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

May combine two claims.

Higher viral load was noted in B.1.351 infections, while lower viral load was noted in vaccinees compared to unvaccinated individuals.

“yet we did note higher VL in B.1.351infections, while noting lower VL in vaccinees as compared to unvaccinated individuals (Supplementary Fig. 6) 29,30 .”

• cites [29] Levine-Tiefenbrun, M. et al. Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine. Nat. Med. 27, 790–792 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [30] Petter, E. et al. Initial real world evidence for lower viral load of individuals who have been vaccinated by BNT162b2. Preprint at medRxiv https://doi.org/10.1101/2021.02.08.21251329 (2021). sourceNot checked yet

  Not checked in the free run.

The quote only partly states this claim.

Among BNT162b2 vaccinees who tested positive between 14 days after the first dose and 6 days after the second dose, the proportion of B.1.1.7 was significantly higher than among matched unvaccinated controls (McNemar OR 26:10, P=0.006).

“a significantly higher rate of B.1.1.7 was observed in dose1 cases versus unvaccinated controls (McNemar OR of 26:10; one-sided exact McNemar test, P = 0.006).”

Probably not a substantial claim: may not pass S3 (load-bearing).

One dose1 control sequence, originally classified as WT (B.1.235), was located within the B.1.351 clade on the phylogenetic tree.

“Following classification by Pangolin, we noted that one dose1 control sequence, originally classified as WT (B.1.235),was located within the B.1.351clade on the phylogenetic tree.”

May combine two claims.

B.1.1.7 was the predominant strain in Israel over the entire sampling period (712/813 sequences), increasing in frequency over time.

“we noted that B.1.1.7 was the predominant strain of the virus in Israel over the entire sampling period (712/813 sequences), increasing in frequency over time (Fig. 1a).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The pair of the misclassified dose1 control sequence was classified as B.1.1.7.

“Its pair was classified as B.1.1.7”

Probably not a substantial claim: may not pass S3 (load-bearing).

The dose2 B.1.351 case shown in the 14-20 days category was isolated exactly 14 days after the second dose.

“The dose2 B.1.351case that is shown in the 14-20 days category was isolated exactly 14 days after the second dose.”

May combine two claims.

These results are generally aligned with in vitro neutralization assays showing a large reduction in neutralization against B.1.351 and little to no reduction against B.1.1.7 in fully vaccinated individuals.

“These results are generally aligned with those from in vitro neutralization assays that have shown a large reduction in neutralization against B.1.351,and little to no reduction against B.1.1.7 in fully vaccinated individuals [7][8][9][10][11]17 .”

• cites [7] Liu, Y. et al. Neutralizing activity of BNT162b2-elicited serum. N. Engl. J. Med. 384, 1466–1468 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [8] Xie, X. et al. Neutralization of SARS-CoV-2 spike 69/70 deletion E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat. Med. 27, 620–621 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [9] Collier, D. A. et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature 593, 136–141 (2021). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Samples for which Pangolin labels of the strict and majority-rule consensuses did not coincide were discarded.

“Samples for which Pangolin labels of the strict and majority-rule consensuses did not coincide were discarded.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Regions with fluctuating ambiguity (continuous subsequence of length 20 or lower flanked by ambiguous bases) were masked as N.

“We also noted some regions with fluctuating ambiguity: if a continuous subsequence of length 20 or lower was flanked on both ends by ambiguous bases, we masked out this entire subsequence by assigning it with N, under the assumption it represents unreliable sequencing.”

• AssumptionThe authors state this as an assumption: A continuous subsequence of length 20 or lower flanked by ambiguous bases represents unreliable sequencing.

Probably not a substantial claim: may not pass S3 (load-bearing).

The failed parameter match was most often age, sex or municipality.

“We found that the failed parameter match was most often age, sex or municipality.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Two consensus sequences were constructed for each sample: one based on majority rule, and a stricter consensus requiring at least 80% of reads to support a given base.

“To overcome these limitations, we constructed two consensus sequences for each sample, one based on majority rule, and a more strict consensus sequence where we required at least 80% of reads to support a given base.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

To increase dose2 matching, matching on date of PCR sampling was enforced, but four out of five matches in the remaining parameters were allowed, prioritizing municipality, then sector, then age, then additional criteria.

“To increase dose2 matching, we enforced matching on the date of PCR sampling, but allowed for four out of five matches in the remaining parameters, while prioritizing municipality, then sector, then age, and then the additional criteria.”

