Abstract
ABSTRACTAlthough antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single-cell screening technology to identify rare monoclonal antibodies (MAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 MAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 MAbs, 3 exhibited low expression in a transient-transfection system, 4 were neutralizers that bound to the HA head region, 11 were stalk-binding nonneutralizers, and 5 were stalk-binding neutralizers, with 4 of these 5 having unique antibody sequences. Of these four unique stalk-binding neutralizing MAbs, all were broadly reactive and neutralizing against a panel of multiple strains spanning both IBV lineages as well as highly effective in treating lethal IBV infections in mice at both 24 and 72 h postinfection. The MAbs in this group were thermostable and bound different epitopes in the highly conserved HA stalk region. These characteristics suggest that these MAbs are suitable for consideration as candidates for clinical studies to address their effectiveness in the treatment of IBV-infected patients.
Highlights
Antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare
We report the application of this technology to isolate monoclonal antibodies (MAbs) that bind and neutralize influenza B viruses (IBV) with the aim of discovering new antiviral agents
For most blood samples the average frequency at which memory B cells secreted a MAb against IBV HA was 2 in 10,000, which was about 10-fold higher than what we previously found when screening for MAbs against influenza A viruses (IAV) HAs
Summary
Antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. Viruses from both group 1 and group 2 strains of IAV by single cross-reactive MAbs has been reported [13, 14], these generally have a lower overall potency than group-specific MAbs [15,16,17] These investigative efforts have focused attention on the stalk region of the HA protein, which is essential for virus-cell fusion and is more conserved than the HA globular head domain. In the case of IAV, high-quality MAbs were obtained directly from memory B cells derived from people vaccinated against or naturally infected with influenza virus [13, 15, 21] This natural repertoire of affinitymatured MAbs has provided effective immunity against influenza in model systems, making them attractive as a source for therapeutic candidates. Blood samples from human donors can vary widely in their frequency of high-quality neutralizing antibodies for a particular pathogen, and the frequency can be low [15]
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