WO2017196318A1 - Composition comprenant des antigènes et un adjuvant pour les muqueuses et méthode d'utilisation - Google Patents

Composition comprenant des antigènes et un adjuvant pour les muqueuses et méthode d'utilisation Download PDF

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Publication number
WO2017196318A1
WO2017196318A1 PCT/US2016/031902 US2016031902W WO2017196318A1 WO 2017196318 A1 WO2017196318 A1 WO 2017196318A1 US 2016031902 W US2016031902 W US 2016031902W WO 2017196318 A1 WO2017196318 A1 WO 2017196318A1
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WIPO (PCT)
Prior art keywords
composition
suis
antigens
inactivated
parasuis
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PCT/US2016/031902
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English (en)
Inventor
Grant WEAVER
Jeff KULA
Boh Chang LIN
Karen Brown
Wesley W. JOHNSON
Michael Dennis MURPHY
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Phibro Animal Health Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Phibro Animal Health Corporation filed Critical Phibro Animal Health Corporation
Priority to CA3022006A priority Critical patent/CA3022006A1/fr
Priority to EP16901833.0A priority patent/EP3454893A4/fr
Priority to PCT/US2016/031902 priority patent/WO2017196318A1/fr
Priority to US15/593,223 priority patent/US10279031B2/en
Publication of WO2017196318A1 publication Critical patent/WO2017196318A1/fr
Priority to US16/353,877 priority patent/US11000585B2/en
Priority to US16/386,535 priority patent/US10918711B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552—Veterinary vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59

Definitions

  • This disclosure relates to a composition comprising antigens and a mucoadhesive adjuvant, and methods of making and using the composition.
  • the majority of the mortality observed in these young pigs occurs between three and five weeks post-weaning for S. suis infections and between four and six weeks post- weaning for H. parasuis infections.
  • S. suis produces signs and/or symptoms including meningitis, polyserositis, arthritis, myocarditis, pericarditis and abortion.
  • H. parasuis often produces an acute septicemia that leads to death. Additionally, the latter is an important component in the Porcine Respiratory Disease Complex.
  • A. suis and the Mycoplasma species are common respiratory diseases of pigs that are transmitted by nose-to-nose contact. M. hyopneumoniae and M. hyorhinis both produce significant respiratory disease, whereas M. hyosynoviae more commonly causes arthritis resulting in lameness.
  • B. bronchiseptica also results in a respiratory disease that is called atrophic rhinitis.
  • P. multocida is another organism associated with atrophic rhinitis and that is spread via mucous membranes.
  • Swine influenza virus and PRRS also produce significant respiratory diseases in pigs. PRRS is also associated with a reproductive syndrome causing abortion.
  • the Salmonella species, E. coli and PEDV cause intestinal diseases that result in diarrhea that can kill neonates and young very quickly.
  • sows and gilts are often already exposed to the diseases for which their offspring, especially neonatal offspring, will be susceptible.
  • sows or gilts are seropositive because of previous exposure or vaccination, they transfer lactogenic antibodies to their neonatal offspring, which may protect the neonates for a period of time.
  • maternal antibodies often interfere with the neonate being able to produce their own antibodies if they are vaccinated at too young an age with a parenteral vaccine.
  • Parenteral vaccination mainly stimulates the development of IgG and IgM antibodies.
  • PQA Plus ® Assurance Plus
  • the present disclosure describes embodiments of a composition
  • a composition comprising inactivated bacterial antigens and a mucosal adjuvant, such as a mucoadhesive adjuvant.
  • the composition can be administered mucosally, such as intranasally, to animals, such as pigs, particularly neonates, to immunize them again against typical neonatal and nursery diseases.
  • Mucosal, such as intranasal administration of the composition may stimulate the production of IgA, a mucosal antibody which may overcome maternal antibody interference.
  • the intranasal may stimulate the production of IgA, a mucosal antibody which may overcome maternal antibody interference.
  • administration technique has several other distinct advantages when compared with traditional parenteral vaccination. Such advantages include ease of administration at processing, lessened risk of tissue loss due to needle use, and reduction of workload. Furthermore, the mucosal route may be less susceptible to maternal immunity interference.
