Quadruple vaccine for poultry and preparation method and application thereof

A technology for poultry and vaccines, which is applied in the field of quadruple vaccines for poultry and its preparation, can solve the problems of aggravating stress and disease susceptibility, increasing manpower and material resources, and reducing the production performance of chicken flocks, and achieves good antigenicity and safety. The effect of high sex and long duration of immune protection

Pending Publication Date: 2020-05-15
WUHAN KEQIAN BIOLOGY CO LTD
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Problems solved by technology

[0005] Most of the current commercialized vaccines are traditional vaccines, and the strains selected were isolated earlier, which are quite different from the current epidemic strains in terms of genes and antigenicity (especially RNA viruses that are highly mutated). Due to the existence of immune deviation, even if chi...
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Abstract

The present invention relates to a quadruple vaccine for poultry and a preparation method and an application thereof. The quadruple vaccine for the poultry is for chicken Newcastle disease, H9 subtypeavian influenza, infectious bursal disease and avian adenovirus disease. Inactivated chicken Newcastle disease virus La Sota strain, inactivated H9 subtype avian influenza virus HB01 strain, infectious bursal disease virus capsid protein VP2 and avian adenovirus structural protein Fiber2 are mixed to prepare an oil-water emulsion. The provided quadruple vaccine for the poultry has high safety, good stability and long duration of immune protection, can provide long-lasting maternal antibodies to the offspring young chicken after immunization of hens, and is extremely low in endotoxin content and small in immune side reactions. In addition, the four antigens have good compatibility, competition and expression inhibition between the different antigens do not exist, and the four components inthe quadruple vaccine for the poultry can all reach the same immune effect as respective monovalent inactivated vaccines.

Application Domain

SsRNA viruses negative-senseViral antigen ingredients +5

Technology Topic

AntigenBiomedical engineering +19

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  • Quadruple vaccine for poultry and preparation method and application thereof
  • Quadruple vaccine for poultry and preparation method and application thereof
  • Quadruple vaccine for poultry and preparation method and application thereof

Examples

  • Experimental program(4)

