , preferably of subtype lb, and one or more attenuated VDVBs of type 2, preferably of subtype 2a. Thus, according to another preferred embodiment of the present invention, the phrase "attenuated VDVB (types 1 and / or 2)" includes, but is not limited to, combinations of the VDVB viruses comprising one or more attenuated VDVBs of the subtype. , one or more attenuated VDVBs of subtype lb and one or more attenuated VDVBs of type 2, preferably of subtype 2a. If more than one attenuated VDVB is used in the combination vaccines described herein, each of the attenuated VDVBs must mutate into the same genomic ERNS and / or Npro site such that none of the attenuated VDVBs can recombine with any of the attenuated VDVBs. the others to eliminate the mutations that are essential and responsible for the attenuation of the viruses. For example, if the VDVB of type la is used with one of the following ERNS mutations: H349K, H349L, H349del, H349Q, H349SV (mutation H349S and V insertion), a VDVB of type lb and / or type must be used. 2, which is or are mutated at the same site of the ERNS, that is, at position 349 or at the position of the amino acid corresponding to position 349 of VDVB type 1 in order to avoid inversion of the attenuated VDVB of type 1 or type 2. This principle also applies to any mutation within the Npro region. Therefore, according to a preferred embodiment of the present invention, the phrase "attenuated VDVB (types 1 and / or 2)" includes, but is not limited to, combinations of DVB viruses comprising one or more attenuated VDVBs of type 1 and one or more attenuated VDVB type 2, where each of the attenuated VDVB mutates in the same genomic site of the ERNS and / or Npro, so that none of the attenuated VDVBs can recombine with any of the other to eliminate mutations within ERN? and Npro that are essential and responsible for the attenuation of viruses. Therefore, according to a preferred embodiment of the present invention, the phrase "attenuated VDVB (types 1 and / or 2)" includes, but is not limited to, combinations of DVB viruses comprising one or more attenuated VDVBs of the subtype the one, one or more attenuated VDVBs of subtype lb and one or more attenuated VDVBs of type 2, preferably of subtype 2a, where each of the attenuated VDVBs mutates in the same genomic site of the ERNS and / or the Npr0, so such that none of the attenuated VDVBs can recombine with any of the others to eliminate the mutations within ERNS and / or Npr0 that are essential and responsible for the attenuation of the viruses. Preparing the VDVB to Tenuate Another important aspect of the invention is a method for attenuating a pestivirus, characterized in that in a genome of the VDVB generates a mutation in the coding sequence of the Erns glycoprotein and / or at least one other mutation is generated in the Npro coding sequence. According to a more preferred embodiment, the method comprises the steps: a) reverse transcription of a wild type pestivirus nucleotide sequence into a cDNA; b) cloning of the cDNA; c) introduction of mutations selected from the group of deletions, insertion mutations and / or substitution mutations in the cDNA, where the mutations are located in the coding sequence of the Erns glycoprotein and / or the Npr ° protease, d) incorporation of the CDNA in a plasmid or in a DNA virus capable of directing the transcription of BVDV cDNA into RNA in vitro or after infection of suitable cells. In connection with the method for attenuating a BVDV according to the invention, the preferred methods comprise the following steps: a) reverse transcription of a nucleotide sequence of wild-type BVDV in a cDNA; b) cloning of the cDNA; c) introduction of mutations selected from the group of deletions, insertion mutations and / or substitution mutations in the cDNA, where the mutations are located in the Erns glycoprotein coding sequence and / or the Npro protease, d) incorporation of the cDNA in a plasmid or in a DNA virus capable of directing the transcription of the BVDV cDNA into RNA in vitro or upon infection of suitable cells. There are several nucleotide sequences known in the art that represent the basis of the production of a polynucleotide molecule encoding an attenuated VDVB according to the present invention, with at least one mutation in the coding sequence of Npro and / or at least one in the Erns glycoprotein coding sequence, wherein the mutations result in a combined inactivation of the RNase activity residing in the Erns glycoprotein and in the inactivation of the immunomodulatory activity residing in Npro. Examples of nucleic acid sequences of wild-type sequences from various strains of BVDV are listed below: Bovine viral diarrhea virus 1 NADL strain Accession number to NCBI GenBank [AF037405] Osloss strain Accession number to NCBI GenBank [M96687] Strain SD-1 N 'access to NCBI GenBank [M96751] Strain CP7 Access number to NCBI GenBank [U63479] Strain KE9 (SEQ ID NO: 1) Bovine viral diarrhea virus 2 Strain 890 Accession number to NCBI GenBank [U18059] Strain C413 Accession number to NCBI GenBank [AF002227] Strain NewYork'93 / CN ° access to NCBI GenBank. [AF502399] Mutations / modifications related to the coding sequences of Npro and Erns were described in detail hereinabove. Possessing this information, a person skilled in the art is capable of making any polynucleotide / polynucleic acid encoding an attenuated VDVB as provided herein. Molecular methods for introducing a mutation into a polynucleotide sequence, as well as the cloning and amplification of the mutated polynucleotide, are provided, for example, by Sambrook et al. 1989 or Ausubel et al.1994. Most preferably, the wild type VDVB to be mutated, as described herein, corresponds to the amino acid sequence SEQ ID No. 5 (referred to as XIKE A) or is a functional variant thereof. Most preferably also, the VDVB has a Npro mutation, as described herein, which corresponds to the amino acid sequence SEQ ID No. 6 (referred to as XIKE-A-NdN) or is a functional variant thereof. Preferably, a functional variant of this type has a homology of at least 65% with the amino acid sequence described herein. At the amino acid level, the homologies are very approximate: VDVB-1 / -VDVB-1: 93 VDVB-1 / -VDVB-2: 84 VDVB-2 / -VDVB-2: 98 Therefore, more preferably, a variant functional of this type has a homology of at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87 %, 88%, 89% or 90% with the amino acid sequence described herein. More preferably also, a functional variant of this type has a homology of at least 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% with the amino acid sequence described herein. Most preferably, a functional variant of this type has a homology of at least 99 or 99.9% with the amino acid sequence described herein. Most preferably also, the attenuated VDVB as described herein has an Erns mutation that has a deletion of the coding codon of histidine 349 (designated XIKE-B), or is a functional variant thereof. Most preferably also, the attenuated VDVB has both an Erns mutation and an Npro mutation as described herein, wherein the codon encoding histidine 349 of Erns is deleted and the entire coding region of Npro is deleted, except codons 1 to 4, thus remain the amino acids MELF of Npro. The mutant corresponds to the amino acid sequence of SEQ ID No. 8 (designated XIKE-B-NdN) or is a functional variant thereof. Preferably, a functional variant of this type has a homology of at least 65% with the amino acid sequence described herein. More preferably, a functional variant of this type has a homology of at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81% , 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% with the amino acid sequence described herein. More preferably also, a functional variant of this type has a homology of at least 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% with the amino acid sequence described herein. Most preferably, a functional variant of this type has a homology of at least 99 or 99.9% with the amino acid sequence described herein. Most preferably also, the VDVB according to the invention has an Erns mutation according to the invention which is a replacement of the codon coding for histidine 300 by the codon encoding leucine (designated XIKE-C) or by a functional variant Of the same. Most preferably also, the BVDV according to the invention has both an Erns mutation and an Npro mutation according to the invention, wherein the codon encoding histidine 300 is replaced by the codon encoding leucine and the entire region is deleted as well. Npro coding, except codons 1 to 4, thus remain the amino acids MELF of Npro. The mutant corresponds to the amino acid sequence of SEQ ID No. 10 (called XIKE-C-NdN) or is a functional variant thereof. Preferably, a functional variant of this type has a homology of at least 65% with the amino acid sequence described herein. More preferably, a functional variant of this thioo has a homology of at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81% , 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% with the amino acid sequence described herein. More preferably also, a functional variant of this type has a homology of at least 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% with the amino acid sequence described herein. Most preferably, a functional variant of this type has a homology of at least 99 or 99.9% with the amino acid sequence described herein.

Possible combinations: As described above, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of bovine cattle against microbiological infections, where the combined vaccine comprises an attenuated VDVB (types 1 and / or 2), as described above, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by a bovine pathogen other than BVDV. As mentioned above, the combined vaccine preferably comprises attenuated VDVB type 1 and attenuated VDVB type 2, both having at least one mutation in the Erns glycoprotein coding sequence and / or at least one other mutation in the Npro coding sequence, where the mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns and / or the mutation in the coding sequence of Npr ° leads to inactivation of the Npr °. Even more preferably, each of the attenuated VDVBs is mutated in the same genomic ERNS and / or Npro site such that none of the attenuated VDVBs can recombine with any of the others to eliminate the mutations within ERNS and / or Npro, which are essential and responsible for the attenuation of viruses. Even more preferably, the combination vaccine comprises VDVB type 1 and attenuated VDVB type 2, both having at least one mutation in the Erns glycoprotein coding sequence and at least one other mutation in the Npro coding sequence, wherein the mutation in the encoding sequence of the Erns glycoprotein leads to the inactivation of the RNase activity residing in Erns and / or the mutation in the Npro coding sequence leads to the inactivation of the Npro. Most preferably, each of the attenuated VDVBs is mutated in the same genomic site of the ERNS and Npro, so that none of the attenuated VDVBs can recombine with any of the others to eliminate the mutations within the ERNS and / or Npr °, which are essential and responsible for the attenuation of viruses. The relevant bovine pathogens other than BVDV include, but are not limited to: i) pathogens of viral origin such as the Paragripal-3 Virus (PI-3), Bovine Infectious Rhinotracheitis (RIB), Bovine Syncytial Respiratory Virus (VRSB), Bovine Herpes (HBV), Bovine Rotavirus (RVB), Bovine Enterovirus (BVD), Bovine Coronovirus (CVB), Bovine Rabies (RB), Bovine Parvovirus (PVB) and Adenovirus and Astrovirus; ii) pathogens of bacterial origin, such as Mannheimia haemolytica (formerly Pasteurella haemolytica), Pasteurella multocida, Haemophilus somnus (Histophilus ovis and Haemophilus agni), Actinomyces (Corynebacterium), Actinomyces pyogenes, Chlamydia psittaci, Campylobacter fetus venerealis and Campylobacter fetus fetus (formerly C fetus intestinalis), Leptospira interrogans, Leptospira pomona and Leptospira grippotyphosa, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardj o-bovis), Brucella abortus, Brucella suis and Brucella melitensis, Listeria monocytogenes, Chlamydia psittaci, Clostridium chauvoei , Clostridium septicum, Clostridium haemolyticum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens, Clostridium tetani, Moraxella bovis, Klebsiella spp, Klebsiella pneumoniae, Salmonella typhimurium; Salmonella newport, Mycobacterium avium paratuberculosis, Staphylococcus aureus, Streptococcus dysgalactiae and Streptococcus uberus iii) pathogens of other origin, such as Mycoplasma dispar, Mycoplasma bovis and Ureaplasma spp., Tritrichomonas fetus, Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton sarkisovii, Neospora caninum (formerly Toxoplasma gondii), Cryptosporidium parvum, Cryptsporidium hominis, Babesia bigemina and Babesia bovis, and Dictyocaulus viviparous (lungworm disease). therefore, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, wherein the vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an additional active immunological component effective for the treatment and / or prophylaxis of infections caused by the Paragripal Virus -3 (PI-). 3), Bovine Infectious Rhinotracheitis Virus (RIB), Bovine Syncytial Respiratory Virus (VRSB), Bovine Herpes Virus (HBV), Bovine Rotavirus (RVB), Bovine Enterovirus (EVB), Bovine Coronovirus (CVB), Bovine Rabies (RB) ), Bovine Parvovirus (PVB), Adenovirus Astrovirus, Mannheimia haemolytica (formerly Pasteurella haemolytica), Pasteurella multocida, Haemophilus somnus (Histophilus ovis and Haemophilus agni), Actinomyces (Corynebacterium), Actinomyces pyogenes, Chlamydia psittaci, Campylobacter fetus venerealis and Campylobacter fetus fetus (formerly C fetus intestinalis), Leptospira interrogans, Leptospira pomona, and Leptospira grippotyphosa, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Brucella abortus, Brucella suis and Brucella melitensis, Listeria monocytogenes, Chlamydia psittaci, Clostridium chauvoei, Clostridium septicum, Clostridium haemolyticum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens, Clostridium tetani, Moraxella bovis, Klebsiella spp, Klebsiella pneumoniae, Salmonella typhimurium; Salmonella newport, Mycobacterium avium paratuberculosis, Cryptosporidium parvum, Cryptsporidium ho inis, Staphylococcus aureus, Streptococcus dysgalactiae, Streptococcus uberus, Mycoplasma spp, Mycoplasma dispar, Mycoplasma bovis, and Ureaplasma spp., Tritrichomonas fetus, Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton sarkisovii, Neospora caninum (formerly Toxoplasma gondii), Babesia bigemina and Babesia bovis, and Dictyocaulus viviparous (disease of the worm of the lungs). According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the vaccine comprises attenuated BVDV (types 1 and / or 2), as described herein, and at least one antigen of Paragripal Virus -3 (PI-3), Bovine Infectious Rhinotracheitis Virus (RIB), Bovine Syncytial Respiratory Virus (VRSB), Bovine Herpes Virus (HBV), Bovine Rotavirus (RVB), Bovine Enterovirus (EVB), Bovine Coronovirus (CVB), Bovine Rabies (RB), Bovine Parvovirus (PV), Adenovirus Astrovirus, Mannheimia haemolytica (formerly Pasteurella haemolytica), Pasteurella multocida, Haemophilus somnus (Histophilus ovis and Haemophilus agni), Actinomyces (Corynebacterium), Actinomyces pyogenes, Chlamydia psittaci, Campylobacter fetus venerealis and Campylobacter fetus fetus (formerly C fetus intestinalis), Leptospira interrogans, Leptospira hardjo, Leptospira pomona, and Leptospira grippotyphosa, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Brucella abortus, Brucella suis and Brucella melitensis, Listeria monocytogenes, Chlamydia psittaci, Clost ridium chauvoei, Clostridium septicum, Clostridium haemolyticum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens, Clostridium tetani, Moraxella bovis, Klebsiella spp, Klebsiella pneumoniae, Salmonella typhimurium; Salmonella newport, Mycobacterium avium paratuberculosis, Cryptosporidium parvum, Cryptsporidium hominis, Staphylococcus aureus, Streptococcus dysgalactiae, Streptococcus uberus, Mycoplasma spp, Mycoplasma dispar, Mycoplasma bovis, and Ureaplasma spp., Tritrichomonas foetus, Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton sarkisovii, Neospora caninum (formerly Toxoplasma gondii), Babesia bigemina and Babesia bovis, and Dictyocaulus viviparous (lungworm disease) According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of bovine cattle against Viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or the prophylaxis of infections caused by RIB [combo 001]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen [combo 002]. According to a preferred embodiment, the RIB antigen is a modified live virus [combo 003]. According to another embodiment, the combined attenuated VDVB vaccine and RIB contains an antibiotic, e.g. ex. , neomycin, for conservation [combo 004]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2) , as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by PI-3 [combo 005]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one PI-3 antigen [combo 006]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by VRSB [combo 007].

