key: cord-0827589-2aoyzj2b authors: Hall, V. J.; Foulkes, S.; Charlett, A.; Atti, A.; Monk, E. J.; 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.; SIREN Sudy Group,; Brown, C. S.; Chand, M. A.; Hopkins, S. title: Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020 date: 2021-01-15 journal: nan DOI: 10.1101/2021.01.13.21249642 sha: 9bbb6788f1078cce0cac1006913ef5ea72840402 doc_id: 827589 cord_uid: 2aoyzj2b Background: There is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection. Methods: A large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis. Findings: Between 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days. Interpretation: A prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included. Funding: Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments. FINAL MANUSCRIPT 94 were seroconversions in participants without a positive PCR test; these are not included 2 0 7 in this interim analysis. 2 0 8 Forty-four reinfections were identified, 15 (34%) were symptomatic: two defined as probable 2 0 9 (described in detail elsewhere 36) , both symptomatic, and 42 possible; 13 symptomatic, two 2 1 0 (23%) of whom reported typical COVID-19 symptoms. Forty (both probable and 38 possible) 2 1 1 reinfections were antibody positive at enrolment; three had previously positive antibody tests 2 1 2 but two were antibody negative and one indeterminate on enrolment; and one individual 2 1 3 remained antibody negative but reported COVID-19 symptoms and a documented PCR 2 1 4 positive status in April 2020. Twenty-one (47.7%)(50%) of these individuals had historic PCR 2 1 5 positives from their primary infection, of whom 19 reported COVID-19 symptoms and two 2 1 6 other symptoms within 14 days of their positive test. Fourteen (31.8%) individuals (including 2 1 7 both probable cases) reported a history of COVID-19-like illness but did not have a PCR test 2 1 8 due to lack of availability at the time of their primary illness; 13 (92.9%) with typical COVID-2 1 9 19 symptoms and one with other symptoms. Nine (20.5%) reported no history of any 2 2 0 potential COVID-19 related symptoms. For the 32 reinfections providing a history of COVID-19 symptoms, used as a proxy to 2 2 2 estimate the date of their primary infection, the median interval between primary infection 2 2 3 and reinfection beyond 90 days was 172 days (90-227) and for the 21 reinfections with a 2 2 4 historic PCR positive test before enrolment, the median interval between the historic PCR 2 2 5 positive date and the reinfection PCR positive date was 162 days (95-223). Between June and November 2020, the cumulative incidence of probable, symptomatic 2 2 7 possible and all reinfections in the positive cohort between June and November 2020 was 2 2 8 0.3, 2.3 and 6.7 per 1,000 participants respectively and incidence of symptomatic and all 2 2 9 new PCR infections in the negative cohort was 17.6 and 22.4 per 1,000 participants 2 3 0 respectively ( Table 3 ). The incidence density per 100,000 days of follow up between June 2 3 1 and November 2020 in the positive cohort was 3 .3 reinfections and in the negative cohort 2 3 2 was 17.0 new PCR positive infections per 100,000 days of follow-up. Figure 3 describes the 2 3 3 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 FINAL MANUSCRIPT cumulative incidence of new episode PCR positive tests per cohort demonstrating the higher 2 3 4 cumulative incidence in the negative cohort reaching 20 per 1000 compared 5 per 1000 2 3 5 cases in the positive cohort. 2 3 6 We estimated the relative odds for reinfections in the positive cohort, with separate analyses 2 3 7 for each reinfection definition described above, compared to new PCR positive infections in 2 3 8 our negative cohort between SIREN enrolment and 24 November 2020 (Table 4, annex B 2 3 9 Tables Bi.