Notícia

The New England Journal of Medicine (EUA)

Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers

Publicado em 23 dezembro 2020

Por Sheila F. Lumley, B.M., B.Ch., Denise O’Donnell, B.Sc., Nicole E. Stoesser, M.B., B.S., D.Phil., Philippa C. Matthews, F.R.C.P., D.Phil., Alison Howarth, Ph.D., Stephanie B. Hatch, Ph.D., Br

The relationship between the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequent reinfection remains unclear.

Methods

We investigated the incidence of SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) in seropositive and seronegative health care workers attending testing of asymptomatic and symptomatic staff at Oxford University Hospitals in the United Kingdom. Baseline antibody status was determined by anti-spike (primary analysis) and anti-nucleocapsid IgG assays, and staff members were followed for up to 31 weeks. We estimated the relative incidence of PCR-positive test results and new symptomatic infection according to antibody status, adjusting for age, participant-reported gender, and changes in incidence over time.

Results

A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike–seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike–seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P=0.002). There were no symptomatic infections in workers with anti-spike antibodies. Rate ratios were similar when the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status.

Conclusions

The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months. (Funded by the U.K. Government Department of Health and Social Care and others.)

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces detectable immune responses in most cases reported to date; however, the extent to which previously infected people are protected from a second infection is uncertain. Understanding whether postinfection immunity exists, how long it lasts, and the degree to which it may prevent symptomatic reinfection or reduce its severity has major implications for the SARS-CoV-2 pandemic.

Postinfection immunity may be conferred by humoral and cell-mediated immune responses. Key considerations when investigating postinfection immunity include identifying functional correlates of protection, identifying measurable surrogate markers, and defining end points, such as prevention of disease, hospitalization, death, or onward transmission.1

The assay-dependent antibody dynamics of SARS-CoV-2 anti-spike and anti-nucleocapsid antibodies are being defined.2-6 Neutralizing antibodies against the spike protein receptor-binding domain may provide some postinfection immunity. However, the association between antibody titers and plasma neutralizing activity is assay- and time-dependent.7-10

Evidence for postinfection immunity is emerging. Despite more than 76 million people infected worldwide and widespread ongoing transmission, reported reinfections with SARS-CoV-2 have been rare, occurring mostly after mild or asymptomatic primary infection,11-20 which suggests that SARS-CoV-2 infection provides some immunity against reinfection in most people. In addition, small-scale reports suggest that neutralizing antibodies may be associated with protection against infection.21 We performed a prospective longitudinal cohort study of health care workers to assess the relative incidence of subsequent positive SARS-CoV-2 polymerase-chain-reaction (PCR) tests and symptomatic infections in health care workers who were seropositive for SARS-CoV-2 antibodies and in those who were seronegative.

Methods

Cohort

Oxford University Hospitals offer SARS-CoV-2 testing to all symptomatic and asymptomatic staff working at four teaching hospitals in Oxfordshire, United Kingdom. SARS-CoV-2 PCR testing of combined nasal and oropharyngeal swab specimens for symptomatic staff (those with new persistent cough, temperature =37.8°C, or anosmia or ageusia) was offered beginning on March 27, 2020. Asymptomatic health care workers were invited to participate in voluntary nasal and oropharyngeal swab PCR testing every 2 weeks and serologic testing every 2 months (with some participating more frequently for related studies) beginning on April 23, 2020, as previously described.5,22 Staff were followed until November 30, 2020. Deidentified data were obtained from the Infections in Oxfordshire Research Database, which has generic research ethics committee, Health Research Authority, and Confidentiality Advisory Group approvals.

Laboratory Assays

Serologic investigations were performed with use of an anti-trimeric spike IgG enzyme-linked immunosorbent assay (ELISA), developed by the University of Oxford,23,24 and an anti-nucleocapsid IgG assay (Abbott). See the Supplementary Appendix, available with the full text of this article at NEJM.org, for details on the assays and PCR tests.

Statistical Analysis

We classified health care workers according to their baseline antibody status. Those with only negative antibody assays were considered to be at risk for infection from their first antibody assay until either the end of the study or their first PCR-positive test, whichever occurred earlier. Those with a positive antibody assay were considered to be at risk for infection (or reinfection) from 60 days after their first positive antibody result to either the end of the study or their next PCR-positive test, whichever occurred earlier, irrespective of subsequent seroreversion (i.e., any negative antibody assay occurring later). The 60-day window was prespecified to exclude persistence of PCR-positive RNA after the index infection that led to seroconversion, on the basis of earlier reports of RNA persistence for 6 weeks or more.22,25,26 Similarly, we considered only PCR-positive tests occurring at least 60 days after the previous PCR-positive test.

