CN109663126A - A kind of vaccine adjuvant and its application and porcine reproductive and respiratory syndrome vaccine - Google Patents
A kind of vaccine adjuvant and its application and porcine reproductive and respiratory syndrome vaccine Download PDFInfo
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Abstract
The present invention is suitable for biomedicine field, provide a kind of vaccine adjuvant and its application and porcine reproductive and respiratory syndrome vaccine, the vaccine adjuvant, in parts by weight, including following component: 1 ~ 10 part of Quillaia saponaria extract, 2 ~ 5 parts of TLR3 receptor effect agent, 2000 ~ 5000 parts and 1000 ~ 3000 parts of stabilizer of diethylin ethyl glucuronide.The cellular immunity of body can be improved in vaccine adjuvant joint porcine reproductive and respiratory syndrome virus (PRRSV) inactivation antigen of the invention, and inducing interferon reduces the immunosupress that PRRSV is generated.To, the faster neutralizing antibody for generating high-content, length of holding time, and can be reduced the viremia virusemia of different strains, enhance safety and the immune efficacy of vaccine.
Description
Technical field
The invention belongs to biomedicine field more particularly to a kind of vaccine adjuvant and its applications and pig breeding to integrate with breathing
Levy vaccine.
Background technique
Porcine reproductive and respiratory syndrome (PRRS, Porcine Reproductive and Respiratory
It Syndrome) is one of swinery highly contagious disease, cause of disease is porcine reproductive and respiratory syndrome virus, the virus
Main host is domestic pig and wild boar in nature.All ages and classes, kind, gender pig can infect PRRSV (Porcine
Reproductive and Respiratory Syndrome Virus), wherein pregnant sow and suckling pig are infected several
Rate highest.Other than infection animal, the sperm of boar also has been identified as the universal source of infection of PRRSV.
The common method of prevention at present and control PRRS are immunization with Vaccine.Common PRRS vaccine mainly has attenuated live
Vaccine and inactivated vaccine.PRRSV attenuated live vaccine protecting effect is obvious, but because PRRSV variation has frequently resulted in vaccine and had
Very strong strain specific, and strong risk is returned there are genetic recombination and virulence.Attenuated live vaccine is in immune early stage (sense
7~9d after dye) it can detecte strong anti-PRRSV antibody response, but the antibody that early stage generates is non-neutrality antibody, they
The infection that virus cannot not only be prevented can also cause the antibody dependent enhancing of virus, and PRRSV specificity neutrality antibody exists
28d can be just detected after virus infection, and maintain a lower level always.The cellular immunity of attenuated live vaccine induction
Reaction occurs in 14d, and horizontal low, growth is slowly.PRRSV attenuated live vaccines can effectively resist the infection of homologous street strain, and reduction is faced
The incidence of bed disease, but it is poor to the protecting effect of heterologous street strain.
Studies have reported that being respectively compared 3 kinds of commercialized vaccines to the Vaccine effectiveness of different velogen strains, the results showed that weak poison
Though attacking malicious body after live vaccine is immune does not show apparent clinical symptoms, virus proliferation diffusion in vivo can not be prevented;Into
One step is not studies have shown that the 3 kinds of vaccines selected have guarantor to the street strain of genetic diversity both from single PRRSV strain
Shield effect or protective effect are limited.Weak live vaccine is caused to dissipate malicious in the propagation of control PRRSV infection pig and continue sexy PRRSV
Dye etc. studies have shown that cannot i.e. " therapeutic vaccine intervention ", after vaccine immunity prevent the persistent infection of street strain, but
The pig quantity of the homologous strain of persistent infection is reduced in which can dramatically, it is limited to the protective effect of heterologous virus strain infection.
The feature that morbidity is slow, the duration is long is shown after pig infection PRRSV, still can in the pig body after infecting the several months
Enough it is separated to communicable strain (Allende et al 2000).The reason of speculating persistent viral infection is because of viral energy
Constantly variation in vivo, or it is related with the age of infected individual and inherent cause, also with viral immune evasion mechanism phase
It closes.Studies have shown that the occurrence frequency that PRRSV makes a variation in vivo is very low, and the immune evasion of virus influences host to PRRS
Humoral and cellular immune response response ineffectivity, lead to virus in blood and antibody long-term existence and viral persistent infection.
