Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.
Methods

At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case–control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.
Results

Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.
Conclusions

Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

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Covid-19 in Vaccinated Health Care Workers
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Since its rollout in late 2020 in Israel, the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) has been highly effective in preventing clinically significant coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1-3 The vaccine has also been shown to reduce the incidence of asymptomatic infection and the associated infectivity.4,5 However, breakthrough infections have emerged in a small percentage of vaccine recipients, a phenomenon that has been described in other countries and health care institutions.6-8 To date, no correlate of protection from breakthrough infection has been reported.9

At the Sheba Medical Center in Ramat Gan, we conducted a prospective cohort study to assess the effectiveness of the BNT162b2 vaccine among health care workers and to examine possible correlates of protection and infectivity in this population.
Methods
Study Setting

Sheba Medical Center is the largest medical center in Israel and is staffed by 12,586 health care workers, including employees, students, and volunteers. From December 19, 2020, to April 28, 2021, a total of 91% of the center personnel received two doses of the BNT162b2 vaccine. This period was followed by a rapid decrease in newly detected cases.4,10 Simultaneously, efforts were extended to identify new cases with the use of daily health questionnaires, a telephone hotline, extensive epidemiologic investigations of exposure events, and contact tracing of infected patients and personnel. Testing for the presence of SARS-CoV-2 by means of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay remained readily available for fully vaccinated staff members who were symptomatic or had been exposed to an infected person, regardless of symptoms. Antigen-detecting rapid diagnostic testing (Ag-RDT) was available as an initial screening tool in the personnel clinic in combination with RT-PCR testing. The study was approved by the institutional review board at Sheba Medical Center.
Study Design and Population

On January 20, 2021, we initiated the study among health care workers at Sheba Medical Center, 11 days after the first staff members had received a second dose of the BNT162b2 vaccine. Data were collected for 14 weeks, until April 28. Concurrently, the third and largest Covid-19 pandemic surge emerged in Israel and reached its peak on January 14, 2021, with reports of an average of 8424 daily cases.
Figure 1. Cases and Controls in Study Design.

The study goal was to identify every breakthrough infection, including asymptomatic infections, that occurred during the study period among the health care workers at the center. A breakthrough infection was defined as the detection of SARS-CoV-2 on RT-PCR assay performed 11 or more days after receipt of a second dose of BNT162b2 if no explicit exposure or symptoms had been reported during the first 6 days. In this study, we characterized all breakthrough infections among fully vaccinated health care workers and conducted a matched case–control analysis to identify possible correlates of breakthrough infection. For the case–control analysis, we selected control serum samples that had been obtained during a prospective cohort study to analyze vaccine-induced immune responses and dynamics at the Sheba Medical Center.11 (Details regarding the serologic study are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) Among the health care workers who had participated in the serologic study, those who had results of neutralizing antibody testing and complete data were eligible as a basis for selecting controls (Figure 1).

 

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