Abstract
The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has propelled research on distinct antigens and delivery methods to efficiently induce broad immunity toward drifted or shifted virus strains. Here, we report that adeno‐associated virus (AAV) vectors expressing influenza virus HA or chimeric HA protected mice against homologous and heterologous virus challenges. Unexpectedly, immunization even with wild‐type HA induced antibodies recognizing the HA‐stalk and activating FcγR‐dependent responses indicating that AAV‐vectored expression balances HA head‐ and HA stalk‐specific humoral responses. Immunization with AAV‐HA partially protected also ferrets against a harsh virus challenge. Results from this study provide a rationale for further clinical development of AAV vectors as influenza vaccine platform, which could benefit from their approved use in human gene therapy.
Highlights
Influenza remains a severe public health threat
We evaluated the potency of associated virus (AAV) vectors expressing influenza virus wild-type HA and NP, or chimeric HA (cHA) and headless HA antigens to confer broad protection from influenza virus challenge in comparison with an inactivated vaccine (Fig 1A)
All vaccine constructs were based on proteins encoded by the prototypic pandemic influenza virus A/California/7/2009 (H1N1)pdm (Cal/7/9) (Fig 1B)
Summary
Influenza remains a severe public health threat. Influenza A viruses of the subtypes H1N1 and H3N2 as well as the influenza B virus lineages Victoria and Yamagata circulate in humans. Influenza viruses are genetically and antigenically highly variable, resulting in recurrent epidemics in humans (“flu season”). Reassortment between influenza A virus subtypes can generate even larger antigenic alterations, which may allow for a pandemic circulation in a naıve population (Palese, 2004). In 1918, the most devastating pandemic caused by an H1N1 virus, the “Spanish flu,” claimed millions of deaths worldwide (Johnson & Mueller, 2002). The most recent influenza pandemic was triggered by a related H1N1 virus in 2009, which arose from the porcine reservoir and imposed a high burden of disease on public health (Fineberg, 2014)
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