CN111840532A - Live vaccine for preventing viral infectious diseases - Google Patents
Live vaccine for preventing viral infectious diseases Download PDFInfo
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- CN111840532A CN111840532A CN202010767025.XA CN202010767025A CN111840532A CN 111840532 A CN111840532 A CN 111840532A CN 202010767025 A CN202010767025 A CN 202010767025A CN 111840532 A CN111840532 A CN 111840532A
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- A—HUMAN NECESSITIES
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- C12N2770/00011—Details
- C12N2770/16011—Caliciviridae
- C12N2770/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Abstract
The invention belongs to the technical field of biological medicines. It discloses a kind of live vaccine for preventing viral infectious disease. The live vaccine contains live virus, and the live virus in the live vaccine is combined with monoclonal antibody, and the pathogenicity of the live virus in the vaccine is inhibited by virtue of the neutralization effect of the monoclonal antibody. With the rapid development of monoclonal antibody technology, the live vaccine prepared based on the immune complex formed by the live virus and the neutralizing monoclonal antibody has the advantages of rapid preparation of vaccine seed virus, no worry about the strong pathogenic capability of the vaccine virus, high safety, good immune protection effect, suitability for the prevention of various viral infectious diseases, no need of preparing a large amount of human or animal serum containing neutralizing antibodies, and the like.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to development, production and application of a live vaccine for preventing viral infectious diseases, and can be used for preventing viral infectious diseases caused by various viruses such as influenza and the like.
Background
Influenza virus, respiratory syncytial virus, newcastle disease virus, coronavirus and other viruses can cause human and animal viral infectious diseases. Viral infections seriously compromise the health and life safety of humans and various animals. Vaccines are important agents for the prevention of viral infectious diseases. There are many classes of vaccines against viral infectious diseases that have been approved for use or are being studied today, including whole virus inactivated vaccines, whole virus live vaccines, genetically engineered viral protein vaccines, DNA vaccines encoding viral proteins, RNA vaccines encoding viral proteins, and the like. Because the prevention effect of the whole virus live vaccine is better, the production cost is lower, and the virus infectious diseases prevented by the whole virus live vaccine far exceed the virus infectious diseases prevented by other vaccines in the human virus infectious diseases prevented by the existing vaccine.
Whole virus live vaccines present a safety risk. To control this risk, one of three strategies is generally adopted.
First, whole virus live vaccines are prepared using viruses with reduced pathogenic capacity (commonly referred to as "attenuated vaccines"), and such vaccines are referred to as "attenuated live vaccines". Live vaccines for preventing viral infectious diseases in humans caused by influenza virus, which have been used and are being developed, are attenuated live vaccines, and there are two methods for attenuation: one is to change the virus genome to make it difficult to proliferate at normal temperature of human body and reduce its pathogenic effect; the other is to change the genome of the virus and replace the codon of the genome encoding the same amino acid with a rare codon, so that the influenza virus carrying more rare codons is difficult to propagate in a human body to reduce the pathogenic effect of the influenza virus. The weak-virus live vaccine has the defects that the preparation of vaccine seed virus is difficult, the risk of the return of pathogenic capability of live virus in the vaccine exists, the vaccine is not suitable for people with immunodeficiency, and the like. In addition, such live vaccines may be interfered with by maternal antibodies when administered to children or young animals.
Secondly, live viruses with stronger pathogenic capability are used for preparing whole virus live vaccines, and the way or the part of the live viruses in the vaccines entering the host body is different from the way or the part of the live viruses entering the host body in natural infection, thereby avoiding diseases caused by natural infection. Such live vaccines are referred to as "live vaccines for ectopic vaccination". The live vaccine for preventing human viral infectious diseases caused by adenovirus, which is applied to the American military forces new soldier population at present, adopts the live vaccine of ectopic inoculation. After the naturally infected adenovirus enters a human body from a respiratory tract, the host immune system and the adenovirus compete in a delicate and weak-immunity lung to cause viral infectious diseases; live adenovirus is filled into an enteric capsule, and the enteric capsule is orally taken by an inoculator, so that the live adenovirus is released in the intestinal tract of the inoculator and infects intestinal tissues with strong immunity, and delicate lung is avoided, so that the inoculator can not generate serious pathological changes such as pneumonia and the like, and can generate good immunity. Such live vaccines for live adenovirus ectopic vaccination have been used for decades in the U.S. recruit population and show high safety and high immunoprotection, but it is not clear whether such vaccines are suitable for the prevention of other viral infectious diseases. In addition, such live vaccines may be interfered with by maternal antibodies when administered to children or young animals.