After PRRSV infection PAM (porcine alveolar macrophages, porcine alveolar macrophage), pass through suppression
PAM, is become suitable for the place of own existence by the immune response that I type interferon processed mediates.PRRSV utilizes intracellular amino acid
Nucleotide completes the duplication of progeny virus, after progeny virus is mature, by promoting the modes releasing virus such as Apoptosis, continues
Other cells and organ are infected, lesion of other systems and organ, such as viremia virusemia, lymphnoditis etc. are caused.PRRSV in addition to
Cell quantity can be caused to significantly reduce by way of promoting apoptosis of alveolar macrophages, pulmonary alveolar macrophage can also be produced
The secretory antiviral agent of raw I type interferon generates inhibiting effect, and in addition to this, PRRSV can also enhance in cell
Inflammatory cytokine (IL-1 and tumor necrosis factor) activity.
Many is the study found that PRRSV infection can increase IL-10 gene mRNA and protein expression, and pass through adjusting IL-10
Express the immune response to inhibit host.Therefore, the ability that pulmonary alveolar macrophage kills virus is suppressed, lymph node cells quilt
It destroys, mucosa injury, the neurological susceptibility of disease is enhanced.Meanwhile the pulmonary alveolar macrophage or peripheral blood mononuclear cells of infection are adjusted
The reduced capability of the antigen presentation of cell surface influences the antigen submission function of cell, leads to infect the antibody in the blood of pig
Virus cannot be removed in time from body, then lead to antibody-dependent enhancement and viremia virusemia and persistent infection
Long-term existence.More about jumpbogroup and above the average age for marriage pig long lasting for infection experiments have shown that, persistent infection when ask or even can prolong
It grows to half a year.For example, infection carries out after 30-100 days with 80 4 monthly age pigs of PRRSV separation strains MN-30-100 artificial challenge
PCR detection, the results showed that, the positive is all presented in the tissue sample of 98% pig, including tonsillotome and body part lymph node.Infection
110,120 and 135 days pigs have 80%, 30% and 20% presentation positive findings respectively.In another similar test, use
109 two week old piggys of PRRSV separation strains VR-2332 artificial challenge, infection detect after 189 days, still there is about 10%-30% pig
Tissue detection be positive.Since PRRSV is hidden for a long time in the intracorporal pulmonary alveolar macrophage of pig, using the side of early diagnosis
Method is difficult to detect virus.More seriously, virus leads to bacillary secondary infection to the immunosupress reaction of body.Example
Such as, by detection 221 infection PRRSV pig samples, the results show that 58% illness pig lung in addition to PRRSV infection with
Outside, there is also other bacterium infections, mainly include Streptococcus suis, haemophilus parasuis.Moreover, PRRSV infection can promote it
The proliferation of his viral such as circovurus type 2 (PCV-2), causes a variety of cause of diseases while infecting, increase the seriousness of the state of an illness.
PRRSV can not only inhibit the generation of the specific antibody of anti-PRRSV, moreover it is possible to the specific antibody of other viruses be inhibited to generate.
For example, piglet infects PRRSVBJ-4 strain first, it is then inoculated with weak malicious (PRV) vaccine of swine fever, then the swine fever that piglet generates is weak
The specific antibody level of virus is substantially less than the piglet resistance of individually inoculation hog cholera vaccine very much.
Although the safety of PRRS inactivated vaccine is good, extremely weak cell immune response, immune protective effect are only induced
It is undesirable.Therefore, how to enhance PRRSV vaccine specific cell immune response, improve the titre of neutralizing antibody, it is anti-to shorten neutralization
The generation time of body, the safety for enhancing vaccine is the important directions of PRRS Vaccine Development.
Summary of the invention
The embodiment of the present invention provides a kind of vaccine adjuvant, it is intended to solve how to enhance PRRSV vaccine specific cellular immunity
Reaction, the problem of improving the titre of neutralizing antibody, shorten the generation time of neutralizing antibody, enhance the safety of vaccine.
The embodiments of the present invention are implemented as follows, a kind of vaccine adjuvant, and in parts by weight, the vaccine adjuvant includes
Following component:
1~10 part of Quillaia saponaria extract, 2~5 parts of TLR3 receptor effect agent, 2000~5000 parts of diethylin ethyl glucuronide
With 1000~3000 parts of stabilizer.
The embodiment of the invention also provides a kind of vaccine adjuvants to prepare the application in porcine reproductive and respiratory syndrome vaccine.
The embodiment of the invention also provides a kind of porcine reproductive and respiratory syndrome vaccine, the porcine reproductive and respiratory syndromes
Vaccine is prepared from the following steps:
Each component is weighed according to the vaccine adjuvant formula as described in claim 1~6 any one, it is spare;
The Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added and gone out
In porcine reproductive and respiratory syndrome inactivation antigen liquid living, stir evenly up to the porcine reproductive and respiratory syndrome vaccine.
