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Cited by 638SARS-CoV-2 and COVID-19 ResearchCOVID-19 epidemiological studiesCOVID-19 Clinical Research Studies

SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN)

Open access
Hall, Victoria Jane, Foulkes, Sarah, Charlett, Andre, Atti, Ana, Monk, Edward J M, Simmons, Ruth, Wellington, Edgar, Cole, Michelle J +323 more·2021·The Lancet
DOI 10.1016/s0140-6736(21)00675-9PMC PMC8040523
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Abstract

Background Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. Methods A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. Findings From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13-0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. Interpretation A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Funding Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

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Crossref · 10.1016/s0140-6736(21)00675-9

Cites

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Claims the paper makes

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  • Findingown data

    The incidence density was 7.6 reinfections per 100,000 person-days in the positive cohort compared with 57.3 primary infections per 100,000 person-days in the negative cohort between June 2020 and January 2021.

    “The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A positive PCR test reliably indicates SARS-CoV-2 infection or reinfection.
    • Rests on an assumption: The SIREN reinfection case definitions correctly distinguish true reinfection from intermittent PCR positivity.
    • Rests on an assumption: Adjustment for the measured covariates is sufficient to control confounding of the association between prior infection and reinfection.
  • Findingown data

    Total follow-up time up to Jan 11, 2021, was 2,047,113 person-days for the positive cohort and 2,971,436 person-days for the negative cohort.

    “The total follow-up time up to Jan 11, 2021, was 2 047 113 person-days for the positive cohort and 2 971 436 person-days for the negative cohort.”
    Quote in the paperSubstantial claim
  • Findingown data

    The adjusted incidence rate ratio for all reinfections compared with PCR-confirmed primary infections was 0.159 (95% CI 0.13-0.19).

    “The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A positive PCR test reliably indicates SARS-CoV-2 infection or reinfection.
    • Rests on an assumption: The SIREN reinfection case definitions correctly distinguish true reinfection from intermittent PCR positivity.
    • Rests on an assumption: Adjustment for the measured covariates is sufficient to control confounding of the association between prior infection and reinfection.
  • Findingown data

    By Jan 11, 2021, SIREN had detected two probable and 153 possible SARS-CoV-2 reinfections among 8,278 participants with previous SARS-CoV-2 infection.

    “In comparison, by Jan 11, 2021, SIREN had detected two cases meeting probable and 153 cases meeting possible SARS-CoV-2 reinfection definition from a cohort of 8278 participants that have previously been infected with SARS-CoV-2.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The SIREN reinfection case definitions correctly distinguish true reinfection from intermittent PCR positivity.
  • Findingown data

    The baseline cohorts assigned 8,278 (32.3%) of 25,661 participants to the positive cohort and 17,383 (67.7%) to the negative cohort.

    “The baseline cohorts assigned 8278 (32·3%) of 25 661 participants to the positive cohort and 17 383 (67·7%) to the negative cohort.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Antibody positivity or a previous positive PCR or antibody test reliably indicates prior SARS-CoV-2 infection.
    • Rests on an assumption: A negative antibody test and no documented previous positive PCR or antibody test reliably indicates absence of prior SARS-CoV-2 infection.
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 29

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Median follow-up per participant was 275 days (IQR 218-291) for the positive cohort and 195 days (IQR 131-214) for the negative cohort.

    “The median length of follow-up per participant was 275 days (IQR 218–291) for the positive cohort and 195 days (131–214) for the negative cohort.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    By Nov 25, 2020, 24 cases of potential SARS-CoV-2 reinfection had been reported in the scientific literature worldwide.

    “By Nov 25, 2020, 24 cases of potential reinfection with SARS-CoV-2 virus had been reported in scientific literature globally.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    An interaction term between protection and SGTF was not strongly associated and was not included in the final model.

    “We investigated the association between protection and SGTF, introducing an interaction term into the model; however, the interaction term was not found to be strongly associated and, therefore, was not included in the final model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    By Jan 11, 2021, 1,859 new infections were detected: 1,704 primary infections in the negative cohort and 155 reinfections in the positive cohort.

