Vaccine adjuvant and its application

Vaccine adjuvant

What is an adjuvant vaccine? Adjuvant, also known as immunomodulator or immunopotentiator, originated from the Latin word "Adjuvare" and is auxiliary or enhanced. An adjuvant is an additive of a vaccine. When it is injected into the body prior to the antigen or mixed with the antigen, it can enhance the body's immune response to the antigen or change the type of immune response. It is a non-specific immunopotentiator and has no antigen itself. An ideal adjuvant not only enhances the immune response, but also provides the body with optimal protective immunity.

Purpose of application

Studies have shown that the interaction of vaccine adjuvants with the body mainly include immunomodulation, cytotoxic T lymphocyte induction, antigen presentation, antigen targeting and storage. Through the above several methods, the purpose of use is achieved as follows:

(1) Enhancing the immunogenicity, immune response rate and tolerance of purified or recombinant antigen;

(2) Reducing the amount of antigen or the amount of inoculation required to achieve immunoprotection;

(3) Improving the immune efficacy of vaccines in infants, the elderly or people with impaired immune systems;

(4) As an antigen delivery system that takes up antigen through the mucosa, it can promote the absorption of the vaccine by the gastrointestinal mucosa. (5) Increasing the infiltration of cells, preventing antigen degradation, transporting antigens to specific antigen-presenting cells, and enhancing antigen presentation or inducing cytokine release.

Classification of adjuvants

At present, there is no uniform standard for the classification of adjuvants in the world. According to the chemical composition, it can be divided into aluminum salt adjuvant, protein adjuvant, nucleic acid adjuvant, lipid-containing adjuvant and mixed adjuvant.

1. Aluminum salt adjuvant

Aluminum salt has been used clinically for more than 80 years and is the first classic adjuvant approved by the US FDA for human use. Many vaccine ingredients contain aluminum salts such as DTP vaccine and Haemophilus influenzae vaccine. Depending on the preparation process, vaccines with aluminum salts as adjuvants can be divided into two types: aluminum adsorption vaccines and aluminum precipitation vaccines. The aluminum adsorption vaccine is to add an antigen to an aluminum hydroxide or aluminum phosphate solution; and the aluminum precipitation vaccine is to add an aluminum suspension to the antigen solution.  Aluminum hydroxide adjuvant and aluminum phosphate adjuvant are the most commonly used adjuvants in vaccine production and development.

2. Protein adjuvant

Most of these adjuvants belong to small molecule polypeptides or glycoproteins, Most of these adjuvants belong to small molecule polypeptides or glycoproteins， which is a class of biologically active substances synthesized and secreted by immune cells and certain non-immune cells, generally cytokines. Protein adjuvants can affect the differentiation of Th cells, enhance the function of NK cells and T lymphocytes, and has a wide-ranging effect on the immune response of the body. The use of a protein adjuvant in combination with an antigen enhances the immunogenic efficacy of the vaccine, and it can also be assembled into a plasmid and mixed with the antigen for injection.

3. Nucleic acid adjuvants

In the process of researching vaccines, some nucleic acid substances are also found to have the characteristics of adjuvants. The most representative one is CPG DNA, in which the unmethylated cytosine deoxynucleotides and guanine deoxynucleotides are Unit oligomers, agonists of TLR9, are currently a hot spot in adjuvant research. It plays an important role in enhancing specific immune responses, inducing non-specific immune responses in the body, and regulating the type of immune response.

4. Liquor-containing adjuvant

Lipid-containing adjuvants include lipopolysaccharide (LPS) and liposomes. LPS is a Gram-negative bacterial outer membrane lipopolysaccharide, and lipid A is the main component of adjuvant action in LPS. The researchers co-immunized mice with LPS as an adjuvant to pertussis vaccine. The results showed that LPS not only improved the immune efficiency of the vaccine, but also reduced the occurrence of type I hypersensitivity. Liposomes are similar to biofilms. Ultrafine spherical preparations, usually formed by bilayers of phospholipids and cholesterol coated with antigens, are capable of transporting antigens and as adjuvants for vaccines. Liposomal adjuvants are not toxic and can reduce the toxicity of the antigen and can degrade in the host itself.

5. Mixed adjuvant

MF59 is an oil-in-water emulsion which is a uniform droplet emulsion formed by mixing Tween 80, sorbitol trioleate and squalene under high pressure conditions. This mixed adjuvant can induce a local immune stimulating environment at the injection site, increase chemokines, cytokine levels, and accumulate MHC+ cells in the muscle. In addition, MF59 is also able to enhance the ability of dendritic cells to take up antigen. Because MF59 enhances the immunogenicity of influenza in people with low immunity, it was certified as an adjuvant to influenza vaccines in the 1990s. A large amount of data shows that MF59 is safer for influenza vaccines.

6. Aggregate structure adjuvant

The researchers compared the immunopotentiating effects of three novel molecular aggregate formula adjuvants [RAM1, Glycolamide (RAM2) and 5th generation dendrimer (RAM3)] and evaluated the ability of an adjuvant to enhance a Th1 or Th2 response when applied with a soluble protein antigen. In this study, ovalbumin (OVA) was used as an antigen, and the above three new aggregates were adjuvanted, and tuberculin, Al (OH)3, and Freund's incomplete adjuvant were used as controls. Results of RAM1 was superior to other adjuvants in the three adjuvants, and the induced cytokines were mainly Th1 type, and induced a Th2-type response in the late stage of inoculation.

why are adjuvants added to vaccines? First, the biological effects of adjuvants include: enhancing immunogenicity, causing delayed type hypersensitivity, increasing antibody titer, and enhancing delayed type hypersensitivity. An adjuvant is a substance that simultaneously or pre-injects with an antigen to non-specifically enhance or alter the body's immune response to an antigen. Therefore, after the adjuvant is added to the vaccine, the immunogenicity of the vaccine can be enhanced, and the vaccine can play a greater role. Although there are some problems with the wide variety of vaccine adjuvants, the effect is obvious, but there are still some inevitable shortcomings:

1. Security issues

The safety of adjuvants is a very important issue, but it is also an easily overlooked problem. 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. In the case of clinical studies of new adjuvants and marketed antigens, there should be comparisons and analyses of adverse reactions with marketed vaccines (adjuvants and antigens).

2. Local side reactions

Some adjuvants induce strong antibody responses and cellular immunity, but there are still individual subjects who have strong local side effects after vaccination, with a frequency of antigen or dose-dependent. Quality control of vaccine adjuvants is a key factor directly related to the safety of their clinical trials.

3. Other issues

In addition to the above two main problems, there are some problems in the adjuvant: if the oil adjuvant is more viscous, it is not conducive to injection, the emulsification is not easy to stratify, and the local reaction is serious at the same time; the aluminum hydroxide adjuvant is difficult to induce weak antigen. The immune response does not induce cellular immunity; the lipopolysaccharide adjuvant has strong toxic side effects, the stability of the liposome needs to be improved, the binding mode of oxidized mannan with antigen is limited, and the propolis adjuvant injection site forms a mass. The understanding of the mechanism of action of certain adjuvants is still not deep enough, making the further development of new adjuvants difficult. Other adjuvants have limited their popularization and application due to the complicated preparation process and high price.