In vaccine adjuvant provided in an embodiment of the present invention the effect of each component/effect is as follows:
Quillaia saponaria extract: being a kind of good surfactant, and perfect hexahedron can increase surface to greatest extent
Product, antigen adhere to the chance for considerably increasing immunocyte identification on each face.Quillaia saponaria extract can induce relatively strong simultaneously
Cellular immunity.Quillaia saponaria extract fights original slow releasing function, so that antigen generation is continued permanent stimulation, maintains neutralizing antibody
Long period.The effect of in order to preferably play Quillaia saponaria extract, preferably Pureness control is 10% or more.
TLR3 receptor effect agent: Toll-like receptor (Toll-like receptors, TLRs) is the PRR found earliest, he
After the identification PAMPs of specificity, raise the adaptor protein point containing Toll/ interleukin-1 receptor (TIR) structural domain immediately
Son starts the signal transduction pathway in downstream, causes the secretion of inflammatory cytokine, I type interferon, chemotactic factor (CF) and antibacterial peptide,
Neutrophil leucocyte and macrophage direct killing pathogen are bitten in activation, play in congenital immunity and acquired immunity important
Effect.It is preferred that double-stranded RNA, double-strandednucleic acid is a kind of high-quality and efficient interferon inducer, preferably body can be induced to produce
Raw I type interferon, to generate stronger cellular immunity.But the size of the effect of double-strandednucleic acid and molecular weight is positively correlated,
Molecular weight is bigger, and it is stronger that induction body generates cell immunocompetent.
Diethylin ethyl glucuronide: as targeted induction agent, identification and the submission energy of antigen presenting cell can be improved
Power.The identification submission ability to joint antigen porcine reproductive and respiratory syndrome virus (PRRSV) not only can be enhanced, and can be with
Enhance the identification submission ability to double-strandednucleic acid, further improves the ability of inducing cellular immune.
Stabilizer: being to maintain the stability of each component, in order to keep the microenvironment of each component to stablize.
Vaccine adjuvant provided in an embodiment of the present invention combines porcine reproductive and respiratory syndrome virus (PRRSV) inactivation antigen
The cellular immunity of body can be improved, inducing interferon reduces the immunosupress that PRRSV is generated.To which the faster height that generates contains
The neutralizing antibody of amount, length of holding time, and can be reduced the viremia virusemia of different strains, enhance the safety of vaccine and be immunized
Power.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, to this
Invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, not
For limiting the present invention.
Vaccine adjuvant provided in an embodiment of the present invention combines porcine reproductive and respiratory syndrome virus (PRRSV) inactivation antigen
The cellular immunity of body can be improved, inducing interferon reduces the immunosupress that PRRSV is generated.To which the faster height that generates contains
The neutralizing antibody of amount, length of holding time, and can be reduced the viremia virusemia of different strains, enhance the safety of vaccine and be immunized
Power.
Technical solution of the present invention and technical effect are described further below by way of specific embodiment.
Embodiment 1:
A kind of vaccine adjuvant, including following component: Quillaia saponaria extract the agent of 1mg, TLR3 receptor effect (double-stranded RNA) 2mg, two
Ethylamino- ethyl glucuronide 5g and stabilizer (phosphate-buffered salt) 1g.
The porcine reproductive and respiratory syndrome vaccine of the embodiment of the present invention is prepared by the following steps to obtain:
Each component is weighed according to above-mentioned vaccine adjuvant formula, it is spare;
Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added into inactivation
In porcine reproductive and respiratory syndrome inactivation antigen liquid, stir evenly to obtain the final product.Adjust the pH of the porcine reproductive and respiratory syndrome vaccine
Value is 6.8.
Embodiment 2:
A kind of vaccine adjuvant, including following component: Quillaia saponaria extract the agent of 10mg, TLR3 receptor effect (double-stranded RNA) 5mg,
Diethylin ethyl glucuronide 2g and stabilizer (phosphate-buffered salt) 3g.
The porcine reproductive and respiratory syndrome vaccine of the embodiment of the present invention is prepared by the following steps to obtain:
Each component is weighed according to above-mentioned vaccine adjuvant formula, it is spare;
Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added into inactivation
In porcine reproductive and respiratory syndrome inactivation antigen liquid, stir evenly to obtain the final product.Adjust the pH of the porcine reproductive and respiratory syndrome vaccine
Value is 7.8.
Embodiment 3:
A kind of vaccine adjuvant, including following component: Quillaia saponaria extract the agent of 5mg, TLR3 receptor effect (double-stranded RNA) 3mg, two
Ethylamino- ethyl glucuronide 4g and stabilizer (phosphate-buffered salt) 3g.
