Cross-protective immune-enhancing mechanisms of combined mRNA and conventional flu vaccines

About This Grant

Project Summary Hemagglutinin (HA) antigenic changes of influenza (flu) viruses and low immunogenicity of conventional flu vaccines result in suboptimal efficacy, ranging between 10% and 60%, and much lower efficacy or no protection against pandemics. It is a high priority to design new universal flu vaccines, develop a novel vaccination strategy, and better understand the innate and adaptive immune mechanisms for vaccine- mediated effective protection. The mRNA vaccine platform would provide many advantages over conventional vaccines. In this project, we designed new mRNA vaccine constructs encoding neuraminidase (NA) conjugated to a highly conserved M2e repeat, which is based on our prior studies reporting that immunity to both NA and M2e could provide broad cross-protection against different subtypes and lineages of flu A and flu B viruses. However, non-neutralizing immunity to conserved domains would have limited efficacy despite broader protection. Lipid nanoparticles (LNP) encapsulating mRNA vaccines are known to be inflammatory. High doses of mRNA LNP vaccines would cause undesirable side effects. We hypothesize that mRNA LNP vaccine targeting conserved domains and inducing cross-protective immunity will enhance the broad cross- protection of co-administered conventional flu split vaccines at low doses of both vaccines. This hypothesis is supported by our new preliminary data demonstrating that a combination of flu A 5xM2e mRNA or B NA mRNA LNP and inactivated split virus vaccines significantly enhanced the efficacy of cross-protection against flu A and flu B viruses. Flu A (not flu B) has pandemic threats, more diverse natural hosts, and antigenic diversity, and is highly pathogenic, rendering flu A viruses more challenging to control than flu B. In Specific Aim 1, we will further test the hypothesis that the combination of new cross-protective mRNA LNP and inactivated flu A virus split vaccines will provide higher efficacy of homologous and heterologous against flu A viruses. In addition, we do not fully understand the innate and adaptive immune mechanisms of how adding an mRNA LNP vaccine to conventional inactivated split virus vaccination will enhance homologous and heterologous protection. In Specific Aim 2, we will determine whether a combination of an mRNA LNP vaccine and conventional inactivated flu split vaccines will activate a unique set of innate immune responses leading to enhanced adaptive immunity. We expect that the outcomes of this project will provide insight into innate and adaptive immune correlates with enhanced homo- and cross-protection by a combination of cross-protective mRNA and conventional vaccines, in addition to developing a new vaccination strategy inducing enhanced protection against seasonal and pandemic potential variants.