Viruses such as HIV-1 and influenza A are genetically diverse, complicating their neutralization by antibody. One potential way that antibodies can neutralize broadly is through recognition of a conserved, functionally important component of the virus. We have used X-ray crystallography to investigate the epitopes of broadly neutralizing antibodies and their mechanisms of neutralization. We have also used next generation sequencing to B cell transcript to understand the developmental processed by which broadly neutralizing antibodies mature. Of particular interest for vaccine design are reproducible or convergent antibodies, which have similar modes of recognition and similar B cell ontogenies in multiple donors, as such antibodies might be induced in the general population with a common set of immunogens. While most of our focus has been on HIV-1, we have recently been examining antibodies against other pathogens, including influenza A virus. Antibodies capable of neutralizing divergent influenza A strains could form the basis of a universal vaccine. 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 group 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.
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