Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2 mRNA vaccinated individuals

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Our take —

In a matched pair case-control study, available as a preprint and thus not yet peer-reviewed, comparing breakthrough cases in 247 partially and 149 fully immunized adults with BNT162b2 vaccine to unvaccinated controls in Israel, the odds of SARS-CoV-2 infection by the B.1.1.7 variant versus the wild-type were twice as high among partially immunized adults compared to unvaccinated controls but there was no difference between fully vaccinated cases and unvaccinated controls. All 8 B.1.351 variant infections in the fully immunized group were detected prior to the 14-day threshold for optimal immune protection by BNT162b2 vaccination. Observed associations are not measures of vaccine effectiveness, as study inclusion was restricted to individuals with confirmed SARS-CoV-2 infections.

Study design


Study population and setting

Between January 3 and March 7, 2021, individuals with SARS-CoV-2 infections, confirmed by RT-PCR and sequenced (for B.1.1.7, B.1.351, or wildtype lineages), were identified in Israel and assigned to one of three study groups: 1) infections detected from two weeks after the first dose to seven days after the 2nd dose of receiving BNT162b2 mRNA SARS-CoV-2 vaccine (“partial effectiveness” cases), 2) infections detected seven days or more following the 2nd BNT162b2 vaccine (“full effectiveness” cases), and 3) infections with no vaccination history (“unvaccinated controls”). Controls were matched to partial and full effectiveness cases, respectively, based on age (+/- 10 years), sex, district of residence, religion, and date of PCR sampling. A conditional logistic regression model was used to determine whether partially or fully vaccinated cases had higher odds of infection with a SARS-CoV-2 variant of concern relative to unvaccinated controls.

Summary of Main Findings

Of 3,491 infections detected among partially or fully vaccinated cases in the 4.7 million patients investigated, only 433 (12.4%) were able to be matched with a control and sequenced. Among the partial effectiveness cases (n = 247), 92% of SARS-CoV-2 infections were detected within 28 days of the 1st vaccine dose; among the full effectiveness cases (n = 149), one-third (31%) were detected 21+ days after the 2nd vaccine dose. The B.1.1.7 variant was responsible for ~90% of SARS-CoV-2 infections in vaccinated cases and unvaccinated controls; only 11 infections of the B.1.351 variant were detected in case-control pairs. No significant difference in B.1.1.7 infections was observed when comparing full effectiveness cases to unvaccinated controls, but for partial effectiveness cases the odds of B.1.1.7 infection was twice as high. The odds of B.1.351 infection was significantly higher among the full effectiveness cases relative to unvaccinated controls, but there was no increased odds in the partial effectiveness group. Importantly, all eight matched B.1.351 cases identified among the full effectiveness cases were detected within 7-13 days of the 2nd vaccine dose and none were detected after that.

Study Strengths

Investigators matched vaccinated individuals to unvaccinated individuals to control for factors (i.e., age, date of PCR test, district of residence) that could bias observed associations between the lineage of SARS-CoV-2 infections and immunization status.


Because this study compares the distributions of strains between vaccinated and unvaccinated individuals, not rates of infection, effect estimates obtained from this study should not be interpreted as measures of vaccine effectiveness; this study cannot directly assess the vaccine effectiveness for any strain but can only assess the relative vaccine effectiveness of one strain versus another (i.e., an odds ratio of 2.0 could equate to vaccine efficacy of 90% relative to 95%). The low number of total B.1.351 and wildtype infections in both the full effectiveness analysis (n=9 and 14, respectively) and partial effectiveness analysis (n=2 and 64, respectively) may have underpowered analyses. SARS-CoV-2 vaccinations in Israel were offered first to older adults, which resulted in age-imbalanced vaccinated case group and unvaccinated control group; SARS-CoV-2 breakthrough cases in the full effectiveness group, therefore, could be partially attributed to older age, which could be associated with an attenuated immune response to vaccination.

Value added

This is among the first studies to assess the relative propensity for breakthrough infections between SARS-CoV-2 lineages among BNT162b2 vaccine recipients in a non-controlled, observational setting.

This review was posted on: 23 April 2021

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