Example Embodiment

[0036] Example 1
[0037] This embodiment provides a method for preparing a quadruple vaccine for Newcastle disease, avian influenza, infectious bursal disease and avian adenovirus disease. figure 1 It is the flow chart of the preparation method, and the specific steps include:
[0038] (1) Source of poison (bacteria) species
[0039] Chicken Newcastle disease virus La Sota strain, H9 subtype avian influenza virus HB01 strain, recombinant E. coli Rosetta(DE3)-rVP2 strain expressing infectious bursal disease virus VP2 protein, expressing avian adenovirus (group I, 4 The recombinant E. coli Rosetta(DE3)-rFiber2 strain of Fiber2 protein was identified, kept and supplied by Wuhan Keqian Biological Co., Ltd.
[0040] Among them, the H9 subtype avian influenza virus HB01 strain has the preservation number of CCTCC NO: V202017, which was deposited in the Chinese Type Culture Collection of Wuhan University on January 7, 2020, and the preservation address is: Wuhan University, Wuhan, China; postcode 430072, classified and named It is: avian influenza virus (H9 subtype) HB01 strain.
[0041] The H9 subtype avian influenza virus HB01 strain has agglutinating effect on chicken red blood cells (that is, it has hemagglutination), and its hemagglutination can be specifically inhibited by avian influenza (H9 subtype) positive serum. The strain is genotyped It belongs to the avian influenza H9N2, which is in line with the characteristics of the H9 subtype avian influenza virus.
[0042] (2) Preparation of poison (bacteria) for production
[0043] 1. Preparation of virus seed for the production of chicken Newcastle disease virus La Sota strain: use sterile physiological saline as 10 4 Double dilution, 10-day-old SPF chicken embryos were inoculated into the allantoic cavity, 0.1ml per embryo. The chicken embryos that died 72 to 120 hours after the inoculation and had obvious disease scars were selected, and the chicken embryo allantoic fluid was harvested and packed in sterilized containers. The allantoic fluid, which has been tested for sterility and has an agglutinating value of 1% chicken red blood cells not less than 1:512 (micro method), is mixed, quantified, and frozen and stored. Indicate the date of harvest, the number of poison seeds, etc.
[0044] 2. Preparation of virus seed for the production of H9 subtype avian influenza virus HB01 strain: The virus seed was diluted 104 times with sterile normal saline, and 10-day-old SPF chicken embryos were inoculated into the allantoic cavity, 0.1ml per embryo. For the chicken embryos 60 to 120 hours after the inoculation, the chicken embryo allantoic fluid was harvested and packed in a sterilized container. The chicken embryo liquid tested for sterility and the agglutination value of 1% chicken erythrocytes is not less than 1:256 (micro method) is mixed, quantified, and frozen and stored. Indicate the date of harvest, the number of poison seeds, etc.
[0045] 3. Preparation of the recombinant Escherichia coli Rosetta(DE3)-rVP2 strain expressing the VP2 protein of infectious bursal disease virus: the freeze-dried Rosetta(DE3)-rVP2 strain was streaked in LA medium ( Incubate at 37℃ for 15 hours, pick and inoculate typical colonies that meet the standard in LB medium (containing 10μg/ml Kana), culture at 37℃ in a shaker at 200r/min until OD600nm is about 1.0. As a first-level seed bacteria, the bacteria solution should be stored at 2~8℃ for no more than 14 days; take the first-level seed bacteria solution of Rosetta(DE3)-rVP2 strain and inoculate it in LB medium (containing 10μg/ ml Kana), cultured in a shaker at 37°C at 200r/min to an OD600nm of about 1.0, and used as secondary seed bacteria after harvest. Bacteria solution should be stored at 2~8℃ for no more than 7 days.
[0046] 4. Preparation of recombinant Escherichia coli Rosetta(DE3)-rFiber2 strain expressing avian adenovirus (group I, type 4) Fiber2 protein: streaking the freeze-dried Rosetta(DE3)-rFiber2 strain in LA Culture medium (containing 10μg/ml Kana), culture at 37℃ for 15 hours, pick and inoculate typical colonies that meet the standard into LB medium (containing 10μg/ml Kana), culture at 37℃ shaker at 200r/min until OD600nm is about 1.0 Harvested, as a first-level seed bacteria, the bacteria liquid should be stored at 2~8℃ for no more than 14 days; take the first-level seed liquid of Rosetta(DE3)-rFiber2 strain and inoculate it in LB medium (containing 10μg/ ml Kana), cultured in a shaker at 37°C at 200r/min to an OD600nm of about 1.0, and used as secondary seed bacteria after harvest. Bacteria solution should be stored at 2~8℃ for no more than 7 days.
