Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

Abstract

Background: 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.

Figure 1. Cases and Controls in Study Design.

Shown is the chronologic sequence of events for health care workers who were included in the case–control study. There was some overlap between the cases and controls, since some of the workers with breakthrough cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection had also been included in the earlier serologic analysis from which control samples were selected. A case–control ratio of 1:4 or 1:5 was selected to maximize the statistical power of the study. RT-PCR denotes reverse transcriptase–polymerase chain reaction.

Figure 2. Neutralizing Antibody and IgG Titers among Cases and Controls, According to Timing.

Among the 39 fully vaccinated health care workers who had breakthrough infection with SARS-CoV-2, shown are the neutralizing antibody titers during the peri-infection period (within a week before SARS-CoV-2 detection) (Panel A) and the peak titers within 1 month after the second dose (Panel B), as compared with matched controls. Also shown are IgG titers during the peri-infection period (Panel C) and peak titers (Panel D) in the two groups. Each case of breakthrough infection was matched with 4 to 5 controls according to sex, age, immunosuppression status, and timing of serologic testing after the second vaccine dose. In each panel, the horizontal bars indicate the mean geometric titers and the 𝙸 bars indicate 95% confidence intervals. Symptomatic cases, which were all mild and did not require hospitalization, are indicated in red.

Figure 3. Correlation between Neutralizing Antibody Titer and N Gene Cycle Threshold as Indication of Infectivity.

The results of antigen-detecting (Ag) rapid diagnostic testing for the presence of SARS-CoV-2 are shown, along with neutralizing antibody titers and N gene cycle threshold (Ct) values in 22 fully vaccinated health care workers with breakthrough infection for whom data were available (slope of regression line, 171.2; 95% CI, 62.9 to 279.4).