According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one VRSB antigen [combo 008]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1). and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by HBV [combo 009]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one HBV antigen [combo 010]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1). and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB and PI-3 [combo 011]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB and PI-3 antigen [combo 012]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB and VRSB [combo 013]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB and VRSB antigen [combo 014]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1). and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by IBR and HBV [combo 015]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB and HBV antigen [combo 016]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1). and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by PI-3 and VRSB [combo 017]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen of PI-3 and VRSB-3 [combo 018]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1). and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by PI-3 and HBV [combo 019]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one PI-3 and HBV antigen [combo 020]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3 and VRSB [combo 021]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and VRSB [combo 022]. Preferably, all viral antigens are modified live viruses [combo 023]. According to another embodiment of the combined vaccine, the RIB and PI-3 antigens are live modified viruses and the VRSB antigen is an inactivated virus [combo 024]. According to another embodiment of the combined vaccine, the RIB, PI-3 and VRSB antigens are inactivated viruses [combo 025]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, VRSB and HBV [combo 026]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, VRSB and HBV [combo 027]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by PI-3, VRSB and HBV [combo 028]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen of PI-3, VRSB and HBV-3 [combo 029]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3 and HBV [combo 030]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and HBV [combo 031]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB and HBV [combo 032]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen., PI-3, VRSB and VHB [combo 033]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by H. somnus [combo 034]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one H antigen. somnus [combo 035]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVBs (types 1). and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB and H. somnus [combo 036]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one H. somnus antigen [combo 037]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3 and H. somnus [combo 038]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and H. somnus [combo 039]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of the respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB and H. somnus [combo 040] . According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB and H. somnus [combo 041 ] Preferably, all viral antigens are live modified viruses. According to another embodiment of the combined vaccine, the RIB and PI-3 antigens are live modified viruses and the VRSB antigen is an inactivated virus [combo 038]. According to another embodiment of the combined vaccine, the RIB, PI-3 and VRSB antigens are inactivated viruses [combo 042]. According to another embodiment, any of the combined vaccines, preferably the combined vaccine comprising inactivated RIB, inactivated PI-3 and inactivated VRSB as antigens, contains neomycin and thimerosal as preservatives [combo 043]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against viral infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, HBV and H. somnus [combo 044]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, HBV and H. somnus [combo 045]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by one or more pathogenic Leptospira species, preferably selected from Leptospira carneóla, Leptospira grippotyphosa , Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona. [combo 046]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from at least one or more pathogenic Leptospira species, preferably selected from Leptospira canicola. , Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 047]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by IBR, and one or more pathogenic Leptospira species, preferably selected from Leptospira canicola. , Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardj opraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona. [combo 048]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen and one or more pathogenic Leptospira species, preferably selected. between Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 049]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB and Leptospira pomona [combo 050]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, preferably a live modified virus, and Leptospira pomona bacterin. [combo 51] According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by IBR, PI-3, and one or more pathogenic Leptospira species, preferably selected. between Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardj opraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 052]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and one or more pathogenic Leptospira species. , preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 053].

According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjoprajitno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae and Leptospira pomona [combo 054]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo, Leptospira icterohaemorrhagiae and Leptospira pomona [combo 055]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB and one or more pathogenic Leptospira species, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona. [combo 056] According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB and a or more pathogenic Leptospira species, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 057]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIBs., PI-3, VRSB, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjoprajitno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae and Leptospira pomona [combo 058]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, Leptospira canicola, Leptospira grippotyphosa. , Leptospira hardjo (Leptospira hardjopraj itno and / or Leptospira hard o-bovis), Leptospira icterohaemorrhagiae and Leptospira pomona [combo 059]. According to a preferred embodiment, the viral antigens are inactivated viruses and the bacterial antigens are bacterins [combo 060]. Preferably, the combined vaccines, as described in this paragraph, also contain neomycin and thimerosal as preservatives [combo 061]. According to another embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, live modified viruses of RIB, PI-3, VRSB and Leptospira canicola bacterin, Leptospira grippotyphosa, Leptospira hardjo. (Leptospira hardjopraj itno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae and Leptospira pomona [combo 062]. According to another preferred embodiment, the combined vaccine, as described in this paragraph, comprises neomycin as a preservative [combo 063]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, HBV and one or more pathogenic Leptospira species. , preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona. [combo 064]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV and one or more Pathogenic species of Leptospira, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 065]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by one or more pathogenic Leptospira species, as described above, and H. somnus [combo 066] . According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from one or more pathogenic Leptospira species, as mentioned previously, and H. somnus [combo 067]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by IBR one or more pathogenic Leptospira species., as described above, and H. somnus [combo 068]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen one or more pathogenic Leptospira species, as mentioned previously, and H. somnus [combo 069].

According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3 and one or more pathogenic Leptospira species, as described above, and H. somnus [combo 070]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and one or more pathogenic species of Leptospira, as mentioned above, and H. somnus [combo 071]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo ( Leptospira hardjoprajitno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae, Leptospira pomona and H. somnus [combo 072]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae, Leptospira pomona and H. somnus [combo 073]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB and one or more pathogenic Leptospira species, as described above. , and H. somnus [combo 074]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB and one or more pathogenic species. of Leptospira, as mentioned above, and H. somnus [combo 075]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections of respiratory and reproductive systems in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo ( Leptospirahardjo prajitno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae, Leptospira pomona and H. somnus [combo 076]. According to a more preferred embodiment, the combined vaccine comprising attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, PI-3, VRSB, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo, Leptospira icterohaemorrhagiae, Leptospira pomona and H. somnus [combo 077]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, HBV and one or more pathogenic Leptospira species, such as previously mentioned, and H. somnus [combo 078]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV and one or more pathogenic species of Leptospira, as mentioned above, and H. somnus [combo 079]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by one or more pathogenic Leptospira species, as described above, and Campylobacter fetus [combo 080] . According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from one or more pathogenic Leptospira species, as mentioned above. , and Campylobacter fetus [combo 081]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjoprajitno and / or Leptospira hardjo-bovis), Leptospira lcterohaemorrhagiae , Leptospira pomona and Campylobacter fetus [combo 082]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira lcterohaemorrhagiae, Leptospira pomona and Campylobacter fetus [combo 083]. According to a more preferred embodiment, the bacterial antigens are complete cultures adsorbed on chemically inactivated aluminum hydroxide of the bacteria [combo 084]. According to another preferred embodiment, the combined vaccine comprises gentamicin and amphotericin B as preservatives [combo 085]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB and one or more pathogenic Leptospira species, as mentioned above, and Campylobacter fetus [combo 086]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen one or more pathogenic Leptospira species, as mentioned previously, and Campylobacter fetus [combo 087]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIBs., PI-3 and one or more pathogenic species of Leptospira, as mentioned above, and Campylobacter fetus [combo 088]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and one or more pathogenic Leptospira species. , as mentioned above, and Campylobacter fetus [combo 089]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB and one or more pathogenic Leptospira species, as mentioned above. , and Campylobacter fetus [combo 090]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB and one or more pathogenic species. of Leptospira, as mentioned above, and Campylobacter fetus [combo 091]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, HBV and one or more pathogenic Leptospira species, as described above, and Campylobacter fetus [combo 092]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV and one or more pathogenic species of Leptospira, as mentioned above, and Campylobacter fetus [combo 093]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by one or more pathogenic Leptospira species, as described above, and H. somnus and Campylobacter fetus. [combo 094] According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from one or more pathogenic Leptospira species, as mentioned above. , H. somnus and Campylobacter fetus [combo 095]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, one or more pathogenic Leptospira species, as described above, and H. somnus and Campylobacter fetus [combo 096]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen one or more pathogenic Leptospira species, as mentioned previously, H somnus and Campylobacter fetus [combo 097]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle., wherein the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI- 3 and one or more pathogenic Leptospira species, as described above, H. somnus and Campylobacter fetus [combo 098]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3 and one or more pathogenic species of Leptospira, as mentioned above, H. somnus and Campylobacter fetus [combo 099]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo, Leptospira icterohaemorrhagiae, Leptospira pomona , H. somnus and Campylobacter fetus [combo 100]. According to another embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo. (Leptospira hardjopraj itno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae, Leptospira pomona, H. somnus and Campylobacter fetus [combo 101]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB and one or more pathogenic Leptospira species, as mentioned above, H. somnus and Campylobacter fetus [combo 102]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB and one or more pathogenic species. of Leptospira, as mentioned above, H. somnus and Campylobacter fetus [combo 100]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardj opraj itno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae, Leptospira Pomona, H. somnus and Campylobacter fetus [combo 103]. According to another embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and / or Leptospira hardjo-bovis), Leptospira icterohaemorrhagiae, Leptospira pomona, H. somnus and Campylobacter fetus [combo 104].

According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI-3, VRSB, HBV and one or more pathogenic Leptospira species, as mentioned above, H. somnus and Campylobacter fetus [combo 105]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV and one or more pathogenic species of Leptospira, as mentioned above, H. somnus and Campylobacter fetus [combo 106]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against respiratory and reproductive system infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by HBV, VRSB, PI-3, RIB, Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii Leptospira hardjo (Leptospira hardj oprajitno and / or Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Campylobacter fetus [combo 107]. According to a more preferred embodiment, the combined vaccine comprises an attenuated VDBV as described herein and at least one HBV antigen, VRSB, PI-3, RIB, Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii Leptospira hardjo ( Leptospira hardj oprajitno and / or Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira borgpetersenii, Leptospira bovis, Leptospira interrogans and Campylobacter fetus [combo 108]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one effective immunological active component for the treatment and / or prophylaxis of infections produced by Pasteurella haemolytica and Pasteurella multocida [combo 109]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one bacterin antigen from Pasteurella haemolytica and Pasteurella multocida bacterin. [combo 110] According to another preferred embodiment, the combined vaccine comprises neomycin and thimerosal as preservatives [combo 111]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, Pasteurella haemolytica and Pasteurella multocida [combo 112]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, preferably as live modified viruses, and Bacterin from Pasteurella haemolytica and Bacterina from Pasteurella multocida [combo 113]. According to another preferred embodiment, the combined vaccine comprises neomycin and thimerosal as preservatives [combo 114]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle., wherein the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by RIB, PI- 3, Pasteurella haemolytica and Pasteurella multocida [combo 115]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, PI-3, preferably as live modified viruses, and bacterin. of Pasteurella haemolytica and bacterin from Pasteurella multocida [combo 116]. According to another preferred embodiment, the combined vaccine comprises neomycin and thimerosal as preservatives [combo 117]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB Pasteurella haemolytica and Pasteurella multocida [combo 118]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, preferably as live modified viruses, and Bacterina from Pasteurella haemolytica and Bacterina from Pasteurella multocida [combo 119]. According to another preferred embodiment, the combined vaccine comprises neomycin and thimerosal as preservatives [combo 120]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB, HBV, Pasteurella haemolytica and Pasteurella multocida [combo 121]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV, preferably live modified viruses. , and Bacterina from Pasteurella haemolytica and Bacterina from Pasteurella multocida [combo 122]. According to another preferred embodiment, the combined vaccine comprises neomycin and thimerosal as preservatives [combo 123]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one effective immunological active component for the treatment and / or prophylaxis of infections caused by Mycoplasma bovis [combo 124]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one Mycoplasma bovis antigen [combo 125]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB and Mycoplasma bovis [combo 126]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, preferably as live modified viruses, and Mycoplasma bovis [combo 127]. ] According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3 and Mycoplasma bovis [combo 128]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, PI-3, preferably as live modified viruses, and Mycoplasma. bovis [combo 129]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB and Mycoplasma bovis [combo 130]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB preferably as live modified viruses, and Mycoplasma bovis [combo 131]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB, HBV and Mycoplasma bovis [combo 132] According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV preferably as live modified viruses. , and Mycoplasma bovis [combo 133]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by Pasteurella haemolytica and Pasteurella multocida, and Mycoplasma bovis [combo 134]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from Pasteurella haemolytica., Pasteurella multocida and Mycoplasma bovis [combo 135]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, Pasteurella haemolytica and Pasteurella multocida, and Mycoplasma bovis [combo 136]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, preferably as live modified viruses, Pasteurella haemolytica, Pasteurella multocida and Mycoplasma bovis [combo 137]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, Pasteurella haemolytica, Pasteurella multocida and Mycoplasma bovis [combo 138]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, PI-3, preferably as live modified viruses, Pasteurella haemolytica. , Pasteurella multocida and Mycoplasma bovis [combo 139]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB, Pasteurella haemolytica, Pasteurella multocida and Mycoplasma bovis [combo 140]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, preferably as live modified viruses, Pasteurella haemolytica, Pasteurella multocida and Mycoplasma bovis [combo 141]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB, HBV, Pasteurella haemolytica , Pasteurella multocida and Mycoplasma bovis [combo 140]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV, preferably as modified viruses. alive, Pasteurella haemolytica, Pasteurella multocida and Mycoplasma bovis [combo 141]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to the invention. described herein, and at least one active immunological component effective for the treatment and / or prophylaxis of infections produced by Pasteurella haemolytica, Pasteurella multocida and H somnus [combo 142]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 143]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to the invention. described herein, and at least one effective immunological active component for the treatment and / or prophylaxis of infections produced by RIB, Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 144]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one RIB antigen, preferably as live modified viruses, and Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 145]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to the invention. described herein, and at least one active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 146]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, preferably live modified viruses, and Pasteurella haemolytica. , Pasteurella multocida and H. somnus [combo 147]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVB (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB, Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 148]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, preferably as live modified viruses, and Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 149]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), according to described herein, and at least one effective immunological active component for the treatment and / or prophylaxis of infections produced by RIB, PI-3, VRSB, HBV, Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 150] . According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one antigen from RIB, PI-3, VRSB, HBV, preferably as modified viruses. alive, and Pasteurella haemolytica, Pasteurella multocida and H. somnus [combo 151]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 , 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150 and 151], which also comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by one or more pathogenic Leptospira species, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo, Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona [combo 152]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 , 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150 and 151], which also comprises an antigen from one or more species of Leptospira, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardj oprajitno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae , Leptospira bovis, Leptospira interrogans and Leptospira pomona. [combo 153] According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 , 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150 and 151], which also comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Campylobacter fetus [combo 154]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 , 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150 and 151], which also comprises a Campylobacter fetus antigen [combo 155]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150 and 151], which further comprises an effective immunological active component for the treatment and / or the prophylaxis of infections caused by one or more pathogenic Leptospira species, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona, and Campylobacter fetus [combo 156]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150 and 151], which also comprises a Campylobacter fetus antigen and one or more species of Leptospira, preferably selected from Leptospira canicola, Leptospira grippotyphosa, Leptospira borgpetersenii, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Leptospira prajitno, Leptospira icterohaemmorrhagiae, Leptospira bovis, Leptospira interrogans and Leptospira pomona, and [combo 157]. According to another embodiment, the present invention relates to a combination vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, wherein the combination vaccine comprises BVDV attenuated (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by Clostridium perfringens, preferably of Types A, C and / or D [combo 158]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and Clostridium perfringens toxins of Types C and D [combo 254]. According to a more preferred embodiment, the vaccine comprises antigens, preferably toxins, of Clostridium perfringens, preferably of Types A, B, C and / or D [combo 159]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028 029, 030, 031, 032, 033, 034, 035, 036, 037, 038, 039, 040 041, 042, 043, 044, 045, 046, 047, 048, 049, 050, 051, 052 053, 054, 055, 056, 057, 058, 059, 060, 061, 062, 063, 064 065, 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088 089, 090, 091, 092, 093, 094, 095, 096, 097, 098, 099, 100 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which further comprises an effective immunological active component for the treatment and / or prophylaxis of infections produced by Clostridium perfringens, preferably of Types A, C and / or D [combo 160]. According to another embodiment, the present invention relates to a combination vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 , 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031, 032, 033, 034, 035, 036, 037, 038, 039, 040 , 041, 042, 043, 044, 045, 046, 047, 048, 049, 050, 051, 052, 053, 054, 055, 056, 057, 058, 059, 060, 061, 062, 063, 064, 065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090, 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which further comprises a Clostridium perfringens antigen, preferably of Types A, C and / or D [combo 161]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021 022, 023, 024 025, 026, 027, 028, 029, 030, 031, 032, 033 034, 035, 036 037, 038, 039, 040, 041, 042, 043, 044, 045 046, 047, 048 049, 050, 051, 052, 053, 054, 055, 056, 057 058, 059, 060 061, 062, 063, 064, 065, 066, 067, 068, 069 070, 071, 072 073, 074, 075, 076, 077, 078, 079, 080, 081 082, 083, 084 085, 086, 087, 088, 089, 090, 091, 092, 093 094, 095, 096 097, 098, 099, 100, 101, 102, 103, 104, 105 106, 107, 108 109, 110, 111, 112, 113, 114, 115, 116, 117 118, 119, 120 121, 122, 123, 124, 125, 126, 127, 128, 129 130, 131, 132 133, 134, 135, 136, 137, 138, 139, 140, 141 142, 143, 144 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which further comprises a Clostridium perfringens antigen of the Types, B, C and / or D [combo 162]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Clostridium perfringens of Types A, C and / or D, and Clostridium tetani [combo 163] . According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and Clostridium perfringens toxins of Types A, C and / or D, and Clostridium tetani [combo 164]. According to a more preferred embodiment, the vaccine comprises antigens, preferably toxins, of Clostridium perfringens of Types A, B, C and / or D, and Clostridium tetani [combo 165]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which also comprises an effective immunological active component for the treatment and / or the prophylaxis of infections produced by Clostridium perfringens of Types A, C and / or D, and Clostridium tetani [combo 166]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 , 041, 042, 043, 044, 045, 046, 047, 048, 049, 050, 051, 052, 053, 054, 055, 056, 057, 058, 059, 060, 061, 062, 063, 064, 065, 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081 , 082, 083, 084, 085, 086, 087, 088, 089, 090, 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which further comprises a Clostridium perfringens antigen of Types A, C and / or D, and Clostridium tetani [combo 167]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which further comprises a Clostridium perfringens antigen of Types A, B , C and / or D, and Clostridium tetani [combo 168]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii and Clostridium perfringens of Types A, C and / or D [combo 169]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and antigens, preferably toxins, from Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii and Clostridium perfringens. of Types A, C and / or D [combo 170]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 , 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031, 032, 033, 034, 035, 036, 037, 038, 039, 040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 ', 155, 156 and 157], which also comprises an effective immunological active component for the treatment and / ol prophylaxis of infections caused by Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii, and Clostridium perfringens Types A, C and / or D [combo 171]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 013, 014, 015, 016, 017, 018, 025, 026, 027, 028, 029, 030, 037, 038, 039, 040, 041, 042, 049, 050, 051, 052, 053, 054, 061, 062, 063, 064, 065, 066, 073, 074, 075, 076, 077, 078, 085, 086, 087, 088, 089, 090, 097, 098, 099, 100, 101, 102, 109, 110, 111, 112, 113, 114, 121, 122, 123, 124, 125, 126, 133, 134, 135, 136, 137, 138, 145, 146, 147, 148, 1 14499, 1 15500, 151, 152, 153, 154, 155, 156 and 157], which also comprises an antigen of Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii and Clostridium perfringens of Types A, C and / or D [combo 172].

