Table of Contents
Breakthrough Infections
Among 11,453 fully vaccinated health care workers, 1497 (13.1%) underwent RT-PCR testing during the study period. Of the tested workers, 39 breakthrough cases were detected. More than 38 persons were tested for every positive case that was detected, for a test positivity of 2.6%. Thus, this percentage was much lower than the test positivity rate in Israel at the time, since the ratio between positive results and the extensive number of tests that were administered in our study was much smaller than that in the national population.
Of the 39 breakthrough case patients, 18 (46%) were nursing staff members, 10 (26%) were administration or maintenance workers, 6 (15%) were allied health professionals, and 5 (13%) were physicians. The average age of the 39 infected workers was 42 years, and the majority were women (64%). The median interval from the second vaccine dose to SARS-CoV-2 detection was 39 days (range, 11 to 102). Only one infected person (3%) had immunosuppression. Other coexisting illnesses are detailed in Table S1.
In all 37 case patients for whom data were available regarding the source of infection, the suspected source was an unvaccinated person; in 21 patients (57%), this person was a household member. Among these case patients were two married couples, in which both sets of spouses worked at Sheba Medical Center and had an unvaccinated child who had tested positive for Covid-19 and was assumed to be the source. In 11 of 37 case patients (30%), the suspected source was an unvaccinated fellow health care worker or patient; in 7 of the 11 case patients, the infection was caused by a nosocomial outbreak of the B.1.1.7 (alpha) variant. These 7 patients, who worked in different hospital sectors and wards, were all found to be linked to the same suspected unvaccinated index patient who had been receiving noninvasive positive-pressure ventilation before her infection had been detected.
Of the 39 cases of infection, 27 occurred in workers who were tested solely because of exposure to a person with known SARS-CoV-2 infection. Of all the workers with breakthrough infection, 26 (67%) had mild symptoms at some stage, and none required hospitalization. The remaining 13 workers (33% of all cases) were asymptomatic during the duration of infection; of these workers, 6 were defined as borderline cases, since they had an N gene Ct value of more than 35 on repeat testing.
The most common symptom that was reported was upper respiratory congestion (36% of all cases), followed by myalgia (28%) and loss of smell or taste (28%); fever or rigors were reported in 21% (Table S1). On follow-up questioning, 31% of all infected workers reported having residual symptoms 14 days after their diagnosis. At 6 weeks after their diagnosis, 19% reported having “long Covid-19” symptoms, which included a prolonged loss of smell, persistent cough, fatigue, weakness, dyspnea, or myalgia. Nine workers (23%) took a leave of absence from work beyond the 10 days of required quarantine; of these workers, 4 returned to work within 2 weeks. One worker had not yet returned after 6 weeks.
Verification Testing and Secondary Infections
Repeat RT-PCR assays were performed on samples obtained from most of the infected workers and for all case patients with an initial N gene Ct value of more than 30 to verify that the initial test was not taken too early, before the worker had become infectious. A total of 29 case patients (74%) had a Ct value of less than 30 at some point during their infection. However, of these workers, only 17 (59%) had positive results on a concurrent Ag-RDT. Ten workers (26%) had an N gene Ct value of more than 30 throughout the entire period; 6 of these workers had values of more than 35 and probably had never been infectious.
Of the 33 isolates that were tested for a variant of concern, 28 (85%) were identified as the B.1.1.7 variant, by either multiplex PCR assay or genomic sequencing. At the time of this study, the B.1.1.7 variant was the most widespread variant in Israel and accounted for up to 94.5% of SARS-CoV-2 isolates.1,16 Since the end of the study, the country has had a surge of cases caused by the delta variant, as have many other countries worldwide.
Thorough epidemiologic investigations of data regarding in-hospital contact tracing did not detect any cases of transmission from infected health care workers (secondary infections) among the 39 primary infections. Among the 31 cases for whom data regarding household transmission (including symptoms and RT-PCR results) were available, no secondary infections were detected, including 10 case patients and their 27 household members in whom the health care worker was the only index case patient.
Data regarding postinfection N-specific IgG antibodies were available for 22 of 39 case patients (56%) on days 8 to 72 after the first positive result on RT-PCR assay. Of these workers, 4 (18%) did not have an immune response, as detected by negative results on N-specific IgG antibody testing. Among these 4 workers were 2 who were asymptomatic (Ct values, 32 and 35), 1 who underwent serologic testing only on day 10 after diagnosis, and 1 who had immunosuppression.
Case–Control Analysis
The results of peri-infection neutralizing antibody tests were available for 22 breakthrough cases. Included in this group were 3 health care workers who had participated in the serologic study and had a test performed in the week preceding detection; in 19 other workers, neutralizing and S-specific IgG antibodies were assessed on detection day. Of these 19 case patients, 12 were asymptomatic at the time of detection. For each case, 4 to 5 controls were matched as described (Fig. S1). In total, 22 breakthrough cases and their 104 matched controls were included in the case–control analysis.
Population Characteristics and Outcomes in the Case–Control Study. 
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 ? bars indicate 95% confidence intervals. Symptomatic cases, which were all mild and did not require hospitalization, are indicated in red.
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).
The predicted GMT of peri-infection neutralizing antibody titers was 192.8 (95% confidence interval [CI], 67.6 to 549.8) for cases and 533.7 (95% CI, 408.1 to 698.0) for controls, for a predicted case-to-control ratio of neutralizing antibody titers of 0.361 (95% CI, 0.165 to 0.787) (Table 1 and Figure 2A). In a subgroup analysis in which the borderline cases were excluded, the ratio was 0.353 (95% CI, 0.185 to 0.674). Peri-infection neutralizing antibody titers in the breakthrough cases were associated with higher N gene Ct values (i.e., a lower viral RNA copy number) (slope of regression line, 171.2; 95% CI, 62.9 to 279.4) (Figure 3).
A peak neutralizing antibody titer within the first month after the second vaccine dose was available for only 12 of the breakthrough cases; the GEE predicted peak neutralizing antibody titer was 152.2 (95% CI, 30.5 to 759.3) in 12 cases and 1027.5 (95% CI, 761.6 to 1386.2) in 56 controls, for a ratio of 0.148 (95% CI, 0.040 to 0.548) (Figure 2B). In the subgroup analysis in which borderline cases were excluded, the ratio was 0.114 (95% CI, 0.042 to 0.309).
The observed and predicted GMTs of peri-infection S-specific IgG antibody levels in breakthrough infection cases were lower than that in controls, with a predicted ratio of 0.514 (95% CI, 0.282 to 0.937) (Figure 2C). The observed and predicted peak IgG GMTs in cases were also somewhat lower than those in controls (0.507; 95% CI, 0.260 to 0.989) (Figure 2D).
To assess whether our practice of measuring antibodies on the day of diagnosis created bias by capturing anamnestic responses to the current infection, we plotted peak (first-month) IgG titers against peri-infection titers on the day of diagnosis in 13 case patients for whom both values were available. In all cases, peri-infection titers were lower than the previous peak titers, indicating that the titers that were obtained on the day of diagnosis were probably representative of peri-infection titers (Fig. S2).