Thirdly, live viruses with stronger or weaker pathogenic ability are used for preparing whole virus live vaccines, and the live viruses in the vaccines are combined with corresponding antibodies to form immune complexes. Such live vaccines are referred to as "immune complex live vaccines". The vaccine is used for preventing and controlling the cattle plague and the yellow fever disease at one time and is also used for preventing and controlling the infectious bursal disease of chickens at present. The immune antibody has the advantages of high safety, good immune effect, capability of avoiding the interference of maternal antibodies and the like. However, the antibodies used in the manufacture of such vaccines are derived from the sera of humans or animals recovered from infection with the corresponding virus, or from humans or animals after immunization with the corresponding vaccine, which sera contain neutralizing antibodies against the virus of interest. The disadvantage of such vaccines is that the source of the serum of the human or animal to provide the corresponding antibodies is limited and other pathogenic pathogens may also be present in these sera.
Disclosure of Invention
The invention discloses a live vaccine for preventing viral infectious diseases, which can overcome the defects of the three live vaccines and has the advantages of quick preparation of vaccine seed virus, no worry about strong pathogenic capability of vaccine virus, suitability for preventing various viral infectious diseases, capability of avoiding maternal antibody interference, capability of overcoming the problem of limited serum sources for providing corresponding antibodies, capability of avoiding the hidden danger of other pathogen pollution in serum for providing corresponding antibodies and the like.
The invention discloses a live vaccine for preventing viral infectious diseases, which contains live viruses, wherein the live viruses in the live vaccine are combined with monoclonal antibodies to form immune complexes.
Further, the live vaccine contains live virus of Orthomyxoviridae for preventing viral infectious diseases caused by virus of Orthomyxoviridae.
Further, the live vaccine contains a virus of Paramyxoviridae family, which is live, and is used for preventing viral infectious diseases caused by the virus of Paramyxoviridae family.
Further, the live vaccine contains a virus of the family Coronaviridae, and is used for preventing viral infectious diseases caused by the virus of the family Coronaviridae.
Further, the live vaccine is a vaccine administered by intramuscular injection, intradermal injection, subcutaneous injection or intravenous injection.
Further, the live virus in the live vaccine binds to two or more monoclonal antibodies to form an immune complex, and the epitopes bound by the two or more monoclonal antibodies are different.
Further, the live vaccine contains two or more live viruses, and each live virus binds to a corresponding monoclonal antibody to form an immune complex.
Further, the live vaccine contains one or more of live respiratory syncytial virus, norovirus, novel coronavirus, African swine fever virus, classical swine fever virus, swine transmissible gastroenteritis virus, swine transmissible diarrhea virus, Newcastle disease virus, Marek's virus, chicken infectious bronchitis virus, canine distemper virus, canine parvovirus and rabies virus.
Further, the monoclonal antibody is a humanized monoclonal antibody.
