Determinants of antibody responses to two doses of ChAdOx1 nCoV-19 or BNT162b2 and a subsequent booster dose of BNT162b2 or mRNA-1273: population-based cohort study (COVIDENCE UK)

Abstract

SummaryBackgroundAntibody responses to SARS-CoV-2 vaccination vary for reasons that remain poorly understood.MethodsWe tested for presence of combined IgG, IgA and IgM (IgGAM) anti-spike antibodies before and after administration of two doses of ChAdOx1 nCoV-19 (ChAdOx1, Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) in UK adults participating in a population-based longitudinal study who received their first dose of vaccine from December 15, 2020 to July 10, 2021. Information on sixty-six potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of serological response to vaccination was captured using serial online questionnaires. We used logistic regression to estimate multivariable-adjusted odds ratios (aORs) for associations between independent variables and risk of seronegativity following two vaccine doses. Participants who were seronegative after receiving two vaccine doses were offered an additional antibody test following subsequent administration of a ‘booster’ dose of BNT162b2 or mRNA-1273 (Moderna) from September 23 to December 12, 2021.FindingsSerology results following two vaccine doses were available for 9,101 participants, of whom 5,770 (63.4%) received ChAdOx1 and 3,331 (36.6%) received BNT162b2. Anti-spike IgGAM was undetectable in 378 (4.2%) participants at a median of 8.6 weeks (IQR 6.4-10.7 weeks) after their second dose of vaccine. Seronegativity following two doses of SARS-CoV-2 vaccination was associated with administration of ChAdOx1 vs BNT162b2 (aOR 7.03, 95% CI 4.39-11.24), shorter interval between first and second vaccine doses (aOR 2.37, 1.06-5.26, for <6 weeks vs >10 weeks; aOR 1.59, 1.18-2.13, for 6-10 weeks vs >10 weeks), poorer self-assessed general health (aOR 3.33, 1.49-7.46, for poor vs excellent), immunodeficiencies (aOR 6.75, 2.63-17.35) and prescription of systemic immunosuppressants (aOR 3.76, 2.44-5.78). By contrast, pre-vaccination SARS-CoV-2 seropositivity (aOR 0.16, 0.04-0.70, for symptomatic seropositives vs seronegatives) and supplemental vitamin D intake (aOR 0.73, 0.53-0.99) were associated with reduced risk of post-vaccination seronegativity. 247/378 (65.3%) of participants who were seronegative after two doses of ChAdOx1 vs BNT162b2 provided a third sample at a median of 7.8 weeks (IQR 5.8-10.4) after receiving a booster dose of BNT162b2 or mRNA-1273: eight (3.2%) of them remained seronegative after three vaccine doses, all of whom either had a primary immunodeficiency or were taking systemic immunosuppressant drugs.InterpretationWe identify multiple determinants of antibody responses to two doses of ChAdOx1 or BNT162b2, many of which are potentially modifiable. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in those who failed to mount antibody responses following two doses of ChAdOx1 or BNT162b2.Study registrationhttps://clinicaltrials.gov/ct2/show/NCT04330599FundingBarts Charity, Fischer Family Trust, The Exilarch’s Foundation, DSM Nutritional Products, Health Data Research UKResearch in contextEvidence before this studyWe searched PubMed, medRxiv, and Google Scholar for papers published from January 1, 2020, to February 1, 2022, using the search terms (antibody OR humoral OR serologic* OR immunogenic*) AND (SARS-CoV-2 vaccine OR ChAdOx1 or BNT162b2 coronavirus), with no language restrictions. Population-based studies investigating multiple potential determinants of vaccine immunogenicity in people with known pre-vaccination SARS-CoV-2 serostatus are lacking.Added value of this studyThis large population-based study, conducted in a population with known pre-vaccination SARS-CoV-2 serostatus, examines a comprehensive range of potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of antibody responses to administration of two major SARS-CoV-2 vaccines (i.e., ChAdOx1 or BNT162b2), many of which have not previously been investigated. It is also the first population-based study to characterise antibody responses to booster doses of SARS-CoV-2 vaccines in adults who were seronegative after their primary course of vaccination.Implications of all the available evidenceIncreased risk of seronegativity following two doses of SARS-CoV-2 vaccines was associated with administration of ChAdOx1 vs BNT162b2, shorter interval between first and second vaccine doses, poorer self-assessed general health, immunocompromise and SARS-CoV-2 seronegativity pre-vaccination. Regular intake of vitamin D supplements was associated with reduced risk of post-vaccination seronegativity. Randomised controlled trials are now needed to test for causality. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in the majority of people who failed to mount antibody responses following a primary course of vaccination, the few exceptions being a subset of those with primary immunodeficiency or systemic immunosuppressant drugs.

Risk factors for SARS-CoV-2 infection after primary vaccination with ChAdOx1 nCoV-19 or BNT1262b2 and after booster vaccination with BNT1262b2 or mRNA-1273: a population-based cohort study (COVIDENCE UK)

“…By contrast with studies showing that a longer inter-dose interval increases immunogenicity, 21,34,35 we found a strong association between longer interval between first and second vaccine doses and increased risk of breakthrough infection. While a correlate of protection that translates immunogenicity findings into real-world protection has yet to be found, some preliminary studies suggest a longer interval is indeed protective.…”

“…Indeed, after a booster vaccination, we observed lower risk of breakthrough infection for participants of south Asian or mixed ethnicity compared with White participants after adjusting for previous infection. This supports both pre-vaccination and post-vaccination serology findings from the same cohort, showing higher antibody titres from natural infection and from vaccination in these ethnic groups than in White participants, independently of pre-vaccination serostatus 21 and disease severity. 19 Few studies to date have observed associations between ethnicity and breakthrough SARS-CoV-2 infection, 14 although lack of diversity in vaccine clinical trials 25 and missing data in some of the larger observational studies 2,9 have hindered investigation.…”

“…In our post-primary cohort, vaccine type was a strong predictor of breakthrough infection, with the weaker performance of ChAdOx1 mirroring studies on vaccine effectiveness in the general population 28 and on post-vaccination serology. 21 However, this difference seems to have been eradicated in our cohort after booster vaccination with BNT162b2. This may reflect both increased immunogenicity after boosting with BNT162b2, regardless of the primary vaccination course, 32 and reduced effectiveness of BNT162b2 against the omicron variant, 5 which became dominant in the UK in mid-December, 2021.…”

“…All included factors have previously been found to be independently associated with risk of COVID-19 or pre-vaccination or post-vaccination SARS-CoV-2 antibody response. 18,19,21 Previous infection was defined as reporting a positive result on a lateral flow or RT-PCR test for SARS-CoV-2 before start of the post-vaccination follow-up period.…”

Cohort Profile: Longitudinal population-based study of COVID-19 in UK adults (COVIDENCE UK)

“…7,9 Participants of Asian/Asian British origin also had higher convalescent titres of combined IgG, IgA and IgM antibodies to the SARS-CoV-2 spike protein following infection (after adjustment for multiple potential confounders including disease severity) and higher titres of the same antibodies after SARS-CoV-2 vaccination (after adjustment for multiple potential confounders including pre-vaccination anti-S titres). 9,10 Taken together, these findings highlight the need to investigate potential biological determinants of ethnic variation in susceptibility to, and severity of, COVID-19.…”