    “By Jan 11, 2021, 1859 new infections were detected in the study population: 1704 primary infections in the negative cohort and 155 reinfections in the positive cohort (table 2 ).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A positive PCR test reliably indicates SARS-CoV-2 infection or reinfection.
    • Rests on an assumption: The SIREN reinfection case definitions correctly distinguish true reinfection from intermittent PCR positivity.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    There were 864 seroconversions in participants without a positive PCR test; these were not included as primary infections in this interim analysis.

    “There were 864 seroconversions in participants without a positive PCR test; these were not included as primary infections in this interim analysis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A positive PCR test reliably indicates SARS-CoV-2 infection or reinfection.

  • May combine two claims.

    Findingown data

    In the positive cohort between June 2020 and January 2021, cumulative incidence was 0.2 cases per 1000 for probable symptoms, 6.0 for COVID-19 symptoms, 3.4 for other symptoms, 9.2 for asymptomatic cases, and 18.7 for all reinfections.

    “Between June, 2020, and January, 2021, the cumulative incidence of probable symptoms was 0·2 cases per 1000 participants, with 6·0 cases per 1000 for COVID-19 symptoms, 3·4 cases per 1000 for other symptoms, 9·2 cases per 1000 for asymptomatic cases, and 18·7 cases per 1000 for all reinfections in the positive cohort.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the reinfections, 78 (50.3%) were symptomatic and 50 (32.3%) had typical COVID-19 symptoms; both probable cases were in the latter group.

    “78 reinfections (50·3%) were symptomatic, 50 (32·3%) with typical COVID-19 symptoms, including both probable cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the negative cohort, cumulative incidence was 64.8 cases per 1000 for COVID-19 symptomatic infections, 14.0 for other symptomatic infections, 16.9 for asymptomatic cases, and 98.0 for all new PCR-positive infections.

    “The incidence of COVID-19 symptomatic infections was 64·8 cases per 1000 participants, other symptomatic infections was 14·0 cases per 1000, asymptomatic cases was 16·9 cases per 1000, and all new PCR positive infections was 98·0 cases per 1000 in the negative cohort (table 3 ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the positive cohort, 155 reinfections were identified, of which two were probable and 153 possible.

    “155 reinfections were identified in the positive cohort, two of which were categorised as probable and 153 as possible (table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Baseline antibody positivity accurately indicates prior SARS-CoV-2 infection.

  • May combine two claims.

    Findingown data

    Models suggested that the protective effect of previous infection increased when the variant was dominant (IRR 0.18, 95% CI 0.15-0.23) compared with IRR 0.13 (0.10-0.17), but the interaction test between cohort and SGTF did not reach conventional statistical significance (p=0.05).

    “Our models suggested that the protective effect of previous infection increased when the variant was dominant (IRR 0·18, 95% CI 0·15–0·23) compared with IRR 0·13 (0·10–0·17), although the formal test of interaction between cohort and SGTF did not reach conventional levels of statistical significance (p=0·05).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: SGTF data are a valid ecological proxy for exposure to the B.1.1.7 variant.

  • May combine two claims.

    Findingown data

    Previous infection offered protection against all five reinfection categories, with the lowest protection against asymptomatic infection (aIRR 0.48, 95% CI 0.37-0.63).

    “Although our results showed that previous infection offered protection against all five categories of reinfection, the lowest protection was provided to asymptomatic infection (aIRR 0·48 95% CI 0·37–0·63).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Baseline antibody positivity accurately indicates prior SARS-CoV-2 infection.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    During site initiation, verification was obtained that sites used validated testing platforms and standardised criteria for reporting into the national laboratory surveillance system.

    “Verification that sites were using validated testing platforms and standardised criteria for reporting into the national laboratory surveillance system was obtained during site initiation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most people infected with SARS-CoV-2 develop antibodies roughly one week after symptoms begin, and these antibodies persist for at least three months.

    “More than 90% of individuals infected with SARS-CoV-2 develop antibodies about 1 week after symptom onset, persisting for at least 3 months.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Wajnberg, 2020, Robust neutralizing antibodies to SARS-CoV-2 infection persist for months, Science source

      Not checked in the free run.

    • cites [24] Gudbjartsson, 2020, Spread of SARS-CoV-2 in the Icelandic population, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    From June 18 to Dec 31, 2020, 30,625 participants were enrolled into the study.

