Vaccine adjuvants are substances that can non-specifically alter or enhance the body's specific immune responses to an antigen and serve as adjuvants. Adjuvants can induce the body to produce long-term and efficient specific immune responses, improve the body's protective ability, reduce the number of immune substances, and save the cost of vaccine production. Generally speaking, traditional live attenuated vaccines and whole bacterial vaccines do not need to add adjuvants due to their adjuvant properties. Inactivated viruses and recombinant proteins are commonly weak in anti-cause immunogenicity, therefore, adjuvants are often used to enhance and regulate their antigen immunogenicity without increasing side effects.
Classifications and Mechanisms
Adjuvants can be classified according to their sources (natural, synthetic, or endogenous), mechanisms, and physical or chemical properties.
1. Enhanced antigen delivery to antigen-presenting cells and/or lymph nodes to improve immune responses, such as aluminum salts and water-in-oil emulsions (e.g. Novartis' MF59, GlaxoSmithKline's AS03 system, and other liposomes).
2. Immune stimulants or immune enhancers, such as lipids monophosphorates (MPL), QS21, cytokines, etc., regulate the quality of immune responses mainly through receptor-mediated signaling pathways.
3. The two above comprise an adjuvant system, such as GlaxoSmithKline's AS04 and AS01. Currently, many adjuvants have been studied, including CpG ODN, adjuvant systems, live viral vectors, and emulsions.
Although a variety of new adjuvants have been applied in clinical practice, their mechanism on the immune system is still not completely clear up to now. At present, it is believed that there are the following kinds:
1. Stimulate lymphocyte proliferation and differentiation;
2. Change the type of antibody production and induce delayed hypersensitivity reaction;
3. Stimulate the mononuclear macrophage system to enhance its ability to process and present antigens;
4. Change the physical properties of antigens, and delay the degradation and elimination of antigens, so as to stimulate the immune system more effectively.
CpG ODN Adjuvants
CPG ODN is a new immune booster, which can be synthesized by chemical methods in large quantities. It has the advantages of easy quality control and low cost. A large number of animal experiments and clinical studies have shown that CpG ODN has a good application prospect in the prevention and treatment of diseases like infections, tumors, and allergies.
Based on Kayraklioglu's statistics, there have been more than 100 clinical trials using K-type CpG ODN as an adjuvant worldwide, and more than 1,500 preclinical studies involving the immune activity of CpG ODN adjuvant vaccines have been published. CpG ODN adjuvant vaccine can be mainly divided into pathogen vaccine, allergen vaccine, and tumor vaccine. In addition, its immune enhancement effect in DNA vaccine is also being gradually explored:
l In the field of pathogen vaccines, HEPLISAV-B®, the world's first commercially available CpG adjuvant hepatitis B vaccine, has shown excellent immune effects. Compared with Engerix-B®, HEPLISAV-B® not only induces protective immunity faster (3 months vs. 7 months) but also has a better immune effect.
l For allergen vaccines, the ragweed allergy CpG adjuvant vaccine TOLAMBA™ reduced the response of immune cells in the nasal mucosa to allergen stimulation in clinical trials, reducing the severity of disease for two seasons and promoting a long-term transition from Th2 to Th1 immunity.
l In terms of tumor vaccines, the CpG ODN TLR9 agonist SD-101, developed by TriSalus Life Sciences, and pembrolizumab can induce extensive immune activation in the tumor sites of patients with advanced melanoma after administration, with little toxicity, and can effectively increase clinical efficacy.
After a global pandemic outbreak in 2020, CpG ODN adjuvant can improve vaccine immune response while reducing the amount of antigen required for each dose of vaccine, thus improving the efficiency of vaccine production. As widely used adjuvants in clinical practice, CpG1018 and CpG2006 are commonly applied in recombinant protein COVID-19 vaccine and become necessary adjuvants with an annual demand of mt, which poses a great challenge to the manufacturing of this product.
The most critical step in the synthesis process of CPG-ODN is solid phase synthesis, which is mainly completed by an oligonucleotide synthesizer at present. However, due to the increasing demand driven by the current research and development of oligonucleotides, a new solution is urgently needed to meet the production demand.