*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

In a recent study posted to the medRxiv* server, researchers evaluated whether serologic testing could help estimate the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vaccinated individuals who had not received a booster dose. They recruited this vaccinated cohort from the National Basketball Association (NBA) in the United States of America (USA).

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To this end, they measured neutralizing antibody (nAb) titers in these individuals accounting for time-lapse since primary vaccination, prior SARS-CoV-2 infection, and vaccine type. Next, they evaluated the association between vaccine-induced nAb titers and the rate of SARS-CoV-2 (re)infection.

Background

Coronavirus disease 2019 (COVID-19) vaccines-induced nAb titers, measured through serologic tests, are a potential correlate of SARS-CoV-2 immunity. However, multiple factors, e.g., age, comorbidities, and medical history, could affect immune response(s) against SARS-CoV-2 post-vaccination. Even otherwise, vaccine-induced nAb titers wane over time after attaining a peak at four weeks, thus, increasing the risk of reinfection.

So rather than following a 'one-size-fits-all' approach for boosting schedule, researchers have begun to think along the lines of a COVID-19 booster schedule that accounts for individual-level heterogeneity. This endeavor requires serological or nAb quantification tests that evaluate an individual's immunity after COVID-19 vaccination over a prolonged duration since vaccination.

Several serological tests have earned Emergency Use Authorization (EUA) from the United States Food and Drug Administration (US-FDA. However, none fully quantify immunity to SARS-CoV-2 infection, especially accounting for the ongoing emergence of SARS-CoV-2 variants. Thus, there is an urgent need to find an objective correlate for SARS-CoV-2 immunity and the optimal booster schedule to protect against SARS-CoV-2 reinfection(s) and help minimize these cases.

About the study

In the present study, researchers used the FDA-approved TrimericS assay to measure nAbs against the SARS-CoV-2 WA-1 spike (S) protein in players and team staff of the 2021-2022 NBA season. These individuals, aged 18 years or above, volunteered to get their SARS-CoV-2 nAb titer measurements via the TrimericS Assay between September 12, 2021, and December 31, 2021. Also, most of them had completed their primary COVID-19 vaccination series by the time of antibody testing.

The team collected all relevant sociodemographic and clinical characteristics, including age, gender, time since completion of primary vaccination, and previous SARS-CoV-2 infection. The primary study outcome was the incidence of SARS-CoV-2 infection within 90 days after nAb titer measurements. The researchers sent COVID-19-positive samples for genomic sequencing to assign an infecting variant. For the samples for which SARS-CoV-2 genome sequencing was not feasible, they considered all cases before March 2021 due to the Delta variant and post-January 2022 to Omicron.

They performed a time-to-event analysis among individuals who had not received a booster before serologic testing to evaluate the association between nAb titers and the risk of SARS-CoV-2 (re)infection. Further, they used Cox proportional hazards regression model alongside Kaplan-Meier curves to estimate rates of SARS-CoV-2 infection with 95% confidence intervals (CIs). They adjusted study models for age, time lapse since the last vaccine dose, and SARS-CoV-2 infection before nAb measurement.

A NAb titer of 100 arbitrary units (AU)/mL in a serological assay typically correlates with a 50% protection against wild-type (wt) SARS-CoV-2 strain. However, on the TrimericS assay, 250 AU/mL denoted a potentially higher risk of SARS-CoV-2 infection. So, the team compared the risk of contracting COVID-19 within 90 days of nAb measurement with the reference group having >800 AU/mL nAb titers overall and stratified by vaccine type. Sensitivity analyses helped the researchers estimate hazard ratios (HRs) for Delta and Omicron infections, modeling them as contending risks.

Study findings

Between 12 September and December 31, 2021, 2,388 vaccinated individuals underwent serological testing via the TrimericS Assay. The final cohort for analysis, however, comprised only 2,323 individuals.

The cohort had 78.2% males, and the majority were under 40. Over 50% had received an mRNA COVID-19 vaccine; however, 75 people had received a booster dose by the time of testing. The rest 1,934 individuals received a booster dose within 90 days after serological testing. Most study participants (~77%) were four to six months post-vaccination at testing time, and boosted individuals were more than seven months primary post-vaccination.

All the study participants fell into three groups with <250, 250 to 800, and >800 AU/mL nAb titer levels. Among unboosted individuals, 2,248 had detectable nAb titer values, with an average titer value of 293.5 AU/mL. Among boosted individuals, nAb titers were highest among those who had completed primary vaccination series in the past four months, i.e., >800 AU/mL, and lowest among those who had taken primary two-doses of a COVID-19 vaccine more than seven months before their serologic testing.

Based on the vaccine type, recipients of the Ad26. COV2. S vaccine had lower nAb titers than Spikevax and Comirnaty vaccine recipients. Compared to those with nAb titers >800 AU/mL, people with <250 AU/mL nAb titers experienced fewer SARS-CoV-2 infections over the 90-day follow-up period (8.6% vs. 5.5%).

Day 70 of the study marked the beginning of the Omicron wave in the US. Compared to the >800 AU/mL group, 709 individuals with nAb titers between 250 and 800 AU/mL experienced a relatively elevated rate of SARS-CoV-2 infection during the Omicron wave, irrespective of primary-series vaccine type.

During the Delta wave, individuals with nAb titers <250 AU/mL were more likely to experience SARS-CoV-2 infections earlier in the follow-up period. Conversely, Omicron caused 79.5% and 88.9% of SARS-CoV-2 infections in the 250 to 800 and >800 AU/mL groups, respectively. Furthermore, the results from the Omicron-specific model indicated that the rate of Omicron infections in individuals with titers less than 250 AU/mL was not markedly different than those with >800 AU/mL titers.

Conclusions

The study findings suggested that serologic testing could inform patient-level assessments of susceptibility to SARS-CoV-2 infection. These tests, thus, could serve as a valuable guide to inform decision-making on the COVID-19 booster schedules. However, more wide-scale studies are needed to define correlates of SARS-CoV-2 immune protection. In addition, it is crucial to assess the durability of immunity and whether the protective effect from infection remains adequate against all SARS-CoV-2 variants.

Serological tests detecting WA-1 S protein have shown a weaker correlation with Omicron-specific nAb titers. So, most importantly, there is an urgent need for new serological assays for emerging SARS-CoV-2 variants. Once these correlates get established in real-world settings, it will encourage the FDA to authorize novel tests that detect variant-specific nAB titers rather than overall immunoglobulin levels.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.