According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 and 157], which further comprises a Clostridium perfringens antigen of the Types, A, B, C and / or D, Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii and Clostridium tetani [combo 173]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens of Types A, C and / or D and Mycoplasma bovis [combo 174]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and antigens, preferably toxins, from Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens. of Types A, C and / or D and Mycoplasma bovis [combo 175]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens of Types A, C and / or D and H. somnus. [combo 176]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and antigens, preferably toxins, from Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii and Clostridium perfringens. of Types C and D, and H somnus. [combo 177] According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Clostridium chauvoei., Clostridium septicum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens of Types A, C and / or D, Mycoplasma bovis and H. somnus [combo 178]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and antigens, preferably toxins, from Clostridium chauvoei, Clostridium septicum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens. of Types A, C and / or D, Mycoplasma bovis and H. somnus [combo 179]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Salmonella, preferably Salmonella dublin, Salmonella newport and Salmonella typhimurium [combo 180]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and Salmonella toxins, preferably Salmonella dublin, Salmonella newport and Salmonella typhimurium [combo 181]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 17 5, 176, 177, 178 and 179], which further comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Salmonella, preferably Salmonella dublin, Salmonella newport and Salmonella typhimurium [combo 182]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 028, 029, 030, 031, 032, 033, 034, 035, 036, 037, 040, 041, 042, 043, 044, 045, 046, 047, 048, 049, 052, 053, 054, 055, 056, 057, 058, 059, 060, 061, 064, 065, 066, 067, 068, 069, 070, 071, 072, 073, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 088, 089, 090, 091, 092, 093, 094, 095, 096, 097, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 171, 172, 173, 174, 175, 176, 177, 178 and 179], which additionally comprises an antigen, preferably a Salmonella toxin. , preferably Salmonella dublin, salmonella newport and Salmonella typhimurium [combo 183].

According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by Pasteurella haemolytica, Pasteurella multocida, Salmonella, preferably Salmonella dublin, Salmonella newport and Salmonella typhimurium [combo 184] . According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and Pasteurella haemolytica, Pasteurella multocida, Salmonella, preferably Salmonella dublin bacterina-toxoid, Salmonella newport and Salmonella typhimurium [combo 185]. According to a more preferred embodiment, the combined vaccine comprises multiple isolates of Pasteurella haemolytica Type Al and an associated toxoid moiety, and single isolates of P multocida, S dublin and S typhimurium [combo 186]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one active immunological component effective for the treatment and / or prophylaxis of infections caused by Moraxella bovis and / or Klebsiella spp., preferably Klebsiella pneumoniae [combo 187]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and toxins from Moraxella bovis and / or Klebsiella spp. preferably Klebsiella pneumoniae [combo 188]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001 002, 003, 004, 005, 006, 007, 008, 009, 010 011, 012, 013 014, 015, 016, 017, 018, 019, 020, 021, 022 023, 024, 025 026, 027, 028 , 029, 030, 031, 032, 033, 034 035, 036, 037 038, 039, 040, 041, 042, 043, 044, 045, 046 047, 048, 049 050, 051, 052, 053, 054, 055 , 056, 057, 058 059, 060, 061 062, 063, 064, 065, 066, 067, 068, 069, 070 071, 072, 073 074, 075, 076, 077, 078, 079, 080, 081, 082 083, 084, 085 086, 087, 088, 089, 090, 091, 092, 093, 094 095, 096, 097 098, 099, 100, 101, 102, 103, 104, 105, 106 107, 108, 109 110 , 111, 112, 113, 114, 115, 116, 117, 118 119, 120, 121 122, 123, 124, 125, 126, 127, 128, 129, 130 131, 132, 133 134, 135, 136, 137 , 138, 139, 140, 141, 142 143, 144, 145 146, 147, 148, 149, 150, 151, 152, 153, 154 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165 166, 167, 168 169, 170, 171, 172, 173, 174, 175, 176, 177 178, 179, 180 181, 182, 183, 184, 185 and 186], which also comprises a component effective immune asset for treatment and / or pr Ophilaxis of infections produced by Moraxella bovis and / or Klebsiella spp., preferably Klebsiella pneumoniae [combo 189]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006 009 010, 011, 012, 013, 014 015, 016, 017, 018 021 022,023,024,025,026,027,028,029,030,033,034,035,036,037,038,039,040,041,042,045,046,047,048,049,050,051,052,053,054 057 058, 059, 060, 061, 062 063, 064, 065, 066 069 070, 071, 072, 073, 074 075, 076, 077, 078 081 082, 083, 084, 085, 086 087, 088, 089, 090 093 094, 095, 096, 097, 098 099, 100, 101, 102 105 106, 107, 108, 109, 110 111, 112, 113, 114 117 118, 119, 120, 121, 122 123, 124, 125 , 126 129 130, 131, 132, 133, 134 135, 136, 137, 138 141 142, 143, 144, 145, 146 147, 148, 149, 150 153 154, 155, 156, 157, 158 254, 159, 163, 164 170 174, 175, 176, 177, 178, 179, 180, 181, 184, 185 and 186], which further comprises an antigen, preferably a toxin from Moraxella bovis and / or Klebsiella spp., Preferably Klebsiella pneumoniae [combo 190] According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one active immunological component effective for the treatment and / or prophylaxis of infections produced by Escherichia coli [combo 191]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and toxins from Escherichia coli [combo 192]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 17 5, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 and 190], which further comprises an effective immunological active component for the treatment and / or prophylaxis of infections produced by Eschericia coli [combo 193]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005 008, 009, 010, 011, 012, 013, 014, 015, 016, 017 020 , 021, 022, 023, 024, 025, 026, 027, 028, 029 032, 033, 034, 035, 036, 037, 038, 039, 040, 041 044, 045, 046, 047, 048, 049, 050 , 051, 052, 053 056, 057, 058, 059, 060, 061, 062, 063, 064, 065 068, 069, 070, 071, 072, 073, 074, 075, 076, 077 080, 081, 082, 083, 084, 085, 086, 087, 088, 089 092, 093, 094, 095, 096, 097, 098, 099, 100, 101 104, 105, 106, 107, 108, 109, 110, 111, 112, 113 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 128, 129, 130, 131, 132, 133, 134, 135, 136, 137 140, 141, 142, 143, 144, 145 , 146, 147, 148, 149 152, 153, 154, 155, 156, 157, 158, 254, 159, 160 163, 164, 165, 166, 167, 168, 169, 170, 171, 172 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 187, 188, 189 and 190], which further comprises an antigen, preferably a toxin, of Escherichia coli [combo 194]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle., wherein the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by Pasteurella haemolytica, Pasteurella multocida, Salmonella dublin, Salmonella typhimurium and Eschericha coli [combo 195]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and bacterin-toxoid from Pasteurella haemolytica, Pasteurella multocida, Salmonella dublin, Salmonella typhimurium and Escherichia coli [combo 196]. According to a more preferred embodiment, the combined vaccine comprises multiple isolates of Pasteurella haemolytica Type Al and an associated toxoid fraction, and simple isolates of P multocida, S dublin and S typhimurium [combo 197]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one effective immunological active component for the treatment and / or prophylaxis of infections caused by bovine Rotavirus [combo 198]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and a bovine Rotavirus antigen [combo 199]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003 010, 011, 012, 013, 014, 015 022, 023, 024, 025, 026, 027 034, 035, 036, 037, 038, 039 046, 047, 048, 049, 050, 051 058, 059, 060, 061, 062, 063 070, 071, 072, 073, 074, 075 082, 083, 084, 085, 086, 087 094, 095, 096, 097, 098, 099 106, 107, 108, 109, 110, 111 118, 119, 120, 121, 122, 123 130, 131, 132, 133, 134, 135 142, 143, 144, 145, 146, 147 154, 155, 156, 157, 158, 254 165, 166, 167, 168, 169, 170 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 1! 189, 190, 191, 192, 195, 196 and 197], which also comprises an active immunological component effective for the treatment and / or prophylaxis of infections caused by bovine Rotavirus [200]. According to another embodiment, the present invention relates to a combined vaccine according to any one of ; combo 001, 002, 003, 004, 005, 006, 007,, t 010, 011, 015 016 020, 021, 022, 023, 027 028 032, 033, 034, 035, 039 040 044, 045, 046, 047 , 051 052 056, 057, 058, 059, 063 064 068, 069, 070, 071, 075 076 080, 081, 082, 083, 087 088 092, 093, 094, 095, 099 100 104, 105, 106, 107 , 111 112 116, 117, 118, 119, 123 124 128, 129, 130, 131, 135 136 140, 141, 142, 143, 147 148 152, 153, 154, 155, 254 159 163, 164, 165, 166 , 170 171 175, 176, 177, 178, 182 183 187, 188, 189, 190, 194, 195, 196 and 197], which also comprises a bovine Rotavirus antigen [combo 201]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of bovine coronavirus infections [combo 202]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and a bovine Coronavirus antigen [combo 203]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, r w -J t U J u, J). - f 013, 014 015, 016, 017 018, 019, 020, 021, 022, 023, 024, 025, 026 027, 028, 029 030, 031, 032, 033, 034, 035, 036, 037, 038 039, 040, 041 042, 043, 044, 045, 046, 047, 048, 049, 050 051, 052, 053 054, 055, 056, 057, 058, 059, 060, 061, 062 063, 064, 065 066, 067, 068, 069, 070, 071, 072, 073, 074 075, 076, 077 078, 079, 080, 081, 082, 083, 084, 085, 086 087, 088, 089 090, 091, 092, 093, 094, 095, 096, 097, 098 099, 100, 101 102, 103, 104, 105, 106, 107, 108, 109, 110 111, 112, 113 114, 115, 116, 117, 118, 119, 120, 121, 122 123, 124, 125 126, 127, 128, 129, 130, 131, 132, 133, 134 135, 136, 137 138, 139, 140, 141, 142, 143, 144, 145, 146 147, 148, 149 150, 151, 152, 153, 154, 155, 156, 157, 158 254, 159, 160 161, 162, 163, 164, 165, 166, 167, 168, 169 170, 171, 172 173, 174, 175, 176, 177, 178, 179, 180, 181 182, 183, 184 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196 and 197], which further comprises an effective immunological active component for the treatment and / or the prophylaxis of infections caused by bovine Coronavirus [combo 204]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 , 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180 , 181, 182, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193, 194, 195, 196 and 197], which also comprises a Bovine Coronavirus antigen [combo 205]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of bovine coronavirus and bovine Rotavirus infections [combo 206]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and a bovine Coronavirus and bovine Rotavirus antigen [combo 207]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 17 5, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196 and 197], which further comprises an effective immunological active component for the treatment and / or prophylaxis of bovine coronavirus and bovine Rotavirus infections [combo 208]. According to another embodiment, the present invention relates to a vaccine any one of [comb or 001, 002, 003, 004, 008, 009, 010, 011, 012, 013, 014, 015, 016, 020, 021, 022 023, 024, 025, 026, 027, 028, 032, 033, 034 035, 036 037, 038 039, 040, 044, 045, 046 047, 048 049, 050 051, 052, 056, 057, 058 059, 060 061, 062 063, 064, 068, 069, 070 071, 072 073, 074 075, 076, 080, 081, 082 083, 084 085, 086 087, 088, 092, 093, 094 095, 096 097, 098 099 , 100, 104, 105, 106 107, 108 109, 110 111, 112, 116, 117, 118 119, 120 121, 122 123, 124, 128, 129, 130 131, 132 133, 134 135, 136, 140, 141, 142 143, 144 145, 146 147, 148, 152, 153, 154 r 155, 156, 157, 158 r 254, 159, 163, 164, 165, 166, 167, 168, 169 r 170, 171, 175 , 176, 177, 178, 179, 180, 181 r 182, 183, 187, 188, 189, 190, 191 r 192, 193 r 194, 195, 196 and 197], which also comprises an antigen of Bovine Coronavirus and Rotavirus bovine [combo 209]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Cryptosporidium parvum [combo 210]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen of Cryptosporidium parvum [combo 211].

