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The neutralizing antibody titer correlate of COVID-19 risk in the COVID-19 variant immunologic landscape (COVAIL) trial was not modified by SARS-CoV-2 amino acid sequence distances
Journal article   Open access   Peer reviewed

The neutralizing antibody titer correlate of COVID-19 risk in the COVID-19 variant immunologic landscape (COVAIL) trial was not modified by SARS-CoV-2 amino acid sequence distances

Fei Heng, Craig A. Magaret, Nadine G. Rouphael, Angela R. Branche, Youyi Fong, Lindsay N. Carpp, Chenchen Yu, Shiyu Chen, Bo Zhang, David J. Diemert, …
Vaccine, Vol.76, 128348
03/19/2026
DOI: 10.1016/j.vaccine.2026.128348
PMID: 41698311
url
https://doi.org/10.1016/j.vaccine.2026.128348View
Published (Version of record) Open Access

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. •The neutralizing antibody correlate of risk did not vary significantly by vaccine insert distance.•This finding was the same among all participants and those who were SARS-CoV-2 naïve.•One explanation for the finding is limited antigenic variability of the circulating strains.
 Deep mutational scanning Immune correlate of protection mRNA vaccine Neutralizing antibody escape Randomized clinical trial Recombinant protein vaccine

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