Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses.
Publication Type:
Journal ArticleSource:
Immunity, Volume 57, Issue 5, p.1141-1159.e11 (2024)Keywords:
Amino Acid Substitution, Animals, Antibodies, Neutralizing, Antibodies, Viral, B-Lymphocytes, Broadly Neutralizing Antibodies, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza A virus, Influenza Vaccines, Influenza, Human, Mice, Orthomyxoviridae Infections, VaccinationAbstract:
<p>Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.</p>