阅读说明：本技术 预防病毒性传染病的活疫苗 (Live vaccine for preventing viral infectious diseases ) 是由 陈继明 于 2020-07-02 设计创作，主要内容包括：本发明属于生物医药技术领域。它公布了一类用于预防病毒性传染病的活疫苗。这类活疫苗特征在于：所述的活疫苗含有活病毒,所述的疫苗中的活病毒,与所述疫苗所防控的病毒比较,既可以是相同的而具有相同的致病能力,也可以高度相似但有所不同而具有较弱的致病能力；所述疫苗与能够抑制疫苗中活病毒增殖的药物联合使用,使疫苗中的活病毒进入人或动物体内后,无法有效增殖,从而使所述疫苗不导致疾病。此类疫苗具有疫苗种毒制备容易、疫苗生产成本低、疫苗安全性好、疫苗免疫效果好等优点。这类疫苗能够用于多种病毒性传染病的预防。(The invention belongs to the technical field of biological medicines. It discloses a kind of live vaccine for preventing viral infectious diseases. Such live vaccines are characterized by: the live vaccine contains live virus, and the live virus in the vaccine can be the same and have the same pathogenic capability or can be highly similar and different and have weaker pathogenic capability compared with the virus controlled by the vaccine; the vaccine is used in combination with a medicament capable of inhibiting the proliferation of live viruses in the vaccine, so that the live viruses in the vaccine cannot be effectively proliferated after entering a human or animal body, and the vaccine does not cause diseases. The vaccine has the advantages of easy preparation of vaccine seed virus, low vaccine production cost, good vaccine safety, good vaccine immunization effect and the like. Such vaccines can be used for the prevention of a variety of viral infectious diseases.)

1. A live vaccine for the prevention of viral infectious diseases, characterized by: the live vaccine contains live virus, the live virus in the live vaccine can be the same and has the same pathogenic capability or can be highly similar but changed and has weaker pathogenic capability compared with the virus controlled by the live vaccine, the live vaccine is combined with a medicament capable of inhibiting the proliferation of the live virus in the vaccine, and the method for combining the medicament is that the medicament capable of inhibiting the proliferation of the live virus in the vaccine enters the bodies of the human beings or animals by oral administration, injection and the like within 24 hours before or after the live vaccine is inoculated to the human beings or animals, and the medicament does not contain protein containing the Fc end of an antibody which is homologous with the inoculated animals.

2. A live vaccine according to claim 1, characterized in that: the virus contained in the live vaccine is coronavirus, and the medicine which is used together with the vaccine and can inhibit the multiplication of the coronavirus in human or animal bodies comprises chloroquine phosphate and Reidcisvir.

3. A live vaccine according to claim 1, characterized in that: the virus contained in the live vaccine is influenza virus, and the certain medicine which is used together with the vaccine and can inhibit the influenza virus from proliferating in human bodies or animal bodies comprises oseltamivir, zalamivir, peramivir and amantadine.

4. A live vaccine according to claim 1, characterized in that: the virus contained in the live vaccine is paramyxovirus, and the medicine which is used together with the vaccine and can inhibit the paramyxovirus from proliferating in the human or animal body comprises a nucleotide analog compound RK-33 with the code number RK-33, and the English name is diimidazolo [4,5-d:4 ', 5' -f ] - [1,3] diazepin.

5. A live vaccine according to claim 1, characterized in that: the live vaccine is a vaccine for intramuscular injection, intradermal injection, subcutaneous injection or intravenous injection, and is a vaccine for preventing infectious diseases such as respiratory symptoms caused by viruses such as coronavirus, influenza virus, paramyxovirus, and adenovirus.

Technical Field

The invention belongs to the technical field of biological medicines, relates to development, production and application of live vaccines for preventing viral infectious diseases, and can be used for preventing various viral infectious diseases such as influenza and the like.

Background

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. Viral infectious disease vaccines that have been approved for use or are being studied today fall into a variety of categories, including whole virus inactivated vaccines, whole virus live vaccines, genetically engineered viral protein vaccines, industrially synthesized viral protein polypeptide vaccines, DNA vaccines encoding viral proteins, RNA vaccines encoding viral proteins, and the like. The whole virus live vaccine is used for preventing human poliomyelitis, measles, mumps, yellow fever, Japanese encephalitis, rabies, varicella and rotavirus-caused diarrhea and adenovirus-caused respiratory system diseases, and is also used for preventing animal viral infectious diseases such as swine fever, newcastle disease and the like.