According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 and 209], which further comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Cryptosporidium parvum [combo 212]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040,041,042,043,044 045, 046, 047, 048, 049, 050, 051, 052, 053, 054, 055, 056, 057, 058, 059, 060, 061, 062, 063, 064, 065, 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081,082,083,084,085,086,087,088,089,090,091,092,093,094,095,096,097,098,099,101,102,102,103,104 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170,171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208 and 209], which further comprises an antigen of Cryptosporidium parvum [combo 213]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Cryptosporidium hominis [combo 214]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and a Cryptosporidium hominis antigen [combo 215].

According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026,027,028,029,030,031,032,033,034,035,036,037,038,039,040,041,042,043,044,045,046,047,048,049,050 051,052,053,054,055,056,057,058,059,060,061,062,063,064,065,066,067,068,069,070,071,072,073,074,075 076,077,078,079,080,081,082,083,084,085,086,087,088,089,090,091,092,093,094,095,096 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204 , 205, 206, 207, 208 and 209], which also comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Cryptosporidium hominis [combo 216]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031, 032, 033, 034, 035, 036, 037, 038, 039, 040, 041, 042, 043, 044, 045, 046, 047, 048, 049, 050, 051, 052, 053, 054, 055, 056, 057, 058, 059, 060, 061, 062, 063, 064, 065, 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090, 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170,171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208 and 209], which also comprises an antigen of Cryptosporidium hominis [combo 217]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Cryptosporidium parvum and Cryptosporidium hominis [combo 218]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Cryptosporidium parvum and Cryptosporidium hominis [combo 219].

According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 , 016, 017, 018, 019, 020, 021, 022, 023, 024, 027, 028, 029, 030, 031, 032, 033, 034, 035,, 036, 039, 040, 041, 042, 043, 044, 045, 046, 047,, 048, 051, 052, 053, 054, 055, 056, 057, 058, 059,, 060, 063, 064, 065, 066, 067, 068, 069, 070, 071, , 072, 075, 076, 077, 078, 079, 080, 081, 082, 083,, 084, 087, 088, 089, 090, 091, 092, 093, 094, 095,, 096, 099, 100, 101 , 102, 103, 104, 105, 106, 107,, 108, 111, 112, 113, 114, 115, 116, 117, 118, 119,, 120, 123, 124, 125, 126, 127, 128, 129 , 130, 131,, 132, 135, 136, 137, 138, 139, 140, 141, 142, 143,, 144, 147, 148, 149, 150, 151, 152, 153, 154, 155,, 156, 254, 159, 160, 161, 162, 163, 164, 165, 166,, 167, 170, 171, 172, 173, 174, 175, 176, 177, 17! , 17 9, 182, 183, 184 184, 185, 186, 187, 188, 189,, 190, 193, 194, 195, 196, 197, 198, 199, 200, 201,, 202, 205, 206, 207 , 208 and 209], which also comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Cryptosporidium parvum and Cryptosporidium hominis [combo 220]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029 , 030,031,032,033,034,035,036,037,038,039,040,041,042,043,044,045,046,047,048,049,050,051,052,053,054 , 055, 056, 057, 058, 059, 060, 061, 062, 063, 064, 065, 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079 , 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090, 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104 , 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129 , 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 , 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170,171, 172, 173, 174, 175, 176, 177, 178, 179 , 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 2 04 205, 206, 207, 208 and 209], which further comprises an antigen of Cryptosporidium parvum and Cryptosporidium hominis [combo 221].

According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Mycobacterium avium paratuberculosis [combo 222]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Mycobacterium avium paratuberculosis [combo 223]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 004, 005, 006, 007, 008, 009, 010, 011, 012, 016, 017, 018, 019, 020, 021 , 022, 023, 024, 028, 029, 030 031, 032, 033, 034, 035, 036, 040, 041, 042 043, 044, 045, 046, 047, 048, 052, 053, 054 055, 056, 057, 058, 059, 060, 064, 065, 066 067, 068, 069, 070, 071, 072, 076, 077, 078 079, 080, 081, 082, 083, 084, 088, 089, 090 091, 092 , 093, 094, 095, 096, 100, 101, 102 103, 104, 105, 106, 107, 108, 112, 113, 114 115, 116, 117, 118, 119, 120, 124, 125, 126 127, 128, 129, 130, 131, 132, 136, 137, 138 139, 140, 141, 142, 143, 144, 148, 149, 150 151, 152, 153, 154, 155, 156, 159, 160, 161 162 , 163, 164, 165, 166, 167, 171, 172, 173 174, 175, 176, 177, 178, 179, 183, 184 184, 185, 186, 187, 188, 189, 190, 194, 195, 196 197, 198, 199, 200, 201, 202, 206, 207, 208, 209, 210, 211, 212, 213, 214, 218, 219, 220 and 221], which also comprises An effective immunological active compound for the treatment and / or prophylaxis of infections caused by Mycobacterium avium paratuberculosis [combo 224]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 , 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220 and 221], which further comprises an antigen of Mycobacterium avium paratuberculosis [ combo 225]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Adenovirus [combo 226]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an Adenovirus antigen [combo 227]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017 018, 019, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029 030, 031, 032, 033, 034, 035, 036, 037, 038, 039, 040, 041 042, 043, 044, 045, 046, 047, 048, 049, 050, 051, 052, 053 054, 055, 056, 057, 058, 059, 060, 061, 062, 063, 064, 065 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089 090, 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181 , 182, 183, 184 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224 and 225], which further comprises an effective immunological active compound for the treatment and / or prophylaxis of infections produced by Adenovirus [combo 228]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009,011, 012,013,014,015,016,017,018,019,020,021,023,024,025,026,027,028,029,030,031,032,033,035,036,037,038,039 040, 041, 042, 043, 044, 045 047, 048, 049, 050 051, 052, 053, 054, 055, 056, 057 059, 060, 061, 062 063, 064, 065, 066, 067, 068, 069,071,072,073,074,075,076,077,078,079,080,081,083,084,085,086,087,088,089,090,091,092,093,095,096,097,098,099 100, 101, 102, 103, 104, 105 107, 108, 109, 110 111, 112, 113, 114, 115, 116, 117 119, 120, 121, 122 123, 124, 125, 126, 127, 128, 129 131, 132, 133, 134 135, 136, 137, 138, 139, 140, 141 143, 144, 145, 146 147, 148, 149, 150, 151, 152, 153 155, 156, 157, 158 254, 159, 160, 161, 162, 163, 164 166, 167, 168, 169, 170,171, 172, 173, 174, 175, 176 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223,224 and 225], which also comp Rende an Adenovirus antigen [combo 229].

