Research ArticleInfluenza

Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans

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Science Translational Medicine  09 Dec 2020:
Vol. 12, Issue 573, eabd3601
DOI: 10.1126/scitranslmed.abd3601

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Influencing influenza immunity

Humans are exposed to influenza virus throughout their lifetimes through a combination of infections and vaccinations. Yet, it remains unclear whether infection and vaccination induce distinct influenza-specific immunological memory. To address this question, Dugan et al. compared antibodies produced by individuals after influenza infection or vaccination. The authors found that infection-induced antibodies reacted to non-neutralizing epitopes of influenza virus, whereas vaccination-induced antibodies reacted to neutralizing epitopes. In addition, infection-induced antibodies preferentially responded to influenza strains present during an individual’s childhood. Last, passive transfer of vaccination-induced antibodies, but not infection-induced antibodies, protected mice in a model of influenza infection. These findings demonstrate that existing influenza-specific memory and route of exposure influence influenza immunity.


Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection–induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes.

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