Targeting A35 to unlock broad-spectrum human immunity against orthopoxviruses

The National Institute of Allergy and Infectious Diseases awarded Icahn School of Medicine at Mount Sinai $840,018 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to define mechanisms by which A35-specific monoclonal antibodies confer protection against monkeypox virus and to characterize qualitative differences in A35-targeted antibody responses elicited by infection versus vaccination.

The research addresses inadequacies in current countermeasures—the Jynneos vaccine elicits only modest and short-lived protection, and the antiviral tecovirimat has failed to demonstrate efficacy in human clinical trials. Preliminary data reveal that natural MPXV infection induces robust antibody responses to the viral protein A35, and three highly protective A35-specific monoclonal antibodies have been isolated from an infected individual. In Aim 1, the recipient will dissect the role of Fc-mediated effector functions in prophylactic and therapeutic activity of these antibodies, including in a mucosal challenge model that mimics human MPXV transmission. In Aim 2, the recipient will isolate and characterize new A35-specific monoclonal antibodies from infected and vaccinated individuals to define structural and functional correlates of protection and analyze B cell responses at single-cell resolution. These studies will provide insights into antibody-mediated immunity to MPXV and establish the foundation for rational design of improved antibody-based therapeutics and next-generation vaccines.

Performance occurs at New York, NY 10029. The project runs through August 31, 2031.

Abstract

The 2022 global outbreak of mpox (monkeypox disease), caused by monkeypox virus (mpxv), underscored the urgent need for more effective tools to combat this RE-emerging pathogen. Current countermeasures-namely, the jynneos vaccine and the antiviral tecovirimat-are inadequate: the vaccine elicits only modest and short-lived protection, and tecovirimat has failed to demonstrate efficacy in human clinical trials. Our preliminary data reveal that natural mpxv infection, but not vaccination, induces a robust antibody response to the viral protein A35, and we have isolated three highly protective A35-specific monoclonal antibodies (mabs) from an infected individual. This proposal aims to define the mechanisms by which these mabs confer protection and to elucidate the qualitative differences in A35-targeted antibody responses elicited by infection versus vaccination. In aim 1, we will dissect the role of FC-mediated effector functions in the prophylactic and therapeutic activity of these antibodies, including in a mucosal challenge model that mimics human mpxv transmission. In aim 2, we will isolate and characterize new A35- specific mabs from infected and vaccinated individuals to define structural and functional correlates of protection and analyze b cell responses at single-cell resolution. These studies will provide critical insights into antibody-mediated immunity to mpxv and lay the foundation for rational design of improved antibody-based therapeutics and next-generation vaccines to prevent future mpox outbreaks.