The preparation method of the live vaccine of the invention is different aiming at different viral infectious diseases, but the preparation method generally comprises the following steps. Firstly, preparing a large amount of monoclonal antibodies capable of inhibiting the living viruses in the live vaccine from proliferating in the human or animal body, and subpackaging and storing; secondly, selecting a proper virus as a vaccine seed virus; thirdly, the vaccine seed virus is utilized to proliferate the virus in cells, chick embryos or animal bodies and is subpackaged into a vaccine progenitor seed virus; fourthly, taking out a vaccine progenitor seed virus, proliferating in cells, chick embryos or animal bodies, subpackaging into vaccine parent seed viruses, taking out a vaccine progenitor seed virus when a certain batch of vaccine parent seed viruses are about to be used up, proliferating in cells, chick embryos or animal bodies, and subpackaging into a new batch of vaccine parent seed viruses; fifthly, taking out a vaccine parental seed virus, proliferating the virus in cells, chick embryos or animal bodies, mixing the proliferated viruses together, measuring the virus content in the virus mixed solution, measuring the neutralizing titer of the preserved monoclonal antibody neutralizing vaccine virus, adding a proper amount of antibody into the virus mixed solution according to the measurement result to ensure that the virus is completely neutralized, and then placing for several minutes to several hours at a proper temperature. Sixthly, purifying the virus-antibody immune complex by combining methods such as high-speed centrifugation, ultrafiltration concentration, ultracentrifugation and the like on the mixed solution of the virus and the monoclonal antibody, detecting the virus content of the purified virus-antibody immune complex, and subpackaging the vaccine according to the detection result, wherein each vaccine contains a set amount of virus. Seventh, the produced vaccine is tested for safety and efficacy.
The live vaccine provided by the invention utilizes the neutralizing monoclonal antibody to eliminate the pathogenicity of the live virus, and utilizes the immunoregulation effect of the virus-antibody immune complex to improve the protection effect of the vaccine.
The novelty and inventive step of the present invention is as follows: the immune complex live vaccine of the invention adopts monoclonal antibody instead of polyclonal antibody in animal serum, and the monoclonal antibody is never used in immune complex vaccine.
The live vaccine has the following practicability or advantages: the live vaccine can be prepared by directly using virus with pathogenic effect separated from a host body, so that the defect that the weak-toxicity live vaccine has difficulty in vaccine seed virus preparation is avoided; the risk of strong pathogenic ability of the live virus in the vaccine is avoided, because the live vaccine can use the virus with strong pathogenic ability as vaccine seed virus; the invention avoids the defect that the prior live vaccine is not suitable for being inoculated to the people with immunodeficiency, because the live vaccine prepared by the virus with strong pathogenic capability is inoculated to the people with immunodeficiency, and the virus in the vaccine can not be proliferated in the bodies of the people under the action of the antibody, so the disease is not caused; compared with the live vaccine which is inoculated in an ectopic way, the live vaccine has certain universality, and the live vaccine can be used for preventing the viral infectious diseases caused by certain viruses in a large probability as long as the neutralizing monoclonal antibody which can effectively inhibit the proliferation of the viruses in a host body is developed; compared with the existing immune complex vaccine, the required antibody is not from polyclonal antibody in human or animal serum, but from monoclonal antibody, which can overcome the problem of limited serum source for providing corresponding antibody, and avoid hidden danger of other pathogen pollution in serum for providing corresponding antibody, and along with the improvement of the in vitro culture technology of the monoclonal antibody, the production cost of the monoclonal antibody is lower, and the quality is more stable; the live vaccine has better immune effect and can avoid the interference of maternal antibodies, because the live vaccine is inoculated in the human body or animal body with the maternal antibodies, and the live vaccine consumes less maternal antibodies in the body.
The safety of the live vaccine provided by the invention is fully guaranteed. This is because the live viruses in the live vaccines of the present invention bind sufficient neutralizing antibodies to ensure that none of these live viruses can propagate in a human or animal body. Factors that disrupt the binding of the virus to the neutralizing antibody, such as high temperature, acids, bases, detergents, alcohol, etc., kill live viruses that cause viral infections. In order to further ensure the safety of the live vaccine, the invention further indicates that the live vaccine aiming at the same virus can be produced by simultaneously using two or more than two monoclonal antibodies aiming at different epitopes so that the same virus particle can be simultaneously combined with two or more than two neutralizing antibodies.
In terms of effectiveness, the live vaccine of the present invention contains intact virus particles, which contain all or most of the T-cell epitopes and B-cell epitopes of the corresponding pathogenic viruses, and thus can stimulate the body to produce a strong immune protective response.
For the prevention of human viral infectious diseases, if the monoclonal antibody used by the live vaccine is a humanized monoclonal antibody, the immune opsonization can be utilized to further improve the protective effect of the vaccine. This is because the Fc terminus of the humanized monoclonal antibody is capable of binding to the Fc receptor of the antigen presenting cell, thereby assisting the antigen presenting cell in capturing the antigen.