[0047] (3) Preparation of virus liquid for vaccine production
[0048] 1 Preparation of virus solution for chicken Newcastle disease virus vaccine production
[0049] 1.1 Inoculation Take the virus seeds for production and use sterile physiological saline as 10 4 Double dilution, inoculate 9-11-day-old susceptible chicken embryos in the allantoic cavity of each embryo, 0.1ml per embryo, seal the pinhole, and continue incubating at 36-37°C without turning the eggs.
[0050] 1.2 Incubation and observation After inoculation, the eggs are irradiated once a day. The embryos that die within 48 hours are discarded. The embryos that die within 48 hours are taken out at any time and stored at 2-8°C until 120 hours. After 120 hours, regardless of whether the chicken embryos are dead or not, all are taken out, the air chamber is upright, and it is placed at 2~8℃ to cool for 4~24 hours.
[0051] 1.3 Harvest Take out the chilled chicken embryos, sterilize the egg shells, and harvest chicken embryo allantoic fluid separately, put several chicken embryos into a group, put them in the same sterile container, take samples for red blood cell agglutination test, and agglutinate 1% chicken red blood cells The price should be no less than 1:512 (micro method), and at the same time, sterility test should be carried out in accordance with the appendix of the current "Chinese Veterinary Pharmacopoeia". It should be grown aseptically and stored below -15°C for later use.
[0052] 1.4 Concentration of virus liquid The chicken embryo allantoic liquid of chicken Newcastle disease virus La Sota strain is coarsely filtered to remove large particles of impurities in the virus liquid, and then concentrated to 1/4 of the original volume by an ultrafiltration concentration system, and the concentrated virus liquid is sampled Then, determine the virus content (after the concentrated virus solution is diluted by 4 times, the virus content per 0.1ml should be ≥10 8.0 EID 50 After concentration, the virus solution should be stored at 2~8℃.
[0053] 1.5 Inactivation of the virus solution Add the tested chicken embryo allantoic solution to the formaldehyde solution to make the final concentration of the formaldehyde solution 0.2%. Stir while adding to make it fully mixed, and inactivate it at 37°C for 20 hours. Store at 2~8℃ after live.
[0054] Preparation of virus liquid for vaccine production of 2H9 subtype avian influenza virus
[0055] 2.1 Inoculation Take the virus seeds for production, dilute 104 times with sterile normal saline, inoculate 9-11-day-old susceptible chicken embryos in the allantoic cavity of each embryo, 0.1ml per embryo, seal the pinhole, and continue at 36-37°C Incubate without turning the eggs.
[0056] 2.2 Incubation and observation After inoculation, the eggs are irradiated once a day. The embryos that die within 24 hours are discarded, and the embryos that die after 24 hours are taken out at any time and stored at 2-8°C until 96 hours. After 96 hours, regardless of whether the chicken embryos are dead or not, all are taken out, the air chamber is upright, and it is placed at 2~8℃ to cool for 4~24 hours.
[0057] 2.3 Harvest Take out the cooled chicken embryos, sterilize the egg shells, and harvest the chicken embryo allantoic fluid. Several chicken embryos are divided into a group and placed in the same sterilized container. Samples are taken for agglutination test of 1% chicken red blood cells. The price should not be less than 1:256 (micro method), and the sterility test should be carried out in accordance with the appendix of the current "Chinese Veterinary Pharmacopoeia". It should be grown aseptically and stored below -15°C for later use.