The porcine reproductive and respiratory syndrome vaccine of the embodiment of the present invention is prepared by the following steps to obtain:
Each component is weighed according to above-mentioned vaccine adjuvant formula, it is spare;
Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added into inactivation
In porcine reproductive and respiratory syndrome inactivation antigen liquid, stir evenly to obtain the final product.Adjust the pH of the porcine reproductive and respiratory syndrome vaccine
Value is 7.0.
Embodiment 4:
A kind of vaccine adjuvant, including following component: Quillaia saponaria extract the agent of 4mg, TLR3 receptor effect (double-stranded RNA) 2mg, two
Ethylamino- ethyl glucuronide 3g and stabilizer (phosphate-buffered salt) 2g.
The porcine reproductive and respiratory syndrome vaccine of the embodiment of the present invention is prepared by the following steps to obtain:
Each component is weighed according to above-mentioned vaccine adjuvant formula, it is spare;
Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added into inactivation
In porcine reproductive and respiratory syndrome inactivation antigen liquid, stir evenly to obtain the final product.Adjust the pH of the porcine reproductive and respiratory syndrome vaccine
Value is 6.8.
Embodiment 5:
A kind of vaccine adjuvant, including following component: Quillaia saponaria extract the agent of 8mg, TLR3 receptor effect (double-stranded RNA) 2.5mg,
Diethylin ethyl glucuronide 3.5g and stabilizer (phosphate-buffered salt) 2.5g.
The porcine reproductive and respiratory syndrome vaccine of the embodiment of the present invention is prepared by the following steps to obtain:
Each component is weighed according to above-mentioned vaccine adjuvant formula, it is spare;
Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added into inactivation
In porcine reproductive and respiratory syndrome inactivation antigen liquid, stir evenly to obtain the final product.Adjust the pH of the porcine reproductive and respiratory syndrome vaccine
Value is 7.8.
To further illustrate technical effect of the invention, below to the user of vaccine adjuvant provided in an embodiment of the present invention
Method, performance evaluation are described in detail:
One, application method
By vaccine adjuvant provided in an embodiment of the present invention and porcine reproductive and respiratory syndrome virus antigen according to weight ratio
After being mixed for 1:1, forms porcine reproductive and respiratory syndrome vaccine and use.
Two, performance evaluation
Following performance evaluations are carried out to the vaccine adjuvant that the embodiment of the present invention 1~5 provides:
1, safety testing:
Weanling pig 50 of 35~45 ages in days of health are randomly choosed, 5 groups is equally divided into, every group 10, gives respectively every
Group piggy injection use the embodiment of the present invention 1~5 offer vaccine adjuvant (4mL/) (normal use dosage is 2mL/) and
PRRSV antigen 1: each group piglet is placed under identical management environment after injection and carries out feeding management, daily by 1 proportioning concentration
The body temperature situation of Timing measurement piglet simultaneously records, and the experiment of completion in 14 days is observed continuously.
Experimental result: in tested period, the body temperature of each group piglet does not occur body temperature and increases (body temperature is more than 40 DEG C)
Situation, i.e., without apparent clinical symptoms, the safety of each group vaccine adjuvant is good.
2, physics and chemistry is tested:
According to " (CH-la plants) of the compound inactivated vaccine of porcine reproductive and respiratory syndrome manufacture and examine Trial Regulation " and " in
Magnificent people's republic's veterinary drug allusion quotation " (2010 editions) related request vaccine adjuvant that the embodiment of the present invention 1~5 is provided and inactivation
PRRSV antigen 1: 1 ratio is made corresponding vaccine and carries out related check, and inspection result is detailed in the following table 1:
Table 1
From the inspection result of upper table 1, it can be concluded that, the vaccine adjuvant that the embodiment of the present invention 1~5 provides meets " the Chinese people
Republic's veterinary drug allusion quotation " (2010 editions) related request, good security.
3, stability test:
9 parts of vaccine adjuvant made from the embodiment of the present invention 1 are randomly selected, and are divided into 3 groups, and this 3 groups of samples are distinguished
Be placed on 2~8 DEG C, room temperature, 1 month under the conditions of 37 DEG C, whether observation each group sample has lamination, if be not layered as
It has good stability.
It should be noted that vaccine adjuvant made from the embodiment of the present invention 2~5 is tried referring to the layering of above-described embodiment 1
Proved recipe method carries out stability test, and test result is shown, the vaccine adjuvant that the embodiment of the present invention 1~5 provides is in 2~8 DEG C, room
Temperature, under the conditions of 37 DEG C after 1 month without there is lamination, that is, have good stability.
