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)
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Abstract
Background
Antibody responses to SARS-CoV-2 vaccination vary for reasons that remain poorly understood.
Methods
We 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.
Findings
Serology 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.
Interpretation
We 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 registration
https://clinicaltrials.gov/ct2/show/NCT04330599
Funding
Barts Charity, Fischer Family Trust, The Exilarch’s Foundation, DSM Nutritional Products, Health Data Research UK
Research in context
Evidence before this study
We 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 study
This 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 evidence
Increased 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.
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SciScore for 10.1101/2022.02.14.22270930: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Participants in the cohort were invited via email to participate in post-vaccination antibody studies and to give additional consent for these.
IRB: COVIDENCE UK was sponsored by Queen Mary University of London and approved by Leicester South Research Ethics Committee (ref 20/EM/0117).Sex as a biological variable not detected. Randomization The primary analysis presented here includes data from all participants for whom a serology result was available following administration of two doses of ChAdOx1 or BNT162b2; an additional antibody test following administration of a third booster dose of vaccine was offered to all participants who were seronegative after two vaccine doses, and a … SciScore for 10.1101/2022.02.14.22270930: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Participants in the cohort were invited via email to participate in post-vaccination antibody studies and to give additional consent for these.
IRB: COVIDENCE UK was sponsored by Queen Mary University of London and approved by Leicester South Research Ethics Committee (ref 20/EM/0117).Sex as a biological variable not detected. Randomization The primary analysis presented here includes data from all participants for whom a serology result was available following administration of two doses of ChAdOx1 or BNT162b2; an additional antibody test following administration of a third booster dose of vaccine was offered to all participants who were seronegative after two vaccine doses, and a randomly selected subset of positive controls who were seropositive after two vaccine doses. Blinding not detected. Power Analysis Statistical analysis: Full details of the sample size calculation and statistical analysis are provided in Supplementary Material. Table 2: Resources
Antibodies Sentences Resources Once returned, the samples were logged by the study team and sent in batches to the Clinical Immunology Service at the Institute of Immunology and Immunotherapy of the University of Birmingham (Birmingham, UK) for semi-quanttative determination of combined IgG, IgM and IgA anti-spike antibody titres using a commercially available ELISA that measures combined IgG, IgA, and IgM (IgGAM) responses to the SARS-CoV-2 trimeric spike glycoprotein (product code MK654; The Binding Site [TBS], Birmingham, UK). anti-spikesuggested: NoneIgM (IgGAMsuggested: NoneSARS-CoV-2 trimeric spike glycoproteinsuggested: NoneOutcomes: Study outcomes were presence vs absence of antibodies against SARS-CoV-2 (analysed as a binary outcome) and antibody titres (continuous outcome restricted to the individuals who were seropositive after receiving two vaccine doses). SARS-CoV-2suggested: NoneGiven reports that peri-vaccination use of antipyretic analgesics may attenuate vaccine immunogenicity,26 we also conducted an exploratory analysis to determine the influence of taking paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) to treat post-vaccination symptoms on post-vaccination antibody titres. anti-inflammatory drugssuggested: NoneSoftware and Algorithms Sentences Resources To produce participant-level covariates for each class of medications investigated, questionnaire responses were mapped to drug classes listed in the British National Formulary (BNF) or the DrugBank and Electronic Medicines Compendium databases if not explicitly listed in the BNF, as previously described. DrugBanksuggested: (DrugBank, RRID:SCR_002700)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study also has some limitations. We did not study cellular responses to vaccination, and these may be discordant with humoral responses.10,27 We also studied responses at an early time point only; a high early peak in antibody titres following vaccination is not necessarily an indicator of durable response.36 As with any observational study, we cannot exclude the possibility that some of the associations we report might be explained by residual or unmeasured confounding. However, we have minimised the risk of this by adjusting for a comprehensive list of putative determinants of vaccine immunogenicity. COVIDENCE UK is also a self-selected cohort, and thus certain demographics—such as people <30 years old, people of lower socioeconomic status, and non-White ethnic groups—are under-represented. This may have limited our power to investigate antibody responses in some sub-groups, such as participants of Black ethnicity (who are at higher risk of SARS-CoV-2 infection39-41 and adverse outcomes42 than White people). In conclusion, this large population-based study reports on the influence of a comprehensive range of potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants on antibody responses to two major SARS-CoV-2 vaccines. Importantly, we also show that booster doses of mRNA vaccines are highly effective in achieving seroconversion in healthy people who fail to mount antibody responses to SARS-CoV-2 trimeric spike glycoprotein after re...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04330599 Active, not recruiting Longitudinal Population-based Observational Study of COVID-1… NCT04579640 Active, not recruiting Trial of Vitamin D to Reduce Risk and Severity of COVID-19 a… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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