We used Poisson regression to model the incidence of PCR-positive infection per at-risk day according to baseline antibody status, adjusting for incidence over time, age, and participant-reported gender. Primary analyses used anti-spike IgG assay results, which were expected before the start of the study to be more closely related to neutralizing activity and protection from infection.7,10 We also investigated anti-nucleocapsid antibody assay results and a combined model with three baseline antibody statuses (both assays negative, both positive, or only one positive). Sensitivity analyses investigated the effect of different asymptomatic testing rates according to antibody status and different follow-up windows (see the Supplementary Appendix).

Results

Baseline Anti-Spike IgG Assays and PCR Testing Rates

A total of 12,541 health care workers underwent measurement of baseline anti-spike antibodies; 11,364 (90.6%) were seronegative and 1177 (9.4%) seropositive at their first anti-spike IgG assay, and seroconversion occurred in 88 workers during the study (Table 1, and Fig. S1A in the Supplementary Appendix). Of 1265 seropositive health care workers, 864 (68%) recalled having had symptoms consistent with those of coronavirus disease 2019 (Covid-19), including symptoms that preceded the widespread availability of PCR testing for SARS-CoV-2; 466 (37%) had had a previous PCR-confirmed SARS-CoV-2 infection, of which 262 were symptomatic. Fewer seronegative health care workers (2860 [25% of the 11,364 who were seronegative]) reported prebaseline symptoms, and 24 (all symptomatic, 0.2%) were previously PCR-positive. The median age of seronegative and seropositive health care workers was 38 years (interquartile range, 29 to 49). Health care workers were followed for a median of 200 days (interquartile range, 180 to 207) after a negative antibody test and for 139 days at risk (interquartile range, 117 to 147) after a positive antibody test.

Rates of symptomatic PCR testing were similar in seronegative and seropositive health care workers: 8.7 and 8.0 tests per 10,000 days at risk, respectively (rate ratio, 0.92; 95% confidence interval [CI], 0.77 to 1.10). A total of 8850 health care workers had at least one postbaseline asymptomatic screening test; seronegative health care workers attended asymptomatic screening more frequently than seropositive health care workers (141 vs. 108 per 10,000 days at risk, respectively; rate ratio, 0.76; 95% CI, 0.73 to 0.80).

Incidence of PCR-Positive Results According to Baseline Anti-Spike IgG Status

Positive baseline anti-spike antibody assays were associated with lower rates of PCR-positive tests. Of 11,364 health care workers with a negative anti-spike IgG assay, 223 had a positive PCR test (1.09 per 10,000 days at risk), 100 during asymptomatic screening and 123 while symptomatic. Of 1265 health care workers with a positive anti-spike IgG assay, 2 had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested. The incidence rate ratio for positive PCR tests in seropositive workers was 0.12 (95% CI, 0.03 to 0.47; P=0.002). The incidence of PCR-confirmed symptomatic infection in seronegative health care workers was 0.60 per 10,000 days at risk, whereas there were no confirmed symptomatic infections in seropositive health care workers. No PCR-positive results occurred in 24 seronegative, previously PCR-positive health care workers; seroconversion occurred in 5 of these workers during follow-up.

Incidence varied by calendar time (Figure 1), reflecting the first (March through April) and second (October and November) waves of the pandemic in the United Kingdom, and was consistently higher in seronegative health care workers. After adjustment for age, gender, and month of testing (Table S1) or calendar time as a continuous variable (Fig. S2), the incidence rate ratio in seropositive workers was 0.11 (95% CI, 0.03 to 0.44; P=0.002). Results were similar in analyses in which follow-up of both seronegative and seropositive workers began 60 days after baseline serologic assay; with a 90-day window after positive serologic assay or PCR testing; and after random removal of PCR results for seronegative health care workers to match asymptomatic testing rates in seropositive health care workers (Tables S2 through S4). The incidence of positive PCR tests was inversely associated with anti-spike antibody titers, including titers below the positive threshold (São Paulo Research Foundation (FAPESP), Takeda, and Wellcome. Prof. Screaton is a Wellcome Trust Senior Investigator with funding from the Schmidt Foundation; Dr. Timothy Walker is a Wellcome Trust Clinical Career Development Fellow (214560/Z/18/Z); and Prof. A. Sarah Walker is an NIHR Senior Investigator.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, the Department of Health, or Public Health England.

This article was published on December 23, 2020, at NEJM.org.

We thank all Oxford University Hospitals personnel who participated in the staff testing program and the staff and medical students who ran the program. This study uses data provided by health care workers and collected by the U.K. National Health Service as part of their care and support. We thank additional members of the Infections in Oxfordshire Research Database team: L. Butcher, H. Boseley, C. Crichton, O. Freeman, J. Gearing (community), R. Harrington, M. Landray, A. Pal, T.P. Quan, J. Robinson (community), J. Sellors, B. Shine, and D. Waller; and the patient and public panel: G. Blower, C. Mancey, P. McLoughlin, and B. Nichols.