    “From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Recall bias was limited by asking enrolled participants to complete surveys every two weeks for exposures and symptoms.

    “Recall bias was limited once participants were enrolled by asking them to complete surveys every 2 weeks for exposures and symptoms.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Data were collected on potential confounders, including site and participant demographics, to permit adjustment in the analysis.

    “Data were collected on potential confounders, including site and participant demographics, to permit adjustment in analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Reinfections with SARS-CoV-2 have been reported internationally since June 2020, but they remain uncommon.

    “Reinfections have been reported internationally since June, 2020, although they remain uncommon.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Iwasaki, 2020, What reinfections mean for COVID-19, Lancet Infect Dis source

      Not checked in the free run.

    • cites [3] Colson, 2020, Evidence of SARS-CoV-2 re-infection with a different genotype, J Infect

      Not checked in the free run.

    • cites [4] Selhorst, 2020, Symptomatic SARS-CoV-2 re-infection of a health care worker in a Belgian nosocomial outbreak despite primary neutralizing antibody response, medRxiv

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A mixed-effects logistic regression analysis was performed as a sensitivity analysis to estimate odds ratios for the association between cohort allocation and PCR test result.

    “In addition to the aforementioned models, we did a mixed-effects logistic regression analysis as a sensitivity analysis to estimate odd ratios (ORs) to measure the association between the exposure (cohort allocation) and the binary outcome (PCR test result).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    SARS-CoV-2 serology was performed using locally validated assays.

    “SARS-CoV-2 serology was done with locally validated assays.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The interim analysis was performed when cumulative incidence in the total cohort reached 7%.

    “The interim analysis was done as the cumulative incidence in the total cohort reached 7%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study was originally powered to detect a difference in infection rate between cohorts with a sample size of 10,000, 25% estimated antibody positive at baseline, cumulative incidence of 2%, and immune efficacy of at least 50%.

    “The study was originally powered to detect a difference in the rate of infection between cohorts with a sample size of 10 000 (25% estimated to be antibody positive at baseline), cumulative incidence of 2%, and immune efficacy of at least 50%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Wallace, 2020, SIREN protocol: impact of detectable anti-SARS-CoV-2 on the subsequent incidence of COVID-19 in 100,000 healthcare workers: do antibody positive healthcare workers have less reinfection than antibody negative healthcare workers?, medRxiv

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The time-varying covariates included in the model were 21 days after COVID-19 vaccination and regional prevalence of the B.1.1.7 variant.

    “Time varying covariates included in the model were 21 days after COVID-19 vaccination and regional prevalence of the B.1.1.7 variant.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The fixed covariates included in the model were age, gender, ethnicity, region, staff group, and index of multiple deprivation.

    “The fixed covariates included in the model were age, gender, ethnicity, region, staff group, and index of multiple deprivation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    After 51 withdrawals and 4,913 exclusions, 25,661 participants with linked antibody and PCR testing were included in the analysis.

    “51 participants withdrew from the study, and then 4913 participants were excluded. A total of 25 661 participants, with linked data on antibody and PCR testing, were included in this analysis”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Questionnaires were piloted and formatted to reduce misclassification bias.

    “Questionnaires were piloted and formatted to reduce misclassification bias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The trial was registered with ISRCTN, ISRCTN11041050.

    “The trial was registered with ISRCTN, ISRCTN11041050.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Some studies have found that people with SARS-CoV-2 antibodies have a lower risk of clinical reinfection than antibody-negative people.

    “A few studies to date have reported that individuals with SARS-CoV-2 antibodies are at lower risk of clinical reinfection than are antibody-negative individuals.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Wajnberg, 2020, Robust neutralizing antibodies to SARS-CoV-2 infection persist for months, Science source

      Not checked in the free run.

    • cites [30] Lumley, 2020, Antibodies to SARS-CoV-2 are associated with protection against reinfection, medRxiv

      Not checked in the free run.

    • cites [31] Addetia, 2020, Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with a high attack rate, J Clin Microbiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Hospital site was included in the models as a random effect to account for extra variation and correlation not explained by risk and covariate variables.

    “The hospital site was added into models as a random effect to account for the extra variation and associated correlation that was not explained by risk and covariate variables.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Participants with a previous positive PCR test were included in the positive cohort irrespective of antibody status, although they accounted for less than 4% of the positive cohort.