Classified as probably not a substantial claim.

Each case was matched to a control using six parameters: date of sampling for PCR (±3 days), sex, age (±10 years), municipality of residence, geographical district of residence and sector.

“Next, each case was matched to a control using six parameters: date of sampling for PCR (±3 days), sex, age (±10 years), municipality of residence, geographical district of residence and sector.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A conditional logistic regression was used as a sensitivity analysis to include age as a possible confounder in case matching was not sufficient.

“A conditional logistic regression was used as a sensitivity analysis to include age as a possible confounder in case that matching was not sufficient, under the assumption that it was sometimes only partially mediated through matching.”

• AssumptionThe authors state this as an assumption: Age effect was sometimes only partially mediated through matching.

Probably not a substantial claim: may not pass S3 (load-bearing).

Ten control samples served as controls for both a dose1 and a dose2 sample.

“We note that ten control samples served as controls for both a dose1 and a dose2 sample.”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

B.1.1.7 is associated with lower Ct values, corresponding to higher viral loads.

“it has been previously reported that B.1.1.7 is associated with lower Ct values, corresponding to higher VLs 3”

• cites [3] Davies, N. G. et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 372, eabg3055 (2021). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Only samples with Ct values of 33 or lower were collected.

“Following matching, RNA from cases and controls was obtained from the main testing laboratories of CHS, with one major limitation: only samples with Ct values of 33 or lower were collected.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Amplicon dropout of amplicons 74 and 76, both covering the spike gene and some lineage-defining alterations of B.1.1.7 and B.1.351 (such as E484K and N501Y), has been previously noted.

“We and others have previously noted amplicon dropout of amplicons 74 and 76 (ref.32 ), both of which cover the spike gene, and in particular some of the lineage-defining alterations of B.1.1.7 and B.1.351(such as E484K and N501Y).”

• cites ref.32Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Breakthrough cases observed might be due to immune evasion mediated by particular alterations present in these strains.

“From a biological point of view, the breakthrough cases observed in this study might be due to immune evasion, mediated by particular alterations present in these strains 9,[23][24][25][26][27] .”

• cites [9] Collier, D. A. et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature 593, 136–141 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [23] Greaney, A. J. et al. Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies. Preprint at bioRxiv https://doi.org/10.1101/2020.12.31.425021 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [24] Weisblum, Y. et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife 9, e61312 (2020). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In both consensus sequencing assignments, sequencing coverage of at least ten reads was required.

“In both types of consensus sequencing assignments, we required sequencing coverage of at least ten reads.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Thirty-two pairs in which one sample did not undergo successful sequencing were discarded from the paired analyses.

“Thirty-two pairs in which one sample did not undergo successful sequencing were discarded from the paired analyses (but see Supplementary Fig. 3).”

Probably not a substantial claim: may not pass S3 (load-bearing).

All sequences in the study were manually verified for phylogenetic location.

“This is in line with recent concerns regarding misclassifications of Pangolin 37 , and led us to manually verify the phylogenetic location of all sequences in our study.”

• cites [37] Dudas, G. et al. Travel-driven emergence and spread of SARS-CoV-2 lineage B.1.620 with multiple VOC-like mutations and deletions in Europe. Preprint at medRxiv https://doi.org/10.1101/2021.05.04.21256637 (2021). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The conditional logistic regression was performed only on the dose1 B.1.1.7 analysis, as not enough data were available in other categories.

“The regression was performed only on the dose1 B.1.1.7 analysis, as not enough data were available in other categories.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study was approved by the CHS institutional review board (no.0016-21-COM2) and was exempt from the requirement for informed consent; it was further approved by the Tel Aviv University ethics committee (0002706-1).

“The study was approved by the CHS institutional review board (no.0016-21-COM2) and was exempt from the requirement for informed consent.The study was further approved by the Tel Aviv University ethics committee (0002706-1).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In preliminary analyses, matching often failed for dose2 samples due to their small sample size and increasing proportions of vaccinated individuals in older age categories across time.

“In preliminary analyses, we noted that matching often failed for dose2 samples due to their small sample size, as well as due to increasing proportions of vaccinated individuals in older age categories across time, in line with the vaccine rollout policy in Israel.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Some vaccinees (7.7%) received the second vaccine dose more than 28 days after the first vaccine, yet were still annotated as described.

“We also note that some vaccinees (7.7%, Table 1) received the second vaccine dose more than 28 days after the first vaccine, yet were still annotated as described above.”