Chimeric Hemagglutinin Influenza Virus Vaccine Constructs Elicit Broadly Protective Stalk-Specific Antibodies

TLDR

Current influenza vaccines target the variable globular head of hemagglutinin, necessitating yearly reformulation. We aim to develop a vaccine that elicits immunity to the conserved stalk domain using chimeric hemagglutinin constructs. By repeatedly immunizing mice with chimeric constructs that share a common stalk but present an irrelevant head, we specifically stimulated a stalk‑directed antibody response. The strategy induced broad heterologous and heterosubtypic protection, including against H5, and showed that humoral mechanisms are critical, supporting its potential as a universal human vaccine.

Abstract

ABSTRACT Current influenza virus vaccine strategies stimulate immune responses toward the globular head domain of the hemagglutinin protein in order to inhibit key steps of the virus life cycle. Because this domain is highly variable across strains, new vaccine formulations are required in most years. Here we demonstrate a novel vaccine strategy that generates immunity to the highly conserved stalk domain by using chimeric hemagglutinin constructs that express unique head and stalk combinations. By repeatedly immunizing mice with constructs that expressed the same stalk but an irrelevant head, we specifically stimulated a stalk-directed response that provided broad-based heterologous and heterosubtypic immunity in mice. Notably, our vaccination scheme provides a universal vaccine approach that protects against challenge with an H5 subtype virus. Furthermore, through in vivo studies using passively transferred antibodies or depletion of CD8 + T cells, we demonstrated the critical role that humoral mechanisms of immunity play in the protection observed. The present data suggest that a vaccine strategy based on the stalk domain of the hemagglutinin protein could be used in humans to broadly protect against a variety of influenza virus subtypes.