  • Mucosal vaccination such as intranasal vaccination
  • non- inactivated antigens such as administering a live virulent virus or bacteria, a live attenuated virus or bacteria, a modified live virus or bacteria, a live vectored viral or bacterial antigen, or a combination thereof.
  • live antigens protect by causing either a low-level of infection or a replication in the animal, which stimulates an immune response.
  • No inactivated or killed antigens have been delivered mucosally, including intranasally, to pigs and demonstrated to either stimulate an IgA response or produce a protective response. Such an intranasal method of immunizing pigs would also meet the requirements of the PQA.
  • compositions comprising one or more inactivated antigens obtained from one or more bacterial strains, such as S. suis, H. parasuis, and/or A. suis, and a mucosal, such as a mucoadhesive, adjuvant.
  • inactivated antigens obtained from one or more bacterial strains, such as S. suis, H. parasuis, and/or A. suis
  • mucosal such as a mucoadhesive, adjuvant.
  • inactivated antigens that may be included in such a composition are M. hyorhinis, M. hyosynoviae, P. multocida, B. bronchiseptica, E.
  • rhusiopathiae S. cholerasuis, S. typhimurium, E. coli, C. perfringens, C. difficile, swine influenza viruses, porcine rotavirus groups A, B and C, PRRS, and/or PEDV.
  • compositions may be formulated for mucosal
  • Adjuvants with mucoadhesive characteristics include, but are not limited to, polymers, such as those comprising Carbopols or acrylic acids (such as polyacrylic acids), such as CarbigenTM adjuvant; oil-in-water based adjuvants, such as Emulsigen ® adjuvant; nanoparticles; or
  • the adjuvants may include immunostimulators, such as dimethyldioctadecyl ammonium bromide (DDA) or chloride (DDAC), pluronics, aluminum hydroxide, aluminum phosphate, and others known to persons of ordinary skill in the art.
  • immunostimulators such as dimethyldioctadecyl ammonium bromide (DDA) or chloride (DDAC), pluronics, aluminum hydroxide, aluminum phosphate, and others known to persons of ordinary skill in the art.
  • an immunogenic composition comprising one or more strains of inactivated S. suis, one or more strains of inactivated H. parasuis and/or one or more strains of A. suis.
  • the disease-producing organisms including one or more isolates or strains of H. parasuis, A. suis and/or S. suis may originally have been isolated from a diseased animal.
  • the bacteria can be grown in culture media to appropriate titers, such as at least 10 5 colony forming units/mL (CFU/mL), and then inactivated prior to incorporation into a vaccine for administering mucosally.
  • compositions stimulate an IgA response when administered intranasally to neonatal pigs.
  • IgA response may be able to overcome inhibition by maternal antibodies that are delivered to the neonate by the sow or gilt.
  • Certain disclosed embodiments includes multivalent immunogenic compositions comprising a combination of antigens from at least two of S. suis, H. parasuis, and A. suis that have been inactivated with an acceptable inactivating agent and a mucosal, such as a mucoadhesive, adjuvant.
  • the multivalent immunogenic composition may comprise antigens from all three organisms. The combination may be then administered to pigs via a mucosal route. One or more administrations may be performed to produce protection from disease.
  • Acceptable inactivating agents for use with these antigens include, but are not limited to, formaldehyde, formalin, binary ethyleneimine, thimerosal, beta propiolactone, detergents such as NP40 and Triton X 100, and combinations thereof.
  • Antigens may include whole culture bacteria, subunits that have been extracted or separated from the culture, subunits that have been extracted or separated from the cells, antigens obtained from recombinant organisms other than S. suis, H. parasuis or A. suis but which protect against S. suis, H. parasuis or A. suis infection or challenge, or a combination thereof. Infection or challenge means that the animal suffers one or more clinical signs of the S. suis, A. suis or H. parasuis diseases when they have been exposed to these live organisms.
  • one or more of the S. suis, A. suis or H. parasuis antigens are present in the composition in an amount of from about 10 2 to about 10 10 CFU/mL.
  • composition may further include a suitable pharmaceutical carrier, such as a diluent, adjuvant, antimicrobial agent, preservative, inactivating agent, or combination thereof.
  • a suitable pharmaceutical carrier such as a diluent, adjuvant, antimicrobial agent, preservative, inactivating agent, or combination thereof.
