Study examines link between antibody response to COVID-19 vaccination and risk of subsequent infection

In a recent study posted to the medRxiv* preprint server, researchers examined the associations between antibody levels against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the risk of subsequent infection.

Background

Immune responses following SARS-CoV-2 infection or vaccination vary over time and between individuals. Antibodies to SARS-CoV-2 nucleocapsid (N) protein are raised in response to infection, but not to vaccination. Therefore, the presence of anti-N antibodies is a valuable surrogate to distinguish infection-induced antibodies from vaccine-induced antibodies.

Previous studies have observed a correlation between higher levels of antibodies to spike (S) protein or its receptor binding domain (RBD) after two vaccine doses and improved protection against subsequent infection. In addition to the transient effects, the neutralizing ability of the antibodies differs based on virulence and divergence of S proteins in emerging variants of the ancestral S protein.

The study and findings

Researchers evaluated the origin and consequences of variation in anti-SARS-CoV-2 antibody levels after vaccination in the current study. They quantified antibody levels of participants from two longitudinal cohorts in the United Kingdom (UK): TwinsUK and Avon Longitudinal Study of Parents and Children (ALSPAC).

Antibody levels were determined at two time points for 9361 individuals from ALSPAC and TwinsUK cohorts in April–May 2021 (designated Q2, as in the calendar year quarter) and 3575 subjects from the TwinsUK cohort between November 2021 and January 2022 (Q4). Those who received more vaccine doses were older and more likely to be on the UK’s “Shielded Patient List” than participants who received fewer doses.

The prevalence of suspected or confirmed cases of 2019 coronavirus disease (COVID-19) in Q2 testing was 26% among the TwinsUK and 20% in the ALSPAC cohort. However, the anti-N antibody positivity was lower at 10% in ALSPAC and 12% in TwinsUK. In the fourth quarter, the prevalence of SARS-CoV-2 infection was higher, with 33% suspected or confirmed cases and 17% based on anti-N antibody levels.

Within the TwinsUK cohort in the fourth quarter, the authors observed more significant and sustained antibody levels after the third dose with less variation between individuals compared to the antibody levels of individuals with fewer vaccinations. For example, the median level of anti-S antibodies was 13,700 binding antibody units (BAU)/ml after the third vaccination, which was 10-fold higher than the levels after the second dose (1300 BAU/ml).

Subjects with the lowest antibody levels had a significant increase in absolute levels after the third dose. TwinsUK subjects sampled two/three weeks after the third vaccination had the highest median antibody levels for up to 16 weeks. The median levels fell between two and eight weeks, and there was no further decline after that. Longer time since vaccination was associated with lower levels of antibodies for individuals sampled between 13 and 33 weeks after the second dose.

In the second quarter, antibody levels peaked nine weeks after the first dose in TwinsUK and ALSPAC subjects. After the second dose, antibody levels exceeded the test limit from the second week. In the TwinsUK cohort, vaccine breakthrough infections were recorded in 276 (9.2%) subjects between the first vaccination and the fourth quarter. Those who were single vaccinated in the second quarter with a subsequent breakthrough infection had lower median antibody levels in the second quarter (40 BAU/ml) than those who had no breakthrough infection (57 BAU/ml).

They noted that individuals with the lowest antibody levels in Q2 were more likely to experience breakthrough infection in univariable (odds ratio, OR: 3.2) and multivariable (OR: 2.9) logistic regression models. A greater likelihood of having the lowest antibody levels after the first vaccination was observed in those on the UK Shielded Patient List in TwinsUK (OR: 4) and ALSPAC cohorts (OR: 4.1).

Individuals vaccinated with AstraZeneca’s AZD1222 vaccine were more likely to have lower antibody levels after the first and second vaccinations compared to Pfizer’s BNT162b2 vaccines. Nevertheless, a double dose of AZD1222 was not associated with lower levels of antibodies after the third vaccination. In the TwinsUK cohort, monozygotic (MZ) twins showed small within-pair mean differences in anti-S antibody levels after the third dose compared to dizygotic twins. The within-pair differences were large for unrelated subjects.

conclusions

The researchers found a high variability in antibody responses after the first vaccination with decreasing variability after administration of second and third vaccine doses. Individuals with low levels of antibodies after the first dose had an increased risk of subsequent breakthrough infection, even after further rounds of vaccination.

Furthermore, an increased likelihood of lower levels of antibodies was observed after vaccination for 1) individuals on the screened patient list, 2) recipients of the first and second doses of the AZD1222 vaccine, 3) those reporting poorer health, and 4) those those prescribed immunosuppressants. However, there were no differences after the third vaccination between subjects who received BNT162b2 or AZD1222 for their first and second vaccinations, supporting the booster effect of the third dose.

These findings suggested that measuring anti-S antibodies induced after the first vaccine dose could serve as an early indicator for identifying those at increased risk for COVID-19 infection in the future.

*Important announcement

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