B cell Response to Respiratory Viruses

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

The B cell Immunobiology Section has evaluated the B cell response in multiple human Phase I clinical trials with experimental influenza vaccines conducted at the Vaccine Research Center with the goal of evaluating the magnitude and quality of the B cell response and mapping B cell epitopes on influenza proteins that could lead to greater protection against infection with seasonal or pandemic influenza strains. Our work this year has focused on three main projects. First, we undertook characterization in two separate studies of the B cell response to the conserved influenza hemagglutinin stem. In one study we evaluated the B cell response to the experimental first-in-human recombinant H10 hemagglutinin (HA) stabilized stem vaccine in a Phase I clinical trial (NCT04579250). Through single-cell sorting, sequencing, and epitope mapping, we determined that B cells target two major epitopes on the HA stem with different functional properties. B cells that target the central stem epitope are more cross-reactive but less potent, while B cells that target the lower stem epitope are less cross-reactive but more potent against seasonal influenza H3 HA strains. These findings allow us to tailor future influenza stem immunogens to better elicit both broad and potent immune responses to Group 2 influenza viruses. In another study we characterized two specific B cell lineages targeting the HA stem obtained from peripheral blood samples that spanned 10 years in one individual to understand the evolution of the B cell response across time. We found that B cell lineages can target the same epitope in very different ways and are remarkably stable despite multiple exposures to influenza. However, exposures to different influenza strains expand B cells within a lineage with different functional properties, highlighting the plasticity of the B cell receptor repertoire. Second, we performed a comprehensive analysis of the B cell response to an H2 HA ferritin nanoparticle vaccine (NCT03186781) in individuals exposed to H2N2 influenza when it circulated in the human population prior to 1968, and those with no prior exposure because they were born after 1968 when H2N2 was no longer circulating. We characterized the B cell phenotype, epitope targeting and functionality of B cells responding to this vaccine in these two populations and found H2 exposed individuals generated a rapid B cell recall response that differed in potency, cross-reactivity, immunoglobulin repertoire, epitope targeting and phenotype from the naïve B cell driven response in individuals without prior exposure. This study clearly established and described the life-long impact of influenza HA-specific memory B cells formed early in life on vaccine responses decades later. Third, we initiated a campaign to identify human antibodies that could protect against highly pathogenic avian influenza (HPAI) H5Nx viruses in the advent of a pandemic. In March of 2024, H5N1 was first detected in dairy cattle and there were reports of HPAI H5N1 infections among farm workers with direct contact with infected cattle and poultry, underscoring the public health risk of this panzootic pathogen. To prepare for a potential human pandemic with H5N1, we undertook isolation and characterization of broadly cross-neutralizing monoclonal antibodies (mAbs) against diverse H5Nx viruses from individuals in a Phase I clinical trial conducted at the Vaccine Research Center 15 years ago who received a monovalent H5N1 vaccine (NCT01086657). In collaboration with other groups at the Vaccine Research Center, we screened over 500 mAbs and identified five mAbs that potently neutralize the majority of H5 clades including the currently circulating 2.3.4.4b. They target three distinct epitopes on the HA head and define conserved sites of vulnerability for H5 HA.