Development and clinical research of vaccine adjuv

Vaccine adjuvant

What is the adjuvant for the vaccine? A vaccine adjuvant (Adjuvant) is a substance that can non-specifically change or enhance the body's specific immune response to an antigen and play a supporting role. Adjuvant can induce long-term, high-efficiency specific immune response, improve the body's protective ability, and at the same time reduce the amount of immune substances and reduce the cost of vaccine production.

The development direction of vaccine adjuvant

Although the knowledge of immunology has made great progress in the past decade, it is surprising that aluminum-based complexes are mainly used as the main adjuvant in human vaccines. This situation will not change in the next few decades for the already established high-efficiency vaccine. However, the introduction of new recombinant subunits and synthetic antigens into HIV, hepatitis C virus, malaria and other serious diseases, as well as the development of therapeutic vaccines for chronic diseases and tumors, will introduce new adjuvants into clinical trials. The dosage form of the new adjuvant should be associated with the development of new vaccines against infectious pathogens that cause pathological conditions characterized by immunodeficiency, low immunity, and high-risk populations. Starting from these high-risk groups, further measures to promote the use of new adjuvants may be affordable in the near future. The study of the mechanism of action will further clarify the molecular interactions behind adjuvant activity. These, together with the development of bioinformatics, will enhance the development of new adjuvants. Adjuvant research has always been an important part of the vaccine research process. The ideal adjuvant should be broad-spectrum, no side effects, effective activation of the immune system, and easy to produce and use. At present, no adjuvant has these requirements. With the deep understanding of the antigenic components of various pathogens and the understanding of the mechanism of anti-infection immunity, the study of adjuvants will be more targeted. In short, multi-source, multi-channel research and development of strong, biodegradable, non-toxic side effects, and even therapeutic effects of new adjuvants is becoming a hot spot in current adjuvant research, adjuvants are moving towards diversification. The advent of new adjuvants has made us more selective in vaccine research and preparation.

Preclinical and clinical research points of vaccine adjuvant

The ultimate goal of human vaccine adjuvant research is to apply it to humans with vaccines for the prevention of infectious diseases. The evaluation of the clinical observation of the vaccine adjuvant determines whether the adjuvant can be used in the clinic. In the preclinical and clinical studies of vaccine adjuvants, the following aspects should be considered.

1. The effect of adjuvant on the immunogenicity of the vaccine:

First of all, it must be proved that the adjuvant can effectively induce the body to produce long-term, high-efficient specific immune response and improve the body's protective ability, which is the basis of adjuvant application. If the results of the study show that the addition of adjuvant has little effect on the enhancement of immunogenicity, it should not be added to avoid other side effects caused by the adjuvant. Immunization effects should include both humoral and cellular immunity. In addition to detecting functional antibodies (neutralizing, opsonophagocytic or bactericidal antibodies), humoral immunity should also be tested for subclasses of immunoglobulins. Cellular immunity should detect antigen-specific T cell responses, including Th1, Th2 and T cell regulatory factors and/or related cytokines.

2. Toxicology and Pharmacology of Adjuvants:

The toxicological aspects of the adjuvant mainly consider the pathological reaction at the site of inoculation, the antibody response produced by the body, and the duration of the antibody. At present, the adjuvant approved for vaccine in China is aluminum hydroxide, and the aluminum hydroxide gel adjuvant usually delays the time for the antibody to produce antibodies and increases the incidence of side effects of injection. If the antigen amount of the vaccine can meet the needs of immunization, it is recommended not to add adjuvant. The pharmacological test of adjuvant should mainly consider the principle of action, the relationship between the effect and the dose, the relationship between the immunization program and the inoculation route and effect.

3. The interaction of the adjuvant with the components of the vaccine:

As part of the vaccine component, adjuvants should be compatible with other ingredients such as adjuvants and preservatives, adjuvants and inactive ingredients. The effect of the adjuvant on the adsorption of different components should be considered, whether there is dissociation and dissociation after adsorption, and the influence of the order of addition of each component on the adsorption.

4. Metabolism in the human body when the adjuvant is administered alone:

New vaccine adjuvants, including marketed adjuvants, varying amounts or routes of administration, require adequate preclinical safety data support. At the same time, it is considered that the adjuvant may accumulate in the body, and the human pharmacokinetic study when the adjuvant is administered alone should also be performed. The design of human pharmacokinetic studies should be based on preclinical research data, based on the nature and characteristics of the adjuvant to obtain scientific and convincing results.

5. Dosage of adjuvant:

The dose of adjuvant used and the ratio of adjuvant to antigen are related to the ability to induce the desired immune response and minimize adverse effects. For the dose range of new adjuvants and marketed antigen conjugates, reference should be made to the amount of similar products already on the market. For the combination of the new adjuvant and the new antigen, it is necessary to study the amount of the adjuvant, and also to select the optimal ratio of the adjuvant to the new antigen. Research should be conducted as far as possible in the target population of the vaccine and multiple dose groups should be designed.

6. Immune enhancement effect:

Clinical observations should follow the principles of GCP. Design should be based not only on random, double-blind, contrast, but also on the characteristics of antigens and adjuvants. Observations should be made in the target population. If the span of the age group is large, stratification or more than one clinical observation should be performed in the design. For most clinical observations, especially if the amount of vaccine antigens that have been approved for marketing has changed, it is important to evaluate the effectiveness of the immune indicators associated with protection. If not, evaluate the immune protection effect. For the new adjuvant,  new antigen vaccine, a marketed vaccine to prevent the same disease is also used as a control. If not, other unrelated vaccines available to the target population can also be used as a placebo control. When necessary, multiple sets of controls should also be established. The sample size should meet the statistical requirements. For non-inferiority trials, thresholds must be set in advance and the basis for setting is provided. When designing the analytical methods and sample sizes used in clinical observations, due consideration should also be given to the effects of multiple factors.

7. Local and systemic reactions:

Studies have shown that absolutely safe adjuvants do not exist. People can only adjust according to the mechanism of action of the adjuvant, as far as possible to maximize the immune stimulation, and minimize the side effects. The clinical observation design should fully consider the collection of adverse reactions caused by adjuvants, and adjuvants vaccine use. If it is a clinical study of new adjuvants and listed antigens, there should be a comparison and analysis of adverse reactions with the marketed vaccines (adjuvants and antigens). In the case of new adjuvants and new antigens, adverse reactions should be systematical in details, including local and systemic reactions, laboratory test indicators of relevant systems, and instrumental examination results, in accordance with national requirements.