Co-delivery of antigens with TLR7/8 agonists leads to an improved Th1-mediated immune response to subunit vaccines.

Abstract

Abstract When designing an effective and safe vaccine, the induction of a protective immune response to a pathogen without unacceptable levels of immunopathology is critical. The use of purified or recombinant antigens in combination with adjuvants that elicit a defined immune response is a promising strategy for eliciting a productive immune response while minimizing toxicity. Our group has developed libraries of novel toll-like receptor (TLR)7 and 8 ligands with a range of activity. Previous clinical trials have shown that the high potency of TLR7/8 adjuvants can lead to unacceptable toxicity. We hypothesized that direct conjugation of the adjuvant to the antigen will limit systemic distribution of the adjuvant, while boosting the immune response by ensuring co-delivery of antigen and adjuvant to antigen presenting cells. We demonstrate that covalent conjugation of TLR7/8 agonists to antigens results in greatly improved humoral and cell-mediated responses, without apparent systemic or local inflammation. This likely improves safety by preventing off-target immune responses from the engagement of PAMPs in the absence of appropriate antigens. When mice were immunized with an antigen/adjuvant conjugate we observed a switch towards IgG2a and away from IgG1 antigen-specific antibodies, plus greater Th1 cytokine production after restimulation of immune cells ex vivo. We hypothesize that co-delivery of a TLR7/8 agonist with antigen leads to activation of CD4+ T cells in the presence of Th1-skewing cytokines. The TLR7/8 agonist also appears to improve cross-presentation, inducing CD8+ T cells. We find this approach has great potential to enhance vaccine efficacy, while reducing potential immunopathology by TLR7/8 adjuvants.