Commercial influenza vaccines vary in both the structural arrangements of HA complexes and in induction of antibodies to cross-reactive HA epitopes

Influenza virus infects millions of people annually and can cause global pandemics. Hemagglutinin (HA) is the primary component of commercial influenza vaccines (CIV), and antibody to HA is a primary correlate of protection. Persistent antigenic variation of HA requires that CIV be reformulated for new strains yearly. Differences in structural organization of HA has not been correlated with induction of broadly reactive antibodies, and CIV formulations can vary in how HA is organized. Using electron microscopy to study four current CIV, we found that these different formulations contained a variety of structures including: individual HAs, starfish-like structures with up to 12 HA molecules, and novel “spiked nanodisc” structures that displayed over 50 HA molecules along the complex’s perimeter. These spiked nanodiscs uniquely exposed conserved stem epitopes and elicited the highest levels of heterosubtypic cross-reactive antibodies. Overall, we found that HA structural organization can be an important CIV parameter and can be associated with the induction of cross-reactive antibodies to conserved HA epitopes.