    “We have included participants in the positive cohort who had a previous positive PCR test, irrespective of their antibody status, although these participants account for less than 4% of the positive cohort.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A previous positive PCR test indicates prior SARS-CoV-2 infection.

  • May combine two claims.

    Interpretationown data

    After 7 months of follow-up, previous SARS-CoV-2 infection protects most individuals against reinfection for an average of 7 months.

    “After 7 months of follow-up, this large observational study showed that previous SARS-CoV-2 infection protects most individuals against reinfection for an average of 7 months.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The use of hierarchical case definitions identifies cases with stronger evidence and allows presentation of the range of potential reinfection scenarios.

    “Our use of hierarchical case definitions identifies cases with stronger evidence and allows us to present the range of potential reinfection scenarios.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Cohort assignment was determined by testing at SIREN sites using a range of platforms and assays, so misclassification bias might have occurred.

    “Because the cohort assignment was determined by testing at SIREN sites, which use a range of testing platforms and assays, misclassification bias might have occurred.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Baseline antibody positivity accurately indicates prior SARS-CoV-2 infection.

  • May combine two claims.

    Study design and conductreasoning

    COVID-19 vaccines were introduced from Dec 8, 2020, but their effect on follow-up time was modest and was adjusted for, so the finding on durability of protection following previous infection is independent of vaccine effect.

    “Although COVID-19 vaccines were introduced to our cohort from Dec 8, 2020, onwards, the effect on the follow-up time in this analysis was modest and has been adjusted for, therefore our finding on the durability of protection following previous infection is independent of the vaccine effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Self-reported COVID-19 symptom onset date was used as a proxy for primary infection date in symptomatic participants, which could be subject to recall bias; validation rules excluded onset dates before March 2020 to reduce recall bias.

    “For those who were symptomatic in their primary episode we have used their self-reported COVID-19 symptom onset date as a proxy, which could be subject to recall bias. However, we have introduced validation rules to reduce the recall bias, excluding onset dates before March, 2020.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Self-reported COVID-19 symptom onset date is a valid proxy for the date of primary infection in symptomatic participants.

  • May combine two claims.

    Interpretationown data

    Primary infection with SARS-CoV-2 provides a high degree of immunity to repeat infection in the short to medium term, with similar levels of prevention of symptomatic infection as newly licensed vaccines for working-age adults.

    “This study supports the hypothesis that primary infection with SARS-CoV-2 provides a high degree of immunity to repeat infection in the short to medium term; with similar levels of prevention of symptomatic infection as the new licenced vaccines for working-age adults.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The finding of 93% lower risk of COVID-19 symptomatic infection after longer follow-up shows equal or higher protection from natural infection for both symptomatic and asymptomatic infection.

    “Our findings of a 93% lower risk of COVID-19 symptomatic infection, after a longer period of follow-up, show equal or higher protection from natural infection, both for symptomatic and asymptomatic infection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The analysis did not include 864 seroconversions in the negative cohort because they were not detected by PCR, and whether a similar rate of undetected infections occurred in the positive cohort remains unknown.

    “Additionally, we did not include 864 seroconversions in the negative cohort, because these seroconversions were not detected by PCR and whether a similar rate of undetected infections occurred in the positive cohort remains unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    First antibody positive date was used for participants with asymptomatic or non-COVID-19 symptomatic primary infections, so the entire susceptible period was not captured, reducing follow-up time, inflating reinfection rates, and reducing intervals between infection episodes.

    “We used the first antibody positive date for participants with asymptomatic or non-COVID-19 symptomatic primary infections. Therefore, we did not capture the entire time period during which participants were susceptible to reinfection, reducing our overall follow-up time for this cohort, and thus inflating our reinfection rates and reducing our intervals between infection episodes.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: First antibody positive date is a valid proxy for the date of primary infection in participants with asymptomatic or non-COVID-19 symptomatic primary infections.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ChAdOx1 trial reported protection against symptomatic infection between 62.1% and 90% over 2 months, and the BNT162b2 phase 3 trial reported 95% protection over 3 months.

