Memory CD4+ T cells guide memory B cell adaptability to drifting influenza vaccination

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Abstract Influenza A annually infects 5–10% of the world’s human population resulting in an estimated one million deaths. Unlike other infectious agents, where either infection or vaccination against the disease confers long-term immunity, influenza causes annual epidemics and re-infects previously exposed individuals as a result of antigenic drift in the surface glycoprotein hemagglutinin (HA). Due to antigenic drift, the human immune system is simultaneously exposed to both novel and conserved parts of the influenza virus through vaccination and/or infection multiple times throughout life. Preexisting immunity by infection or vaccination influences subsequent neutralizing antibody responses, the correlate of protection for influenza. To understand how preexisting immunity augments future responses to drifted influenza immunization, we established mouse models, sequentially infecting mice with a H1N1 strain and then immunizing with a second drifted H1N1 strain. Mice previously infected with A/CA have increased neutralizing antibody response (nAb) to A/PR upon immunization with A/PR HA. This increase in nAbs was dependent on CD4+ T cell and memory B cell, correlating with CD4+ T cell reactivity conserved across both influenza HA’s. We also found increased germinal center PR8-specific B and T follicular helper cells post vaccination in the draining lymph node. These results suggest conserved MHC Class II restricted epitopes within HA are critical for B cells to adapt to drifting influenza and could be leveraged to boost out subsequent neutralizing antibody responses. Understanding the mechanism by which preexisting immune responses shape future responses is essential to optimize and leverage vaccination strategies.