In a recent study posted to the medRxiv* preprint server, researchers investigated the associations between antibody levels against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the risk of subsequent infection.
Immune responses after SARS-CoV-2 infection or vaccination vary over time and between individuals. Antibodies against SARS-CoV-2 nucleocapsid (N) protein are elicited in response to infection but not vaccination. Hence, the presence of anti-N antibodies is a valuable surrogate to differentiate infection-elicited antibodies from vaccine-induced antibodies.
Earlier studies observed a correlation between higher levels of antibodies against spike (S) protein or its receptor-binding domain (RBD) after two vaccine doses and enhanced protection against subsequent infection. Besides the temporal effects, the neutralizing capacity of the antibodies differs based on virulence and divergence of S proteins in emergent variants from the ancestral S protein.
The study and findings
Researchers evaluated the origins 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).
Antibodies levels were determined at two time points for 9361 individuals from ALSPAC and TwinsUK cohorts during April-May 2021 (referred to as 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 likely enlisted in the UK “Shielded Patient List” than participants who received fewer doses.
The prevalence of suspected or confirmed coronavirus disease 2019 (COVID-19) cases at Q2 testing was 26% among the TwinsUK and 20% in the ALSPAC cohort. However, anti-N antibody positivity was lower at 10% in ALSPAC and 12% in TwinsUK. In Q4, SARS-CoV-2 infection prevalence was higher, with 33% suspected or confirmed cases and 17% based on anti-N antibody levels.
Within the TwinsUK cohort in Q4, the authors observed more significant and sustained antibody levels post-third dose with less variation between individuals when compared to the antibody levels of individuals with fewer vaccinations. For instance, 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 post-second dose (1300 BAU/ml).
Individuals with the lowest antibody levels had substantial increases in absolute levels following 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 declined 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 post-second dose.
At Q2, antibody levels peaked nine weeks post-first dose among TwinsUK and ALSPAC subjects. After the second dose, antibody levels surpassed the assay limit from the second week onwards. In the TwinsUK cohort, vaccine breakthrough infections were recorded in 276 (9.2%) individuals between the first vaccination and Q4. Those who were single-vaccinated at Q2 with a subsequent breakthrough infection had lower Q2 median antibody levels (40 BAU/ml) than those who did not experience breakthrough infection (57 BAU/ml).
They noted that individuals with the lowest antibody levels at Q2 were at higher odds of experiencing a breakthrough infection in univariable (odds ratio, OR: 3.2) and multivariable (OR: 2.9) logistic regression models. Increased odds 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 had greater odds of having lower antibody levels after the first and second vaccination relative to Pfizer’s BNT162b2 vaccinees. Nevertheless, a double AZD1222 dose was not associated with lower levels of antibodies after the third vaccination. In the TwinsUK cohort, monozygotic (MZ) twins exhibited minor average intra-pair differences in anti-S antibody levels post-third dose relative to dizygotic twins. The intra-pair differences were large for non-related subjects.
The researchers found high variability in antibody responses after the first vaccination with decreasing variability after administration of second and third vaccine doses. Individuals who had low levels of antibodies post-first dose were at an elevated risk of subsequent breakthrough infection even after further rounds of vaccination.
Furthermore, increased odds of having lower levels of antibodies post-vaccination were observed for 1) individuals on the Shielded Patient List, 2) first and second-dose recipients of the AZD1222 vaccine, 3) those who reported poorer health, and 4) those who were prescribed immunosuppressants. However, there were no differences after the third vaccination between individuals who received BNT162b2 or AZD1222 for their first and second vaccination, underpinning the booster effect of the third dose.
These findings suggested that measuring anti-S antibodies induced after the first vaccine dose might serve as an early indicator for identifying those at increased risk of COVID-19 infection in the future.
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.