    “The ChAdOx1 trial reported protection against symptomatic infection (COVID-19 typical symptoms) of between 62·1% and 90% over 2 months of follow-up, and the BNT162b2 vaccine phase 3 results reported 95% protection over 3 months of follow-up.28, 29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Voysey, 2021, Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK, Lancet source

      Not checked in the free run.

    • cites [29] Polack, 2020, Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mRNA-1273 phase 3 trial showed 94.1% efficacy against symptomatic SARS-CoV-2 infection, including severe illness, over a median of 2 months.

    “Another phase 3 trial of the mRNA-1273 vaccine showed 94·1% efficacy against symptomatic (COVID-19 typical symptoms) SARS-CoV-2 infection, including severe illness, over a median of 2 months of follow-up.43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Baden, 2021, Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    More potential reinfections were identified and investigated than reported in the global literature to date, supporting the value of large prospective cohort studies such as SIREN.

    “We have identified and investigated more potential reinfections than reported in the global literature to date, supporting the value of large prospective cohort studies such as SIREN.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    That study did not routinely perform PCR tests on all cohort individuals, and its three potential reinfections were asymptomatic.

    “However, this study did not routinely do PCR tests on all individuals in the cohort and the three potential reinfections were asymptomatic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Lumley, 2020, Antibodies to SARS-CoV-2 are associated with protection against reinfection, medRxiv

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Primary infection reduces the risk of asymptomatic infection and thus onward transmission.

    “Primary infection also reduces the risk of asymptomatic infection and thus onward transmission; this is particularly important as health care was considered a potential driver for ongoing community transmission during the first wave in the UK.45”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    None of the identified reinfections were confirmed by the stringent case definitions; most were considered only possible and were undergoing further serological investigation.

    “None of the reinfections we have identified are confirmed by our stringent case definitions, most reinfections we only consider possible and are undergoing further serological investigation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    In a separate SIREN analysis, the BNT162b2 vaccine offered 70% protection from symptomatic and asymptomatic infection 21 days after the first dose, increasing to 85% 7 days after the second dose.

    “In a separate analysis on the SIREN cohort, we showed that the BNT162b2 vaccine offered 70% protection from both symptomatic and asymptomatic infection, 21 days after the first dose, which increased to 85% 7 days after the second dose.44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Hall, 2021, Effectiveness of BNT162b2 mRNA vaccine against infection and COVID-19 vaccine coverage in healthcare workers in England, multicentre prospective cohort study (the SIREN Study), SSRN

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Investigations were restricted by scarce data and samples from historic infections, with most swabs discarded without sequencing, preventing the genomic comparison between infection episodes needed to confirm reinfection.

    “Investigations have been restricted by the scarce data and samples from historic infections, with most swabs discarded without sequencing, preventing the genomic comparison between infection episodes required to confirm a reinfection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Some PCR results, especially early in the epidemic, might have been false positives or laboratory contamination, particularly because cycle threshold/relative light unit values were not available.

    “Some of those PCR results, especially early in the epidemic, might have been false positives or laboratory contamination episodes, particularly when considering that cycle threshold/relative light unit values are not available.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    Antibody positivity or a previous positive PCR or antibody test reliably indicates prior SARS-CoV-2 infection.

    “Participants were assigned to the positive cohort if they met one of the following criteria: antibody positive on enrolment or antibody positive from previous clinical laboratory samples, with or without a previous positive PCR test; antibody negative on enrolment with a positive PCR result before enrolment.”

  • The paper relies on this without support.

    A negative antibody test and no documented previous positive PCR or antibody test reliably indicates absence of prior SARS-CoV-2 infection.

    “Participants were assigned to the negative cohort if they had a negative antibody test and no documented previous positive PCR or antibody test.”

  • The paper relies on this without support.

    A positive PCR test reliably indicates SARS-CoV-2 infection or reinfection.

    “The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests.”

  • The paper relies on this without support.

    The SIREN reinfection case definitions correctly distinguish true reinfection from intermittent PCR positivity.

    “A possible reinfection was defined as a participant with two positive PCR samples 90 or more days apart (based on previous national surveillance analysis) or an antibody positive participant with a new positive PCR test at least 4 weeks after the first antibody-positive result.”

  • The paper relies on this without support.

