Codelivery of antigens with TLR7/8 agonists leads to an improved immune response to influenza vaccination

Abstract

Abstract When designing an effective and safe vaccine, inducing a protective immune response to a pathogen without also inducing unacceptable levels of immunopathology is a major challenge. One promising strategy is the use of purified or recombinant antigens along with adjuvants that specifically engage pathogen-associated molecular pattern (PAMP) receptors. This targeted approach aims to minimize immune-mediated reactogenicity. Our group has developed libraries of novel toll-like receptor (TLR)7 and/or TLR8 ligands which show a range in receptor activity. Previous studies have shown that the high potency of TLR7/8 adjuvants leads to unacceptable toxicity in human clinical trials. One strategy to overcome this toxicity is direct adjuvant-antigen conjugation, which serves to limit systemic distribution of the adjuvant through the codelivery of the antigen and adjuvant to APCs. We have demonstrated that covalent conjugation of a TLR7/8 agonist to an antigen results in improved humoral and cell-mediated responses, with decreased systemic and local inflammation. This approach allows for the use of a reduced adjuvant dose by preventing the engagement of PAMPs in the absence of antigen. We hypothesize that antigen/adjuvant codelivery boosts the engagement of CD4+ T cells and elicits the necessary cytokines to promote a Th1-related switch to antigen-specific IgG2a antibodies. In addition, engagement of TLR7/8 appears to improve cross-presentation, thereby boosting the CD8+ T cell response, which is desirable for improved immunity to influenza and other viruses. We find this approach has great potential to enhance vaccine efficacy, while reducing the immunopathology often associated with highly active TLR7/8 adjuvants.