[0058] 2.4 Concentration of virus liquid The chicken embryo allantoic liquid of the H9 subtype avian influenza HB01 strain is coarsely filtered to remove large particles of impurities in the virus liquid, and then concentrated to 1/4 of the original volume by an ultrafiltration concentration system, and the concentrated virus After sampling the solution, determine the virus content (after 4-fold dilution of the concentrated virus solution, the virus content per 0.1ml should be ≥10 7.0 EID 50 After concentration, the virus solution should be stored at 2~8℃.
[0059] 2.5 Virus liquid inactivation Add the tested chicken embryo allantoic liquid to the formaldehyde solution, the final concentration of the formaldehyde solution is 0.2%, stir while adding to make it fully mixed, inactivate at 37 ℃ for 24 hours, inactivate Store at 2~8℃ for later use.
[0060] 3 Preparation of infectious bursal disease virus VP2 protein antigen
[0061] 3.1 Bacterial culture and induction The production strains were inoculated into synthetic medium (containing 10μg/ml Kana) at a volume ratio of 2%, cultured in a fermenter at 36~37℃, stirred at 200r/min, and dissolved oxygen (DO ) Is 10%, pH 7.2~7.3. After culturing under this condition until OD600nm reaches about 60, add isopropylthiogalactoside (IPTG) to a final concentration of 0.1mmol/L, and induce culture at 16℃ for 14 hours Then collect the fermentation broth.
[0062] 3.2 Extraction of the antigen. After the culture is completed, the bacteria are collected by centrifugation. After resuspending and washing 3 times in PBS buffer (pH7.4, 0.01M), add 10ml of PBS buffer (pH7.4, 0.01M) per gram of wet weight of the bacteria. M) Resuspend the bacterial cells under pressure, and centrifuge to collect the supernatant.
[0063] 3.3 Purification of protein antigens Purify VP2 protein by ion exchange method. The purified rVP2 protein is filtered and sterilized through a 0.22μm pore filter and stored at 2-8°C.
[0064] 4 Preparation of avian adenovirus (group I, type 4) Fiber2 protein antigen
[0065] 4.1 Bacterial culture and induction The secondary seeds are inoculated into synthetic medium (containing 10μg/mlKana) at a volume ratio of 2%, cultured in a fermenter at 36~37℃, stirring speed is 200r/min, and dissolved oxygen (DO) is 10%, pH 7.2-7.3, cultured under this condition until OD600nm reaches about 60, add isopropylthiogalactoside (IPTG) to a final concentration of 1.0mmol/L, and induce culture at 36~37℃6 Collect the fermentation broth after hours.
[0066] 4.2 Extraction of the antigen. After the culture is completed, the bacteria are collected by centrifugation. After resuspending and washing 3 times in PBS buffer (pH7.4, 0.01M), add 10ml PBS buffer (pH7.4, 0.01M) per gram of wet weight of the bacteria. M) Resuspend the bacterial cells under pressure, and centrifuge to collect the supernatant.
[0067] 4.3 Protein antigen purification The target protein is purified by His tag affinity chromatography. The purified Fiber2 protein is filtered and sterilized by a 0.22μm pore filter and stored at 2-8°C.
[0068] (4) Preparation of vaccine
[0069] 1 Oil phase preparation Take 94 parts of white oil for injection (in milliliters), add 1 part of aluminum stearate (in grams), stir while adding until it is completely transparent, and then add 6 parts of Spen-80 (In milliliters), sterilize at 121°C for 30 minutes after mixing, and cool to room temperature for later use.
[0070] 2 Aqueous phase preparation. Dilute the inactivated chicken Newcastle disease virus, H9 subtype avian influenza virus, infectious bursal disease virus VP2 protein and avian adenovirus Fiber2 protein to the required concentration for the vaccine and according to 1:1:1: 1 Volume ratio is fully mixed, and the antigen content of chicken Newcastle disease virus in the antigen solution after mixing is 10 8.0 EID 50 /0.1ml, H9 subtype avian influenza virus antigen content is 10 7.0 EID 50 /0.1ml, the titer of infectious bursal disease virus VP2 protein antigen is 1:16, and the antigen content of avian adenovirus Fiber2 protein is 50μg/0.1ml. Take 96 parts of the mixed antigen solution, add 4 parts of sterilized Tween-80, and stir for 20-30 minutes to completely dissolve the Tween-80.
[0071] 3 Emulsification Inject 2 parts of the oil phase into the emulsification tank, stir slowly while slowly adding 1 part of the water phase, after the addition, perform shear emulsification.
[0072] 4 Dispense Pack the emulsified vaccine in a quantitative manner and seal it. Label and store at 2~8℃.

