Characterizing virologic and immunologic features of RSV immunoprophylaxis and escape

The National Institute of Allergy and Infectious Diseases, part of the Department of Health and Human Services, awarded $853,847 to Massachusetts General Hospital on August 21, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds characterization of virologic and immunologic features of RSV immunoprophylaxis and escape. The recipient will sequence the genomes of approximately 3,000 biobanked and prospectively collected respiratory syncytial virus specimens spanning pre- and post-vaccination periods from 2022 through 2028 to identify mutations and genotypes associated with viral escape from RSV vaccines and monoclonal antibodies. The work will also determine how RSV immunoprophylaxis impacts viral decay and clearance, leveraging established clinical, laboratory, and genomics research infrastructure within an integrated health system that includes thousands of banked clinical RSV specimens and enrollment capacity.

Performance occurs in Boston, Massachusetts. The ultimate completion date is July 31, 2027. This is a Project Grant, classified as assistance funding.

Abstract

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection among young children and elderly adults. The food and drug administration (FDA) has recently approved several vaccines and monoclonal antibodies (mabs) against RSV. All immunoprophylaxis strategies generate immune responses to the f-glycoprotein, which is relatively conserved, but they differ in their approach to generating anti-f immunity. Most mabs target conserved f epitopes, whereas approved vaccines generate a polyclonal response against prefusion-stabilized f protein. Emerging data indicate that RSV genetic diversity can undermine the efficacy of immunoprophylaxis, particularly mabs. For example, the MAB suptavumab failed in clinical trials due to the evolution of two amino acid mutations in RSV b that rendered IT ineffective. While vaccines appear to be more robust to this phenomenon, laboratory and clinical efficacy studies document the influence of RSV genotype, with monovalent a vaccines generating weaker responses against b viruses than bivalent vaccines. To identify RSV genetic variants associated with escape from immune prophylaxis and characterize the viral and immunological determinants of breakthrough infection, we will leverage established and highly collaborative clinical, laboratory and genomics research infrastructure (positives) that includes thousands of banked clinical RSV specimens and enrollment infrastructure within a large, integrated health system. In aim 1, we will sequence the genomes of 3,000 biobanked and prospectively during pre- and post-vaccination periods spanning 2022-2028, and compare genetic diversity over time in the entire population and genomes between groups to identify mutations and genotypes associated with escape from vaccines and mabs. In aim 2, we will determine how RSV immunoprophylaxis impacts viral decay and clearance. We will enroll a prospective cohort of 200 individuals divided into two groups: 1) prior RSV vaccination (n=100); and 2) age-matched individuals in group 1 with no prior RSV vaccination (n=100). We will collect nasal swabs for RSV quantitative PCR and viral culture three times weekly until PCR negative on two consecutive swabs. We will measure viral decay rates and time to cessation of replication-competent viral shedding, and compare genetic diversity between groups. In aim 3, we will determine how BTI after MAB and vaccine BTI alters mucosal and humoral immune responses and measure whether the evolution of f glycoprotein leads to escape from vaccines and monoclonal antibodies. We will assess binding and neutralizing antibody responses against RSV genotypes using live virus neutralization, measure cellular responses against RSV using elispot, and define the immune correlates of rapid RSV clearance among individuals with and without RSV immunoprophylaxis. The results will quantify the impact of RSV evolution on immune escape and characterize the immunological and virological determinants of RSV infection after immunoprophylaxis, informing current and future RSV prevention efforts.