-Biii). Restricting reinfections to probable reinfections only, we estimated that between June and 2 4 1 November 2020, participants in the positive cohort had 99% lower odds of probable 2 4 2 reinfection, adjusted OR (aOR) 0.01 (95% CI 0.00-0.03). Restricting reinfections to those 2 4 3 who were symptomatic we estimated participants in the positive cohort had 95% lower odds 2 4 4 of reinfection, aOR 0.08 (95% CI 0.05-0.13). Using our most sensitive definition of 2 4 5 reinfections, including all those who were possible or probable the adjusted odds ratio was 2 4 6 0.17 (95% CI 0.13-0.24). The two approaches to account for temporal changes in incidence provided very similar 2 4 8 estimates, we have opted to present results from the model with calendar time categorised. This also shows how the probability of exposure to an infectious individual has changed over 2 5 0 time in a piecewise constant manner, increasing over time as incidence of new infections in 2 5 1 the population increased in September and October 2020. We have presented the interim findings after five months of follow-up from the SIREN study, 2 5 5 a unique large-scale multi-centre prospective cohort study of healthcare staff undergoing 2 5 6 frequent asymptomatic testing, powered to detect and characterise reinfections and estimate 2 5 7 the protective effect of SARS-CoV-2 antibodies. 2 5 8 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 We have detected two probable reinfections (both symptomatic with high viral loads, 2 5 9 genome sequencing demonstrating phylogenetic relatedness to concurrently circulating 2 6 0 strains, and a boosted antibody response), which have been characterised and reported 2 6 1 separately, 36 and 42 possible reinfections in our positive cohort. This compares with 318 2 6 2 new PCR positive infections, 249 of whom were symptomatic, 78% with typical COVID-19 2 6 3 symptoms, in our negative cohort. Using a symptomatic case definition aligned with positive 2 6 4 PCR results, previous infection reduced the odds of infection by at least 90% (aOR 0.06 with 2 6 5 95%CI of 0.03 to 0.09) and even when we included all possible and probable reinfections 2 6 6 3 3 7 5. Funding 3 3 8 The study is funded by the United Kingdom's Department of Health and Social Care and 3 3 9 Public Health England, with contributions from the Scottish, Welsh and Northern Irish shedding-threat-assessment-brief.pdf (accessed 19th December 2020). (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.13.21249642 doi: medRxiv preprint antibody response. Preprint available at 3 6 3 https://www.medrxiv.org/content/10.1101/2020.11.05.20225052v1 (2020). CoV-2 reinfection in an intense re-exposure setting. Preprint available 3 6 9 at https://www.medrxiv.org/content/10.1101/2020.08.24.20179457v2 (2020). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. MedRxiv. 2020 Jan 1. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Marsden BD, Cox S, James T, Warren F, Peck LJ. Antibodies to SARS-CoV-2 are 4 4 8 associated with protection against reinfection. medRxiv. 2020 Jan 1. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; Note: odds ratio (OR); adjusted odds ratio (aOR); aOR adjusted for week group: reference group week 25 to 30; remaining week groups: week 31 to 47 (two-week timeperiods) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. excluded; due to: no antibody or PCR data available or withdraw from the study All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Appendix A. Symptom list in questionnaire Cough, Fever, Anosmia, Dysgeusia, Sore throat, runny nose, headache, muscle aches, fatigue, diarrhoea, vomiting, itchy red patches. Nursing/Healthcare Assistant --All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Yorkshire and the Humber 1.67 (0.90-3.08) 0.10 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.13.21249642 doi: medRxiv preprint East Midlands --All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.13.21249642 doi: medRxiv preprint Participating SIREN sites: Site Principal and co-investigators All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. FINAL MANUSCRIPT Calderdale and Huddersfield NHS Foundation Trust: Dr G Boyd, Dr A Rajgopal Central and North West London NHS Foundation Trust: Dr A Arenas-Pinto, R Matthews Chesterfield Royal Hospital NHS Foundation Trust: A Whileman Cornwall Partnership NHS Foundation Trust: Dr R Laugharne Lincolnshire Partnership NHS Foundation Trust: Dr A Dave, D Brennan All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted