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

BackgroundCoronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is estimated to have caused more than 18 million deaths worldwide as of end-May 2022. MethodsCOVIDENCE UK is a longitudinal population-based study that investigates risk factors for, and impacts of, COVID-19 in UK residents aged [≥]16 years. A unique feature is the capacity to support trial-within-cohort studies to evaluate interventions for prevention of COVID-19 and other acute respiratory illnesses. Participants complete a detailed online baseline questionnaire capturing self-reported information relating to their socio-demographic characteristics, occupation, lifestyle, quality of life, weight, height, longstanding medical conditions, medication use, vaccination status, diet and supplemental micronutrient intake. Follow-up on-line questionnaires capturing incident symptoms of COVID-19 and other acute respiratory infections, incident swab test-confirmed COVID-19, doses of SARS-CoV-2 vaccine received, and quality of life are completed at monthly intervals. ResultsThe study was launched on 1st May 2020 and closed to recruitment on 6th October 2021. A total of 19,981 participants enrolled and consented to 5-year follow-up with medical record linkage. Their mean age was 59.1 years (range 16.0 to 94.4 years), 70.2% were female, and 93.7% identified their ethnic origin as White. Analyses conducted to date have provided key insights into risk factors for SARS-CoV-2 infection and COVID-19 disease, determinants of SARS-CoV-2 vaccine immunogenicity and efficacy, and impacts of COVID-19 on health economic outcomes. The cohort has also supported conduct of a Phase 3 randomised trial-within-cohort study (CORONAVIT) evaluating implementation of a test-and-treat approach to correcting sub-optimal vitamin D status on incidence and severity of acute respiratory infections, including COVID-19. ConclusionsThe COVIDENCE UK dataset represents a valuable resource containing granular information on factors influencing susceptibility to, and impacts of, COVID-19 in UK adults. Researchers wishing to access anonymised participant-level data should contacting the corresponding author for further information.

Vitamin D Supplements for Prevention of Covid-19 or other Acute Respiratory Infections: a Phase 3 Randomized Controlled Trial (CORONAVIT)

OBJECTIVESTo determine whether population-level implementation of a test-and- treat approach to correction of sub-optimal vitamin D status (25-hydroxyvitamin D [25(OH)D] <75 nmol/L) influences risk of all-cause acute respiratory infection (ARI) or coronavirus disease 2019 (COVID-19). DESIGNPhase 3 open-label randomised controlled trial (CORONAVIT) utilising trials-within-cohorts (TwiCs) methodology. SETTINGUnited Kingdom. PARTICIPANTS6200 adults aged 16 years or older, who were not already taking vitamin D supplements at baseline. INTERVENTIONSOffer of a postal finger-prick test of blood 25(OH)D concentration with provision of a 6-month supply of higher-dose vitamin D (3200 IU/day, n=1550) or lower-dose vitamin D (800 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, vs. no offer of testing or supplementation (n=3100). Follow-up was from 17th December 2020 to 16th June 2021. MAIN OUTCOME MEASURESThe primary outcome was the proportion of participants experiencing at least one doctor- or swab test-confirmed ARI of any cause. Secondary outcomes included the proportion of participants developing swab test-confirmed COVID-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. RESULTSOf 3100 participants offered 25(OH)D testing, 2958 (95.4%) accepted, and 2690 (86.8%) had 25(OH)D <75 nmol/L and were sent vitamin D supplements (1356 higher-dose, 1334 lower-dose). 76 (5.0%) vs. 87 (5.7%) vs. 136 (4.6%) participants in higher-dose vs. lower-dose vs. no offer groups experienced at least one ARI of any cause (odds ratio [OR] for higher-dose vs. no offer 1.09, 95% CI 0.82-1.46; lower-dose vs. no offer 1.26, 0.96-1.66). 45 (3.0%) vs. 55 (3.6%) vs. 78 (2.6%) participants in higher-dose vs. lower-dose vs. no offer groups developed COVID-19 (OR for higher-dose vs. no offer 1.13, 0.78-1.63; lower-dose vs. no offer 1.39, 0.98-1.97). CONCLUSIONSAmong adults with a high baseline prevalence of sub-optimal vitamin D status, implementation of a population-level test-and-treat approach to vitamin D replacement did not reduce risk of all-cause ARI or COVID-19. TRIAL REGISTRATIONClinicalTrials.gov no. NCT04579640 SUMMARY BOXO_ST_ABSWhat is already known on this topic?C_ST_ABSVitamin D metabolites support innate immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory pathogens. Sub-optimal vitamin D status (25-hydroxyvitamin D <75 nmol/L) associates with increased susceptibility to all-cause acute respiratory infections (ARI) and coronavirus disease 2019 (COVID-19). Phase 3 randomised controlled trials of vitamin D to prevent COVID-19 have not yet reported. What this study addsThis phase 3 randomised controlled trial, including 6200 participants, shows that implementation of a population-level test-and-treat approach to oral vitamin D replacement at a dose of 800 IU or 3200 IU per day did not reduce risk of all-cause ARI or COVID-19 among adults with a high baseline prevalence of sub-optimal vitamin D status.

