A mosaic hemagglutinin-based influenza virus vaccine candidate protects mice from challenge with divergent H3N2 strains

By F. Broecker, Sean T. H. Liu, N. Suntronwong, Weina Sun, M. Bailey, R. Nachbagauer, F. Krammer, P. Palese. 2019

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Current seasonal influenza virus vaccines only provide limited, short-lived protection, and antigenic drift in the hemagglutinin surface glycoprotein necessitates their annual re-formulation and re-administration. To overcome these limitations, universal vaccine strategies that aim at eliciting broadly protective antibodies to conserved epitopes of the hemagglutinin show promise for protecting against diverse and drifted influenza viruses. Here a vaccination strategy that focuses antibody responses to conserved epitopes of the H3 hemagglutinin is described. The approach is based on antigenic silencing of the immunodominant major antigenic sites of an H3 protein from 2014 by replacing them with corresponding sequences of exotic avian hemagglutinins, yielding “mosaic” hemagglutinins. In mice, vaccination with inactivated viruses expressing mosaic hemagglutinins induced highly cross-reactive antibodies against the H3 stalk domain that elicited Fc-mediated effector functions in vitro. In addition, the mosaic viruses elicited head-specific antibodies with neutralizing and hemagglutination-inhibiting activity against recent H3N2 viruses in vitro. Immune sera protected mice from heterologous challenge with viruses carrying H3 proteins from 1968 and 1982, whereas immune sera generated with a seasonal vaccine did not protect. Consequently, the mosaic vaccination approach provides a promising avenue toward a universal influenza virus vaccine. Flu vaccines that target the head domain of the viral hemagglutinin (HA) surface glycoprotein are highly immunogenic, yet the variable nature of this domain across viral strains and its continuous antigenic drift limit vaccine efficacy. As the HA stalk domain is conserved across influenza viruses, targeting this region is a promising strategy to generate universal flu vaccines. However, eliciting high antibody levels against the HA stalk domain and conserved regions in the head domain remains challenging. Here Peter Palese and colleagues at Mount Sinai develop “mosaic” HAs (mHAs) aimed at eliciting antibodies targeting both the stalk domain and epitopes in the head domain outside of the major antigenic sites. These mHAs are based on antigenic silencing of the immunodominant antigenic sites of an H3 protein, which are exchanged with exotic HA sequences from avian influenza viruses. Vaccination of mice with inactivated viruses expressing mHAs induced both stalk- and head-specific antibodies active in vitro, and transfer of sera from mice immunized with mHAs was better than sera from mice immunized with a seasonal vaccine at protecting mice from heterologous challenge with viruses carrying different H3 proteins, demonstrating the potential of mHAs as universal influenza virus vaccine candidates.

Subfields: Epidemiology, Immunology