Research ArticleInfluenza

Immune history profoundly affects broadly protective B cell responses to influenza

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Science Translational Medicine  02 Dec 2015:
Vol. 7, Issue 316, pp. 316ra192
DOI: 10.1126/scitranslmed.aad0522

Stalking a flu vaccine

A universal flu vaccine has been a Sisyphean trial—despite successful seasonal vaccines, the immune system has to start over with newly mutated influenza strains. Now, Andrews et al. look in depth at the B cell response to the pandemic 2009 H1N1 vaccine over time. They found that people with low titers of preexisting antibodies were more likely to generate a broadly reactive response that targets the more conserved hemagglutinin (HA) stalk region, whereas those with higher levels of preexisting antibodies responded by targeting the more variable HA head. The preexisting head antibodies were immunodominant and prevented clear access to the stalk. These data suggest that exposure history is critical in designing a universal flu vaccine.


Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal antibodies generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, hemagglutinin (HA) stalk–biased response. Higher preexisting serum antibody levels correlated with a strain-specific HA head–dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk–reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory B cells against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.

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