    The earliest date of previous infection can be reliably estimated from the first positive PCR, symptom onset, or first positive antibody test.

    “The earliest date for previous infection was taken as whichever was first of the positive PCR result or the onset of COVID-19 typical symptoms (if there was no positive PCR test result), or if neither was available, the first positive antibody test.”

  • The paper relies on this without support.

    Adjustment for the measured covariates is sufficient to control confounding of the association between prior infection and reinfection.

    “The fixed covariates included in the model were age, gender, ethnicity, region, staff group, and index of multiple deprivation.”

  • The authors state this as an assumption.

    Self-reported COVID-19 symptom onset date is a valid proxy for the date of primary infection in symptomatic participants.

    “For those who were symptomatic in their primary episode we have used their self-reported COVID-19 symptom onset date as a proxy, which could be subject to recall bias.”

  • The authors state this as an assumption.

    First antibody positive date is a valid proxy for the date of primary infection in participants with asymptomatic or non-COVID-19 symptomatic primary infections.

    “We used the first antibody positive date for participants with asymptomatic or non-COVID-19 symptomatic primary infections.”

  • The paper relies on this without support.

    SGTF data are a valid ecological proxy for exposure to the B.1.1.7 variant.

    “Additionally, the ecological nature of the SGTF data available to use precludes the ability to definitively answer the question of protection conferred to new variants.”

  • The paper relies on this without support.

    Baseline antibody positivity accurately indicates prior SARS-CoV-2 infection.

    “Because the cohort assignment was determined by testing at SIREN sites, which use a range of testing platforms and assays, misclassification bias might have occurred.”

  • The paper relies on this without support.

    A previous positive PCR test indicates prior SARS-CoV-2 infection.

    “We have included participants in the positive cohort who had a previous positive PCR test, irrespective of their antibody status”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The different antibody kinetics between recovered and vaccinated people may explain the lower incidence of breakthrough infection among previously infected people than among vaccinated people.

    “This striking difference in antibody kinetics between convalescent persons and vaccinated persons may be the reason for the substantially lower incidence of breakthrough infection among previously infected persons than among vaccinated persons.24,25”

    From Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months (2021) · cites this paper as [25]

  • Taken together, evidence from this study and others indicates that previously infected people have better long-term humoral response and vaccine effectiveness than recipients of two vaccine doses.

    “Overall, the accumulating evidence from our study and others22-25 shows that long-term humoral response and vaccine effectiveness in previously infected persons were superior to that in recipients of two doses of vaccine.”

    From Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months (2021) · cites this paper as [25]

  • Studies conducted before the emergence of the Omicron variant indicated that convalescent COVID-19 patients are efficiently protected against reinfection and that antibody responses likely play an important role in protection.

    “Studies conducted before the emergence of the Omicron variant indicated that convalescent COVID-19 patients are efficiently protected against reinfection and antibody responses likely play an important role in protection”

    From The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic (2022) · cites this paper as Hall et al., 2021

  • Analyses of reinfection with Omicron in the United Kingdom and Qatar support the finding of increased reinfection risk associated with Omicron.

    “This finding has now been supported by analyses of reinfection with Omicron in the United Kingdom and Qatar ( 14 – 16 ).”

    From Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa (2021) · cites this paper as [16]

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. Selhorst, 2020, Symptomatic SARS-CoV-2 re-infection of a health care worker in a Belgian nosocomial outbreak despite primary neutralizing antibody response, medRxiv
  2. Abu-Raddad, 2020, Assessment of the risk of SARS-CoV-2 reinfection in an intense re-exposure setting, medRxiv
  3. Bongiovanni, 2020, COVID-19 re-infection in an healthcare worker, J Med Virol
  4. Gupta, 2020, Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS-CoV-2, Clin Infect Dis
  5. Larson, 2020, A case of early re-infection with SARS-CoV-2, Clin Infect Dis
  6. Mulder, 2020, Reinfection of SARS-CoV-2 in an immunocompromised patient: a case report, Clin Infect Dis
  7. To, 2020, COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing, Clin Infect Dis
  8. Van Elslande, 2020, Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain, Clin Infect Dis

