Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

Abstract

Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin-cross reactive memory-B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and 2-influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and -in half the subjects- multidonor-class sequences were recovered from >40% of cross reactive-B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies; we propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A-immunization strategies.

Structural insights into the design of novel anti-influenza therapies

“…However, the V H 3–30 family uses an extended CDR H3 to occupy the same pockets as the IFY motif of the V H 1–69 antibodies. More recently, a number of vaccine-induced antibodies that arise from other heavy chain germline families have been shown to target this same site 60 . Thus, these finding have led to the concept of a headless HA as an immunogen that would focus the immune response on the HA stem and away from the more immunogenic head region 61 .…”

Vaccine approaches conferring cross-protection against influenza viruses

“…In a recent study, HA cross-reactive memory B cells were isolated from subjects immunized with an H5N1 DNA/inactivated virus prime-boost influenza vaccine[120]. Three antibody classes were recognized, and each of them were able to neutralize distinct subtypes of group 1 and group 2 influenza A viruses.…”

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

“…In non‐human primates, for instance, we showed that while the choice of adjuvant could impact the ELISA titer of the vaccine response, it did not increase the levels of somatic hypermutation (SHM) in vaccine‐elicited lineages, which remained far below those seen in models of infection 23. Antibodyomics2 was used to monitor the elicitation and expansion of influenza broadly neutralizing antibodies in response to immunization with an H5N1 strain [16 and manuscript in preparation]. We have also used longitudinal information to analyze the rate of antibody evolution.…”

“…More recently, mouse models incorporating knock‐in germline genes has demonstrated the priming of multidonor VRC01 class antibodies in response to germline‐targeting immunogens 58, 60, 67. We have also applied Antibodyomics5 to the quantification of multidonor class antibodies that neutralize both group 1 and group 2 influenza A viruses 16. We delineated antibody sequence signatures and quantified antibodies that satisfy these sequence signatures in NGS datasets from multiple donors with different vaccination histories 52, 68.…”

“…We delineated antibody sequence signatures and quantified antibodies that satisfy these sequence signatures in NGS datasets from multiple donors with different vaccination histories 52, 68. Notably, one vaccination regimen from the VRC 310 trial involving immunization with a diverse H5 hemagglutinin increased the frequency of two multidonor classes by over 100‐fold,16 despite titers too low to detect in sera. This demonstrates the exquisite sensitivity of B‐cell quantification, where one transcript in about one million can be detected—a more sensitive quantification than allowed by assessment of serum neutralization.…”