Vaccine R&D to Vaccination (Part One)

  • In the last decade or so, the cycle of drug discovery and development has become longer, and trials have become more expensive. It may take 8-20 years to develop a vaccine to market, even if the vaccine already on the market may be withdrawn due to unacceptable adverse reactions. For the development of vaccines, the process is mainly divided into two parts, namely pre-clinical trials and clinical trials, including three phases and four steps: 1. Discovery, characteristics and evaluation of target sites (biological target phase); 2. Lead compounds discovery and optimization (drug discovery phase); 3. Vaccine ADMET test (absorption, distribution, metabolism, excretion and toxicity), vaccine PK study, PD study (drug discovery and development phase); and 4. Clinical trials (drug development phase).

    Preclinical studies of vaccines, including vaccine synthesis, extraction methods, physicochemical properties and purity, dosage form selection, prescription screening, preparation techniques, testing methods, quality indicators, stability, pharmacology, vaccine toxicology, animal pharmacokinetic studies, It also includes sources, quality standards, storage conditions, biological characteristics, genetic stability, and immunological studies of starting materials such as bacterial strains, cell strains, and biological tissues.

    In preclinical studies of new vaccines, it is important to examine the safety of vaccines by conducting preclinical safety assessments of relevant animals. The vaccine safety test in the preclinical study of vaccine refers to the use of drugs larger than the clinical dose, or longer than the clinical use time, to find and evaluate the potential toxic effects, toxicity performance, and reversibility of the target organ damage. This study helps to identify toxic doses, detect toxic effects, determine safe dose ranges, find toxic target organs, and determine the reversibility of toxicity.

    The difficulty in drug safety evaluation in preclinical studies of new vaccine drugs is that the vaccine itself does not directly exert its preventive or therapeutic effect, but acts by inducing the immune system to produce antibodies or activate T cells. Preclinical CRO studies mainly provide customized vaccine development, including preclinical testing services, drug metabolism, pharmacokinetics, pharmacodynamic studies, and toxicology.

    1. What are the safety issues that the vaccine may have?

    (1) The vaccine component itself acts as a direct damage to the body as a toxic substance.

    For chemical drugs, the toxic effect of the substance is the most important safety concern. Because of the low dose of vaccine and the low number of immunizations, the direct toxicity of vaccine components are rare and easy to test from acute toxicity. Get prompted.

    (2) The vaccine induces immune-related toxicity caused by the immune system.

     These include immunotoxicity associated with the immunostimulatory effects of vaccines and the stimulating effects of vaccines on existing immune responses in the body. Preclinical safety evaluation of new drugs may be found in the relevant animals, but for the latter, preclinical animal experiments cannot be predicted due to the lack of suitable animal models.

    (3) Toxicity caused by pollutants and residual impurities.

    The various aspects of the vaccine preparation process may bring in the presence of contaminants or lead to the presence of residual impurities. Controlling such toxicity is also the main purpose of quality control research.

    (4) If the vaccine vector mutates in the body, it will threaten the patient's life.

    (5) Other unknown toxicity.

    1. Contents of vaccine toxicology testingin preclinical studies of new vaccine drugs

     (1) Acute toxicity test

    In principle, all new active ingredients should be tested. Two or more animals should be selected. The focus is on mastering the symptoms of poisoning and the changes over time and the dose-response relationship. It is not necessary to determine the LD50. The main purpose of the vaccine acute toxicity test is to investigate the direct damage of the vaccine component itself as a toxic substance to the body. Therefore, the toxicity test does not necessarily require the use of related animals.

     (2) Repeated dose toxicity test

    It is the core part of vaccine safety evaluation. The main idea of ​​its experimental design is to simulate the clinical immune effect of the human body as much as possible. The test should select the relevant animal as the test animal. The route of administration should try to simulate the clinical route of administration. The immune interval is generally determined according to the time of the animal's immune response.

     (3) General pharmacological test

    Conventional general pharmacological tests are not applicable to vaccines, and are established in repeated drug delivery tests for the detection of indicators related to general pharmacological tests.

     (4) Reproductive toxicity test

    The FDA believes that all vaccines for adolescents, adults, and women who may become pregnant should undergo a reproductive toxicity test. Vaccines for pregnant women should complete a reproductive toxicity test before the start of clinical studies. Vaccines for pregnancy may provide reproductive toxicity test data at the time of production, but subjects should use contraception during clinical studies.

    (5) Allergy test

    The most common clinical vaccine is allergic reactions. However, how to predict the allergic reaction of biological products including vaccines through preclinical animal tests is a major problem faced by toxicologists and drug review departments. The guinea pig active systemic allergic reaction (ASA) and the passive skin sensitization test (PCA) are currently commonly used in the country to predict the likelihood of a compound or biological product causing an allergic reaction in the clinic. In addition, the mouse regional lymph node test (LLNA) is a test method that may be used to predict allergic reactions in humans in recent years.

    (6) Adjuvant

    Adjuvants are used to increase the immunogenicity of non-replicating inactivated vaccines, enhance the immune response of low-response populations such as elderly or immunosuppressed patients, improve the immunogenicity of vaccines vaccinated by the mucosal route, and modulate inappropriate immune responses. Thereby improving protective immunity. The use of an adjuvant can reduce the cost by the amount of antigen used. Aluminium salt adjuvant is currently the most widely used adjuvant. In addition, many active ingredients (such as glycosides, polysaccharides, etc.) have been found to have good immunomodulatory effects. Among them, QS-21 and ISCOM have entered the clinical trial stage, and APS has also shown better. Application prospects.

    At present, there are different opinions on the preclinical safety evaluation of new adjuvants. One is considered to be a routine toxicological test of an adjuvant before a safety evaluation is performed. One is considered to be a combination of an adjuvant and an antigen, and its physical and chemical properties or biological activity are different from those used alone, so that the conventional adjuvant is conventional. Toxicology research has no practical significance.

     Because vaccines are essentially a special class of drugs that are vaccinated against healthy people, most of which are used in healthy children, safety considerations are particularly important in their research.

    To be continued in Part Two.


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