Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

A universal influenza vaccine that elicits a strong and lasting stalk-specific antibody response is advantageous. We utilize nucleoside-modified mRNA in lipid nanoparticles (mRNA-LNP) and unmodified self-amplifying mRNA in modified dendritic nanoparticles (sam-MDNP), expressing chimeric hemagglutinin (cHA) antigens to induce stalk-specific humoral immunity in non-human primates (NHPs) with preexisting influenza virus immunity. mRNA-LNP immunization induces strong stalk-specific binding antibodies, protecting mice from lethal heterologous influenza virus challenges, along with bone marrow plasma cells (BMPC) that persist for up to 8 months. sam-MDNP vaccine induces lower humoral immunity, despite showing strong innate activation. Transcriptomic and cytokine analyses reveal a more persistent induction of interferon responses, IL-1ß signaling, and IL-6 production in the mRNA-LNP group, correlating with the induction of serum antibody responses and BMPC. We identify a transcriptional signature associated with induction of BMPC following mRNA vaccination and highlight the utility of cHA-based mRNA-LNP vaccines in inducing persistent stalk-directed protective antibody responses. Overall design: Ten male RMs were immunized intramuscularly (IM) with the 2020/2021 quadrivalent influenza vaccine (QIV) at weeks 0 and 6 to induce influenza specific immunity (Fig. 1A). Eighteen weeks post QIV booster, RMs were divided into two groups based on their binding antibody response to influenza stalk and immunized IM with 100?g of cH8/1 LNP-mRNA or 30?g of cH8/1 samRNA vaccine. Twelve weeks later, RMs were again immunized IM with 100?g of cH5/1 LNP-mRNA or 30?g of cH5/1 samRNA. Animals were followed for up to 40 weeks after the final vaccination.