In an Israeli single-institution prospective cohort study reported in The New England Journal of Medicine, Bergwerk et al identified breakthrough COVID-19 infections among 39 of 1,497 health-care workers fully vaccinated with the BNT162b2 (Pfizer-BioNTech) vaccine.

As stated by the investigators: “Despite the high efficacy of the BNT162b2 messenger RNA vaccine against 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.”

Study Details

The study was conducted at Sheba Medical Center in Tel Aviv, where 91% of 12,586 personnel received two doses of the BNT162b2 vaccine between December 19, 2020, and April 28, 2021. The largest COVID-19 pandemic surge in Israel had reached its peak on January 14, 2021. The study was initiated on January 20, 2021, 11 days after the first staff members had received a second dose of the BNT162b2 vaccine; data were collected for 14 weeks, through April 28, 2021.

The current analysis included 1,497 fully vaccinated workers with available repeat reverse-transcriptase polymerase chain reaction (RT-PCR) assay data. Workers were evaluated by RT-PCR, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Breakthrough infection was defined as detection of SARS–CoV-2 on RT-PCR assay performed 11 or more days after receipt of a second vaccine dose if no explicit exposure or symptoms had been reported during the first 6 days. In a matched case-control analysis, workers with breakthrough infection with antibody titers obtained within a week before SARS–CoV-2 detection (peri-infection period) were matched with four to five uninfected controls with prospectively collected serum samples. Infectivity was assessed via correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values (viral RNA copy numbers).

Key Findings

Among 1,497 fully vaccinated workers with available RT-PCR data, 39 had documented breakthrough infections. Geometric mean titers of neutralizing antibodies during the peri-infection period were 192.8 among cases vs 533.7 among controls, yielding a case:control ratio of 0.361 (95% confidence interval [CI] = 0.165­–0.787).

Peri-infection neutralizing antibody titers in breakthrough cases were associated with higher Ct values, indicating lower infectivity. Higher viral load (Ct value < 30) at some point during infection was observed in 29 breakthrough cases (74%); however, of these cases, 17 (59%) had positive results on concurrent Ag-RDT.

Of the 33 isolates from breakthrough cases tested, 28 (85%) were identified as the B.1.1.7 variant by either multiplex PCR assay or genomic sequencing.

Among all breakthrough cases, 26 (67%) had mild symptoms at some point during infection, with none requiring hospitalization, and 13 (33%) were asymptomatic throughout infection. Among all breakthrough cases, the most common symptoms included upper respiratory congestion (36%), myalgia (28%), loss of smell or taste (28%), and fever/rigors (21%). Residual symptoms 14 days after diagnosis were reported in 31% of cases. Long COVID-19 symptoms (> 6 weeks), including prolonged loss of smell, persistent cough, fatigue, weakness, dyspnea, or myalgia, were reported by 19%.

No cases of transmission from infected workers were documented.

The investigators concluded: “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.”

Disclosure: The study was supported by the Morris–Singer Foundation and by a cooperative agreement with the U.S. National Cancer Institute. For full disclosures of the study authors, visit nejm.org.