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Review 1: "Delta variant and mRNA Covid-19 vaccines effectiveness: higher odds of vaccine infection breakthroughs"

This preprint claims that, compared to Alpha, Delta cases have higher odds of vaccine breakthrough infections and lower mean Ct values. Although reviewers agree on the timeliness of this paper, they had concerns with the statistical methods used to get to the conclusions.

Published onSep 27, 2021
Review 1: "Delta variant and mRNA Covid-19 vaccines effectiveness: higher odds of vaccine infection breakthroughs"
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key-enterThis Pub is a Review of
Delta variant and mRNA Covid-19 vaccines effectiveness: higher odds of vaccine infection breakthroughs

AbstractBackgroundThe SARS-CoV-2 Delta variant (B.1.617.2), initially identified in India, has become predominant in several countries, including Portugal. Few studies have compared the effectiveness of mRNA vaccines against Delta versus Alpha variant of concern (VOC) and estimated variant-specific viral loads in vaccine infection breakthroughs cases. In the context of Delta dominance, this information is critical to inform decision-makers regarding the planning of restrictions and vaccination roll-out.MethodsWe developed a case-case study to compare mRNA vaccines’ effectiveness against Delta (B.1.617.2) versus Alpha (B.1.1.7) variants. We used RT-PCR positive cases notified to the National Surveillance System between 17th of May and 4th of July 2021 (week 20 to 26) and information about demographics and vaccination status through the electronic vaccination register. Whole-genome sequencing (WGS) or spike (S) gene target failure (SGTF) data were used to classify SARS-CoV-2 variants. The odds of vaccinated individuals to become infected (odds of vaccine infection breakthrough) in Delta cases compared to Alpha SARS-CoV-2 cases was estimated by conditional logistic regression adjusted for age group, sex, and matched by the week of diagnosis. As a surrogate of viral load, mean RT-PCR Ct values were stratified and compared between vaccine status and VOC.ResultsOf the 2 097 SARS-CoV-2 RT-PCR positive cases included in the analysis, 966 (46.1%) were classified with WGS and 1131 (53.9%) with SGTF. Individuals infected with the Delta variant were more frequently vaccinated 162 (12%) than individuals infected with the Alpha variant 38 (5%). We report a statistically significant higher odds of vaccine infection breakthrough for partial (OR=1.70; CI95% 1.18 to 2.47) and complete vaccination (OR=1.96; CI95% 1.22 to 3.14) in the Delta cases when compared to the Alpha cases, suggesting lower mRNA vaccine effectiveness against Delta cases. On our secondary analysis, we observed lower mean Ct values for the Delta VOC cases versus Alpha, regardless the vaccination status. Additionally, the Delta variant cases revealed a Ct-value mean increase of 2.24 (CI95% 0.85 to 3.64) between unvaccinated and fully vaccinated breakthrough cases contrasting with 4.49 (CI95% 2.07 to 6.91) in the Alpha VOC, suggesting a lower impact of vaccine on viral load of Delta cases.ConclusionsWe found significantly higher odds of vaccine infection breakthrough in Delta cases when compared to Alpha cases, suggesting lower effectiveness of the mRNA vaccines in preventing infection with the Delta variant. Additionally, the vaccine breakthrough cases are estimated to be of higher mean Ct values, suggesting higher infectiousness with the Delta variant infection. These findings can help decision-makers weigh on the application or lifting of control measures and adjusting vaccine roll-out depending on the predominance of the Delta variant and the coverage of partial and complete mRNA vaccination.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



Summary: Kislaya et al. present a case-case study of SARS-CoV-2 infections attributed to the Alpha and Delta variants. Using WGS and SGTF, they identified causative VOC in infections that occurred in unvaccinated, partially vaccinated, and fully vaccinated patients. The authors observed an increased rate of breakthrough infections attributed to the Delta variant. Additionally, the authors observed an increased viral load among all patients with Delta variant infections.

Overall, I think the claims are generally supported by the data and methods used. The data is important for awareness of the scientific community as it will impact public health efforts to combat the surge of Delta cases. This study further expands on the growing evidence of vaccine breakthroughs by the Delta variant. This information must be published promptly. 

The authors use sound statistical analysis to determine the rate of vaccine breakthrough by Delta and Alpha SARS-CoV-2 variants among unvaccinated, partially vaccinated, and fully vaccinated individuals. The data supports the conclusion that an increased number of breakthrough infections are attributed to the Delta variant.

One weakness of the manuscript is their reliance on Ct values to determine viral load. As COVID-19 progresses, viral load changes drastically. As we do not fully understand the symptom onset/severity differences between Alpha and Delta, it is difficult to determine if this could confound the lower observed Ct values. If Delta tends to cause COVID-19 symptoms earlier, are patients more likely to get tested during a period of higher viral load? I see the citations about previous studies using Ct to estimate viral load. However, the authors are not assessing the differences between the two variants. Depending on the authors' depth of metadata on each individual, an analysis of the date of symptom onset and RT-PCR test could help position the results in more context.

Decision-makers should consider the claims in this study actionable with limitations based on the methods and data.

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