Strategically leveraging Influenza A induced trained immunity to shape immune profiles to subsequent vaccination with heterologous antigens 2309699

Abstract

Abstract Introduction Trained immunity, the epigenetic and metabolic reprogramming of innate immune cells upon inflammatory signaling shapes subsequent immune responses to the same as well as unrelated antigens within both local tissues and broadly within the hematopoietic compartment. However, the role trained immunity plays in vaccination remains to be fully elucidated. Here, we demonstrate that vaccination through different routes (mucosal vs. systemic) differentially harnesses trained immune responses established by prior viral respiratory infection Methods Mice were infected with A/New/Caledonia/20/1999 H1N1 influenza virus. 4 weeks post infection, mice were immunized according to a prime/boost/boost schedule. To examine the responses to homologous vs. heterologous antigen and the impact of route, mice were immunized with tetrameric influenza neuraminidase (tetNA) or the spike protein from SARS-CoV-2 (WT-S) given intramuscularly (IM) with Addavax, or intranasally (IN) with our rationally designed adjuvant, NE/IVT, a nanoemulsion combined with IVT, a RIG-I agonist. Results Despite similar serum antibody levels between regimens to respective antigens, the mucosal antibody response to heterologous antigen, WT-S was enhanced by prior IAV infection but only with IN vaccination. Further, while IN NE/IVT/S increased the neutrophil frequencies within the lungs, IM Addavax formulations increased eosinophil frequencies regardless of antigen. However, infection with IAV before IM Addavax immunization enhanced the frequency of CD101+eosinophils. These unique changes were associated with shifts in Th balance upon antigen recall response, with prior-infection increasing Th1 cytokines to heterologous WT-S antigen in the mucosal lymph nodes in both immunization regimens and suppression of Th2 cytokines to homologous tetNA antigen in IM Addavax regimens. Conclusion Respiratory viral infection shapes the local inflammatory cell composition and subsequently alters the Th and mucosal antibody response induced by immunization. Funding Source Supported by National Institutes of Health (NIAID) grants R01AI160706, R21AI176069, R21AI180874 (PW, MS) Topic Categories Vaccines and Immunotherapy (VAC)