  • Antimicrobial agents can include, but are not limited to, antibiotics such as gentamicin, penicillin, neomycin, polymyxin B and mycostatin.
  • a method for reducing the incidence or lessening the severity of clinical signs associated with or caused by bacterial infections such as infection by S. suis, A. suis and/or H. parasuis.
  • the method comprises reducing the incidence or lessening the severity of clinical signs associated with or caused by additional bacterial infections, such as infection by M. hyorhinis, M. hyosynoviae, P. multocida, B. bronchiseptica, E. rhusiopathiae , S. cholerasuis, S. typhimurium, E.
  • coli swine influenza viruses, PRRS, or PEDV comprising administering the composition to a subject, such as a pig, via a mucosal, such as intranasal, route.
  • a mucosal such as intranasal, route.
  • hyorhinis M. hyosynoviae, P. multocida
  • B. bronchiseptica E. rhusiopathiae
  • S. cholerasuis S. typhimurium
  • E. coli swine influenza viruses
  • PRRS PEDV or a combination thereof
  • FIG. 1 is a graph of ELISA titer versus administration protocol, illustrating the measured IgA and IgG serum levels resulting from the various administration protocols, establishing that intranasal administration resulted in the production of IgA and IgG antibodies in the pigs.
  • FIG. 2 is a Western Blot of H. parasuis antigens, comparing pig antibody responses produced by intranasal (lanes 1, 2, and 3) or intramuscular (lanes 4, 5, and 6) vaccination with a combination of inactivated H. parasuis, A. suis, and S. suis, establishing that intranasal
  • adjuvant includes any adjuvant suitable for administration to the subject.
  • the adjuvant is, or comprises, a carbomer-based or carbopol-based polymer, such as CarbigenTM adjuvant (Phibro Animal Health Corporation, Omaha, NE, USA), HRA-3, and HRA-5; an aluminum salt, such as aluminum hydroxide or aluminum phosphate; a saponin such as Quil A ® adjuvant or StimulonTM adjuvant QS- 21 (Antigenics, Framingham, MA.); an oil-in-water adjuvant such as an Emulsigen ® adjuvant (Phibro Animal Health Corporation, Omaha, NE, USA) containing a non-metabolizable oil, paraffin oil, mineral and/or plant/vegetable and/or animal oils; a surfactant; a lipid; nanoparticles including but not limited to oil-in-water based nanoparticles; cholesterol; water-in-oil emulsions; water-in-oil-in water emulsions;
  • the emulsion can be based in particular on light liquid paraffin oil, isoprenoid oil such as squalane or squalene, oil resulting from the oligomerization of alkenes, in particular of isobutene or decene, esters of acids or of alcohols containing a linear alkyl group, more particularly plant oils, ethyl oleate, propylene glycol di- (caprylate/caprate), glyceryl tri-(caprylate/caprate) or propylene glycol dioleate, esters of branched fatty acids or alcohols, in particular isostearic acid esters.
  • isoprenoid oil such as squalane or squalene
  • oil resulting from the oligomerization of alkenes in particular of isobutene or decene
  • esters of acids or of alcohols containing a linear alkyl group more particularly plant oils, ethyl oleate, propylene glycol
  • the oil may be used in combination with emulsifiers to form the emulsion.
  • the emulsifiers are preferably nonionic surfactants, in particular esters of sorbitan, of mannide, of glycol, of polyglycerol, of propylene glycol and of oleic, isostearic, ricinoleic or hydroxystearic acid, which are optionally ethoxylated, and
  • the adjuvant is at a concentration of from 0.01% to 70%, such as from 1% to 50%, 1% to 30%, 5% to 20%, 7% to 20%, or 10% to 20% by volume of the final product.
  • mucoadhesive refers to an adjuvant that has the capability to adhere to mucosal membranes and stimulate an immune response.
  • Mucous membranes include the nasopharyngeal, oral, optic (eye), vaginal or anal membranes.
  • the immune response that is stimulated may include IgA, IgG, or a combination thereof, which are found in the serum and in mucosal washings. Compositions comprising such adjuvants are applied to the mucosal membranes of animals.
