Advances in vaccine adjuvants research (part one)

  1. 1.Definition of vaccine adjuvant?

What is a vaccine adjuvant? Before answering the question, let’s see what is an adjuvant. Adjuvant, also known as immunomodulator or immunepotentiator, originated from the Latin word “Adjuvare” and is meant to aid or enhance. An adjuvant is an additive of a vaccine. When it is mixed with an antigen and injected into the body, 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 itself has no antigenicity. The ideal adjuvant not only enhances the immune response, but also provides the body with optimal protective immunity.

  1. 2.Application of vaccine adjuvant

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

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

(3) Improve 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. The concept of adjuvants is derived from ulcers formed at the site of inoculation and promotes the production of high levels of specific antibodies, even those produced by inoculation of unrelated substances can induce the production of highly specific antibodies;

(5) Adjuvants can increase the infiltration of cells, prevent antigen degradation, transport antigens to specific antigen-presenting cells, enhance antigen presentation or induce cytokine release.

  1. 3.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 or aluminum phosphate is an aluminum adjuvant that is often used. The study found that aluminum adjuvant vaccine can reduce the amount of antigen used and enhance the strength and durability of the body’s immune response. The mechanism of action of aluminum salts is still not clear. It is generally believed that the antigen-adsorbed aluminum salt particles form a gel state and are injected into animals to form an antigen reservoir. These insoluble particles can adsorb antigenic substances and increase the surface area of the antigen. In addition, the adjuvant can form a macrophage-rich granuloma at the injection site, delaying the absorption of the antigen, thereby prolonging the stimulation time of the antigen, and retaining the antigen for several days under normal conditions for a few weeks, and the antigen is taken at the injection site. Ability is enhanced. Studies have shown that aluminum hydroxide as an adjuvant can also activate Th2 cells to secrete IL-4, induce the expression of CD83, CD86 and MHC-II molecules, and then produce a Th2 type humoral immune response. Aluminum salts have many advantages as vaccine adjuvants, but there are also deficiencies. Although it can effectively induce a humoral immune response, it does not act on cellular immunity and cannot induce a cellular immune response.

(2) Protein adjuvant

Most of protein adjuvants belong to small molecule polypeptides or glycoproteins. A class of biologically active substances synthesized and secreted by immune cells and certain non-immune cells, generally cytokines, play an important role in the differentiation of Th cells. It can also 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. IL-12 is produced by monocytes and B cells and has a variety of biological activities. It can significantly reduce the number of bacterial invasions and increase the expression levels of IgG2a and IgA in the mucosa and immune system. It is a cytokine with broad application prospects. Adjuvant. It induces a Th1-type immune response, and the treatment of tumors and AIDS is in clinical trials.

 (3) Nucleic acid adjuvant

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. The characteristic sequence of CPG-ODN can activate a variety of immune effector cells, such as T cells, B cells and NK and other immunocompetent cells, so CPG-ODN is used in more experimental studies. Bacterial DNA is a source of CPG-ODN, and its role includes enhancing both humoral and cellular immunity. It is more likely to be used in tumors and infectious diseases. It has not been reported that CPG-ODN has serious side effects on humans, but it has been found in animal models that CPG-ODN can induce autoimmune diseases.

(4) Lipid-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. Studies have shown that liposome vaccine delivery can enhance the body’s humoral and cellular immune responses, and the structure of the liposome facilitates the presentation of antigens to antigen-treated cells. Studies have also shown that liposomes combined with Freund’s reagent or aluminum hydroxide have a multiplier effect. However, it also has shortcomings, such as poor stability, easy oxidation, and high production costs. Therefore, current research on the application of liposomes has been suspended for medical research.

(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 these adjuvants 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 adjuvants, and tuberculin, Al (OH)3, and Freund’s incomplete adjuvant were used as controls. Results 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. In this study, ovalbumin (OVA) was used as an antigen, and the above three new aggregates were adjuvants, and tuberculin, Al (OH)3, and Freund’s incomplete adjuvant were used as controls. Results 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.

To be continued in Part Two.

Reference

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[4] O’Hagan D T, Valiante N M. Recent advances in the discovery and delivery of vaccine adjuvants[J]. Nature Reviews Drug Discovery, 2003, 2(9):727-35.