4, challenge test:
Sodium selenite 15 of 35~45 ages in days are randomly choosed, is equally divided into 3 groups, every group each 5, and numbering is 1~3
Group, wherein organizing 1 is the immune PRRSV vaccine test group for adding the vaccine adjuvant that the embodiment of the present invention 1 provides, group 2 is to be immunized not
The PRRSV vaccine test group of vaccine adjuvant is added, group 3 is used as blank control group to be not immune.
Each group is 7 days after immune, takes a blood sample within 14,21,120, separates serum, measures the neutralizing antibody of every test pig
Amount, and its average value is taken, test result is detailed in the following table 2.And it is strong with highly pathogenic PRRSV after immune 21 days have adopted blood
Strain (106.0TCID50/ ml) and NADC30 strain (106.0TCID50/ ml) it carries out attacking poison simultaneously, every kind of virus respectively infuse by muscle
Penetrate 3mL, collunarium 3mL.Thermometric and clinical observation are carried out daily.At least body temperature is at 40 DEG C or more for three days on end, while it is heavy spirit occur
Strongly fragrant, the clinical symptoms such as feeding decline are judged to fall ill, and statistics incidence result is detailed in the following table 3.
The vaccine adjuvant provided for the embodiment of the present invention 2~5 is surveyed referring to the challenge test method of above-described embodiment 1
Examination, the difference is that changing the vaccine adjuvant of the embodiment 1 in the group 1 in above-mentioned challenge test group into implementation of the present invention respectively
The vaccine adjuvant of example 2~5 is tested, and see Table 2 for details and table 3 for test result.
2 each group neutralizing antibody testing result of table
Table 3
From the test result of upper table 2 and 3, it can be concluded that, the vaccine adjuvant that this hair inventive embodiments provide can enhance
PRRSV vaccine specific cell immune response, improves the titre of neutralizing antibody, shortens the generation time of neutralizing antibody, safety
It is good.
Body can be improved in vaccine adjuvant joint porcine reproductive and respiratory syndrome virus (PRRSV) inactivation antigen of the invention
Cellular immunity, inducing interferon, reduce PRRSV generate immunosupress.To which the faster neutralization for generating high-content is anti-
Body, length of holding time, and can be reduced the viremia virusemia of different strains, enhance safety and the immune efficacy of vaccine.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (9)
1. a kind of vaccine adjuvant, which is characterized in that in parts by weight, the vaccine adjuvant includes following component:
1 ~ 10 part of Quillaia saponaria extract, 2 ~ 5 parts of TLR3 receptor effect agent, 2000 ~ 5000 parts of diethylin ethyl glucuronide and stabilization
1000 ~ 3000 parts of agent.
2. vaccine adjuvant as described in claim 1, which is characterized in that the purity of the Quillaia saponaria extract is greater than 10%.
3. vaccine adjuvant as described in claim 1, which is characterized in that the TLR3 receptor effect agent is double-stranded RNA.
4. vaccine adjuvant as claimed in claim 3, which is characterized in that the molecular weight of the double-stranded RNA is greater than 200Kbp.
5. vaccine adjuvant as described in claim 1, which is characterized in that the vaccine adjuvant includes following component:
1 ~ 10 part of Quillaia saponaria extract, 2 ~ 5 parts of TLR3 receptor effect agent, 3000 ~ 4000 parts of diethylin ethyl glucuronide and stabilization
1000 ~ 3000 parts of agent.
6. vaccine adjuvant as claimed in claim 1 or 5, which is characterized in that the stabilizer is phosphate-buffered salt.
7. vaccine adjuvant is preparing the application in porcine reproductive and respiratory syndrome vaccine as described in claim 1 ~ 6 any one.
8. a kind of porcine reproductive and respiratory syndrome vaccine, which is characterized in that the porcine reproductive and respiratory syndrome vaccine is by following
Step is prepared:
Each component is weighed according to the vaccine adjuvant formula as described in claim 1 ~ 6 any one, it is spare;
The Quillaia saponaria extract, the agent of TLR3 receptor effect, diethylin ethyl glucuronide and stabilizer are sequentially added into inactivation
In porcine reproductive and respiratory syndrome inactivation antigen liquid, stir evenly up to the porcine reproductive and respiratory syndrome vaccine.
9. porcine reproductive and respiratory syndrome vaccine as claimed in claim 8, which is characterized in that the pig breeding is integrated with breathing
The pH value for levying vaccine is 6.8~7.8.
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