  • adjuvants with mucoadhesive characteristics include, but are not limited to, adjuvants comprising polymers, such as those comprising polyacrylic acids such as Carbopols or Carbomers (e.g. Carbigen TM adjuvant, HRA-3, HRA-5, Carbigen-M, Carbigen-P, or combinations thereof); or oil-in-water based adjuvants, such as Emulsigen ® adjuvant, Emulsigen ® -D adjuvant, Emulsigen ® -DL90 adjuvant, Emulsigen ® -BCL adjuvant, Emulsigen ® -P adjuvant, Emulsigen ® -M adjuvant, and combinations thereof.
  • adjuvants comprising polymers such as those comprising polyacrylic acids such as Carbopols or Carbomers (e.g. Carbigen TM adjuvant, HRA-3, HRA-5, Carbigen-M, Carbigen-P, or combinations thereof);
  • adjuvants containing nanoparticles can be used for intranasal administration.
  • a mucoadhesive adjuvant could contain any combination of the above adjuvants as well.
  • Acceptable mucoadhesive adjuvants also include any adjuvant that when administered mucosally, such as intranasally, stimulates an IgA response in pigs and/or protects pigs from challenge with a live organism.
  • Formulations for mucosal administration may comprise vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function.
  • Diluents such as water, aqueous saline or other known substances can be used in combination with other components of disclosed compositions.
  • the nasal formulations may also contain
  • preservatives such as, but not limited to, gentamicin, formaldehyde, formalin, thimerosal, binaryethyleneimine, and/or beta propiolactone, and/or may contain neutralizing agents such as sodium thiosulfate and/or sodium bisulfite.
  • a surfactant may be present to enhance absorption of the subject proteins by the nasal mucosa. Acceptable surfactants include but are not limited to tweens, spans and detergents such as NP40 and Triton X 100.
  • Acceptable inactivating agents for inactivating bacterial antigens include, but are not limited to, formaldehyde, formalin, binary ethyleneimine, thimerosal, beta-propiolactone, and combinations thereof.
  • Infection or challenge means that the subject has been exposed to live organisms that may produce disease causing the subject to suffer one or more clinical signs of the diseases when they have been exposed to these live organisms.
  • an active agent such as one or more embodiments provided herein alone, in combination, or potentially in combination with other therapeutic agent(s)
  • that result may be amelioration or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • effective amount or therapeutically effective amount is used herein to denote any amount of a therapeutic and/or preventative that causes an improvement in a disease condition, or prevention of disease symptoms. The amount can vary with the condition being treated, the stage of advancement of the condition, and the type and concentration of formulation applied.
  • compositions comprising one or more inactivated antigens and a mucosal, such as a mucoadhesive, adjuvant.
  • the antigens may be any suitable antigen, but certain embodiments particularly may be obtained from one or more bacterial strains, particularly strains of S. suis, A. suis and/or H. parasuis.
  • the composition may be formulated for mucosal administration to a subject to stimulate an immune response, the response helping to reduce the severity and incidence of disease when the subject is later challenged by exposure to live organisms.
  • the subject may be a human or an animal.
  • the term "animal" refers to a non-human animal.
  • the animal may be a mammal, such as a swine or pig.
  • the immune response may comprise an IgA immune response.
  • the composition comprises inactivated antigens from one or more S. suis strains or serovars, such as from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more S. suis strains or serovars. In some embodiments, the composition comprises inactivated antigens from one or more H.
  • the composition comprises inactivated antigens from one or more A. suis strains or serovars, such as from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more A. suis strains or serovars.
  • the composition may comprise inactivated antigens from one or more S. suis strains or serovars and one or more H. parasuis strains or serovars; inactivated antigens from one or more A. suis strains or serovars and one or more H. parasuis strains or serovars; inactivated antigens from one or more S.
  • the one or more antigens from S. suis comprise one or more antigens from serovars 1/2, 2, or 3. Additionally, or alternatively, the composition may comprise one or more antigens having at least a 90% sequence identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%) to any strain and/or serovar of S. suis currently known or later discovered or developed, and particularly to serovars 1/2, 2, or 3. In some embodiments, the one or more antigens from H.
  • parasuis comprise one or more antigens from serovars 2 or 7. Additionally, or alternatively, the composition may comprise one or more antigens having at least a 90% sequence identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%) to any strain and/or serovar of H. parasuis currently known or later discovered or developed, particularly serovars 2, or 7.
