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

Abstract

The BNT162b2 mRNA vaccine is highly effective against SARS-CoV-2. However, apprehension exists that variants of concern (VOCs) may evade vaccine protection, due to evidence of reduced neutralization of the VOCs B.1.1.7 and B.1.351 by vaccine sera in laboratory assays. We performed a matched cohort study to examine the distribution of VOCs in infections of BNT162b2 mRNA vaccinees from Clalit Health Services (Israel) using viral genomic sequencing, and hypothesized that if vaccine effectiveness against a VOC is reduced, its proportion among breakthrough cases would be higher than in unvaccinated controls. Analyzing 813 viral genome sequences from nasopharyngeal swabs, we showed that vaccinees who tested positive at least 7 days after the second dose were disproportionally infected with B.1.351, compared with controls. Those who tested positive between 2 weeks after the first dose and 6 days after the second dose were disproportionally infected by B.1.1.7. These findings suggest reduced vaccine effectiveness against both VOCs within particular time windows. Our results emphasize the importance of rigorously tracking viral variants, and of increasing vaccination to prevent the spread of VOCs.

Fig. 1. Variant frequencies of SARS-CoV-2-positive samples.

a, Variant frequencies across the time of the study, including the number of samples collected throughout the study. All values were calculated by averaging over a sliding window of 7 days. All samples sequenced in this study are included herein, including unpaired samples. b, Breakdown of variant frequencies based on the four groups of this study. The pie charts display the proportion of each variant (B.1.1.7, B.1.351 and WT) for paired vaccinated cases versus non-vaccinated controls separated by dosage (as defined in the main text), with cases on the left and their associated control on the right. Only paired samples are shown in the figure.

Fig. 2. Results of matched vaccinated cases and non-vaccinated controls separated by effectiveness and VOC.

In each table, a cell reflects the number of pairs concordant (upper left and lower right) or discordant (upper right or lower left) for a given variant. The left panel focuses on the comparison between B.1.1.7 and WT (pairs with B.1.351 were removed), whereas the right panel focuses on comparing B.1.351 and either WT or B.1.1.7 (denoted collectively as ‘other’). Of note, the McNemar test focuses on a comparison of only discordant samples. Under a null hypothesis of equal vaccine effectiveness against all variants, we expect an equal number of discordant pairs in the upper right cell and the lower left cell, in each of the tables.

Fig. 3. Breakdown of SARS-CoV-2 variant distribution during windows of weeks post vaccination.

The first three panels correspond to the dose1 group and the last three panels correspond to the dose2 group. The number of pairs and the isolation date range of the samples are noted for each panel. The dose2 B.1.351 case that is shown in the 14–20 days category was isolated exactly 14 days after the second dose.

Fig. 4. A maximum-likelihood phylogenetic tree of Israeli SARS-CoV-2 samples including those sequenced herein.

Vaccinees are colored in violet or green, non-vaccinees are colored in brown, and black sequences are publicly available sequences from Israel (marked as ‘other’, Supplementary Table 2). Clades composed of the B.1.1.7, B.1.351 and WT sequences are encircled in blue, orange and gray, respectively.