Cited by

Sorted by citations

Authors
Hall, V. J., Foulkes, S., Charlett, A., Atti, A., Monk, E. J. M., Simmons, R., Wellington, E., Cole, M. J., Saei, A., Oguti, B., Munro, K., Wallace, S., Kirwan, P. D., Shrotri, M., Vusirikala, A., Rokadiya, S., Kall, M., Zambon, M., Ramsay, M., Brooks, T., Brown, C. S., Chand, M. A., Hopkins, S., Andrews, N., Atti, A., Aziz, H., Brooks, T., Brown, C., Camero, D., Carr, C., Chand, M., Charlett, A., Crawford, H., Cole, M., Conneely, J., D'Arcangelo, S., Ellis, J., Evans, S., Foulkes, S., Gillson, N., Gopal, R., Hall, L., Hall, V., Harrington, P., Hopkins, S., Hewson, J., Hoschler, K., Ironmonger, D., Islam, J., Kall, M., Karagiannis, I., Kay, O., Khawam, J., King, E., Kirwan, P., Kyffin, R., Lackenby, A., Lattimore, M., Linley, E., Lopez-Bernal, J., Mabey, L., McGregor, R., Miah, S., Monk, E., Munro, K., Naheed, Z., Nissr, A., O'Connell, A., Oguti, B., Okafor, H., Organ, S., Osbourne, J., Otter, A., Patel, M., Platt, S., Pople, D., Potts, K., Ramsay, M., Robotham, J., Rokadiya, S., Rowe, C., Saei, A., Sebbage, G., Semper, A., Shrotri, M., Simmons, R., Soriano, A., Staves, P., Taylor, S., Taylor, A., Tengbe, A., Tonge, S., Vusirikala, A., Wallace, S., Wellington, E., Zambon, M., Corrigan, D., Sartaj, M., Cromey, L., Campbell, S., Braithwaite, K., Price, L., Haahr, L., Stewart, S., Lacey, E., Partridge, L., Stevens, G., Ellis, Y., Hodgson, H., Norman, C., Larru, B., Mcwilliam, S., Winchester, S., Cieciwa, P., Pai, A., Loughrey, C., Watt, A., Adair, F., Hawkins, A., Grant, A., Temple-Purcell, R., Howard, J., Slawson, N., Subudhi, C., Davies, S., Bexley, A., Penn, R., Wong, N., Boyd, G., Rajgopal, A., Arenas-Pinto, A., Matthews, R., Whileman, A., Laugharne, R., Ledger, J., Barnes, T., Jones, C., Botes, D., Chitalia, N., Akhtar, S., Harrison, G., Horne, S., Walker, N., Agwuh, K., Maxwell, V, Graves, J., Williams, S., O'Kelly, A., Ridley, P., Cowley, A., Johnstone, H., Swift, P., Democratis, J., Meda, M., Callens, C., Beazer, S., Hams, S., Irvine, V, Chandrasekaran, B., Forsyth, C., Radmore, J., Thomas, C., Brown, K., Roberts, S., Burns, P., Gajee, K., Byrne, T., Sanderson, F., Knight, S., Macnaughton, E., Burton, B., Smith, H., Chaudhuri, R., Hollinshead, K., Shorten, R., Swan, A., Shorten, R., Favager, C., Murira, J., Baillon, S., Hamer, S., Gantert, K., Russell, J., Brennan, D., Dave, A., Chawla, A., Westell, F., Adeboyeku, D., Papineni, P., Pegg, C., Williams, M., Ahmad, S., Ingram, S., Gabriel, C., Pagget, K., Cieciwa, P., Maloney, G., Ashcroft, J., Del Rosario, I., Crosby-Nwaobi, R., Reeks, C., Fowler, S., Prentice, L., Spears, M., McKerron, G., McLelland-Brooks, K., Anderson, J., Donaldson, S., Templeton, K., Coke, L., Elumogo, N., Elliott, J., Padgett, D., Mirfenderesky, M., Cross, A., Price, J., Joyce, S., Sinanovic, I., Howard, M., Lewis, T., Cowling, P., Potoczna, D., Brand, S., Sheridan, L., Wadams, B., Lloyd, A., Mouland, J., Giles, J., Pottinger, G., Coles, H., Joseph, M., Lee, M., Orr, S., Chenoweth, H., Auckland, C., Lear, R., Mahungu, T., Rodger, A., Penny-Thomas, K., Pai, S., Zamikula, J., Smith, E., Stone, S., Boldock, E., Howcroft, D., Thompson, C., Aga, M., Domingos, P., Gormley, S., Kerrison, C., Marsh, L., Tazzyman, S., Allsop, L., Ambalkar, S., Beekes, M., Jose, S., Tomlinson, J., Jones, A., Price, C., Pepperell, J., Schultz, M., Day, J., Boulos, A., Defever, E., McCracken, D., Brown, K., Gray, K., Houston, A., Planche, T., Pritchard