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". Most of all-virus live vaccines are attenuated live vaccines. For example, the pathogenic ability of classical swine fever virus is reduced by repeated passage in rabbits, and then the classical swine fever virus with reduced pathogenic ability is used to prepare whole virus live vaccine, after the vaccine is used to inoculate pigs, the pigs can not be attacked, and can generate strong immunity. 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.

Secondly, live viruses with strong pathogenic ability are used to prepare whole virus live vaccines, and in the preparation process, the live viruses are combined with homologous specific antibodies to form immune complexes. Such live vaccines are referred to as "immune complex live vaccines". To illustrate the meaning of "homologous": if the vaccine is administered to humans, the human antibodies are homologous, while the equine antibodies are heterologous. Because the live viruses in the vaccine are neutralized by the specific antibodies, so that the live viruses no longer have pathogenic capability, the live vaccine is used for vaccinating humans or animals, and the humans or animals do not have diseases, so that the vaccine is safe. The whole virus can generate stronger immunity, which is partly because after the live virus is combined with the homologous antibody, the Fc end of the antibody is exposed and can be combined with the Fc receptor of some immune cells, and the immune cells are triggered to generate a series of immune reactions, thereby generating immune protection. The immune complex live vaccine has commercial application for years in the prevention and control of infectious bursal disease of chicken. It was also used in 1930 for the prevention of yellow fever in america and the uk, but overall such vaccines were less useful due to the need to produce large quantities of homologous specific antibodies that were difficult to produce.

Thirdly, 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". For example, adenovirus causes respiratory diseases because naturally infected adenovirus enters human body from respiratory tract, and after respiratory infection, the host immune system and adenovirus struggle in delicate and weak-immunity lung, resulting in pneumonia (people and animals are easy to breathe difficultly and even die because of pneumonia); 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. The live vaccine of the live adenovirus ectopic inoculation is used for decades in the American new soldier population, and shows strong safety and high immune protection effect. It is not clear whether such vaccines are suitable for the prevention of other viral infectious diseases.

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 the strong reversion of the pathogenic capability of vaccine virus, no need of preparing a large amount of homologous specific antibodies, suitability for various infectious diseases and the like. So far, the whole virus live vaccine prepared by the new safety strategy is not reported.

The invention discloses a live vaccine for preventing viral infectious diseases, which contains live viruses, wherein the live viruses in the live vaccine can be the same and have the same pathogenic capability or can be highly similar but changed and have weaker pathogenic capability compared with the viruses controlled by the live vaccine, the live vaccine is combined with a medicament capable of inhibiting the proliferation of the live viruses in the vaccine, and the method for combining the medicaments is that the medicaments capable of inhibiting the proliferation of the live viruses in the vaccine are introduced into the bodies of human beings or animals by oral administration, injection and the like within 24 hours before or after the live vaccine is inoculated to the human beings or animals, and the medicaments do not contain antibodies.

Furthermore, the virus contained in the live vaccine is coronavirus, and the medicine which is combined with the vaccine and can inhibit the proliferation of the coronavirus in human or animal bodies comprises chloroquine phosphate and Reidcisvir.

Furthermore, the virus contained in the live vaccine is influenza virus, and the certain medicine which is used together with the vaccine and can inhibit the influenza virus from proliferating in human bodies or animals comprises oseltamivir, zalamivir, peramivir and amantadine.

Further, the live vaccine comprises a virus which is a paramyxovirus, and the agent used in combination with the vaccine to inhibit the proliferation of the paramyxovirus in the human or animal body comprises a nucleotide mimetic compound RK-33 having the code RK-33 and having the English name diimidazolo [4,5-d:4 ', 5' -f ] - [1,3] diazepine.

Further, the live vaccine is a vaccine administered by intramuscular injection, intradermal injection, subcutaneous injection or intravenous injection, and is a vaccine for preventing infectious diseases such as respiratory symptoms caused by viruses such as coronavirus, influenza virus, paramyxovirus, and adenovirus.

