Abstract
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.
Highlights
Infections with influenza viruses cause significant morbidity and mortality every year.[1]
As a number of mutations in contrast, there were no significant differences in the IgG titers the mosaic” HAs (mHAs) proteins within sites A and B are in close proximity to the between adjuvanted mHA and chimeric HAs (cHAs) vaccines against HA1 of A/ receptor-binding site (RBS), the hemagglutination inhibition (HI) active antibodies induced by
Our results demonstrate that mHA-based vaccines allow for the generation of broad antibody-mediated immunity against antigenically divergent H3N2 viruses in vivo
Summary
Infections with influenza viruses cause significant morbidity and mortality every year.[1]. We assessed the presence of stalk-reactive antibodies by performing ELISAs with a chimeric cH5/3 HA protein that has a group 1 head domain (H5) on top of the stalk domain of HK2014 (Fig. 2e) Both the mHA and cHA vaccines induced robust levels of stalk-reactive IgG and again a significant increase of these antibody titers was observed when the vaccines were adjuvanted. The ability to engage Fc-mediated effector functions such as ADCC is one of the mechanisms by which stalk-specific antibodies contribute to protection in vivo.[31,32,33] To assess whether antibodies mediating effector functions were induced by the various vaccine candidates, we performed an established in vitro ADCC reporter assay.[34] Pooled sera of mHA- and cHA-vaccinated mice induced ADCC reporter activity on MDCK cells infected with HK2014 and HK1968 viruses to comparable levels (Fig. 3d, e), whereby the inclusion of adjuvant further boosted the detected activity. Antibody levels against trimeric H3 as well as the HA1 polypeptide of HK2014 were were capable of eliciting ADCC reporter activity, which is likely attributable to the stalk-specific IgG both vaccines elicited.[32] npj Vaccines (2019) 31
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