If the live vaccine of the present invention contains two or more live viruses, and each live virus is conjugated to a corresponding neutralizing monoclonal antibody, the live vaccine can prevent infection of two or more viruses at the same time, i.e., can prevent two or more viral infectious diseases.
Detailed Description
Example 1
Example 1 illustrates the preparation and use of a live vaccine for the prevention of newcastle disease virus. Example 1 is a specific mode of application of the present invention. The examples are not intended to limit the scope of the invention and the scope of the invention's patent.
The preparation of the live vaccine described in example 1 comprises the following five steps. Firstly, through molecular epidemiological investigation, determining that a certain newcastle disease virus is very similar to a local newcastle disease virus epidemic strain and does not contain other known animal viruses, and determining the newcastle disease virus as a vaccine seed virus; secondly, inoculating a large number of chick embryos with the vaccine seed viruses to prepare grand progenitor seed viruses, packaging the chick embryos into ten thousand, wherein each chick embryo contains at least 1 million and half of live viruses, and storing the chick embryos at minus 80 ℃; taking out one stored vaccine ancestral seed virus, inoculating a large number of chick embryos, preparing vaccine ancestral seed viruses, and subpackaging into ten thousand, wherein each chick embryo infection amount of the live viruses is at least 1 million and half of chick embryos; thirdly, entrusting a monoclonal antibody preparation company to complete the screening of hybridoma cells, inoculating BALB/C mice with vaccine seed virus muscles, inoculating 10 ten thousand and a half of chick embryo infection amount to each mouse, inoculating the vaccine seed virus to the mice again on the 28 th day after inoculation, inoculating 100 ten thousand and a half of chick embryo infection amount to each mouse, on day 16 after the second inoculation, the mice were sacrificed with carbon dioxide gas, the spleens of the mice were removed aseptically, squeezing and grinding in a plate to prepare spleen cell suspension, screening two hybridoma cell clones according to a conventional monoclonal antibody preparation method, secreting IgG antibody capable of neutralizing vaccine seed virus, and the IgG antibodies secreted by them bind to different epitopes of the vaccine virus, so that they can bind to the vaccine virus simultaneously and do not interfere with each other; fourthly, performing expanded culture on the obtained hybridoma cells, subpackaging into 1000 cells, storing at minus 80 ℃ for serving as progenitor seeds of the cells, taking out 1 parent seed cell, performing expanded culture, subpackaging into 1000 cells, storing at minus 80 ℃ for serving as parent seeds of the cells; fifthly, taking out 1 parent seed from each hybridoma cell, culturing by using an in vitro cell culture system, harvesting monoclonal antibodies secreted by the hybridoma cells, measuring the neutralization titer of the monoclonal antibodies, and subpackaging and freezing; sixthly, taking out a vaccine parent seed virus, inoculating a large amount of chick embryos, proliferating the virus, harvesting chick embryo allantoic fluid containing a large amount of virus, mixing, and measuring the virus content in the mixed allantoic fluid by a hemagglutination test; seventhly, the frozen monoclonal antibodies are taken out and added into the mixed solution of the chick embryo allantoic fluid containing a large amount of viruses according to the neutralization titer of the monoclonal antibodies, each monoclonal antibody is required to be capable of completely neutralizing 4 times of the viruses in the mixed solution to ensure that the viruses are completely neutralized, and after the monoclonal antibodies are added and uniformly mixed, the mixture is placed for 3 hours at 25 ℃; eighthly, centrifuging the mixed solution of the antibody and the virus at a high speed, removing precipitates, filtering the supernatant by using a 0.45nm filter membrane, adding magnesium chloride, glycerol and gentamicin into the filtered solution, subpackaging and preparing the vaccine for preventing the Newcastle disease of the poultry.