  • the one or more antigens from A may comprise one or more antigens having at least a 90% sequence identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%.
  • suis comprise one or more antigens having at least a 90% sequence identity (i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%) to any strain and/or serovar of A. suis currently known or later discovered or developed.
  • 90% sequence identity i.e., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%
  • the inactivated antigens include, but are not limited to, whole culture bacteria; subunits obtained from the S. suis, A. suis and/or H. parasuis, and/or from any other bacteria or virus that may be included, that have been extracted or separated from the culture; subunits that have been extracted or separated from the cells; antigens obtained from recombinant organisms other than S. suis, A. suis or H. parasuis but which protect against S. suis, A. suis or H. parasuis infection or challenge; or combinations thereof.
  • Such antigens may also be combined with other antigens that are typically administered to subjects, such as pigs, particularly neonatal pigs.
  • additional antigens include, but are not limited to, antigens from M.
  • administering the composition mucosally, such as intranasally, to a neonatal pig results in an IgA immune response that also may help to overcome maternal antibodies that the piglet may receive from a sow or gilt that is positive for S. suis or H. parasuis. If the neonatal pig receives maternal antibodies and then receives a parenteral vaccination, the maternal antibodies often block the neonate from developing its own protective antibodies.
  • the method of mucosal, such as intranasal, administration described herein may produce an IgA response that can help overcome the maternal antibodies transferred to neonates.
  • Immunogenic compositions for mucosal administration have several advantages over compositions that are administered by other routes, such as the intramuscular or subcutaneous route.
  • the advantages include, but are not limited to: 1) protecting the neonatal pigs using humane techniques; 2) not exposing the neonate to stressful needle injections; 3) not involving injecting the neonates with live or modified live organisms that can shed and spread disease; 4) allowing the neonate to develop IgA antibodies that can overcome maternal IgG antibodies transferred from the sow or gilt; 5) not leaving any injection site lesions and thus allowing a zero day withdrawal time; 6) being easier to administer and reducing the workload; 7) reducing or substantially eliminating the risk of accidental self-injection of the worker; and/or 8) being able to be administered in the face of an outbreak to stop disease spread in a herd.
  • Embodiments of the composition may be able to provide better protection against diseases caused by S. suis, A. suis and H. parasuis following revaccination or additional administration of an immunogenic composition.
  • the revaccination or additional administration may be delivered via the intranasal route or by a parenteral route such as intramuscular, subcutaneous or intravenous.
  • the disclosed composition may also be able to overcome maternal antibody inhibition of piglet antibody production, thus providing a greater protection of neonatal pigs throughout their development, compared to neonatal pigs that are not administered the disclosed composition.
  • the disclosed composition are able to induce protective levels of antibodies as measured by the ELISA in >50%, typically in >80% of the individuals that are administered the composition.
  • the mucoadhesive composition also is able to maintain protective levels of antibodies against the S. suis, A. suis and/or H. parasuis strains throughout the piglet growth phase from the neonatal or pre- weaning phase through the nursery phase, which is typically from weaning at about 21 days of age to about 10 weeks of age.
  • the composition can produce a persistent immune response against S. suis, A. suis and/or H. parasuis related diseases.
  • a "persistent immune response” refers to a protective antibody immune response which is capable of protecting the pigs throughout their growth period in the nursery.
  • Embodiments of the immunogenic composition that comprise one or more strains of inactivated S. suis, A. suis and/or inactivated H. parasuis, that are each independently grown to titers greater than 10 2 CFU/mL, preferably greater than 10 5 CFU/mL, and more preferably greater than 10 7 CFU/mL, induce high titers of IgA antibodies in neonatal pigs.
  • IgA titers measured in serum will be at least 50 ELISA units, preferably greater than 100 ELISA units.
  • embodiments of the disclosed immunogenic composition when delivered to neonatal pigs via the mucosal route, such as an intranasal route, also induced serum IgG responses as demonstrated in the piglets (see FIGS. 1 and 2 and Table 2).
  • such titers are from 0 to 50 ELISA units, but in other embodiments, the titers are greater than 50 ELISA units.
