Design and testing of immunogens to elicit 10E8-like broadly neutralizing antibodies against HIV

Scripps Research Institute, The, La Jolla CA

Investigators

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Abstract

Abstract Induction of broadly neutralizing antibodies (bnAbs) against HIV remains a global health priority. bnAbs targeting the membrane-proximal external region (MPER) of the HIV envelope protein (Env) offer broad and potent protection, but their elicitation through vaccination is challenging due to the recessed epitope close to the membrane. To overcome these challenges, we recently developed germline-targeting epitope- scaffold nanoparticles with affinity for MPER bnAb precursors and demonstrated consistent priming of 10E8-class and LN01-class precursors in stringent mouse models and rhesus macaques. However, heterologous boost immunizations with antigens of increasing similarity to native Env will be required to induce bnAbs. Our strategy involves boosting with (1) epitope-scaffold nanoparticles stabilizing a wildtype MPER, (2) membrane-bound Env stabilized in a conformation with increased MPER binding, and (3) membrane-bound wildtype Env. Here, we propose a four-aim approach to develop an immunization regimen that induces bnAbs by shepherding 10E8-class and LN01-class B cells. Aim 1 will employ artificial intelligence-based computational design to develop epitope-scaffold boost#1 immunogens, Aim 2 will test these candidates in stringent mouse models, Aim 3 will utilize computational design and mammalian display directed evolution to design stabilized transmembrane Env boost#2 immunogens that preferentially bind intermediate 10E8-class or LN01-class antibodies, and Aim 4 will demonstrate induction of bnAbs in new intermediate BCR knock-in mice. Successful completion of this project will be a major step in the development of an effective HIV vaccine and provide valuable insights into the design of germline-targeting vaccines for other infectious diseases.