Mutation-Guided Vaccine Design: A Strategy for Developing Boosting Immunogens for HIV Broadly Neutralizing Antibody Induction

A major goal of HIV-1 vaccine development is induction of broadly neutralizing antibodies (bnAbs). While 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 knock-in 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 towards development of an HIV vaccine. ### Competing Interest Statement KW, KOS, and BFH have patent applications on some of the concepts and immunogens discussed in this paper. MAT is an employee of 3M Company. 3M company had no role in the execution of the study, data collection, or data interpretation. CB and YKT are employees of Acuitas Therapeutics, a company focused on development of LNP for therapeutic applications; YKT is named on patents describing the use of modified mRNA LNP. CBF is an inventor on patents and patent applications held/submitted by AAHI associated with adjuvant formulations containing GLA or 3M-052. All other authors declare no competing interests.