Mutation-guided vaccine design: A process for developing boosting immunogens for HIV broadly neutralizing antibody induction.

A major goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs). Although success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here, we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knockin mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof of concept and milestone toward development of an HIV-1 vaccine.

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Copyright © 2024. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of interests K.W., K.O.S., and B.F.H. have patent applications on some of the concepts and immunogens discussed in this paper. M.A.T. is an employee of 3M Company. 3M Company had no role in the execution of the study, data collection, or data interpretation. C.B. and Y.K.T. are employees of Acuitas Therapeutics; Y.K.T. is named on patents describing the use of modified mRNA LNP. C.B.F. is an inventor on patents and patent applications held/submitted by AAHI, associated with adjuvant formulations containing GLA or 3M-052.