The preparation method of the live vaccine of the invention is different aiming at different viral infectious diseases, but comprises the following steps. First, a suitable virus is selected as the vaccine seed virus. Secondly, utilizing the vaccine seed virus to proliferate the virus in cells, chick embryos or animal bodies, and subpackaging the virus into vaccine progenitor seed virus; taking out one vaccine ancestral seed virus, proliferating in cell, chick embryo or animal body, and subpackaging into vaccine ancestral seed virus. Thirdly, producing and subpackaging live vaccines by using the vaccine parent seed virus; after the first vaccine parent seed virus is used up, one vaccine ancestor seed virus is taken out, proliferated in cell, chick embryo or animal body and packed into vaccine parent seed virus. Fourthly, purchasing or producing the antiviral drug, purifying, detecting and subpackaging the antiviral drug to be used as the antiviral drug combined with the vaccine. And fifthly, the split-packaged live vaccine and the split-packaged antiviral drug are combined and packaged to form the live vaccine, a part of samples are randomly extracted, and the content, safety and effectiveness of the live virus are verified. In the above step, the antiviral agent may be mixed with the virus to be propagated or may not be mixed. In the case of mixing an antiviral drug with a live virus, the antiviral drug may be mixed with the proliferated virus first and then purified, or the virus may be purified first and then mixed with the proliferated virus.

The anti-virus drugs used in combination with the live vaccine of the invention include compounds such as oseltamivir for resisting influenza virus, but can not be homologous antibodies or recovered plasma or serum with anti-virus effect, otherwise, the anti-virus drugs are equivalent to the above-mentioned immune complex live vaccine which is already available. It should be noted that the antiviral drugs used in the live vaccine of the present invention are different for different viral infectious diseases. For example, oseltamivir can be used as an antiviral drug to be used in combination (because oseltamivir can inhibit the proliferation of influenza virus) for the live vaccine of the present invention for the prevention of a novel coronavirus disease, but oseltamivir cannot be used as an antiviral drug to be used in combination (because oseltamivir cannot inhibit the proliferation of a novel coronavirus) but Reidesvir can be used as an antiviral drug to be used in combination (because Reidesvir can inhibit the proliferation of a novel coronavirus).

The invention, in its novel, inventive and practical aspects, is described below. The live vaccine adopts a novel safety strategy, namely, the proliferation of the live virus in vivo is inhibited through an antiviral drug, so that a series of pathological changes caused by the proliferation of the live virus in vivo are avoided. This strategy has not been reported in the literature. The live vaccine of the present invention can be prepared directly with virus with pathogenic effect separated from host body according to this new strategy, so that the disadvantage that weak live vaccine has difficulty in preparing vaccine seed virus is avoided, the risk that the live virus in the vaccine has strong pathogenic ability (because the live vaccine of the present invention can use virus with strong pathogenic ability as vaccine seed virus) is also avoided, and the disadvantage that the existing live vaccine is not suitable for the inoculation of people with immunodeficiency is also avoided (because the virus with strong pathogenic ability is used to inoculate people with immunodeficiency under the action of antiviral drug, the virus is also difficult to proliferate in the body of these people, so that the virus is also not pathogenic). In addition, compared with immune complex live vaccines, the live vaccine of the invention does not need to prepare a large amount of homologous specific antibodies which are difficult to prepare; compared with the live vaccine which is inoculated in an ectopic way, the live vaccine has certain universality, and as long as people research the medicine which can effectively inhibit the replication of certain virus in a host body, the live vaccine can be used for preventing infectious diseases caused by the virus with high probability. In the past, antiviral drugs are few, so that the live vaccine is difficult to develop; now and in the future, more and more highly effective antiviral drugs are used, and the difficulty in developing and producing the live vaccine of the present invention will be significantly reduced. The live vaccine comprises the steps of preparing the prior live vaccine, and adding the steps of preparing the antiviral drug and jointly using the antiviral drug; the steps and details of the preparation of the live vaccine can be consistent with those of the preparation of the live vaccine.

The live vaccine of the invention does not exclude the existing live vaccine and adopts the safety mechanism, namely: the live virus used by the live vaccine can also be a live virus with reduced pathogenic capability, and an ectopic inoculation method can also be adopted to increase the safety of the live vaccine. If the live vaccine of the invention adopts the safety mechanism of the prior live vaccine, the safety mechanism of inhibiting virus proliferation by adopting antiviral drugs is also required.

In terms of effectiveness, the live vaccine of the present invention comprises intact virus particles, which contain all or most of the T-cell epitopes and B-cell epitopes of the corresponding pathogenic virus, and which contain live viruses that sometimes proliferate in small amounts in the vaccinee, thus stimulating the body to produce a strong or even a strong immune protective response.

Detailed Description