Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 24:12:e80428.
doi: 10.7554/eLife.80428.

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors in two UK longitudinal studies

Nathan J Cheetham  1 , Milla Kibble  1   2   3 , Andrew Wong  4 , Richard J Silverwood  5 , Anika Knuppel  4 , Dylan M Williams  4   6 , Olivia K L Hamilton  7 , Paul H Lee  8 , Charis Bridger Staatz  5 , Giorgio Di Gessa  9 , Jingmin Zhu  9 , Srinivasa Vittal Katikireddi  7 , George B Ploubidis  5 , Ellen J Thompson  1   4 , Ruth C E Bowyer  1   2   10 , Xinyuan Zhang  1 , Golboo Abbasian  1 , Maria Paz Garcia  1 , Deborah Hart  1 , Jeffrey Seow  11 , Carl Graham  11 , Neophytos Kouphou  11 , Sam Acors  11 , Michael H Malim  11 , Ruth E Mitchell  2 , Kate Northstone  2 , Daniel Major-Smith  2 , Sarah Matthews  2 , Thomas Breeze  2 , Michael Crawford  2 , Lynn Molloy  2 , Alex S F Kwong  2   12 , Katie Doores  11 , Nishi Chaturvedi  4 , Emma L Duncan  1   13 , Nicholas J Timpson  2 , Claire J Steves  1   13
Affiliations

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors in two UK longitudinal studies

Nathan J Cheetham et al. Elife. .

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. Higher levels of SARS-CoV-2 anti-Spike antibodies are known to be associated with increased protection against future SARS-CoV-2 infection. However, variation in antibody levels and risk factors for lower antibody levels following each round of SARS-CoV-2 vaccination have not been explored across a wide range of socio-demographic, SARS-CoV-2 infection and vaccination, and health factors within population-based cohorts.

Methods: Samples were collected from 9361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies and tested for SARS-CoV-2 antibodies. Cross-sectional sampling was undertaken jointly in April-May 2021 (TwinsUK, N=4256; ALSPAC, N=4622), and in TwinsUK only in November 2021-January 2022 (N=3575). Variation in antibody levels after first, second, and third SARS-CoV-2 vaccination with health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables were analysed. Using multivariable logistic regression models, we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables.

Results: Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had threefold greater odds of SARS-CoV-2 infection over the next 6-9 months (OR = 2.9, 95% CI: 1.4, 6.0), compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK 'Shielded Patient List' had consistently greater odds (two- to fourfold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations.

Conclusions: These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies.

Funding: Antibody testing was funded by UK Health Security Agency. The National Core Studies program is funded by COVID-19 Longitudinal Health and Wellbeing - National Core Study (LHW-NCS) HMT/UKRI/MRC ([MC_PC_20030] and [MC_PC_20059]). Related funding was also provided by the NIHR 606 (CONVALESCENCE grant [COV-LT-0009]). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The UK Medical Research Council and Wellcome (Grant ref: [217065/Z/19/Z]) and the University of Bristol provide core support for ALSPAC.

Keywords: ALSPAC; COVID-19; SARS-CoV-2; TwinsUK; antibodies; epidemiology; global health; human; medicine; vaccination.

Plain language summary

Vaccination against the virus that causes COVID-19 triggers the body to produce antibodies that help fight future infections. But some people generate more antibodies after vaccination than others. People with lower levels of antibodies are more likely to get COVID-19 in the future. Identifying people with low antibody levels after COVID-19 vaccination is important. It could help decide who receives priority for future vaccination. Previous studies show that people with certain health conditions produce fewer antibodies after one or two doses of a COVID-19 vaccine. For example, people with weakened immune systems. Now that third booster doses are available, it is vital to determine if they increase antibody levels for those most at risk of severe COVID-19. Cheetham et al. show that a third booster dose of a COVID-19 vaccine boosts antibodies to high levels in 90% of individuals, including those at increased risk. In the experiments, Cheetham et al. measured antibodies against the virus that causes COVID-19 in 9,361 individuals participating in two large long-term health studies in the United Kingdom. The experiments found that UK individuals advised to shield from the virus because they were at increased risk of complications had lower levels of antibodies after one or two vaccine doses than individuals without such risk factors. This difference was also seen after a third booster dose, but overall antibody levels had large increases. People who received the Oxford/AstraZeneca vaccine as their first dose also had lower antibody levels after one or two doses than those who received the Pfizer/BioNTech vaccine first. Positively, this difference in antibody levels was no longer seen after a third booster dose. Individuals with lower antibody levels after their first dose were also more likely to have a case of COVID-19 in the following months. Antibody levels were high in most individuals after the third dose. The results may help governments and public health officials identify individuals who may need extra protection after the first two vaccine doses. They also support current policies promoting booster doses of the vaccine and may support prioritizing booster doses for those at the highest risk from COVID-19 in future vaccination campaigns.

