Editors' ChoiceInfectious Disease

Teaching an old antibody response new tricks

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Science Translational Medicine  27 Mar 2019:
Vol. 11, Issue 485, eaax1716
DOI: 10.1126/scitranslmed.aax1716


The human antibody repertoire against influenza virus is shaped by prior infection and vaccination.

Despite yearly vaccination, preventing influenza virus infection remains a global public health priority with infections resulting in tens of thousands of deaths annually, particularly in the very young and the elderly. As influenza replicates, the gene encoding the viral hemagglutinin protein (HA) continues to accumulate mutations. HA is the primary target of the neutralizing antibody response. Therefore, these mutations, termed antigenic drift, allow the virus to evade herd immunity. Antigenic drift also complicates the formulation of the annual influenza vaccine, which contains the HA protein from several circulating influenza virus strains in order to elicit antibodies capable of preventing infection against the backdrop of extensive HA variability.

A new generation of influenza vaccines currently under development aims to induce antibodies that neutralize a broad range of, and potentially all, influenza virus strains. One promising approach for the development of a “universal” influenza vaccine is the targeting of conserved regions of the virus, such as the relatively conserved HA stalk and the nucleoprotein. How previous vaccination and infection will impact the success of these new vaccine candidates in humans is unclear.

To address this question, Henry et al. and Lee et al. longitudinally analyzed the human anti-influenza virus antibody repertoire after annual vaccination. Using sophisticated mass spectrometric analyses paired with antibody sequencing, Lee et al. demonstrated dominant antibody clonotypes induced by natural influenza virus infection could persist for many years and that some of these persistent antibodies were broadly cross-reactive. Henry et al. isolated B cells responding to vaccination from cohorts in different age groups. Antibody genes in elderly adults had fewer de novo mutations than those in young adults, suggesting a reduced capacity to respond to new viral strains. Antibodies from the elderly instead targeted conserved viral proteins to which B cells had previously been exposed. Both of these studies point to a substantial contribution of prior exposure on the response to new vaccination in humans, a phenomenon termed “serological imprinting” or “original antigenic sin.” Although more individuals will need to be included in future studies, these new data raise the possibility that a universal vaccine is achievable, provided potent cross-reactive antibody responses can be formed or boosted in the presence of older responses.

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