Glycan-reactive antibodies isolated from human HIV-1 vaccine trial participants show broad pathogen cross-reactivity

HIV-1 continues to pose a significant global health challenge, requiring ongoing research into effective prevention and treatment strategies. Understanding the B-cell repertoire that can be engaged upon vaccination in humans is crucial for the development of future preventive vaccines. In this study, peripheral blood mononuclear cells from HIV-negative participants in the multivalent HVTN124 human HIV-1 vaccine clinical trial were interrogated for HIV-reactive B cells using LIBRA-seq, a high-throughput B-cell mapping technology. We report the discovery of glycan-reactive antibodies, with one of these being capable of neutralizing diverse heterologous HIV-1 virus strains. Furthermore, isolated antibodies showed broad cross-reactivity against antigens from a variety of other pathogens. The emerging class of glycan-reactive virus-neutralizing antibodies with exceptional breadth of pathogen cross-reactivity may present an effective target for vaccination at the population level.

Understanding how the human immune system recognizes and combats viruses is crucial for developing better vaccines and treatments. Here, through characterization of the B-cell receptor repertoires of participants in HVTN124, a multivalent HIV-1 vaccine human clinical trial, we discovered antibodies that recognize sugar molecules (glycans) on antigens from a range of unrelated viral families. In addition to their binding breadth, these antibodies can also neutralize multiple diverse strains of HIV-1. Our findings reveal an emerging and underappreciated mechanism for antibodies to counteract virus infection, potentially opening doors for developing vaccines that preferentially elicit glycan-reactive antibody species to broadly protect against different viruses.This study is registered with ClinicalTrials.gov as NCT03409276.