According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Astrovirus [combo 230]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an Astrovirus antigen [combo 231]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228 and 229], which further comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Astrovirus [combo 232]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 , 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227 , 228 and 229], which also comprises an Astrovirus antigen [combo 233]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by bovine Parvovirus [combo 234]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and a bovine Parvovirus antigen [combo 235]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 004, 005, 006, 007, 008, 009, 010, 011, 012, 016, 017, 018, 019, 020, 021 , 022, 023, 024, 028, 029, 030, 031, 032, 033, 034, 035, 036, 040, 041, 042, 043, 044, 045, 046, 047, 048, 052, 053, 054, 055 , 056, 057, 058, 059, 060, 064, 065 066 067 068, 069, 070, 071, 072, 076, 077 078 079 080, 081, 082, 083, 084, 088, 089 090 091 092, 093, 094, 095, 096, 100, 101 102 103 104, 105, 106, 107, 108, 112, 113 114 115 116, 117, 118, 119, 120, 124, 125 126 127 128, 129, 130, 131, 132 , 136, 137 138 139 140, 141, 142, 143, 144, 148, 149 150 151 152, 153, 154, 155, 156, 159, 160 161, 162 163, 164, 165, 166, 167, 171, 172 173 r 174 175, 176, 177, 178, 179, 183, 184 184, 185, 186, 187, 188, 189, 190, 194, 195 196, 197, 198, 199, 200, 201, 202, 206, 207 208, 209 r 210, 211, 212, 213, 214, 218, 219, 220, 221, 222, 223, 224, 225, 226, 230, 231, 232 and 233], which and further comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by bovine Parvovirus [combo 236]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009 011, 012 013, 014 015, 016, 017, 018, 019, 020, 021 023, 024 025, 026 027, 028, 029, 030, 031, 032, 033 035, 036 037, 038 039, 040, 041 , 042, 043, 044, 045 047, 048 049, 050 051, 052, 053, 054, 055, 056, 057 059, 060 061, 062 063, 064, 065, 066, 067, 068, 069 071, 072 073 , 074 075, 076, 077, 078, 079, 080, 081 083, 084 085, 086 087, 088, 089, 090, 091, 092, 093 095, 096 097, 098 099, 100, 101, 102, 103, 104, 105 107, 108 109, 110 111, 112, 113, 114, 115, 116, 117 119, 120 121, 122 123, 124, 125, 126, 127, 128, 129 131, 132 133, 134 135, 136 , 137, 138, 139, 140, 141 143, 144 145, 146 147, 148, 149, 150, 151, 152, 153 155, 156 157, 158 254, 159, 160, 161, 162, 163, 164 166 , 167, 168, 169, 170,171, 172, 173, 17, 175, 176 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188 190, 191, 192, 193, 194, 195, 196, 197 19, 199, 200, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224 226, 227, 228, 229, 230, 231, 23 2, and 233], which also comprises a bovine Parvovirus antigen [combo 237]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Cryptosporidium parvum, Adenovirus, Astrovirus, Bovine Parvovirus and Mycobacterim avium paratuberculosis [combo 238]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Cryptosporidium parvum, Adenovirus, Astrovirus, bovine Parvovirus and Mycobacterim avium paratuberculosis [combo 239] . According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections produced by Escherichia coli, Salmonella spp., preferably Salmonella dublin, Salmonella typhimurium and Salmonella newport, Bovine Rotavirus and Coronavirus, Cryptosporidium parvum, Adenovirus, Astrovirus, Bovine Parvovirus and Mycobacterim avium paratuberculosis [combo 240]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Escherichia coli, Salmonella spp., Preferably Salmonella dublin, Salmonella typhimurium and Salmonella newport, bovine rotavirus and bovine coronavirus, Cryptosporidium parvum, Adenovirus, Astrovirus, bovine Parvovirus and Mycobacterim avium paratuberculosis [combo 241]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Streptococcus spp., preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae [combo 242]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Streptococcus spp., Preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, [combo 243] . According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types I and / or 2), as described herein, and a Streptococcus spp antigen., preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae [combo 244]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Streptococcus spp., preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae and / or Staphylococcus aureus [combo 245] . According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Streptococcus spp., Preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, and / or Staphylococcus. aureus [combo 246]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 17 5, 176, 177, 178, 179, 180, 181, 182, 183, 184, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199 , 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224 , 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240 and 241], which also comprises an effective immunological active component for the treatment and / or prophylaxis of infections caused by Streptococcus spp., preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, and / or Staphylococcus aureus [combo 247]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 , 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227 , 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240 and 241], which further comprises an antigen of Streptococcus spp., Preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, and / o Staphylococcus aureus [combo 248]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040,041,042, 043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065,066,067 068,069,070,071,072,073,074,075,076,077,078,079,080,081,082,083,084,085,086,087,088,089,090,091,092 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170,171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240 and 241], which further comprises an antigen of Streptococcus spp., Preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, and / or Staphylococcus aureus [combo 249]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Streptococcus spp., preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, Staphylococcus aureus, Klebsiella spp. and Mycoplasma spp .. [combo 250]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen from Streptococcus spp., Preferably Streptoccoccus uberus, Streptococcus dysgalactiae, and / or Streptococcus aureus, Klebsiella spp. and Mycoplasma spp. [combo 251]. According to a more preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and an antigen of Streptococcus spp., Preferably Streptoccoccus uberus and / or Streptococcus dysgalactiae, Staphylococcus aureus, Klebsiella spp., Mycoplasma spp. and endotoxin [combo 252]. According to another embodiment, the present invention relates to a combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections in cattle, where the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and at least one additional active immunological component effective for the treatment and / or prophylaxis of infections caused by Trichophyten and Microsporus, preferably selected from Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton equinum, Trichophyton sarkisovii, Microsporum canis. , Microsporum canis var. obesum, Microsporum canis var. distortum and Microsporum gypseum [combo 253]. According to a preferred embodiment, the combined vaccine comprises attenuated VDVBs (types 1 and / or 2), as described herein, and a Trichophyten antigen, and Microsporus, preferably selected from Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton equinum, Trichophyton sarkisovii, Microsporum canis, Microsporum canis var. obesum, Microsporum canis var. distortum and Microsporum gypseum [combo 254]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 025, 026 027, 028 029, 030, 031 032, 033 034, 035, 036, 037, 038 039, 040 041, 042, 043 044, 045 046, 047, 048, 049, 050 051, 052 053, 054, 055 056, 057 058, 059, 060, 061, 062 063, 064 065, 066, 067 068, 069 070, 071, 072, 073, 074 075, 076 077, 078, 079 080, 081 082, 083, 084, 085, 086 087, 088 089, 090, 091 092, 093 094, 095, 096, 097, 098 099, 100 101, 102, 103 104, 105 106, 107, 108, 109, 110 111, 112 113, 114, 115 116, 117, H8, 119, 120, 121, 122 123, 124 125, 126, 127, 128, 129 130, 131, 132, 133, 134 135, 136 137, 138, 139 140, 141 142, 143, 144, 145, 146 147, 148 149, -150, 151 152, 153 154, 155, 156, 157, 158 254, 159, 160, 161, 162 r 163, 164, 165, 166, 167, 168, 169 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181 182, 183 184, 185, 186, 187, 188, 189, 190, 191, 192, 193 194, 195, 196, 197, 19? 5, 199, 20 D, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222 , 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247 , 248, 249, 250 and 251], which also comprises an effective immunological active component for the treatment and / or prophylaxis of infections produced by Trichophyten and Microsporus, preferably selected from Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton equinum, Trichophyton sarkisovii, Microsporum canis, Microsporum canis var. obesum, Microsporum canis var. distortum and Microsporum gypseum [combo 255]. According to another embodiment, the present invention relates to a combined vaccine according to any one of [combo 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015 016,017,018,019,020,021,022,023,024,025,026,027,028,029,030,031,032,033,034,035,036,037,038,039,040 041,042,043,044,045,046,047,048,049,050,051,052,053,054,055,056,057,058,059,060,061,062,063,064,065 , 066, 067, 068, 069, 070, 071, 072, 073, 074, 075, 076, 077, 078, 079, 080, 081, 082, 083, 084, 085, 086, 087, 088, 089, 090 , 091, 092, 093, 094, 095, 096, 097, 098, 099, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 , 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 , 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 254, 159, 160, 161, 162, 163, 164 , 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 17 5, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251 and 252], which further comprises an antigen of Trichophyten and Microsporus, preferably selected from Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton equinum, Trichophyton sarkisovii, Microsporum canis, Microsporum canis var. obesum, Microsporum canis var. distortum and Microsporum gypseum [combo 256]. According to another embodiment, the origin of the combined vaccine is Alpha 7 ™, ALPHA-7 / MB ™, ALPHA-CD ™, BAR-VAC® 7, BAR-VAC® 7 / SOMNUS, BAR-VAC® 8, BAR -VAC® CD, BAR-VAC® C / DT, BREED-BACK ™ FP 10, BREED-BACK ™ FP 10 HS, BREED-BACK ™ FP 5, BREED-BACK ™ FP 5 HS, BREED-BACK-10 ™, CALIBER® 3, CALIBER® 7, ELITE 4 ™, ELITE 9 ™, ELITE 9-HS ™, EXPRESS®10, EXPRESS®10-HS, EXPRESS® 3, EXPRESS® 3 / Lp, EXPRESS 4®, EXPRESS® 5, EXPRESS® 5-HS, EXPRESS® 5-PHM, EXPRESS® I, EXPRESS® I / LP, OCU-GUARD® MB, PULMO-GUARD ™ MpB, PULMO-GUARD ™ PH-M, PULMO-GUARD ™ PH-M / SDT, PULMO-GUARD ™ PHM-1, TETGUARD ™, VIBRIO-LEPTO-5 ™ (all from Boehringer Ingelheim, St. Joseph, MO); Cobalt ™ 7, I-Site ™, Lepto 5, Master Guard® Preg 5, Master Guard® 10, Master Guard® 10 + Vibrio, Master Guard® J5, P.H.M. Bac® 1, Pre-vent 6 ™, Respromune® 4, Respromune® 4 + Somnumune® (IM, SC), Respromune® 5 IB-P + VRSB, Respromune® 5 + L5, Respromune® 5 + L5 Somnus, Respromune® 5 + Somnumune, Respromune® 5 + VL5, Respromune® 8, Respromune® 9, Respromune® 10, Scour Vac ™ 4, Scour Vac ™ 9, Scour Vac ™ E coli + C, Somnumune®, Titanium ™ 3, Titanium ™ 4 , Titanium ™ 4 L5, Titanium ™ 5, Titanium ™ 5 L5, Titanium® 5 + PHM Bac®-1, Titanium ™ VRSB 3, Titanium ™ RIB, Titanium ™ RIB-LP (all from Agri Laboratories Inc., St. Joseph, MO); Herd-Vac® 3, Herd-Vac® 3 S, Herd-Vac® 8, Herd-Vac® 9, Surround ™ 4, Surround ™ 4 + HS, Surround ™ 8, Surround ™ 9, Surround ™ 9 + HS, Surround ™ HS, Surround ™ L5, Surround ™ V-L5 (all from BioCor, Omaha, NE (Pfizer)); Mycomune® (Biomune Co., Lenexa, KS); Bluetongue vaccine, Bovine Viral Diarrhea Virus Vaccine, Campylobacter fetus bovine Bacterine, Essential 1, Essential 2, Essential 2 + P, Essential 3, Essential 3 + T, Essential 4, Lepto-5, Mannheimia bacterin Haemolytica-Pasteurella multocida, Pre-breed 6, Pre-breed 8, Breathe-1, Breathe-3, Wart Vaccine (all from Colorado Serum Company, Denver, CO); Pyramid® 3, Pyramid® 4, Pyramid® 4 + Presponse® SQ, Pyramid® 5, Pyramid® 8, Pyramid® 9, Pyramid® IBR, Pyramid® IBR + Lepto, Triangle® 1 + VDB Type, Triangle® 3 + VL5 , Triangle® 4 + HS, Triangle® 4 + PH / HS, Triangle® 4 + PH-K, Triangle® 4 + VDB Type II, Triangle® 9 + HS, Triangle® 9 + PH-K, Triangle® + VDB Type II, Tpchguard®, Tnchguard® + V5L, TriVib 5L® (all from Fort Dodge Animal Health, Overland Park, KS (yeth)); J-5 Bactepna from Escherichia coli, Bacterina from Serpens; bacepina-toxoid from Staphylococcus aureus (all from Hygieia Biological Laboratories, Woodland, CA); Endovac-Boví® with Immuneplus® (Immvac, Inc., Columbia, MO); 20/20 Vision® with Spur®, L5 SQ, Neoguard ™, MasterGuard® Preg 5, Once PMH®, Once PMH® SQ, V? Bralone ™ -L5, Vision® 7 Somnus with Spur®, Vision® 7 with Spur® , Vision® 8 Somnus with Spur®, Vision® 8 with Spur®, Vision® CD-T with Spur®, Vision® CD with Spur®, Vista ™ IBR SQ, Vista ™ 3 SQ, Vista ™ 5 SQ, Vista ™ 5 L5 SQ, Vista ™ Once SQ, VL5 SQ, Volar®, (all from Intervet Inc., Millsboro, DE); Vac®, Reliant® 3, Reliant® 4, Reliant® IBR, Reliant® IBR / BVD, Reliant® IBR / Lepto, Reliant® Plus BVD-K (Dual IBR ™), Reliant® Plus (Dual IBR ™), Respishield ™ 4, Respishield ™ 4 L5, Respishield ™ HM (all from Merial LTD, Duluth, GA); Arsenal® 4.1, Arsenal® IBR, Arsenal® IBR BVD, Bovine Pili Shield ™, Bovine Pili Sh? Eld ™ + C, Clostp Shield® 7, Clostri Shield® BCD, Fusogard®, Lepto Shield ™ 5, Pinkeye Shield ™ XT4, Salmo Shield® T, Salmo Shield® TD, Scour Bos ™ 4, Scour Bos ™ 9, Somnu Shield ™, Trep Shield ™ HW, Vib Shield® L5, Vib Shield® Plus, Vib Shield® Plus L5, Vira Shield® 2, Vira Shield® 2 + BRSV, Vira Shield® 3, Vira Shield® 3 + VL5, Vira Shield® 4, Vira Shield® 4 + L5, Vira Shield® 5, Vira Shield® 5 + L5, Vira Shield® 5 + L5 Somnus , Vira Shield® 5 + Somnus, Vira Shield © 5 + VL5, Vira Shield® 5 + VL5 Somnus, Vira Shield® 6, Vira Shield® 6 + Somnus, Wart Shield ™ (all from Novartis Animal Health, Basel, Switzerland); Bovi-K® 4, Bovi-Shield ™ 3, Bovi-Shield ™ 4, Bovi-Shield ™ BRSV, Bovi-Shield® FP ™ 4 + L5, Bovi-Shield® GOLD 3, Bovi-Shield® GOLD 5, Bovi- Shield® GOLD FP ™ 5 L5, Bovi-Shield® GOLD FP ™ 5 VL5, Bovi-Shield® Gold IBR-BVD, Bovi-Shield © Gold IBR-BVD-BRSV-LP, Bovi-Shield ™ IBR, Bovi-Shield ™ IBR-BRSV-LP, Bovi-Shield ™ IBR-BVD, Bovi-Shield ™ IBR-BVD-BRSV-LP, Bovi-Shield ™ IBR-PI3-BRSV, Calf-Guard®, CattleMaster® 4, CattleMaster® 4 + L5 , CattleMaster® 4 + VL5, CattleMaster® BVD-K, CattleMaster® Gold FP ™ 5, CattleMaster® Gold FP ™ 5 L5, Defensor® 3, Fortress® 7, Fortress® 8, Fortress® CD, Leptoferm®-5, One Shot®, One Shot Ultra ™ 7, One Shot Ultra ™ 8, PregGuard ™ FP 9, PregGuard® Gold FP ™ 10, Resvac® BRSV / Somubac®, Resvac® 4 / Somubac®, ScourGuard 3® (K), ScourGuard 3 ® (K) / C, Somubac®, Spirovac®, Spirovac® L5, Spirovac® VL5, StayBred ™ VL5, TSV-2 ™, Ultrabac® 7, Ultrabac® 7 / Somubac®, Ultrabac® 8, Ultrabac® CD, UltraChoice ™ 7, UltraChoice ™ 8, UltraChoice ™ CD, Upjohn J-5 Bacterin ™, Vibrin® (all from Pfizer Inc., New York, NY); Covexin® vaccine 8, Electroid® 7, Electroid® D, Guardian ™, Jencine® 2, Jencine® 3, Jencine® 4, Nasalgen® IP Vaccine, Piliguard® Pinkeye-1 Trivalent, Piliguard® Pinkeye + 7, Piliguard® Pinkeye Triview®, Siteguard® G, Siteguard® MLG Vaccine (all from Schering-Plow Animal Health Corporation, Kenilworth, NJ); Myco-Bac ™ B, Poly-Bac B® 3, Poly-Bac B® Somnus, Super Poly-Bac B® Somnus (all of Texas Vet Lab, Inc., San Angelo, TX), Virabos ™ -3 with Immunostim®, Virabos ™ -4 + H. somnus with Immunostim®, Virabos ™ -4 with Immunostim® (all from Bioniche Animal Health, Athens, GA), to which the attenuated VDVB is added, as described herein. Alternatively, when VDVB antigen is present in any of those vaccines, the attenuated VDVB is added, as described herein, or the BVDV present in any of those vaccines is replaced with the attenuated VDVB, as described herein. . Formulations: An important aspect of the present invention is the preparation of the vaccine or combination vaccines. The skilled person knows additional components that may be contained in the composition (see also Remington's Pharmaceutical Sciences, (1990), 18th ed Mack Publ., Easton). The skilled person can use sterile, injectable, physiologically acceptable solutions known. To prepare a ready-to-use solution for parenteral injection or infusion, aqueous isotonic solutions, such as, e.g. ex. , saline solution or corresponding solutions of proteins in the plasma. The pharmaceutical compositions can be present in the form of lyophilizates or dry preparations, which can be reconstituted with a known injectable solution, directly before use under sterile conditions, e.g. ex. in the form of a kit of parts. In addition, the immunogenic vaccine compositions of the present invention may include one or more veterinarily acceptable carriers. As used herein, "a veterinarily acceptable vehicle" includes solvents, dispersing media, coatings, adjuvants, stabilizing agents, diluents, preservatives, antibacterial and antifungal agents, isotonic agents, agents that delay adsorption and Similar. The diluents may include water, saline, dextrose, ethanol, glycerol and the like. Isotonic agents may include sodium chloride, dextrose, mannitol, sorbitol and lactose, among others. The stabilizers include albumin and alkaline salts of ethylenediaminetetraacetic acid, among others.

Adjuvants include, but are not limited to, the RIBI adjuvant system (Ribi Inc.), alum, aluminum hydroxide gel, Cholesterol, oil-in-water emulsions, water-in-oil emulsions such as p. ex. , complete and incomplete Freund's adjuvants, block copolymers (CytRx, Atlanta GA), SAF-M (Chiron, Emeryville CA), CARBOPOL®, adjuvant AMPHIGENO, saponin, Quil A, QS-21 (Cambridge Biotech Inc., Cambridge MA ), GPI-0100 (Gallenica Pharmaceuticals, Inc., Birmingham, AL) or other fractions of saponin, monosphoryl lipid A, lipid adjuvant -amidine Avridine, thermolabile enterotoxin of E. coli (recombinant or other), cholera toxin or muramyl dipeptide, among many others. Immunogenic compositions may also include one or more other immunomodulatory agents such as e.g. ex. , interleukins, interferons or other cytokines. Immunogenic compositions may also include Gentamycin and Merthiolate. While the amounts and concentrations of the adjuvants and additives useful in the context of the present invention can be readily determined by the person skilled in the art, the present invention contemplates compositions comprising between about 50 ug and about 2000 ug of adjuvant and preferably about 250 ug / ml dose of the vaccine composition. In another preferred embodiment, the present invention contemplates vaccine compositions comprising between about 1 ug / ml and about 60 ug / ml of antibiotics, and more preferably less than about 30 ug / ml of antibiotics. For example, in a composition according to the invention, 104 to 106 TCID50 of attenuated VDVB can be dissolved in 25% (vol / vol) of SGS (Sucrose 75 mg, Gelatin 20 mg, potassium hydroxide 0.274 mg, L-glutamic acid 0 , 72 mg, potassium hydrogen-diphosphate 0.516 mg, potassium diphosphate 1.254 mg and 2 ml with water for injection), and 5% (vol / vol) cell culture medium, and 1 ml with water for injection. This is further mixed with at least one antigen of a bovine pathogen, such as those mentioned above. According to another embodiment, the combined vaccine is first dehydrated. If the composition is lyophilized or dehydrated first by other methods, then, prior to vaccination, the composition is rehydrated in aqueous solutions (eg, saline, STP (phosphate buffered saline)) or non-aqueous solutions (eg. emulsion in oil (mineral oil, or based on vegetable oil / metabolizable / based on single or double emulsion), based on aluminum, adjuvant based on carbomer). Dosage and administration: According to the present invention, an effective amount of a combined vaccine administered to cattle, including pregnant cows and calves that are suckled from pregnant cows, provides effective immunity against microbiological infections caused by the BVDV and at least one other pathogen such as those mentioned above. Preferred combinations of antigens for the treatment and prophylaxis of biological diseases in cattle are listed hereinabove. According to one embodiment, the combined vaccine is administered to calves in two doses with an interval of approximately 3 to 4 weeks. For example, the first administration is performed when the animal is approximately 1 to approximately 3 months old. The second administration is performed about 1 to about 4 weeks after the first administration of the combined vaccine. According to a further embodiment, the revaccination is carried out in a range of 6 to 12 months from the administration of the second dose. In a preferred embodiment, the first administration is performed approximately 5 weeks prior to the crossing of the animal. The second administration is carried out approximately 2 weeks before the animal crosses. The administration of subsequent doses of the vaccine is preferably performed on a semi-annual or annual basis. In another preferred embodiment, animals vaccinated before about 6 months of age should be vaccinated after 6 months of age. The administration of subsequent doses of the vaccine is preferably performed every year. The amount of the combination vaccine that is effective depends on the ingredients of the vaccine and the administration catalog. Typically, when a preparation with an inactivated virus or a modified live virus is used in the combined vaccine, an amount of the vaccine containing about 102 to about 109 TCID50 per dose, preferably about 103 to about 10 TCID 50 per dose, will be used. preferably, about 104 to about 108 TCID50 per dose. For example, about 105 to about 108 TCID 50 per dose of attenuated VDVB (types 1 and 2) is effective when administered twice to the animal over a period of about 3 to 4 weeks. In general, the inactivated antigen is normally used in larger amounts than the live modified virus. Typically, when the bacterial antigen is used in the combined vaccine, the vaccine contains an amount of about 103 to about 109 colony forming units (CFU) per dose, preferably, about 104 to about 108 (CFU) per dose., more preferably about 105 to about 106 (CFU) per dose. In case the combined vaccine comprises live modified RIB, the amount of RIB antigen will preferably be in a range of about 105 to 107.5 TCID50 per dose. In case the combined vaccine comprises modified PI3 alive, the amount of PI3 antigen will preferably be in a range of about 107 to 109 TCID50 per dose. In case the combined vaccine comprises modified VRSB alive, the amount of the VRSB antigen will preferably be in a range of about 104.5 to 106.5 TCID50 per dose. In case the combined vaccine comprises inactivated RIB, the amount of RIB antigen will preferably be in a range of about 107.0 to 109.0 TCID5 per dose. In case the combined vaccine comprises inactivated PI3, the amount of PI3 antigen will preferably be in a range of about 107.2 to 109.2 TCID50 per dose. In case the combined vaccine comprises inactivated VRSB, the amount of VRSB antigen will preferably be in a range of about 105'0 to 107'5 TCID50 per dose. In case the combined vaccine comprises Leptospira spp. inactivated, the amount of each antigen of Leptospira spp. it will preferably be in a range of about 107'0 to 1010 (CFU) per dose. In case the combined vaccine comprises inactivated H somuns, the amount of H. somnus antigen will preferably be in a range of about 106.0 to 109 (CFU) per dose. The composition according to the invention can be applied by the intradermal, intratracheal, intravaginal, intramuscular or intranasal routes, and preferably intramuscular or intranasal. In an animal body, it may be advantageous to apply the pharmaceutical compositions, as described above, to target tissues through an intravenous injection or direct injection. For systemic application, intravenous, intravascular, intramuscular, intranasal, intraarterial, intraperitoneal, oral or intrathecal routes are preferred. A more local application can be made subcutaneously, intradermally, intracutaneously, intracardially, intralobally, intramedullaryly, intrapulmonaryly, or directly in or near the tissue to be treated (connective, bony, muscular, nervous, epithelial tissue). Depending on the desired treatment duration and efficacy, the compositions according to the invention can be administered once or several times, also intermittently, for example on a daily basis for several days, weeks or months and in different dosages. Methods for the treatment: Even another important embodiment of the invention consists of a method for the prophylaxis or treatment of diseases caused by the BVDV, and one or more other bovine pathogenic microorganisms, where the attenuated BVDV, as described herein. , and the other effective immunological active components for the treatment and / or prophylaxis of the infection caused by the other bovine pathogenic microorganism are administered to an animal in need thereof in a suitable dose, according to the knowledge of the person skilled in the art.