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)

BackgroundAntibody 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/NCT04330599 FundingBarts Charity, Fischer Family Trust, The Exilarchs Foundation, DSM Nutritional Products, Health Data Research UK Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe 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.

Determinants of pre-vaccination antibody responses to SARS-CoV-2: a population-based longitudinal study (COVIDENCE UK)

BackgroundProspective population-based studies investigating multiple determinants of pre-vaccination antibody responses to SARS-CoV-2 are lacking. MethodsWe did a prospective population-based study in SARS-CoV-2 vaccine-naive UK adults recruited between May 1 and November 2, 2020, without a positive swab test result for SARS-CoV-2 prior to enrolment. Information on 88 potential sociodemographic, behavioural, nutritional, clinical and pharmacological risk factors was obtained through online questionnaires, and combined IgG/IgA/IgM responses to SARS-CoV-2 spike glycoprotein were determined in dried blood spots obtained between November 6, 2020 and April 18, 2021. We used logistic and linear regression to estimate adjusted odds ratios (aORs) and adjusted geometric mean ratios (aGMRs) for potential determinants of SARS-CoV-2 seropositivity (all participants) and antibody titres (seropositive participants only), respectively. Results1696 (15.2%) of 11,130 participants were seropositive. Factors independently associated with increased risk of SARS-CoV-2 seropositivity included frontline health/care occupation (aOR 1.86, 95% CI 1.48-2.33), international travel (1.20, 1.07-1.35), number of visits to shops and other indoor public places ([≥]5 vs. 0/week: 1.29, 1.06-1.57, P-trend=0.01), body mass index (BMI) [≥]25 vs <25 kg/m2 (1.24, 1.11-1.39), Asian/Asian British vs White ethnicity (1.65, 1.10-2.49), and alcohol consumption [≥]15 vs 0 units/week (1.23, 1.04-1.46). Light physical exercise associated with decreased risk (0.80, 0.70-0.93, for [≥]10 vs 0-4 h/week). Among seropositive participants, higher titres of anti-Spike antibodies associated with factors including BMI [≥]30 vs <25 kg/m2 (aGMR 1.10, 1.02-1.19), Asian/Asian British vs White ethnicity (1.22, 1.04-1.44), frontline health/care occupation (1.24, 95% CI 1.11-1.39), international travel (1.11, 1.05-1.16), and number of visits to shops and other indoor public places ([≥]5 vs. 0/week: 1.12, 1.02-1.23, P-trend=0.01); these associations were not substantially attenuated by adjustment for COVID-19 disease severity. ConclusionsHigher alcohol consumption and reduced light physical exercise represent new modifiable risk factors for SARS-CoV-2 infection. Recognised associations between Asian/Asian British ethnic origin and obesity and increased risk of SARS-CoV-2 seropositivity were independent of other sociodemographic, behavioural, nutritional, clinical and pharmacological factors investigated. Among seropositive participants, higher titres of anti-Spike antibodies in people of Asian ancestry and in obese people were not explained by greater COVID-19 disease severity in these groups. FundingBarts Charity, Health Data Research UK.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

BackgroundRisk factors for severe COVID-19 include older age, male sex, obesity, Black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. MethodsWe undertook a prospective, population-based cohort study (COVIDENCE UK) from 1st May 2020 to 5th February 2021. Baseline information on potential risk factors was captured by online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted odds ratios (aORs) for associations between potential risk factors and risk of COVID-19. FindingsWe recorded 446 incident cases of COVID-19 in 15,227 participants (2.9%). Increased risk of developing COVID-19 was independently associated with Asian/Asian British vs. White ethnicity (aOR 2.31, 95% CI 1.35-3.95), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11-1.43), any vs. no visits to/from other households in previous week (aOR 1.33, 1.07-1.64), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.01-1.09), frontline occupation excluding health/social care vs. no frontline occupation (aOR 1.49, 1.12-1.98), and raised body mass index (BMI) (aOR 1.51 [1.20-1.90] for BMI 25.0-30.0 kg/m2 and 1.38 [1.05-1.82] for BMI >30.0 kg/m2 vs. BMI <25.0 kg/m2). Atopic disease was independently associated with decreased risk (aOR 0.76, 0.59-0.98). No independent associations were seen for age, sex, other medical conditions, diet, or micronutrient supplement use. InterpretationAfter rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased risk of developing COVID-19, while atopic disease was associated with decreased risk. FundingBarts Charity, Health Data Research UK