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NIH grant 1R56AI199269-01: Characterizing virologic and immunologic features of RSV immunoprophylaxis and escape
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Jacob Eric Lemieux. Award: $853847.
Start: 2026-08-21T00:00:00.
PROJECT 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.document fetched 2026-08-30 02:46