Search

The resurgence of yellow fever in South America has prompted vaccination against the etiologic agent, yellow fever virus (YFV). Current vaccines are based on a live-attenuated YF-17D virus derived from a virulent African isolate. The capacity of these vaccines to induce neutralizing antibodies against the vaccine strain is used as a surrogate for protection. However, the sensitivity of genetically distinct South American strains to vaccine-induced antibodies is unknown. We show that antiviral potency of the polyclonal antibody response in vaccinees is attenuated against an emergent Brazilian strain. This reduction was attributable to amino acid changes at two sites in central domain II of the glycoprotein E, including multiple changes at the domain I-domain II hinge, which are unique to and shared among most South American YFV strains. Our findings call for a reevaluation of current approaches to YFV immunological surveillance in South America and suggest approaches for updating vaccines., Competing Interests: Declaration of interests K.C. is a member of the scientific advisory boards of Integrum Scientific, Biovaxys Technology, and the Pandemic Security Initiative of Celdara Medical. A.Z.W., M.S., and L.M.W. are/were employees of Adimab, and may hold shares in Adimab. L.M.W. is an employee of Adagio Therapeutics, and holds shares in Adagio Therapeutics. C.L.M. and Z.A.B. are employees of Mapp Biopharmaceutical., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM + CD27 + ) and switched immunoglobulin (swIg + ) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg + and atypical IgM + and IgD + MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination., Competing Interests: Competing interest statement: A.Z.W., L.S., A.L., J.H.N., M.B., and L.M.W. are employees and equity holders in Adimab LLC. C.L.M. and Z.A.B. are employees of and shareholders in Mapp Biopharmaceutical, Inc., (Copyright © 2020 the Author(s). Published by PNAS.)