Immune history profoundly affects broadly protective B cell responses to influenza

By Sarah F. Andrews, Yunping Huang, K. Kaur, Lyubov I. Popova, Irvin Ho, Noel T. Pauli, C. Dunand, W. Taylor, Samuel Lim, Min Huang and 8 more. 2015

398 citations recorded by the source corpus.

The quality of the B cell response to influenza vaccination is dependent on the preexisting memory B cell repertoire. 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.

Subfields: Epidemiology, Immunology

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Citations in the corpus

Next-Generation Influenza Vaccines. (2020, background): “In the presence of the head domain, immune responses directed to the stem are outcompeted by the head-directed response (Ellebedy et al. 2014; Andrews et al. 2015; Tan et al. 2019).”
Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals (2020, positive): “This issue is also relevant for vaccine development, as crossreactive immunity could influence responsiveness to candidate vaccines (Andrews et al., 2015).”
Potent Protection against H5N1 and H7N9 Influenza via Childhood Hemagglutinin Imprinting (2016, background): “Furthermore, re-exposure to a seasonal subtype typically elicits memory responses against the immunodominant HA head, which mask subdominant broadlyprotective responses involved in group-level imprinting (26).”
Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines (2020, background): “Instead, antibodies targeting immunodominant hypervariable epitopes in the head domain often dominate the response to HA, resulting in strain-specific immunity and limited breadth of protection 23–25 .”
Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin (2019, background): “Prior work has shown that exposure history shapes human immunity to influenza (Li et al., 2013; Andrews et al., 2015b; Gostic et al., 2016; Cobey and Hensley, 2017), and variation in exposure history is a plausible cause of the person-to-person variation we observe in the antigenic effects of viral ”