# Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-like antibodies

## TL;DR

Increasing the valency of vaccine immunogens improves the maturation of HIV-1 antibodies that can broadly neutralize the virus.

## Contribution

The study demonstrates that higher valency immunogens preferentially select and mature antibodies with mutations found in broadly neutralizing HIV antibodies.

## Key findings

- Higher valency immunogens lead to antibodies with mutations similar to those in broadly neutralizing VRC01-class antibodies.
- These antibodies show improved and broader binding to HIV envelope proteins.
- The findings are relevant for designing clinical trials targeting VRC01-class antibody responses.

## Abstract

Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be one component of an effective HIV-1 vaccine elicited response. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-like antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.

HIV continues to be a major global public health issue with ~39.9 million people living with it at the end of 2023 (https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics). An effective vaccine is therefore needed to prevent viral acquisition. Such a vaccine would most likely elicit diverse immune responses including broadly neutralizing antibodies (bnAbs) such as VRC01-class bnAbs. Although VRC01-class bnAbs have been isolated from several people living with HIV-1 (PLWH), so far, they have not been elicited through immunization. Here we examined whether valency of immunogens that are specifically designed to activate VRC01-class B cells influences VRC01-class antibody-maturation. We found that higher valency nanoparticles preferentially selected VRC01-like antibodies with not only higher somatic mutations but also mutations at key residues that are present in broadly neutralizing VRC01-class antibodies isolated from PLWH. Consequently, these antibodies showed improved and broader Env binding and neutralizing properties. Our efforts provide important information for the development of phase 1 clinical trials focused on the elicitation of broadly neutralizing HIV-1 antibody responses.