EXAMPLES The following examples serve to further illustrate the present invention; but these should not be construed as limiting the scope of the invention described herein.

Example 1 VDVB XIKE-B: determination of fetopathogenicity in VDVB pregnant heifers XIKE-B, a negative RNase mutant of the highly pathogenic NewYork'93 / C isolate of VDVB type 2 was recovered from infectious cDNA clone pKANE40B and showed similar growth characteristics to the wild type (ts) in tissue culture. In animal experiments, the mutant virus was found to be considerably attenuated, so that it represented a promising candidate for the development of an attenuated live vaccine virus (Meyer et al., 2002). To test if this attenuated virus is still able to cross the placenta and infest the fetus, pregnant heifers were infested with XIKE-B. As a control, wild type VDVB recovered from a pKANE40A cDNA clone was used. The respective virus, designated XIKE-A, expresses an active Erns RNase in the transfected cell. The study aimed to confirm the safety of XIKE-A and XIKE-B in pregnant animals. EXPERIMENTAL DESIGN Ten pregnant heifers were selected from a negative VDVB herd. The following groups of 5 heifers were included in the trial: The heifers were transported to the experimental facilities 8 days before the inoculations. The pregnancy status was confirmed after transport to the experimental facility. On the day of the inoculation, the heifers were between 60 and 90 days of gestation. The inoculation took place for all the animals at the same time. Heifers were monitored for the presence of clinical symptoms of BVDV infection, including abortions during the observation period. Blood samples were taken from the animals for serology, antigen detection and leukocytes were counted. The experiment was completed 9 weeks after the infestation. The cows that were not aborted were sacrificed, and the uterus was examined and collected. Organ samples from the fetus were collected during routine necropsy and examined for BVDV infection. The presence of an infection of the fetus was the main evaluation parameter, composed of the number of cow deaths related to the BVDV, the number of abortions related to the BVDV and the number of VDVB fetuses positive at the conclusion. In addition to the main parameter, clinical signs characteristic of BVDV infection, viremia and leukocyte counts in cows and rectal temperature after challenge were evaluated. Animals Heifers were purchased from a VDVB-free farm. Only animals that met the following inclusion criteria were used. Inclusion criteria DVB antibody exemption; each individual was tested on the serum antibody before transport and at the start of the study (at the animal testing facility). VDVB exemption; The preparation of plasma and / or the surface layer of the coagulated plasma of each individual was tested by means of a suitable test. Clinically healthy at the beginning of the study, judged after a physical examination. The animal health examination was accomplished in accordance with current veterinary practice, generally accepted. Pregnancy confirmed by a physical examination before inoculation. The pregnancy was between days 60 - 90 at the time of inoculation, demonstrated by insemination records. Test strain A Description: XIKE A, strain of live VDVB virus Composition: The experimental material comprising supernatant of the cell culture of XIKE-A ba or step VDVB strain components Type II: XIKE-A DVB: Supplied by: Dr . Gregor Meyers, "Bundesforschungsanstalt fur Viruskrankheiten der Tiere" (BFAV), Paul-Ehrlich-Straße 28, 72076 Tubingen, Germany Virus dose Type 1 strain: 10 ^ Oi ^^ r / ßval DVB applied: (DICT = Infectious dose of Tissue Culture) Volume of vaccine 3 ml for each nasal window applied: Intranasal route Test strain B Description: XIKE A, live VDVB virus strain Composition: The experimental material comprising supernatant of the cell culture of low-pass XIKE-B Strain Components of VDVB type II: XIKE-I DVB: Supplied by: Dr. Gregor Meyers, "Bundesforschungsanstalt fur Viruskrankheiten der Tiere" (BFAV), Paul-Ehrlich-Straße 28, 72076 Tubingen, Germany Virus dose Type 1 strain: l? 5 Dj i ^ o / dml DVB applied: (DICT = Infectious dose of Tissue Tissue) Volume of vaccine 3 ml for each nasal window applied: Intranasal route application: Preparation of the inoculum was sent in a frozen form pre-diluted in a dosage: 50 ml vial in dry ice and was stored at -70 ° C before inoculation. Immediately before the inoculation of Group 2 heifers, the material was thawed, avoiding local temperatures above 37 ° C. Once no ice was visible in the fluid, the material was gently stirred and immediately used for inoculation of the animals. Vaccine No The volume of material used was used: not used and divided into two aliquots before freezing immediately in dry ice or liquid nitrogen and stored for re-titration purposes. The virus and the contaminated plastic or glass objects were incubated with a volume Pregnancy Control Pregnancy was confirmed immediately before inoculation. Inoculation of heifers Inoculation is Day 0 of the experiment. In each nasal window, 3 ml of the test material was administered intranasally via a syringe without needle. Each time a new sterile syringe was taken. The administration was carried out during the aspiration phase in order to minimize the loss of fluid through the expiration of the material. Post-inoculation observations Collection and examination of blood samples The blood was collected following conventional aseptic procedures (disinfecting the site of bleeding). For each animal a new sterile syringe and needle was used.

Collection of blood to prepare serum At least 10 ml of blood was collected from the heifers, immediately before inoculation, and then weekly after infection and at the conclusion of the study. The serum was stored at -20 ° C until required. Blood collection for leukocyte count and preparations of the surface layer of coagulated plasma with a white blood For the leukocyte count, 3 ml of blood were transferred immediately after collection to suitable sterile containers (Venoject, Terumo Europe NV, Leuven, Belgium) , pre-filled with 0.06 ml of EDTA (0.235 MOL / L). For the preparations of the surface layer of antegrade coagulated plasma, at least 15 ml of blood were transferred immediately after collection to suitable sterile containers, pre-loaded with 0.1 ml of heparin solution (Na heparin for iny., 5,000 Ul / ml batch A7B163A expiration date: 11/2000: Gedeon Richter RT, Budapest, Hungary), providing at least 20 IU of heparin per ml of blood in the blood sample. Then the content was carefully mixed. For the preparation of the superficial layer of antegrade coagulated plasma and the leukocyte count, blood was drawn from the heifers • every day, between Day 0 and Day 14 after the infestation; • every two days, between Day 15 and Day 40, or until all animals were negative for virus isolation during three consecutive sampling times. Preparation of serum The blood was allowed to clot at room temperature, and was separated by centrifugation. Each serum sample was divided into two aliquots of at least 2 ml each. A set of aliquots was tested by ELISA for BVDV-specific antibodies. The rest of the sera were frozen and stored at -20 ° C until required. Leukocyte counts Leukocyte counts were determined with a semi-automated electronic counter Coulter device (Diatron Minicell-16, Messtechnik GmbH, Vienna, Austria) with a claimed accuracy of 0.1 x 109/1, 100 / DI. The instrument was used (calibration and leukocyte counts) according to the manufacturer's recommendations. Preparation of surface layers of antegrade coagulated plasma Samples of heparin blood were transported to the laboratory as soon as possible. The process of preparation of the surface layer of coagulated plasma before, following a conventional laboratory procedure under aseptic conditions (sterile pipettes, manipulation, clean bench, etc.). The obtained surface coats of antegrade coagulated plasma were re-suspended in a small volume (2 ml) of RPMI 1640 and frozen at -70 ° C in two aliquots of 0.5 ml. The residual 1 ml of the surface layers of antegrade coagulated plasma was used immediately for the determination of BVDV associated with blood cells by co-culture in a permissive cell culture. ELISA assay of DVB serum antibodies Each serum sample was assayed for the presence of BVDV antibodies using a suitable and validated ELISA assay (VDVB Svanovir® antibody test cat no. 10-2200-10 ). The assay was validated and performed in accordance with the manufacturer's recommendations. The positive samples were diluted according to the log2 scale to determine the BVDV antibody titers. DVB antigen assay (s) Each surface layer sample of antegrade coagulated plasma was assayed for the presence of BVDV by co-culturing the freshly prepared buffy coat surface layers with susceptible cells or a cell line . Freezing was not allowed before co-cultivation. The plasma was collected and supplied to Man-Gene from each sample.

Clinical observations Observation of heifers The animals were examined daily from Days 0 to 42 post inoculation for the presence of clinical symptoms by a sufficiently trained veterinarian. All clinical signs were recorded and described by their nature, consistency / touch, severity (mild, medium or severe), location, size of the affected area, and were assessed according to the agreed and conventional definitions. Special attention was given to respiratory signs (respiration, frequency, nasal or ocular discharge, conjunctivitis, sneezing, cough, etc.) and diarrhea. Rectal temperatures The rectal temperatures were measured daily in each heifer, at the same time of the day (preferably in the morning) 5 days before the inoculation until 21 days post infection. The measurement of rectal temperature was continued until each animal had rectal temperatures below or equal to 39 ° C for at least 3 consecutive days.

Detection of interrupted pregnancy Pregnancy was confirmed and suspicion of abortion or resorption of the fetus was established by rectal examination. A trained veterinarian examined all the animals in the inoculation, 1 and 2 months post-inoculation. The examination was carried out in accordance with generally accepted veterinary practice. Heifers were examined daily for any signs of abortion until the conclusion of the study (8 -12 weeks post-challenge). Termination of the Study The study concluded by sacrificing the heifers and extracting the fetuses. The fetuses and fetal material were transferred to closed transport containers marked with the number of cows and date / time. The containers were transported to a selected necropsy room. Heifer necropsy was not required. The necropsy was performed on fetuses, the findings were recorded and a panel of samples was collected as described above. Post-Mortem Examination In each case of death, a detailed necropsy of the experimental animals was performed. The post-mortem examinations were carried out by an experienced veterinary surgeon and the data were recorded on appropriate data sheets. Additional laboratory tests were performed according to the clinical signs and the lesions observed. If the diagnosis of the necropsy referred to was related to a disease caused by the microbial agent, the diagnosis was verified by an appropriate test, specific for the agent. Each tissue sample was collected in at least 2 separate labeled containers that were frozen in liquid nitrogen. Samples were stored at -70 ° C until required. Aborted fetuses and conclusion of the study From the fetuses at least the following tissue samples were collected: • exudate from the peritoneal cavity or chest, if present, • Mesenteric lymph nodes, • spleen, • thymus, • cerebellum, • kidney, • bone marrow from the sternum, • sample of the placenta, if available. Dead or slaughtered heifers At least the following tissue samples were collected: • blood for the surface layer of coagulated plasma before, • blood for serum, if available, • Peyer's patches, • mesenteric lymph nodes, • spleen, kidney , • uterus, including a sample of the placenta, if available.

Storage and transport of samples Samples: Storage Serum -20 ° C Layer -70 ° C surface of plasma coagulated buffalo Virus -70 ° C Fabric -70 ° C from heifers Wool -70 ° C from fetuses Samples were sent for laboratory analysis as required by the sponsor. The choice of samples and the regulation of transport were agreed with the study monitor or the project director. As a matter of general principle, samples from the aborted material or neonatal calves were investigated as soon as possible. RESULTS Summary of clinical and laboratory data related to DVB Group Animal Conclusion DVB 526 A Abboorrttoo ppoorr DDVVBB ((úútteerroo ccoonn NE (no placenta post-mortem) sample found) 598 Abortion by DVB (post-fetus + fetus * mortem) 615 Abortion by DVB clinical - (fetus) * 618 Abortion by DVB ( fetus post- - (fetus) * mortem) 626 Died due to DVB + (fetus) / [heifer ^ NE untested Group Animal Conclusion DVB n ° 469 Abortion by DVB Clinical - (fetus) * 565 Abortion expected by DVB; Fetus + (fetus) not viable 588 Normal - (fetus) 608 Normal + (fetus) 619 Abortion by DVB (fetus post- - (fetus) * mortem) * The fetuses autolisaron at the time of sampling Conclusion: The study aimed to confirm the safety of XIKE-A and XIKE-B in pregnant animals. Ten pregnant heifers were selected from a negative VDVB herd. In the trial, two groups of 5 heifers were included: one was inoculated with the XIKE-A virus strain and the other with the XIKE-B virus strain. On the day of the inoculation, the heifers were between 60 and 90 days of gestation. Heifers were monitored for the presence of clinical signs of BVDV infection, including abortions during the observation period. Blood samples were taken from the animals for serology, antigen detection and leukocytes were counted. The experiment was completed 9 weeks after the infestation. The cows that were not aborted were sacrificed, and the uterus was examined and collected. Organ samples from the fetus were collected during routine necropsy and examined for BVDV infection. The XIKE-B virus proved to be less pathogenic than XIKE-A, however in the XIKE-B group an abortion related to DVB and infestation of the fetus was also observed. Therefore, it can be concluded that the inactivation of Erns RNase does not prevent a fetal infestation. Example 2 VDVB XIKE-A-NdN: determination of fetopathogenicity in pregnant heifers The Npro gene has been shown not to be essential for the development of VFPC in tissue culture (Tratschin et al., 1998). Although a VDVB attenuation test is still missing as a consequence of the Npro deletion, a role for this protein in the interaction between virus and host seemed to be possible and was actually indicated by recent experiments for the VFPC (Mayer et al. , 2004; Rüggli et al., 2003). Therefore, the inventors wanted to investigate whether the deletion of the main part of the Npro coding sequence leads to a virus that no longer infests the fetus in pregnant heifers. The Npro gene, except for the 4 terminal 5 'codons, was deleted from the full-length cDNA clone pKANE40A according to conventional processes. The resulting mutant full-length clone was used as a template for in vitro transcription and the resulting cRNA was transfected into MDBK cells, as described (Meyer et al., 2002). The recovered virus was amplified in the tissue culture and then used in the animal experiment described below. XIKE-B from VDVB served as a control, since it was previously shown to be able to cross the placenta (EXAMPLE 1). OBJECTIVE (S) / PURPOSE OF THE STUDY The study aims to confirm the safety of a live attenuated VDVB with a genomic deletion of the majority of the coding region of Npro in pregnant animals. The material and methods employed are described in Example 1 STUDY DESIGN Eight pregnant heifers were randomly assigned to two groups. These were treated and observed according to the following catalog: RESULTS All heifers were healthy and pregnant at the beginning of the study. All animals were shown to be free of BVDV and BVDV antibodies before the start of the study.