As shown in table 1, the vaccines were tested for safety and efficacy: SPF chickens 60 were randomly divided into 6 groups, A, B, C, D, E, F groups, of 10 chickens each; group A is directly inoculated with vaccine seed virus (with high pathogenicity), and each chicken is inoculated with 1 ten thousand and half of chick embryo; group B live vaccine of example 1, each chicken was inoculated with 1 ten thousand and half of the chick embryos (calculated from the virus content measured before antibody addition); group C live vaccines of example 1 were inoculated with 1000 ten thousand and a half of the chick embryos of virus per chick (calculated from the virus content measured before antibody addition); group D is inoculated with inactivated vaccine prepared by the vaccine seed virus according to a conventional formaldehyde inactivation method, and each chicken is inoculated with 1 ten thousand of half of the chick embryo infection amount (calculated according to the virus content measured before virus inactivation); group E is inoculated with an inactivated vaccine prepared by the vaccine seed virus according to a conventional formaldehyde inactivation method, and each chicken is inoculated with 1000 ten thousand of half of the chick embryo infection amount (calculated according to the virus content measured before virus inactivation); group F, without virus or vaccine, injected with the same volume of physiological saline; after inoculation, all the chickens in group A were attacked and all died within 5 days, and all the other 5 groups of chickens showed no clinical symptoms and all survived. And (3) performing challenge on the 30 th day after inoculation, namely inoculating vaccine seed virus to 5 groups of surviving chickens, inoculating 100 ten thousand and half of chick embryo infection amount to each chicken, and as a result, all the chickens in the groups D and F are attacked and died within 5 days after challenge, and all the chickens in the other 4 groups do not show clinical symptoms and are all survived. The test results suggest that the live vaccine of example 1 has high safety, and the live vaccine inoculated to each chicken contains 1000 ten thousand viruses (measured before adding the antibody) with half of the infection amount of chicken embryos, and does not cause diseases and death; although the inactivated vaccine has the same safety, the immune effect is poor, all the chickens do not produce enough immune protection when the inoculation dose is small (the infection amount of half ten thousand chick embryos is inoculated to each chicken and is measured before virus inactivation), and the chickens die after challenge. In contrast, the live vaccine of example 1 has high safety and good immune effect, and all chickens have sufficient immune protection when the inoculation dose is small (the infection amount of 1 ten thousand and half of chick embryos is inoculated to each chicken and is measured before the antibody is added), and the live vaccine has no morbidity and no mortality after challenge.
TABLE 1.5 mortality rates following group chicken vaccination and challenge
Claims (10)
1. A live vaccine for the prevention of viral infectious diseases, characterized by: the live vaccine contains live virus, and the live virus in the live vaccine is combined with a monoclonal antibody to form an immune complex.
2. A live vaccine according to claim 1, wherein: the live vaccine contains live virus of Orthomyxoviridae, and is used for preventing viral infectious disease caused by virus of Orthomyxoviridae.
3. A live vaccine according to claim 1, wherein: the live vaccine contains live virus of Paramyxoviridae, and is used for preventing virus infectious disease caused by virus of Paramyxoviridae.
4. A live vaccine according to claim 1, wherein: the live vaccine contains live virus of Coronaviridae, and is used for preventing viral infectious diseases caused by virus of Coronaviridae.
5. A live vaccine according to claim 1, wherein: the live vaccine contains live Caliciviridae virus, and is used for preventing viral infectious diseases caused by Caliciviridae virus.
6. A live vaccine according to claim 1, wherein: the live virus in the live vaccine is combined with two or more monoclonal antibodies to form immune complexes, and the epitope combined by the two or more monoclonal antibodies is different.
7. A live vaccine according to claim 1, wherein: the live vaccine contains two or more live viruses, and the two or more live viruses are combined with corresponding monoclonal antibodies to form immune complexes.
8. A live vaccine according to claim 1, wherein: the live vaccine contains one or more of live respiratory syncytial virus, norovirus, novel coronavirus, African swine fever virus, classical swine fever virus, swine transmissible gastroenteritis virus, swine infectious diarrhea virus, newcastle disease virus, Marek's virus, avian infectious bronchitis virus, canine distemper virus, canine parvovirus and rabies virus.
9. A live vaccine according to claim 1, wherein: the live vaccine contains live virus that is matched or identical, on a genetic profile, to the predominant circulating strain of the corresponding virus in the area where the live vaccine is used.
10. A live vaccine according to claim 1, wherein: the monoclonal antibody is a humanized monoclonal antibody.
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