Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses

Abstract

f Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.

Preexisting human antibodies neutralize recently emerged H7N9 influenza strains

“…Although the level of serum protection in the general population remains to be determined, our results suggest that prior immunity against the H7N9 strain and other novel strains could be boosted with a vaccine eliciting cross-reactive memory B cells. Indeed, as recently demonstrated in mice, immunization with a chimeric HA protein expressing the H3 stalk domain induces broad protection against divergent H3N2 and H7 virus infection (31,32). It will be important to determine whether booster immunizations with divergent influenza strains in the general human population can lead to universal protection against most influenza strains.…”

Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

“…A variety of approaches for eliciting HA stalkspecific antibody responses have been evaluated in animal models with various degrees of success (43,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Collectively, these approaches aim to elicit HA stalk-specific responses through tactics that subvert HA globular head immunodominance.…”

The emergence of H7N9 viruses: a chance to redefine correlates of protection for influenza virus vaccines

“…These antibodies exhibit no HI activity but neutralize the virus by inhibiting the fusion of viral and endosomal membranes, by inhibiting the maturation of the HA and possibly by other mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC). Stalk-reactive antibodies are being investigated as a possible correlate of protection and universal influenza virus vaccines based on the induction of stalk-reactive antibodies are under development [12][13][14][15][16]. Humans are usually exposed to the HA of H3 influenza viruses, which is phylogenetically related to H7 HA and shares conserved epitopes in the stalk domain.…”