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.
The incidence of polymerase-chain-reaction (PCR) tests that were positive for SARS-CoV-2 infection during the period from April through November 2020 is shown per 10,000 days at risk among health care workers according to their antibody status at baseline. In seronegative health care workers, 1775 PCR tests (8.7 per 10,000 days at risk) were undertaken in symptomatic persons and 28,878 (141 per 10,000 days at risk) in asymptomatic persons; in seropositive health care workers, 126 (8.0 per 10,000 days at risk) were undertaken in symptomatic persons and 1704 (108 per 10,000 days at risk) in asymptomatic persons. RR denotes rate ratio.
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 (P<0.001 for trend) (Fig. S3A).
Anti-Nucleocapsid IgG Status
With anti-nucleocapsid IgG used as a marker for prior infection in 12,666 health care workers (Fig. S1B and Table S5), 226 of 11,543 (1.10 per 10,000 days at risk) seronegative health care workers tested PCR-positive, as compared with 2 of 1172 (0.13 per 10,000 days at risk) antibody-positive health care workers (incidence rate ratio adjusted for calendar time, age, and gender, 0.11; 95% CI, 0.03 to 0.45; P=0.002) (Table S6). The incidence of PCR-positive results fell with increasing anti-nucleocapsid antibody titers (P<0.001 for trend) (Fig. S3B).
A total of 12,479 health care workers had both anti-spike and anti-nucleocapsid baseline results (Fig. S1C and Tables S7 and S8); 218 of 11,182 workers (1.08 per 10,000 days at risk) with both immunoassays negative had subsequent PCR-positive tests, as compared with 1 of 1021 workers (0.07 per 10,000 days at risk) with both baseline assays positive (incidence rate ratio, 0.06; 95% CI, 0.01 to 0.46) and 2 of 344 workers (0.49 per 10,000 days at risk) with mixed antibody assay results (incidence rate ratio, 0.42; 95% CI, 0.10 to 1.69).
Seropositive Health Care Workers with PCR-Positive Results
Three seropositive health care workers subsequently had PCR-positive tests for SARS-CoV-2 infection (one with anti-spike IgG only, one with anti-nucleocapsid IgG only, and one with both antibodies). The time between initial symptoms or seropositivity and subsequent positive PCR testing ranged from 160 to 199 days. Information on the workers’ clinical histories and on PCR and serologic testing results is shown in Table 2 and Figure S4.
Only the health care worker with both antibodies had a history of PCR-confirmed symptomatic infection that preceded serologic testing; after five negative PCR tests, this worker had one positive PCR test (low viral load: cycle number, 21 [approximate equivalent cycle threshold, 31]) at day 190 after infection while the worker was asymptomatic, with subsequent negative PCR tests 2 and 4 days later and no subsequent rise in antibody titers. If this worker’s single PCR-positive result was a false positive, the incidence rate ratio for PCR positivity if anti-spike IgG–seropositive would fall to 0.05 (95% CI, 0.01 to 0.39) and if anti-nucleocapsid IgG–seropositive would fall to 0.06 (95% CI, 0.01 to 0.40).
A fourth dual-seropositive health care worker had a PCR-positive test 231 days after the worker’s index symptomatic infection, but retesting of the worker’s sample was negative twice, which suggests a laboratory error in the original PCR result. Subsequent serologic assays showed waning anti-nucleocapsid and stable anti-spike antibodies.