Preparation and Control of the Virus used for the Infestation Samples were collected throughout the dilution steps and analyzed on the day of preparation, ie without freezing by co-culture in an appropriate tissue culture. The results of the titration of the virus are shown in the following table Clinical symptoms of BVDV infestation The table below provides a summary of the animals with clinical signs during the observation period. Clinical signs and days post-inoculation (DPI) when observed Group 2 (XIKE- Group 1 (XIKE-A NdN; In some of the animals in each group only mild and transient clinical signs were observed.) In Group 1, one of 5 heifers suffered inappetence on day 8 Pl. 2, two out of 3 animals suffered clinical signs, both heifers experienced a cough around day 21 PI that was accompanied by loss of appetite in one of the animals.

Rectal temperatures No abnormal changes in temperature were detected before inoculation of the animals. The few cases of elevated temperatures measured after inoculation are summarized in the table below.

Group Animal ID Temperature day Pl (° C) 1 1583 39, 9 8 1621 39.0 5 2 1438 39.0 2 1585 40.8 9 In each group one animal had a slightly elevated temperature, and also in each group one animal had a fever. The fever was detected on day 8 or 9 PI. The temperature values always returned to normal values the next day. Leukocyte counts A certain leukopenia was observed in all groups between days 3 - 8 Pl. The number of animals with at least a 40% reduction in the leukocyte count was as follows: Group Number of animals with leukopenia / total 1 3/5 (60% 2 1/3 (33% Serology (VDVB antibodies) According to the study protocol, all heifers were free of BVDV antibodies before vaccination. In Group 1 (inoculated with XIKE-A NdN) and Group 2 (inoculated with XIKE-B), complete seroconversion only at the end of the study (2 months after inoculation). Isolation of 1 DVB virus from surface layers of coagulated plasma with no viremia detected Isolation of DVB virus from fetal tissue samples Conclusion The Npro deletion resulted in a considerable attenuation of the BVDV compared to the XIKE-A virus which proved to be very pathogenic (Meyer et al., 2002). However, the Npro deletion alone does not prevent the transmission of a recombinant NY93-based virus to the fetus after inoculation of pregnant cows. Example 3 VDVB XIKE-B-NdN: determination of fetopathogenicity in pregnant heifers To be able to test the potential of a combination of RNase inactivation and Npro deletion with respect to attenuation of BVDV and fetal transmission, they were established different VDVB-2 mutants with deletions within the coding region of Npro, based on the pKANE40B clone of infectious cDNA, the RNase negative mutant of pKANE40A with a deletion of codon 349. The recovered viruses were analyzed for the presence of the mutations desired, the absence of second site mutations in the regions flanking the changes introduced and their growth characteristics in tissue culture. XIKE-B-NdN (V-pK88C), a variant containing a deletion of the complete coding region of Npro, except codons 1 to 4, in addition to the inactivating RNase deletion of codon 349, was chosen for an animal experiment, since it combined the desired mutations with acceptable growth characteristics. The objective of the study was to confirm the safety of a live attenuated VDVB isolate in pregnant animals. Five pregnant BVDV-negative heifers were inoculated intransally with an infective dose of 105 TCID50 / animal XIKE-B-NdN. Clinical data were recorded daily. Blood samples were collected for leukocyte count, for preparation of the surface layer of coagulated plasma and serology. After the study was completed, fetal tissues were collected for virus isolation. MATERIAL AND METHODS: As detailed for example 1: RESULTS No clinical data were observed (data not shown). The leukocyte counts remained virtually unchanged, except for a significant decrease in approx. 40% below the baseline value (day 0) in heifer No. 1015 in a single day (day 6 p.i.) (data not shown). Analysis of preparations of the surface layer of antegrade coagulated plasma: Approximately 106 leukocytes were cultured in duplicate with MDBK cells in 24-well tissue culture plates for 5 days. The samples were frozen-thawed twice. Aliquots of one hundred microliters of thawed samples were inoculated onto freshly seeded 24-well tissue culture plates and tested for virus by indirect immunofluorescence staining (monoclonal antibody (ame) code 4, directed against an epitope retained in the non-structural NS3 protein). No VDVB could be isolated from the preparations of the surface layer of the coagulated plasma of animals 921, 1013, 1015, 1055 and 1075, whereas the positive controls clearly showed the correct performance of the test. b) Post-mortem examination of fetal tissues After finishing the study, the following fetal tissues were collected for virus isolation: spleen, kidney, thymus, sternum, cerebellum, placenta, intestine and abdominal fluid. In summary, tissue suspensions were performed in a mortar using sterile sea sand and frozen PBS without Ca2 + or Mg2 +. The mortars were rinsed with 1 ml of ice cold PBS without Ca2 + or Mg2 + and the suspensions were centrifuged for 10 min at 2000 x g (4 ° C). The supernatant was first passed through a 0.45 μm disposable filter holder, followed by a passage through a second filter (0.2 μm pore size). Virus isolation was carried out in duplicate (400 μl of fetal tissue suspension or 00 μl of abdominal fetal fluid) in a monolayer of MDBK cells in a 24-well tissue culture plate (37 ° C, 7% C02). ). Tissue samples were monitored daily for cytopathic effects or bacterial contamination, and after an incubation time of 5 days, the plates were frozen and thawed twice. 100 μl of samples were passed to freshly seeded MDBK cells. The virus was detected by indirect immunofluorescence staining (ame code 4). No VDVB was detected in tissue samples or fetal abdominal fluid. c) Serological Findings The serum neutralization titers were determined before inoculation, 1 month post-inoculation and at the conclusion of the study. Sera from all animals were assayed in triplicate to neutralize antibodies against NY93 / C, and the endpoint dilution was read by indirect immunofluorescence staining. The results were expressed as the endpoint dilution, which neutralized approximately 100 DCIT50 and were calculated by the Kaerber method. No definitive data could be obtained for day 0, and 1 and 2 weeks post infection, since the sera were toxic for MBDK cells in dilutions up to 1:16 and neutralization could not be detected at higher dilutions. Beginning with the third post-vaccination week, all animals developed neutralizing antibodies against the NY '93 / C homologous VDVB-2 virus and last until the end of the experiment (Table and Fig.1) - d) Conclusions The data obtained during the study with the animals clearly demonstrate that XIKE-B-NdN of BVDV represents a very attenuated virus. In contrast to the wild-type virus or the simple XIKE-B or XIKE-A-NdN mutants that show a fetal transmission in pregnant heifers at high rates, the double mutant did not cross the placenta. XIKE-B-NdN of VDVB, as well as similar double mutants are extremely suitable for use in a live attenuated vaccine. Efficacy and cross-protection study Two possible problems have to be faced with respect to vaccination with attenuated virus mutants XIKE-B from VDVB or XIKE-B-NdN from BVDV. First, there is a general problem concerning cross-protection between VDVB-1 and VDVB-2. At least vaccination with inactivated BVDV-1 vaccines did not prevent the transmission of BVDV-2 to the fetus in pregnant animals. Since protection against fetal infection represents the main objective of an anti-BVDV vaccination, vaccines of this type can not be considered to induce protective immunity over a wide range. Therefore, the question of whether live attenuated VDVB-2 vaccination can not prevent transmission to the fetus. Secondly, the reduced growth rates of VDVB XIKE-B-NdN could result in only one ba or level of protection, unable to prevent transplacental infection of the fetus in pregnant heifers. To deal with these problems, an animal study was initiated. The animals (2 groups of 10 animals each) were vaccinated with XIKE-B or XIKE-B-NdN from BVDV (intended dosage: 1 ml of supernatant with 105 DCIT50 of virus). None of the animals showed significant clinical signs after vaccination, except one animal from the control group not vaccinated with mild cough for one day. The rectal temperature values were below 39 ° C, except for one animal from the unvaccinated control group that had 39.1 ° C for one day. Samples of the surface layer of antegrade coagulated plasma, prepared after vaccination, were analyzed for the presence of virus as described above. The experiments showed that only 5 of the 20 animals contained viruses in the blood for 1 or 2 days at 4 to 8 days post-infection. Four weeks after the vaccination, the insemination of the animals was carried out. The challenge infections were performed 60 to 90 days later, using a strain of BVDV-1 (KE-9 from BVDV, heterologous challenge, animals vaccinated with XIKE-B) or a heterologous strain of BVDV-2 (KE-13 from VDVB, homologous confrontation, animals vaccinated with XIKE-B-NdN) (intended dosage: 105 TCID50 in dml). From each group of vaccinated animals, 5 pregnant heifers selected for the challenge infection were randomly selected. Animals vaccinated with VDVB XIKE-B were challenged with strain KE-9 from VDVB-1, while heifers vaccinated with VDVB XIKE-B / NdN were challenged with KE-13 from BVDV-2. In addition, 2 unvaccinated control animals were infested with each of the confrontation viruses. The vaccinated animals showed no viraemia or clinical symptoms after the challenge infection. The confrontation was successful, since all the unvaccinated controls were VDVB positive. In the control groups only mild signs of the disease were observed. The white blood cell counts were almost normal (not shown). The serum neutralization titers were determined before the inoculation, 1 month post-inoculation, before the confrontation, 1 month after the confrontation and at the conclusion of the study. Sera from all animals were tested in triplicate to neutralize antibodies against KE9 and NY93 / C (1456NAsa), and the endpoint dilution was read by indirect immunofluorescence staining. The results were expressed as the final point dilution, which neutralized approximately 100 and were calculated by the method of Kaerber. In some of the high titers of antibodies, the dilution of endpoint used was not high enough. Against KE9, only animals vaccinated with XIKE-B developed low antibody titers, beginning approximately at week 4. In the confrontation, all animals had antibody titers that increased considerably beginning around week 4 post-challenge. Animals vaccinated with XIKE-B had higher antibody titers than those vaccinated with XIKE-B-NdN. All animals developed approximately the same neutralization titer against NY93 / C four weeks post vaccination, with marginally lower titres in animals vaccinated with XIKE-B-NdN. After the confrontation, all animals had high antibody titers. Fig. 2 shows the serum neutralization assay against KE9 (VDVB-1) and FIG. 3 shows the neutralization assay of the serum against NY93 / C (VDVB-2). The analysis of the tissue samples obtained after the conclusion of the study of the fetuses revealed that the material obtained from the vaccinated animals gave negative results, while the transmission had occurred in the 4 control animals. Thus, it is clear that the established BVDV-2 mutants are well suited as effective cross-protection vaccine viruses. Conclusion: The confrontation was successful, since all unvaccinated controls were VDVB viremic and the fetuses of all unvaccinated controls were VDVB positive. The two isolates provided complete protection under the present assay and the conditions of analysis. The XIKE-B isolate, with the simple genetic marker, proved to cross-protect against the confrontation of type 1 VDVB in terms of virema by DVB and the transmission of the fetus after the confrontation. The isolation XIKE-B-NdN, with the double genetic marker was able to completely protect against the confrontation of heterodic type VDVB in terms of virema by DVB and the transmission of the fetus after the confrontation: 1. The isolated XIKE-B ( type 2 isolate) demonstrated cross-protection against VDVB type 1 challenge in terms of virema by DVB and fetal transmission after challenge under the present test and analysis conditions (n = 4). 2. The XIKE-B isolate (isolated type 2) fully protected against the VDVB type 2 challenge in terms of virema by DVB and the transmission of the fetus after confrontation under the present test and analysis conditions (n = 5) . Example 4 Establishment of Npro mutants This Example further analyzes mutants of VDVB-2 with Npro deletions. Different mutants were established with deletions in the coding region of Npro of the genome. Initially, only true deletions or a deletion accompanied by a point mutation were introduced. A: [Npro] i- [C-term]; B: [Npr0] 3- [C-term]; C: [Npro] 4- [C-term]; D: [Npro] 6- [C-term]; E: [Npro] 4- [C-term]; In the formulas [Npro] x represents the number of amino end residues of Npro that are left in the amino acids of the mutated polyprotein, [C-term] is the complete polyprotein, except Npro (which starts with protein C and ends with NS5B), and [C-term *] is the same as [C-term], but with a mutation at position 2 of protein C (N instead of D). The growth rates of the recovered viruses were considerably lower than those of wild type XIKE-A or the XIKE-B RNase negative mutant. There are two possible explanations for this finding: (i) dependent on the virus strain, the variable length sequences of the coding region of Npro are necessary for the initiation of an efficient translation (Mayers et al., 2001; Tautz et al. , 1999) and (ii) fusion of additional sequences to the amino terminus of the capsid protein interferes with the function of the capsid protein. To obtain better mutants by Npro deletion in development, a second set of mutants was generated with a bovine ubiquitin gene or a fragment of the bovine LC3 coding sequence that replaces the main part of the Npro gene. These constructions allow efficient translation and generate a capsid protein with the correct amino terminus. [Npro] 22- [PS] - [C-term] where PS is ubiquitin or LC3, C-term is the complete polyprotein, except Npro (starting with protein C and ending with NS5B). The growth rates of these mutants were more similar to what was determined for XIKE-A. It even appeared that the two positive RNase viruses according to the formula D Npro [22-] PS [-] C-term, designated V-pK87F and V-pK87G, showed no significant retardation of growth at all, while the Antagonist V-pk88G RNase negative was, again, somewhat impeded in the propagation, but to a lesser extent than the mutants described above.

Additional examples of Npro deletion mutants can be: MgSDEGSK ... (SEQ ID NO. 28) ME FSSDEGSK ... (SEQ ID NO. 29) MELFSNESDEGSK ... (SEQ ID NO. 30) MELFSNELSDEGSK ... (SEQ ID NO. 31) MELFSNELLSDEGSK ... (SEQ ID NO. 32) MELFSNELLYS DEGSK ... (SEQ ID NO. 33) MELFSNELLYKSDEGSK ... (SEQ ID NO. 34) MELFSNELLYKTSDEGSK ... (SEQ ID NO. 35) MELFSNELLYKT represents the amino-terminal sequence of Npro of the isolate NewYork93 / C of VDVB. It may also be possible to use variants of this sequence with one or more mutations. Naturally occurring variations such as found in other pestiviruses can be expected to be functional. Therefore, the complete list of tested or proposed variants with the different parts of the amino terminal Npro can be extended by equivalent sets with amino acid exchanges. In the following, typical examples of the respective sequences for several pestiviruses are given, but possible variations are not limited to these examples. NewYork93 / C from VDVB: MELFSNELLYKT CP13 from VDVB: MELISNELLYKT (SEQ ID NO 36) SD1 from VDVB: MELITNELLYKT (SEQ ID NO 37) VFPC Brescia: MELNHFELLYKT (SEQ ID NO 38) DV8 X818: MELNKFELLYKT (SEQ ID NO 39) Thus, these variants can include, for example: MELI- [PS] 0- [C-term] MELIS- [PS] 0- [C-term] MELISN- [PS] or- [C-term] MELISNE- [PS ] o- [C-term] MELISNEL- [PS] 0- [C-term] MELISNELL- [PS] 0- [C-term] MELISNELLY- [PS] 0- [C-term] MELISNELLYK- [PS] o - [C-ter] MELISNELLYKT- [PS] 0- [C-term] MELIT- [PS] o- [C-term] MELITN- [PS] or- [C-term] MELITNE- [PS] o- [ C-term] MELITNEL- [PS] 0- [C-term] MELITNELL- [PS] 0- [C-term] MELITNELLY- [PS] 0- [C-term] MELITNELLYK- [PS] 0- [C- term] M £ LITW £ LLY T- [PS] 0- [C-term] These formulas can also have DPSDi, ie PS can also be one of the PS as described in this specification. The sequences belonging to the Npro protein are listed in italics. The amino acid exchanges with respect to the NewYork93 / C sequence of VDVB are shown in bold type. Additional examples can be found, e.g. ex. , using the GenBank access numbers given in Becher et al., 2003, Virology 311, 96-104) or by searches of conventional sequence data. A further possibility could be the use of a processing signal (SP) inserted between the Npro (residual) sequence and the amino terminus of the capsid protein. SP leads to a cleavage that generates a functional capsid protein. The configuration of this type of constructions could be as follows: [Npro] 22-SP [C-term] SP: processing signal, may well be a target of a protease (e.g., ubiquitin, LC3 as defined in this memory, or a protease or an unstable peptide that leads to a processing in its own carboxy terminus, such as, for example, intein (Chong et al., 1998 and references therein) or 3C of picornavirus, 2A of cardiovirus or aftovirus, pl5 of rabbit hemorrhagic disease virus or the corresponding protease of other caliciviruses (Proter 1993, and references therein; Meyers et al., 2000 and references therein). When an SP is used, a large number of different variants, since the SP ensures the generation of the correct amino terminus of the capsid protein C. Thus, when an SP construct is used, all types of deletions or mutations of the Npro sequence in viable mutants are expected to result. while the frame of l ect is not moved or the translation is stopped by a frame stop codon. As an example, the inventors established a Npro deletion mutant of VDVB according to the formula [Npr0] 29-SP [C-term] Especially interesting could be Npr0 mutations that block the proteolytic activity of the protein.

