Study examines associations between antibody response to COVID-19 vaccine and risk of subsequent infection

In a recently published study medRxiv* Preprint servers, researchers examined the associations between antibody levels to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the risk of subsequent infection.

Study: Antibody levels after vaccination against SARS-CoV-2: associations with post-vaccination infections and risk factors. Credit: Kateryna Kon/Shutterstock


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. Therefore, the presence of anti-N antibodies is a valuable surrogate to distinguish infection-induced antibodies from vaccine-induced antibodies.

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

The study and results

In the current study, the researchers assessed the origins and consequences of the fluctuations in anti-SARS-CoV-2 antibody levels after vaccination. They quantified the antibody levels of participants from two longitudinal United Kingdom (UK) cohorts: 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 (referred to as Q2, as in calendar year quarter) and for 3575 individuals from TwinsUK cohort between November 2021 and January 2022 (Q4). . . Those who received more vaccine doses were older and likely on the UK Shielded Patient List than participants who received fewer doses.

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

Within the TwinsUK Q4 cohort, the authors observed more significant and sustained antibody levels after the third dose with less inter-subject variation compared to the antibody levels of individuals with fewer vaccinations. For example, the median value of anti-S antibodies was 13,700 binding antibody units (BAU)/mL after the third vaccination, which was 10-fold higher than the value after the second dose (1300 BAU/mL).

Individuals with the lowest antibody levels had a significant increase in absolute levels after the third dose. TwinsUK subjects collected 2/3 weeks after the third vaccination had the highest mean antibody levels up to 16 weeks. Mean levels decreased between two and eight weeks, and after that there was no further decrease. A longer time since vaccination was associated with lower antibody levels in subjects 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 assay limit from the second week. In the TwinsUK cohort, 276 (9.2%) had breakthrough vaccine infections between the first vaccination and Q4. Those vaccinated with a single breakthrough infection in Q2 had lower median antibody levels (40 BAU/mL) in Q2 than those who did not experience breakthrough infection (57 BAU/mL).

They found that in univariable (odds ratio, OR: 3.2) and multivariable (OR: 2.9) logistic regression models, people with the lowest Q2 antibody levels had a higher likelihood of experiencing breakthrough infection. An increased likelihood of having the lowest antibody levels after the first vaccination was observed in patients 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 individuals vaccinated with Pfizer’s BNT162b2. However, a double dose of AZD1222 was not associated with lower antibody levels after the third vaccination. In the TwinsUK cohort, identical (MZ) twins compared to dizygotic twins showed minor intra-pair mean differences in anti-S antibody levels after the third dose. Intra-pair differences were large in unrelated subjects.


Researchers found high variability in antibody responses after the first vaccination, with variability decreasing after administration of the second and third doses of vaccine. People who had low antibody levels after the first dose were also at increased risk of subsequent breakthrough infection after additional rounds of vaccination.

In addition, an increased likelihood of lower post-vaccination antibody levels was observed in 1) subjects on the Shielded Patient List, 2) first and second dose recipients of AZD1222 vaccine, 3) subjects reporting worse health, and 4) subjects who have been prescribed immunosuppressants. However, there were no differences after the third vaccination between people who received BNT162b2 or AZD1222 for their first and second vaccination, supporting the booster effect of the third dose.

These results suggest that measuring anti-S antibodies induced after the first vaccine dose could serve as an early indicator for identifying individuals at increased risk of future COVID-19 infection.

*Important NOTE

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

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