Improving the innate activity of broadly neutralizing vectored antibodies against HIV

The National Institute of Allergy and Infectious Diseases, part of the Department of Health and Human Services National Institutes of Health, awarded $1,032,783 to Massachusetts General Hospital on August 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research on broadly neutralizing antibodies against HIV.

The research, led by Dr. Alejandro Balazs at the Ragon Institute of MGH, MIT & Harvard, focuses on engineering the immune system through gene transfer to enhance HIV prevention and therapy. The project will use in vitro cell-based assays to evaluate how next-generation HIV broadly neutralizing antibodies engage effector functions, particularly antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. The work will modify vectored immunoprophylaxis technology to generate sustained expression of antibodies with engineered Fc-region mutations designed to enhance or abrogate Fc-receptor interactions, thereby defining the rules governing Fc-receptor engagement for HIV prevention and determining the potential for Fc-enhanced antibodies to increase broadly neutralizing antibody protection.

The award recipient is The General Hospital Corporation, operating as Massachusetts General Hospital Research Management Division, a nonprofit academic medical center and Harvard Medical School teaching hospital. Place of performance is Boston, Massachusetts. The period of performance runs from August 1, 2026, through July 31, 2027. The assistance type is a project grant with $1,032,783 obligated.

Abstract

This proposal describes an R01 grant for alejandro balazs, PHD. DR. Balazs is currently an associate professor at harvard medical school working as a principal investigator at the ragon institute of MGH, MIT & harvard. DR. Balazs' research is focused on engineering the immune system via gene transfer as a novel means of creating protection against HIV. Broadly neutralizing antibodies (bnabs) against human immunodeficiency virus (HIV) show great promise in HIV prevention and therapy as they potently neutralize a significant breadth of globally circulating HIV strains. A number of animal experiments and clinical trials have demonstrated the ability of bnabs to confer protection from viral challenge and reduce viremia of established infections. Bnabs can inhibit HIV infection by blocking viral attachment or membrane fusion; however, recent work suggests that the fragment crystallizable (FC) region of antibodies may also contribute significantly to bnab-mediated HIV inhibition through interactions with innate immunity in animal models. This proposal seeks to use in vitro cell-based assays to determine the extent to which a newly selected set of next-generation HIV bnabs engage effector functions, such as antibody-dependent cellular cytotoxicity (adcc) and antibody- dependent cellular phagocytosis (adcp). This proposal will modify the vectored immunoprophylaxis technology pioneered by DR. Balazs to generate sustained expression of antibodies harboring precise FC- region mutations previously demonstrated to enhance or abrogate, FC-receptor interactions. By encoding the specificity and manipulating the concentration of these antibodies, this study will define the rules governing FC- receptor engagement that apply to prevention of HIV acquisition. Furthermore, IT will determine the potential for FC-enhanced antibodies to increase the potency of bnab protection against HIV transmission. Finally, this proposal will manipulate the immune system of humanized mice as a means of dissecting and precisely quantifying the contribution of specific immune cells to prevention of HIV transmission. Together, this work will reveal optimal epitope targets and innate immune mechanisms to produce next-generation AAV vectors encoding bnabs with enhanced innate immune function to prevent HIV transmission.