Development of vaccination strategies to elicit broadly protective immunity against influenza

ABSTRACT Licensed influenza vaccines commonly elicit strain-specific immunity, failing to provide protection against antigenically distinct strains with the capacity to cause pandemic outbreaks. Therefore, the development of a universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains is critically needed to prevent future influenza pandemics. Influenza hemagglutinin (HA) represents a key vaccine target, as it is the major glycoprotein expressed on the surface of influenza virions and mediates viral entry and fusion. HA comprises two distinct functional domains: (i) the globular head, which is highly variable due to antigenic drift, and (ii) the stalk domain, which is structurally conserved among diverse influenza strains. Influenza infection or vaccination commonly elicits immune responses against immunodominant, strain-specific epitopes on the HA head. By contrast, immune responses against highly conserved epitopes are limited and short-lived, despite conferring broad and heterologous protection. Refocusing the immune response towards conserved, immunosubdominant HA epitopes, while avoiding eliciting strain-specific immunity, represents a promising strategy for the development of a universal influenza vaccine that would confer broad protection against diverse influenza strains. To achieve this, the proposed studies aim to develop and evaluate novel HA immunogens, termed mosaic HAs (mHA), in which the immunodominant, strain-specific epitopes at the head domain have been replaced from those of exotic HAs which humans are naïve, while immunosubdominant, conserved epitopes have been retained. In previous studies, we have dissected the mechanisms by which antibodies, through specific interactions of their Fc domains with activating Type I Fcγ receptors (FcγRs), such as FcγRIIa on dendritic cells and with the Type II FcγR, CD23, on B cells modulate cellular and humoral immunity against influenza, respectively. Given the immunomodulatory consequences of Fc-FcγR interactions, the proposed studies will develop Fc-engineered mHA immunogens that will engage and activate specific FcγR pathways on defined effector cell populations to elicit broad and long-lasting immunity against diverse influenza strains. We anticipate that the proposed studies will lead to the design, selection, and pre-clinical evaluation of innovative immunogens with the capacity to confer durable and heterologous protection against influenza. These studies are expected to have important implications not only for our efforts towards the development of a universal influenza vaccine, but also provide the framework for the design of vaccines with long-lasting and broad protection against other viral pathogens, such as SARS-CoV-2.