Rumenapf et al. (1998) have published the identification of residues of the active site of the protease for Alfort Tubingen of CSFV. The respective amino acids (glutamic acid in position 22, histidine in position 49 and cysteine in position 69) are conserved for other pestiviruses. Thus, exchanges of any amino acid, except serine or threonine for the cysteine at position 69, will result in the destruction of the protease activity. Similarly, the change of glutamic acid in the position 22 will most likely result in the inactivation of the protease, unless the new amino acid is aspartic acid. Similarly, most, if not all, exchanges in position 49 will lead to an inactive protease. Example 5 Preparation of combination vaccines according to the invention Vaccine A RIB, VDVB types 1 and 2, VRSB Vaccinated VDVB virus strains of type 1 and 2, which have at least one mutation in the Erns glycoprotein coding sequence and / or at least one other mutation in the coding sequence of Npr0, where such a mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns and / or a mutation of this type in the coding sequence of Npro leads to inactivation of Npro, develop in MDBK cells to TCID50 of approximately 105.0 to 108.1 per ml of cell culture fluid. An attenuated strain of RIB is developed in MDBK cells to TCID50 of about 105.0 to 108.6 per ml of cell culture fluid. An attenuated VRSB strain is developed in MDBK cells to TCID50 of about 105'0 to 107'2 per ml of cell culture fluid. Each culture fluid containing the virus is collected and lyophilized. Equal amounts of lyophilized antigens are mixed. For reconstitution, an aqueous solution containing 1 to 3%: 0.8 ml of Alhydrogel is used. One dose of the combined vaccine contains 4 ml of the reconstituted antigens. A final dose includes RIB (105 '° to 108'6 TCID50), VDVB-1 (105' to 108'1 TCID50), VDVB-2 (105 '' to 108'1 TCID50) and VRSB (105 '' to 107'2 DICT50). Vaccine B RIB, VDVB types 1 and 2, PI3, VRSB Preparation of RIB antigens, VDVB 1 and 2, and VRSB is carried out as described for vaccine A. In turn, an attenuated strain of PI3 is developed in MDBK cells to TCID50 of approximately 104.2 to 106.5 per ml cell culture fluid. Then, the culture fluid containing PI3 is harvested and lyophilized. An amount of 104'2 is mixed 106'5 (TCID50) lyophilized antigen with lyophilized RIB antigens, VDVB types 1 and 2, and VRSB. The mixture is then reconstituted in 4 ml as described for Vaccine A. A final dose includes RIB (105 'to 108'6 TCID50), VDVB-1 (105' to 108'1 TCID50), VDVB-2 (105 '° to 108'1 TCID50), VRSB (105' to 107'2 TCID50) and PI3 (104.2 to 106.5 TCID50). Vaccine C VDVB types 1 and 2, PI3, VRSB, Mannheimi a (Pasteurella) haemolytica VDVB 1 and 2, VRSB and PI3 viruses are developed as described for vaccines A and B. After harvesting the culture fluids, the inactivate and lyophilize viruses. Mannheima (Pasteurella) haemalytica is grown to 108.0 to 1011.0 cells per ml of culture. The bacteria are inactivated and the culture fluid is lyophilized. An amount of 108'0 to 1011'0 cells with lyophilized bacteria is mixed with lyophilized VDVB type 1 and 2 antigens (each in an amount of 105'0 to 108'1 TCID50), PI3 antigen (107'3 a 108'3 TCID50) and VRSB antigen (105.0 to 107'2 TCID50). The reconstituted suspension (5 ml per dose) also contains 30 to 50 mg of aluminum hydroxide, 0.4 to 0.8 mg of Quil A (Saponin), 0.04 to 0.06 mg of sodium thimerphonate and traces of neomycin . The final amounts of antigen per dose are BVDV-1 (105.0 to 108'1 TCID50), VDVB-2 (105 'to 108'1 TCID50), PI3 (107'3 to 108'3 TCID50) VRSB (105 , 0 to 107'2 TCID50) and Mannheima (Pasteurella) haemalytica (108 '' to 1011'0 cells). Vaccine D VDVB types 1 and 2, RIB, VRSB, PI3, Leptospira canicola, Leptospira grippo, Leptospira hardjo, Leptospira ponoma, Leptospora borgpetersenii hardjo-bovis The viruses VDVB 1 and 2, VRSB, RIB and PI3 are developed as described for Vaccines A and B. After harvesting the culture fluids, the viruses are lyophilized. Leptospira canicola, Leptospira grippo, Leptospira hardjo, Leptospira ponoma, Leptospora borgpetersenii hardjo-bovis are grown separately until they reach 108'0 to 1011.0 cells per ml of culture. The bacteria are inactivated and the culture fluids are lyophilized. Each of the cells with the lyophilized bacteria from 108.0 to 1011.0 is reconstituted with VDVB types 1 and 2 modified and lyophilized (each in an amount of 105'0 to 107'0 TCID50), modified live PI3 (107'3 to 108'3 TCID50), Live VRSB modified (105.0 to 107.0 TCID50) and modified live RIB (106.1 to 107.7 TCID50). The reconstituted suspension (2 ml per dose) contains traces of neomycin as a preservative. The final antigen mutants per dose are VDVB-1 (105.0 to 107.0 TCID50), VDVB-2 (105 'to 107'0 TCID50), PI3 (107.3 to 108'3 TCID50) VRSB (105 '° to 107'0 TCID50), PI3 (107'3 to 108'3 TCID50) and Leptospira canicola, Leptospira grippo, Leptospira hardjo, Leptospira ponoma and Leptospora borgpetersenii hardjo-bovis (each 108.0 to 1111 cells) . Vaccine E VDVB types 1 and 2, RIB, VRSB, PI3 and H. somnus VDVB 1 and 2, VRSB, RIB and PI3 viruses are developed as described for vaccines A and B. After harvesting the culture fluids, the viruses are lyophilized. H. somnus is grown to achieve 107'1 to 109'2 cells per ml of culture. The bacterial culture is inactivated and the culture fluid is lyophilized. 107'1 to 109'2 of the lyophilized bacteria are reconstituted with the VDVB of types 1 and 2 (each in an amount of 105'0 to 107'0 TCID50), modified PI3 alive (107'3 to 108'3 TCID50 ), Live modified VRSB (105.0 to 107'0 TCID50) and live modified RIB (106.1 to 107'7 TCID50). The reconstituted suspension (2 ml per dose) contains traces of neomycin as a preservative. The final amounts of antigen per dose are BVDV-1 (105 'to 107'0 TCID50), VDVB-2 (105' to 107'0 TCID50), PI3 (107'3 to 108'3 TCID50), VRSB ( 105 'to 107'0 TCID50), PI3 (107'3 to 108'3 TCID50) and H. somnus (107'1 to 109'2 cells). References: The descriptions and contents of all references (articles, patents, parts of books, presentations and the like) cited herein, including those mentioned below, are expressly incorporated herein by reference. Ausubel, F.M. et al., Current Protocols in molecular biology.

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Windisch, J.M., Schneider, R., Stark, R., Weiland, E., Meyers, G., and Thiel, H.-J. 1996. RNase of classical swine fever virus: biochemical characterization and inhibition by virus-neutralizing monoclonal antibodies. J. Virol. 70: 352-358 Wiskerchen, M., Belzer, S.K., and Collett, M.S. 1991. Pestivirus gene expression: the first protein product of the bovine viral diarrhea virus large open reading frame, p20, possesses proteolytic activity J. Virol. 65: 4508-4514. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (7)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A combined vaccine for the treatment and / or prophylaxis of cattle against microbiological infections, characterized in that the combined vaccine comprises a. one or more attenuated VDVBs, which have at least one mutation in the Erns glycoprotein coding sequence and / or at least one other mutation in the Npro coding sequence, where the mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns and / or the mutation in the coding sequence of Npro leads to the inactivation of the Npro; and b. one or more effective immunological active components for the treatment and / or prophylaxis of microbiological infections in cattle produced by a bovine pathogen other than BVDV.
2. 2. The vaccine according to claim 1, characterized in that the combination comprises a. one or more attenuated VDVBs, which have at least one mutation in the Erns glycoprotein coding sequence, where the mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns, and b. one or more effective immunological active components for the treatment and / or prophylaxis of microbiological infections in cattle produced by a bovine pathogen other than BVDV.
3. 3. The vaccine according to claim 1, characterized in that the combination comprises a. one or more attenuated VDVBs, which have at least one mutation in the Npro coding sequence, the mutation in the Npro coding sequence leads to the inactivation of the Npro, and b. one or more effective immunological active components for the treatment and / or prophylaxis of microbiological infections in cattle produced by a bovine pathogen other than BVDV.
4. 4. The vaccine according to claim 1, characterized in that the combination comprises a. one or more attenuated VDVBs, which have at least one mutation in the Erns glycoprotein coding sequence and at least one other mutation in the Npro coding sequence, wherein the mutation in the Erns glycoprotein coding sequence leads to inactivation of the RNase activity residing in Erns and / or the mutation in the coding sequence of Npro leads to inactivation of the Npro; and b. one or more effective immunological active components for the treatment and / or prophylaxis of microbiological infections in cattle produced by a bovine pathogen other than BVDV.
5. 5. The vaccine according to any one of claims 1 to 4, characterized in that the combined vaccine comprises the attenuated VDVB of type 1 and the attenuated VDVB of type 2, both having at least one mutation in the coding sequence of the glycoprotein Erns. and at least one other mutation in the Npro coding sequence, where the mutation in the Erns glycoprotein coding sequence leads to the inactivation of the RNase activity residing in Erns and / or the mutation in the coding sequence of Npro leads to the inactivation of Npro.
6. 6. The combination vaccine according to any of claims 1 to 5, characterized in that the infection in cattle other than BVDV is produced by at least one pathogen selected from the group consisting of: Paragripal-3 Virus (PI-3) , Bovine Infectious Rhinotracheitis Virus (RIB), Bovine Syncytial Respiratory Virus (VRSB), Bovine Herpes Virus (HBV), Bovine Rotavirus (RVB), Bovine Enterovirus (EVB), Bovine Coronovirus (CVB), Bovine Rabies (RB), Bovine Parvovirus (PVB), Adenovirus Astrovirus, Mannheimia haemolytica (formerly Pasteurella haemolytica), Pasteurella multocida, Haemophilus somnus (Histophilus ovis and Haemophilus agni), Actinomyces (Corynebacterium), Actinomyces pyogenes, Chlamydia psittaci, Campylobacter fetus venerealis and Campylobacter fetus fetus (formerly C fetus intestinalis), Leptospira interrogans, Leptospira hardjo, Leptospira pomona, and Leptospira grippotyphosa, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj itno and Leptospira hardjo-bovis), Brucella abortus, Brucella suis and Brucella melitensis, Listeria monocytogenes, Chlamydia psittaci, Clostridium chauvoei, Clostridium septicum, Clostridium haemolyticum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens, Clostridium tetani, Moraxella bovis, Klebsiella spp, Klebsiella pneumoniae, Salmonella typhimurium; Salmonella newport, Mycobacterium avium paratuberculosis, Cryptosporidium parvum, Cryptsporidium hominis, Staphylococcus aureus, Streptococcus dysgalactiae, Streptococcus uberus, Mycoplasma spp, Mycoplasma dispar, Mycoplasma bovis, and Ureaplasma spp., Tritrichomonas foetus, Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton sarkisovii, Neospora caninum (formerly Toxoplasma gondii), Babesia bigemina and Babesia bovis, Dictyocaulus viviparous (worm disease of the lungs).
7. 7. The combined vaccine according to any of claims 1 to 6, characterized in that the active immunological component is an antigen of at least one pathogen selected from the group consisting of: Parainfluenza Virus-3 (PI-3), Bovine Infectious Rhinotracheitis Virus (RIB), Bovine Syncytial Respiratory Virus (VRSB), Bovine Herpes Virus (HBV), Bovine Rotavirus (RVB), Bovine Enterovirus (EVB), Bovine Coronovirus (CVB), Bovine Rabies (RB), Bovine Parvovirus (PVB), Adenovirus Astrovirus, Mannheimia haemolytica (formerly Pasteurella haemolytica), Pasteurella multocida, Haemophilus somnus (Histophilus ovis and Haemophilus agni), Actinomyces (Corynebacterium), Actinomyces pyogenes, Chlamydia psittaci, Campylobacter fetus venerealis and Campylobacter fetus fetus (formerly C fetus intestinalis), Leptospira interrogans, Leptospira hardjo, Leptospira pomona, and Leptospira grippotyphosa, Leptospira canicola, Leptospira grippotyphosa, Leptospira hardjo (Leptospira hardjopraj Itno and Leptospira hardjo-bovis), Brucella abortus, Brucella suis and Brucella melitensis, Listeria monocytogenes, Chlamydia psittaci, Clostridium chauvoei, Clostridium septicum, Clostridium haemolyticum, Clostridium novyi, Clostridium sordellii, Clostridium perfringens, Clostridium tetani, Moraxella bovis, Klebsiella spp. Klebsiella pneumoniae, Salmonella typhimurium; Salmonella newport, Mycobacterium avium paratuberculosis, Cryptosporidium parvum, Cryptsporidium hominis, Staphylococcus aureus, Streptococcus dysgalactiae, Streptococcus uberus, Mycoplasma spp, Mycoplasma dispar, Mycoplasma bovis, and Ureaplasma spp., Tritrichomonas foetus, Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophyton sarkisovii, Neospora caninum (formerly Toxoplasma gondii), Babesia bigemina and Babesia bovis, Dictyocaulus viviparous (worm disease of the lungs).