Publication Date

3-19-2026

Journal

Vaccine

DOI

10.1016/j.vaccine.2026.128348

PMID

41698311

PMCID

PMC13008134

PubMedCentral® Posted Date

3-24-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

In the Coronavirus Variant Immunologic Landscape Trial (COVAIL) conducted in the United States in 2022–2023, 985 participants received a second COVID-19 booster with one of twelve monovalent or bivalent mRNA inserts. Pseudovirus serum inhibitory dilution 50% neutralizing antibody titer (nAb titer) measured two-weeks post booster significantly associated with lower COVID-19 incidence over six months follow-up in this trial. COVAIL investigators sequenced SARS-CoV-2 Spike amino acid sequences for all COVID-19 cases, with a sequence successfully obtained from 129 of 195 cases. For COVID-19 endpoint cases we calculated five distances of the case-causing sequence to a reference sequence, the first two physico-chemical weighted Hamming distances of Spike or receptor binding domain (RBD) to a participant’s nearest Spike or RBD vaccine-insert sequence, and the other three estimated degrees of neutralizing antibody escape from the XBB.1.5 RBD strain calculated with deep mutational scanning. Hypothesizing that the nAb titer correlate of risk may have a stronger association with COVID-19 when focusing on COVID-19 infections more closely matched to the vaccine insert in Spike or RBD amino acid sequence or with lower RBD antibody escape score, we tested this hypothesis for the combined group receiving a monovalent Prototype (ancestral strain) booster (n = 143) and for the combined group receiving an Omicron-containing booster (n = 744). For both combined groups, the nAb titer correlate of risk did not significantly vary across any of the assessed sequence distances from the vaccine insert (all p-values >0.10), although RBD Hamming distance had point estimates consistent with a weakening correlate with distance, motivating further exploration in settings with greater antigenic heterogeneity. Indeed, statistical power was bounded by the limited antigenic variability of viruses infecting trial participants over the follow-up period (April 21, 2022 to May 25, 2023), which spanned only a 3.02-fold nAb titer range of differential sensitivity to sera from XBB.1.5-infected individuals. ClinicalTrials.gov Identifier: NCT05289037.

Keywords

Antibodies, Neutralizing, Humans, Antibodies, Viral, SARS-CoV-2, COVID-19, Spike Glycoprotein, Coronavirus, COVID-19 Vaccines, Amino Acid Sequence, Immunization, Secondary, Deep mutational scanning, Immune correlate of protection, mRNA vaccine, Neutralizing antibody escape, Randomized clinical trial, Recombinant protein vaccine

Published Open-Access

yes

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