The authors investigated breakthrough SARS-CoV-2 infections in health care workers by performing extensive evaluations of those who were symptomatic or had known infection exposure.
Study design
In this prospective cohort study, breakthrough SARS-CoV-2 infections in health care workers at the largest medical center in Israel were identified by performing extensive evaluations of those who were symptomatic (including mild COVID-19 symptoms) or had known infection exposure from June 20, 2020, until April 28, 2021. These evaluations included epidemiologic investigations, repeat RT-PCR assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. The authors conducted a matched case–control analysis to identify possible correlates of breakthrough infection. 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 the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) if no explicit exposure or symptoms had been reported during the first 6 days.
Outcomes
Among 1,497 fully vaccinated health care workers, 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. Higher peri-infection neutralizing antibody titers were associated with lower infectivity. 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 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.
Limitations
The authors could not determine the correlate of protection from severe infection or infection in vulnerable populations of older individuals with coexisting illnesses as the cohort in the study represented mostly young and healthy workers. The authors may have missed asymptomatic cases. The controls were not matched according to testing or exposure but only according to the timing of serologic testing in vaccinated, uninfected health care workers. Therefore, the authors could not control for differences in the risk of exposure to COVID-19. This factor may have led to an underestimation of the difference in protection between cases and controls. In addition, in many cases, the peri-infection antibody titer that was available had been obtained on the day of detection of the infection (which in some cases could have been a few days into the infection period) and therefore was possibly already elevated due to the infection. However, since most cases were detected in the presymptomatic stage, the authors expected that such contamination of results was minor. Additionally, among the case patients in whom both peri-infection and earlier neutralizing antibody results were available, the majority of titers were lower during the peri-infection period than during the earlier period, which also suggests that this contamination was negligible. If such contamination was substantial, the result would likely be biased toward the null hypothesis of no relationship between antibody titers and breakthrough infection.
Clinical significance
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. Breakthrough infections have emerged in a small percentage of vaccine recipients, a phenomenon that has been described in other countries and health care institutions. To date, no correlate of protection from breakthrough infection has been reported. In conclusion, although the BNT162b2 vaccine is extremely effective, rare breakthrough infections carry an infectious potential and create a special challenge, since such infections are often asymptomatic and may pose a risk to vulnerable populations.