PubMed Disclaimer

Conflict of interest statement

NC, AW, RS, AK, DW, OH, PL, GD, JZ, GP, ET, RB, XZ, GA, DH, JS, CG, NK, SA, MM, RM, KN, DM, SM, TB, MC, LM, AK, KD, ED, NT No competing interests declared, MK received payment for attending the Health and Safety Executive (HSE) symposium. The author has no other competing interests to declare, CB received an ESRC and NIHR funded Grant, and MRC Funded Studentship. The author has no other competing interests to declare, SK participates on the Scottish Government Expert Reference Group on Ethnicity and COVID-19, and UK Scientific Advisory Group on Emergencies (SAGE) subgroup on Ethnicity. The author has no other competing interests to declare, MG is a member of the King's College London Health Faculties Research Ethics Subcommittee (Purple), and a Chair of the TwinsUK Volunteer Advisory Panel. The author has no other competing interests to declare, NC received payment for clinical trials of a diabetes drug from AstraZeneca. Nishi Chaturvedi is Chair of British Heart Foundation Fellowships Committee, a member of Diabetes UK research committee and a member of NWO Gravitational Awards Committee. The author has no other competing interests to declare, CS received payment for consultancy work for Zoe Ltd. The author has no other competing interests to declare

Figures

Figure 1.
Figure 1.. Anti-Spike antibody levels stratified by cohort and vaccination status at Q2 and Q4 antibody testing.
Dot and box plots showing distribution of anti-Spike antibody levels within Avon Longitudinal Study of Parents and Children (ALSPAC) and TwinsUK, for those not vaccinated or individuals single-, double- or triple-vaccinated at time of sampling. Data shown for individuals sampled at least 4 weeks after first vaccination, and at least 2 weeks after second or third vaccination to allow time for antibody generation. Length of box plot whiskers are limited to 1.5 times the interquartile range. Red lines show 10th percentile levels. Assay upper limit is shown by black dotted lines, with 0.4–250 BAU/mL range for Q2 results and 0.4–25000 BAU/mL for Q4 results, with a positive threshold of 0.8 BAU/mL. Percentage of values above assay upper limit is given on right side of plots.
Figure 1—figure supplement 1.
Figure 1—figure supplement 1.. Flow chart showing identification of analysis samples from Q2 antibody testing within TwinsUK.
The use of groups of individuals in various analyses is highlighted with symbols. Unknown vaccination status included a small number of individuals with contradictory vaccination dates (e.g., first vaccination dated after second vaccination), in addition to those who did not complete vaccination status questions.
Figure 1—figure supplement 2.
Figure 1—figure supplement 2.. Flow chart showing identification of analysis samples from Q4 antibody testing within TwinsUK.
The use of groups of individuals in various analyses is highlighted with symbols. Unknown vaccination status included a small number of individuals with contradictory vaccination dates (e.g., first vaccination dated after second vaccination), in addition to those who did not complete vaccination status questions.
Figure 1—figure supplement 3.
Figure 1—figure supplement 3.. Flow chart showing identification of analysis samples from Q2 antibody testing within Avon Longitudinal Study of Parents and Children (ALSPAC).
The use of groups of individuals in various analyses is highlighted with symbols. Unknown vaccination status included a small number of individuals with contradictory vaccination dates (e.g., first vaccination dated after second vaccination), in addition to those who did not complete vaccination status questions.
Figure 1—figure supplement 4.
Figure 1—figure supplement 4.. SARS-CoV-2 infection prevalence by socio-demographic factors in TwinsUK.
Prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for serology-based and self-reported measures of infection, for all individuals sampled in TwinsUK Q4 antibody testing, overall and split by socio-demographic variables: age, sex, ethnicity, local area deprivation (IMD), and rural-urban classification. Anti-N: anti-Nucleocapsid.