  • the immunogenic composition comprises one or more strains or isolates of inactivated S. suis, one or more strains or isolates of A. suis, and/or one or more strains or isolates of H. parasuis, which have been isolated from infected pigs.
  • the S. suis, A. suis and/or H. parasuis strains may not have been passaged in artificial culture (in vitro) more than 20 times.
  • the one or more strains of S. suis and/or H. parasuis would not be passaged more than 10 times in vitro.
  • the immunogenic composition is a vaccine.
  • the composition may be administered to a subject, such as a pig, of any age.
  • the initial administration is to pigs of from birth to 10 days of age, such as from one to ten days of age, from one to five days of age, or from one to three days of age.
  • One or more additional administrations of a composition comprising one or more inactivated antigens obtained from one or more strains of S. suis, A. suis and/or H. parasuis, may be necessary in two to six weeks from the initial administration of the disclosed composition.
  • This second administration may be delivered parenterally and may include non-mucoadhesive adjuvants.
  • any additional administrations may be administered via a mucosal route, such as intranasal, or any other route that is preferred by the administrator.
  • the additional administrations may be mucosal such as intranasal, intramuscular, subcutaneous, intraperitoneal, intravenous, or a combination thereof.
  • Example 1 Composition preparation
  • compositions were prepared for vaccination of neonates farrowed to sows in the farm described in Example 2. The object was to determine whether intranasal administration of the disclosed composition to neonates within the first five days of life would help to reduce morbidity and mortality among the pigs.
  • Multiple isolates of S. suis (serovars 1/2, 2, and 3) and H. parasuis (serovars 2, 7, and non-typeable) and one isolate of A. suis were identified and found to be responsible for causing clinical disease and mortality in the nursery pigs.
  • Bacterins inactivated bacterial vaccines
  • Each isolate was inactivated with 0.1% formalin after which isolates were pooled in equal amounts. After pooling, the pool was split into two equal aliquots. One aliquot was first adjuvanted with 4% aluminum hydroxide. This was followed by adding an oil-in-water adjuvant called Emulsigen® at 12% v/v. The second aliquot was adjuvanted with 10% CarbigenTM, a mucoadhesive polyacrylic acid adjuvant.
  • a commercial sow farm of 2,000 sows experiencing significant nursery mortality from S. suis, A. suis and/or H. parasuis infection was selected for evaluation of the different administration routes/regimens of piglets.
  • Nursery pigs from this source were also positive for porcine reproductive and respiratory syndrome virus (PRRS), porcine circovirus type 2 (PCV2), swine influenza A (IAV-S), and M. hyopneumoniae. Pigs were weaned at 21 days of age and transferred to a single- source, off-site nursery. The nursery contained four rooms which were filled with approximately 900 pigs each. When clinical disease occurred in the nursery, individual animals were given an antibiotic injection. No feed or mass water medications were administered.
  • PRRS porcine reproductive and respiratory syndrome virus
  • PCV2 porcine circovirus type 2
  • IAV-S swine influenza A
  • M. hyopneumoniae M. hyopneumoniae.
  • Neonatal piglets were enrolled at the sow farm into the study over five consecutive weeks of farrowing. Administration occurred at the time of processing which was between the third and fifth day post farrowing.
  • the piglets were randomly assigned to one of four groups by colored ear tags. The groups are shown in Table 1 and were:
  • Piglets within litters were placed in different groups so as to equally represent each of the four treatment groups as much as possible.
  • treatment groups of pigs were not sorted to separate pens. The animals were randomly mixed together in order to promote uniform exposure to pathogens.
  • Example 4 Western Blot analysis of antibody response to antigens of H. parasuis Blood samples were obtained randomly from 10 pigs in each of the IN/IN and IM/IM groups of pigs from Example 2. Equal aliquots were pooled and were used in a Western Blot analysis to evaluate the antibody responses of pigs to antigens of H. parasuis known to be important for protection.
  • FIG. 2 provides the Western Blot for the IN/IN and IM/IM groups, with lanes 1, 2 and 3 representing the IN/IN group, and lanes 4, 5 and 6 representing the IM/IM group.
  • Lanes 1 and 4 are molecular weight markers (Bio-Rad #161-0373); lanes 2 and 5 are loaded with 20 ug/well of Hps #32575; and lanes 3 and 6 are loaded with 20 ug/well of Hps #31136.
