March 2016, Vol 4, No 3 - Inside Influenza Readiness
Christine Erickson

The antigenicity of the influenza virus changes so that it can evade the immune protection of the host, and antibody lineages of the host then become more potent. Approaches for creating a universal influenza vaccine that produces antibody lineages that do not undergo these changes and protects against seasonal variation and pandemic viruses require directing B-cell ontogeny to focus the humoral response on conserved epitopes on the viral hemagglutinin (HA). A more effective influenza vaccine approach would protect against several rounds of seasonal influenza variations, and, hopefully, the initiation of new serotypes from other circulating viruses.

To further explore this subject, Aaron G. Schmidt, PhD, Laboratory of Molecular Medicine, Children’s Hospital, Harvard Medical School, Boston, MA, and colleagues analyzed how immunologic memory impacted 1 study participant’s response to later influenza exposures. They found that the unmutated common ancestors (UCAs) of 6, individual, broadly neutralizing antibody lineages had bound the HA of a virus that had been circulating at the time of the study participant’s birth in 1990, and that although the HAs of viruses circulating >5 years later no longer bound the UCAs, they did bind mature antibodies in the lineages’ bound strains from the participant’s birth up to age 18 years. This suggests that early imprinting by the right influenza antigen may enhance the possibility of a longer immunologic span, according to the study authors.

“When stimulated by a new exposure (infection or vaccination), memory cells can re-enter germinal centers and undergo new rounds of somatic hypermutation and selection,” Dr Schmidt and colleagues explained. “The net effect of this ongoing selection across the entire population exposed to the virus is a virus-immunity ‘arms race.’”

The study participant was aged 18 years at the time of the 2008 study, and had no previous vaccination history to report. The authors prepared a panel of HA1 head domains from H1 strains circulating since 1990, and evaluated their similarities to the UCAs of antibodies in 6 lineages of receptor-binding site (RBS)-directed antibodies. The authors deduced that the antibodies identified in the day 7 samples represented a recall response, and that mutation may have occurred as a result of an influenza virus infection the participant contracted between 1990 and 2006, and also during the response to the vaccine. At least 90% of the 174 HA-positive antibodies from the participant had somatic mutation levels >2.5%; therefore, the lineages that were analyzed were part of a secondary response.

The results indicate that RBS-directed antibodies from the participant’s lineages amplified by the short-term, 7-day response to vaccination bound strongly to HAs from most of the potential previous exposures, but that their UCAs dated back to the earliest exposure, and lost affinity as the virus mutated. The majority of the antibodies from the participant had somatic mutation levels high enough to signify a recall rather than a primary response. Therefore, the antigenic distance, regardless of epitope, between influenza virus isolates and well-separated time points, appears to be within a range that strongly supports recall. This indicates that successive influenza virus infections or vaccinations update the existing collection, but do not add many new elements.

“The results show that we can study the virus-immunity arms race in humans by sampling an appropriate cohort of individuals and that we can reconstruct patterns of B-cell affinity maturation in those individuals,” the study authors explained. Their analysis that early exposure seems to have caused predisposed immunologic memory in the participant proposes that administering vaccines in infants with HA immunogens selectively exposing conserved epitopes may be a productive step in formulating a vaccine that causes long-term immunity.




  1. Schmidt AG, Do KT, McCarthy KR. Immunogenic stimulus for germline precursors of antibodies that engage the influenza hemagglutinin receptor-binding site. Cell Rep. 2015;13:2842-2850.
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Last modified: April 23, 2016
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