Jones, R., Wycherley, D., Bennett, S., Marrs, J., Nimako, K., Stewart, B., Kalakonda, N., Khanduri, S., Ashby, A., Holden, M., Mahabir, N., Harwood, J., Payne, B., Court, K., Staines, N., Longfellow, R., Green, M., Hughes, L., Halkes, M., Mercer, P., Roebuck, A., Wilson-Davies, E., Gallego, L., Lazarus, R., Aldridge, N., Berry, L., Game, F., Reynolds, T., Holmes, C., Wiselka, M., Higham, A., Booth, M., Duff, C., Alderton, J., Jory, H., Virgilio, E., Chin, T., Qazzafi, M., Moody, A., Tilley, R., Donaghy, T., Shipman, K., Sierra, R., Jones, N., Mills, G., Harvey, D., Huang, Y., Birch, J., Robinson, L., Board, S., Broadley, A., Laven, C., Todd, N., Eyre, D., Jeffery, K., Dunachie, S., Duncan, C., Klenerman, P., Turtle, L., De Silva, T., Baxendale, H., & Heeney, J.
Affiliations
  • Public Health England (GB)
  • St Thomas' Hospital (GB)
  • Guy's Hospital (GB)
Corresponding author
  • Andrews, N
  • Aziz, H
  • Carr, C
  • Crawford, H
  • Okafor, H
  • Potts, K
  • Rowe, C
  • Braithwaite, K
  • Hodgson, H
  • Norman, C
  • Loughrey, C
  • Adair, F
  • Subudhi, C
  • Jones, C
  • Agwuh, K
  • Johnstone, H
  • Callens, C
  • Forsyth, C
  • Thomas, C
  • Gajee, K
  • Sanderson, F
  • Smith, H
  • Hollinshead, K
  • Favager, C
  • Gantert, K
  • Westell, F
  • Pegg, C
  • Gabriel, C
  • Pagget, K
  • Reeks, C
  • McLelland-Brooks, K
  • Templeton, K
  • Coles, H
  • Chenoweth, H
  • Auckland, C
  • Penny-Thomas, K
  • Thompson, C
  • Kerrison, C
  • Price, C
  • Gray, K
  • Nimako, K
  • Court, K
  • Game, F
  • Holmes, C
  • Duff, C
  • Jory, H
  • Shipman, K
  • Laven, C
  • Jeffery, K
  • Duncan, C
  • Baxendale, H
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2021-04
Volume
397
Issue
10283
Pages
1459-1469
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(21)00675-9
PMC
PMC8040523
OpenAlex
W3153039449
Cited by
638
References
35
Citations by year
2026: 13 · 2025: 31 · 2024: 75 · 2023: 105 · 2022: 241 · 2021: 171 · 2020: 2
FWCI
46.95
Type
journal article
Language
en
Update notices
erratum (2021-05-08)
Open access
Licence
Locations
  • The Lancet (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ResearchOnline (Glasgow Caledonian University) (acceptedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Public Health England
  • National Institute for Health Research (NIHR200915)
  • United Kingdom Department of Health and Social Care
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
SARS-CoV-2 reinfection, COVID-19 pandemic, SARS-CoV-2 antibodies, seroprevalence, healthcare workers, hospital staff, asymptomatic infection, symptomatic infection, primary infection, SIREN study, infection rate, seroconversion, PCR testing, nosocomial infections, 2020-2021 pandemic period
MeSH terms
Reinfection, COVID-19, SARS-CoV-2, COVID-19 Nucleic Acid Testing, Adult, Antibodies, Viral, England, Female, Follow-Up Studies, Health Personnel, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Asymptomatic Infections, Pandemics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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