Example Embodiment

[0073] Example 2
[0074] In this example, the quadruple vaccine prepared in Example 1 was tested. The specific steps are as follows:
[0075] 1 traits
[0076] 1.1 Appearance Milky white homogeneous emulsion.
[0077] 1.2 The dosage form is water-in-oil type. Take a clean straw and draw a small amount of vaccine drop into cold water. Except for the first drop that spreads like a cloud, all subsequent drops should not spread.
[0078] 1.3 Stability Take 10ml of vaccine and add it to a centrifuge tube, centrifuge at 3000r/min for 15min, and the water at the bottom of the tube should not exceed 0.5ml.
[0079] 1.4 Viscosity is measured according to the appendix of the current "Chinese Veterinary Pharmacopoeia" and should meet the requirements.
[0080] 2 Packing quantity inspection It is determined according to the appendix of the current "Chinese Veterinary Pharmacopoeia", and it should meet the requirements.
[0081] 3 Sterility test According to the current "Chinese Veterinary Pharmacopoeia" appendix, it should grow aseptically.
[0082] 4 Safety inspection 10 SPF chickens aged 3 to 4 weeks were injected with 0.6ml of vaccine each intramuscularly or subcutaneously. Observed for 14 consecutive days, there should be no local and systemic adverse reactions caused by the vaccine.
[0083] 5 effectiveness test
[0084] 5.1 Newcastle disease part of chickens 15 SPF chickens aged 3 to 4 weeks were used, 10 of which were injected subcutaneously or intramuscularly with 12μl (1/25 feathers), and the other 5 were used as controls. On 21-28 days after inoculation, each chicken was intramuscularly injected with 0.2ml of virus solution of Newcastle Disease Virus Beijing strain (CVCC AV1611 strain) (the virus content is 10 5.0 ELD 50 ). After continuous observation for 14 days, all control chickens should die, and at least 7 immunized chickens should be protected.
[0085] Part of 5.2H9 subtype avian influenza 15 SPF chickens aged 3 to 4 weeks were used, 10 of which were injected subcutaneously or intramuscularly with 0.3ml of vaccine, and the other 5 were used as controls. From 21 to 28 days after inoculation, each chicken wing was intravenously injected with 0.2ml of the virus solution of the H9 subtype avian influenza virus HB01 strain (the virus content is 2×10 6.0 EID 50 ), on the 5th day after the challenge, the throat swab and cloaca swab of each chicken were collected separately, and the throat swab and cloaca swab of the same chicken were mixed into 1 sample, and each sample was inoculated through the allantoic cavity 10 5 day-old SPF chicken embryos, 0.2ml per embryo, incubated and observed for 5 days, the HA titer of chicken embryo allantoic fluid was determined embryo by embryo, and only 1 chicken embryo allantoic fluid was inoculated with each sample. If the blood clotting value is not less than 1:16 (micro method), it can be judged as positive for virus isolation; the chicken embryo allantoic fluid with blood clotting value lower than 1:16 (micro method) should be mixed and then blindly transmitted again for judgment . The immunized chickens should have at least 9 virus isolations as negative, and the control chickens should have at least 4 virus isolations as positive.
[0086] 5.3 Part of infectious bursal disease 20 SPF chickens aged 3 to 4 weeks were used, 10 of which were injected subcutaneously or intramuscularly with 0.3ml vaccine, and the other 10 were used as controls. 21 to 28 days after inoculation, each of all test chickens was orally infected with infectious bursal disease virus HN-14 strain (bursal tissue virus) virus solution 0.2ml (virus volume 2×10 4.0 ELD 50 ). After the challenge, the clinical manifestations of the test chickens were observed daily and the incidence of disease was recorded. 72 hours after the challenge, the patients were dissected and observed for bursal disease. At least 8 immunized chickens should be protected and cannot have bursal disease; control chickens should have at least 8 disease and obvious bursal disease (enlargement or atrophy of the cyst, bleeding, yellowing, jelly-like secretions, etc.) One or more lesions).
[0087] 5.4 Part of avian adenovirus disease (group I, type 4) 20 SPF chickens aged 7-10 days were used, 10 of which were injected subcutaneously or intramuscularly with 0.3ml vaccine, and the other 10 were used as controls. On the 21st day after inoculation, together with the control chickens, each chicken’s leg was injected intramuscularly with 0.2 ml of avian adenovirus (group I, type 4) KQ-HB strain virus solution (virus volume 2×10 5.0 TCID 50 ), continuous observation for 10 days, at least 8 immunized chickens should be protected, and at least 8 control chickens should die.
[0088] 6 Determination of formaldehyde residue should be carried out in accordance with the appendix of the current "Chinese Veterinary Pharmacopoeia" and should meet the requirements.
[0089] After the above-mentioned vaccine efficacy test, the quadruple vaccine of Example 1 meets the standards of the test method, which proves that the four antigen parts in the quadruple vaccine of Example 1 can exert their own efficacy without causing competition or expression between antigens. Suppress and other situations. At the same time, there will be no aggravation of adverse reactions due to differences in solubility, physical compatibility and stability between antigen components.

