Humans are constantly exposed to diverse microbial environments to maintain their survival. Human populations exhibit heterogeneous infection responsiveness from individual to individual through infectious selection. Host responsiveness, rather than the microorganisms themselves, is the mainstay of infectious diseases. Vaccines, on the other hand, have been discussed empirically in the context of the ‘twice-never phenomenon of infection’ and ‘vaccines since Jenner’. Vaccines consist of an antigen and an adjuvant. It can be said that the immune response was established as an essential mechanism to avoid micro-organisms, but the immune response to vaccines varies from individual to individual infection, and vaccines need to be boosted by adjuvants. There are also adverse reactions where an over-response induces an inappropriate response in the host. The development of safe and versatile adjuvants that can be used in vaccines against infectious diseases, even in the elderly and patients with underlying diseases, is an essential issue.
- Needs for non-inflammatory adjuvant in corona vaccine
The development of mRNA vaccines, including the Corona vaccine, is currently a hot topic. The government-sponsored ‘100-day vaccine’ project and other projects also call for mRNA vaccines, but we wonder whether vaccines that cause fever in more than 50% of vaccinees, do not establish memory immunity even after three shots and exacerbate underlying diseases are worthy of development. By this logic, the immune system should destroy the autologous cells (S-protein expression) with each additional vaccination. In contrast, the superiority of antigen and adjuvant component vaccines has historical support, and if the antigen itself is not toxic, adverse reactions are limited to an adjuvant-induced inflammatory response. Indeed, it is the toxicity of the adjuvant that has prevented the approval of many vaccine candidates; the TLR3 agonist ARNAX is a non-inflammatory adjuvant that could overcome this problem.
There are currently no approved TLR3 adjuvants and polyI:C and its derivatives are in clinical trials for COVID-19 vaccine. polyI:C activates cytoplasmic RNA sensor pathways in systemic cells besides the TLR3-TICAM-1 pathway, causing cytokinaemia. Hence, it has been dismissed in cancer and infectious disease trials. On the other hand, ARNAX has passed safety studies up to the monkey GLP study without triggering such adverse reactions.
- Perspectives
Our proposal is to develop non-inflammatory adjuvants (immune boosters without inflammation) and establish ways to complement component vaccines. Once a stockpile of safe adjuvants has been created, any infectious disease can be vaccinated by combining it with a specific antigen. In the future, ARNAX can be used as a safe and versatile adjuvant for a variety of microbial antigens and component vaccines. A tailored component vaccine regime can be established.
The creation of vaccines free from inflammatory side-effects has been a longstanding social demand, but has not yet been achieved. Through the development of ARNAX, we are taking up the challenge of developing highly versatile vaccines against cancer and infectious diseases.