Figure 2.
Figure 2.. Anti-Spike antibody levels versus time since most recent vaccination, stratified by cohort and vaccination status at Q2 and Q4 antibody testing.
Dot and box plots showing distribution of anti-Spike (anti-S) antibody levels within unvaccinated, single-, double- and triple-vaccinated individuals within Avon Longitudinal Study of Parents and Children (ALSPAC) (Q2 testing) and TwinsUK (Q2 and Q4 testing), plotted against the number of weeks since most recent vaccination at time of sampling. Length of box plot whiskers are limited to 1.5 times the interquartile range. Red lines show 10th percentile levels. Assay upper limit is shown by black dotted lines, with 0.4–250 BAU/mL range for Q2 results and 0.4–25000 BAU/mL for Q4 results, with a positive threshold of 0.8 BAU/mL. X-axes are limited to weeks with results for five or more individuals, noting TwinsUK Q4 second vaccination sub-plot begins at 13 weeks since vaccination.
Figure 3.
Figure 3.. Associations with low relative anti-Spike antibody levels within TwinsUK and Avon Longitudinal Study of Parents and Children (ALSPAC).
Odds ratios with unadjusted 95% confidence intervals for selected exposure variables, testing associations with low anti-Spike antibody levels, for sub-samples of TwinsUK (purple circles) and ALSPAC (red diamonds) individuals tested in Q2 or Q4, while single-, double-, or triple- vaccinated. Low antibody levels were defined as the lowest 10% within the given sub-sample, except for ALSPAC and TwinsUK Q2 double-vaccinated sub-samples where lowest 8% is used due to assay upper limit. Each point estimate originates from a distinct multivariate logistic regression model, including the exposure variable of interest and adjustment variables of age, sex, name of most recent vaccine received and weeks since most recent vaccination. Note x-axis ranges on sub-plots vary, and vaccine received panel uses a logarithmic x-axis. Odds ratio = 1 is indicated with a dashed black line.
Figure 3—figure supplement 1.
Figure 3—figure supplement 1.. Antibody level differences after third vaccination between related twins and non-related pairs.
Empirical cumulative distribution functions describing the difference in anti-Spike antibody levels after third severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination within TwinsUK, with pair differences calculated between all complete pairs of related monozygotic (MZ) twins, dizygotic (DZ) twins, and all combinations of non-related pairs.
See this image and copyright information in PMC

References

    1. Bates TA, McBride SK, Leier HC, Guzman G, Lyski ZL, Schoen D, Winders B, Lee J-Y, Lee DX, Messer WB, Curlin ME, Tafesse FG. Vaccination before or after SARS-cov-2 infection leads to robust humoral response and antibodies that effectively neutralize variants. Science Immunology. 2022;7:eabn8014. doi: 10.1126/sciimmunol.abn8014. - DOI - PMC - PubMed
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. 1995;57:289–300. doi: 10.1111/j.2517-6161.1995.tb02031.x. - DOI
    1. Boyd A, Golding J, Macleod J, Lawlor DA, Fraser A, Henderson J, Molloy L, Ness A, Ring S, Davey Smith G. Cohort profile: the '’Children of the 90s’’-- the index offspring of the avon longitudinal study of parents and children. International Journal of Epidemiology. 2013;42:111–127. doi: 10.1093/ije/dys064. - DOI - PMC - PubMed
    1. Brochot E, Demey B, Touzé A, Belouzard S, Dubuisson J, Schmit JL, Duverlie G, Francois C, Castelain S, Helle F. Anti-spike, anti-nucleocapsid and neutralizing antibodies in SARS-cov-2 inpatients and asymptomatic individuals. Frontiers in Microbiology. 2020;11:584251. doi: 10.3389/fmicb.2020.584251. - DOI - PMC - PubMed
    1. Carlin JB, Gurrin LC, Sterne JA, Morley R, Dwyer T. Regression models for twin studies: a critical review. International Journal of Epidemiology. 2005;34:1089–1099. doi: 10.1093/ije/dyi153. - DOI - PubMed

Publication types