Example Embodiment

[0090] Example 3
[0091] 1. Sequencing and sequence analysis of H9 subtype avian influenza virus HB01 strain
[0092] According to the genome sequence of avian influenza virus in the GeneBank database, primers were designed to amplify the HA and NA gene fragments of HB01 strain. The primer sequences are as follows:
[0093] HA-F: 5'-GGGAGCAAAAGCAGGGG-3' (SEQ ID NO. 1);
[0094] HA-R: 5'-GGAGTAGAAACAAGGGTGTTTT-3' (SEQ ID NO. 2);
[0095] NA-F: 5'-GGGAGCAAAAGCAGGAGT-3' (SEQ ID NO. 3);
[0096] NA-R: 5'-GGAGTAGAAACAAGGAGTTTTTT-3' (SEQ ID NO. 4).
[0097] After sequencing the HA and NA gene fragments, the genetic evolution information of HA and NA genes were analyzed by MEGA6 software.
[0098] Comparing the HA gene sequence of the HB01 strain with the nucleotide sequence of the representative 16 H9 subtype avian influenza virus reference strains registered on GenBank, it can be seen that the HB01 strain has low homology with the earlier epidemic strains. In recent years, the epidemic strains (2015-2018 strains) can reach 96.7%-97.3%, indicating that the HA gene continues to mutate over time. The results are as follows figure 2 with image 3 As shown, image 3 No. 1 is the H9 subtype avian influenza virus HB01 strain, and No. 2-17 is the more representative 16 reference strains of H9 subtype avian influenza virus registered on GenBank.
[0099] Comparing the NA gene sequence of the HB01 strain with the nucleotide sequences of 14 representative H9 subtype avian influenza viruses registered on GenBank, it can be seen that the NA of the HB01 strain has the same law as the HA gene: it is similar to the earlier epidemic strains. The homology is low, and the homology performance with recent epidemic strains (2014-2016 strains) reached 95.9%-97.8%; it shows that NA genes are also constantly mutating over time, the results are as follows Figure 4 with Figure 5 As shown, Figure 5 No. 1 is the H9 subtype avian influenza virus HB01 strain, and Nos. 2-15 are the 14 representative H9 subtype avian influenza virus reference strains registered on GenBank.
[0100] 2Immune protection effect
[0101] Twenty SPF chickens aged 3 to 4 weeks were randomly divided into 2 groups, each with 10 chickens. One group was subcutaneously immunized with the H9 subtype avian influenza virus HB01 strain inactivated vaccine, 0.3ml/bird, and the remaining group did not Inoculated as a control group. On the 21st day after immunization, blood was collected from the wing vein, the serum was separated, and the antibody level was determined. After immunization on the 21st day after the completion of blood collection, the immunization group and the control group of 5 chickens, each chicken wing intravenous injection of H9 subtype avian influenza virus HB01 strain 0.2ml (virus content is 2 × 10 6.0 EID 50 ), on the 5th day after the challenge, the swabs of each chicken were collected respectively, and 10-day-old SPF chicken embryos were inoculated into the allantoic cavity to isolate the virus, and the protection rate of the challenge after immunization was calculated, and the results shown in Table 1 were obtained. On 21 days after immunization, the immunized group can induce the body to produce a serum HI titer of H9 subtype avian influenza virus HB01 strain with an average value of 10log2, and the H9 standard antigen was used to determine the average serum HI titer of 4log2. The H9 subtype of the immune group The protection rate of the HB01 strain of avian influenza virus reached 100% after challenge.
[0102] The above results show that the H9 subtype avian influenza virus HB01 strain has good immunogenicity, while the antibody level determined by the H9 standard antigen is low and the effect is not good. This reflects the H9 subtype avian influenza virus HB01 strain due to the strain The mutation causes a big difference in antigenicity between it and the H9 standard antigen strain.
[0103] Table 1 HI antibody titer and protection rate after immunization with HB01 strain
[0104]

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