  • Table 5 shows the percentage of piglets treated with antibiotics.
  • the IN/IN and IN/IM groups had an average treatment mortality rate of 8.78% (s.d. 3.84%) and 9.53% (s.d. 6.17%), respectively.
  • the IM/IM group was 7.63% (s.d. 3.53%) while the average treatment rate observed in the IN (only at processing) group was 6.88% (s.d. 4.82%).
  • piglets receiving a single intranasal administration at 3-5 days of age or intranasal administration at 3-5 days of age followed by a second intranasal administration at weaning (about 21 days) required no more antibiotic treatments than piglets receiving regimens including intranasal administration followed by intramuscular or two intramuscular administration (/?>0.05).
  • the IN/IN and IN/IM groups had average poor quality of 22.60% (s.d. 4.91%) and 24.53% (s.d. 8.39%), respectively.
  • "Poor quality” was defined as any pig that could be downgraded for any reason (for example, lighter weight).
  • the IM/IM group was 22.65% (s.d. 6.02%) whereas the rate of poor quality pigs observed in the IN (only at processing) group was 22.23% (s.d. 11.63%).
  • the nursery performance for the parameters measured demonstrated that a single intranasal dose administered at 3-5 days of age or two intranasal doses administered at 3-5 days of age and again at about 21 days of age were as effective as regimens that included intramuscular administration.
  • the intranasal administration has additional advantages over intramuscular administration, including not involving stressful needle injections to neonatal pigs, not involving injecting the neonates with live or modified live organisms that can shed and spread disease, not leaving any injection site lesions and thus allowing a zero day withdrawal time, and being easier to administer and thus reducing the workload and worker's risk of accidental self- injection for those administrating the composition.
  • the intranasal administration may result in the neonate developing IgA antibodies that can overcome maternal IgG antibodies that are transferred from the sow or gilt.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

La majorité de la mortalité observée chez les jeunes porcs se produit entre trois et cinq semaines après le sevrage pour des infections par S. suis et entre quatre et six semaines après le sevrage pour des infections par H. parasuis et des infections par Actinobacillus suis. La lutte contre les maladies cliniques associées à S. suis, A. suis et H. parasuis a été entreprise au moyen d'un traitement antibiotique, par une exposition contrôlée à des organismes vivants, et par une vaccination, à l'aide de bactérines commerciales ou autogènes inactivées administrées par voie parentérale. L'invention concerne une composition immunogène comprenant des antigènes et un adjuvant pour les muqueuses. La composition peut être administrée à des sujets, tels que des animaux, en particulier des porcelets pendant la période allant du pré-sevrage jusqu'à la phase de nourricerie, telle qu'à partir de la naissance ou de trois à cinq jours d'âge, pour les protéger de ces maladies.
PCT/US2016/031902 2016-05-11 2016-05-11 Composition comprenant des antigènes et un adjuvant pour les muqueuses et méthode d'utilisation WO2017196318A1 (fr)

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CA3022006A CA3022006A1 (fr) 2016-05-11 2016-05-11 Composition comprenant des antigenes et un adjuvant pour les muqueuses et methode d'utilisation
EP16901833.0A EP3454893A4 (fr) 2016-05-11 2016-05-11 Composition comprenant des antigènes et un adjuvant pour les muqueuses et méthode d'utilisation
PCT/US2016/031902 WO2017196318A1 (fr) 2016-05-11 2016-05-11 Composition comprenant des antigènes et un adjuvant pour les muqueuses et méthode d'utilisation
US15/593,223 US10279031B2 (en) 2016-05-11 2017-05-11 Composition comprising antigens and a mucosal adjuvant and a method for using
US16/353,877 US11000585B2 (en) 2016-05-11 2019-03-14 Composition comprising antigens and a mucosal adjuvant and a method for using
US16/386,535 US10918711B2 (en) 2016-05-11 2019-04-17 Composition comprising antigens and a mucosal adjuvant and a method for using

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CN112457397A (zh) * 2020-11-26 2021-03-09 西北农林科技大学 一种prrsv n蛋白的纳米抗体及其制备方法和应用

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CA3022006A1 (fr) 2017-11-16
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