Review 1: "Assessing Healthy Vaccinee Bias in COVID-19 Vaccine Effectiveness Studies: A National Cohort Study in Qatar"

Thiago Cerqueira Silva

doi:doi:10.1162/2e3983f5.3d0b08a4

Assessing Healthy Vaccinee Effect in COVID-19 Vaccine Effectiveness Studies: A National Cohort Study in Qatar

by Hiam Chemaitelly, Houssein H. Ayoub, Peter Coyle, Patrick Tang, Mohammad R. Hasan, Hadi M. Yassine, Asmaa A. Al Thani, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar Hassan Kaleeckal, Ali Nizar Latif, Riyazuddin Mohammad Shaik, Hanan F. Abdul-Rahim, Gheyath K. Nasrallah, Mohamed Ghaith Al-Kuwari, Hamad Eid Al-Romaihi, Mohamed H. Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Adeel A. Butt, and Laith J. Abu-Raddad

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Published on Sep 03, 2024
www.medrxiv.org

Description

Abstract Background This study investigated the presence of the healthy vaccinee effect—the imbalance in health status between vaccinated and unvaccinated individuals—in two COVID-19 vaccine effectiveness studies involving primary series and booster vaccinations. It also examined the temporal patterns and variability of this effect across different subpopulations by analyzing the association between COVID-19 vaccination and non-COVID-19 mortality in Qatar.Methods Two matched, retrospective cohort studies assessed the incidence of non-COVID-19 death in national cohorts of individuals with a primary series vaccination versus no vaccination (two-dose analysis), and individuals with three-dose (booster) vaccination versus primary series vaccination (three-dose analysis), from January 5, 2021, to April 9, 2024.Results The adjusted hazard ratio (aHR) for non-COVID-19 death was 0.76 (95% CI: 0.64-0.90) in the two-dose analysis and 0.85 (95% CI: 0.67-1.07) in the three-dose analysis. In the first six months of follow-up in the two-dose analysis, the aHR was 0.35 (95% CI: 0.27-0.46); however, the combined analysis of all subsequent periods showed an aHR of 1.52 (95% CI: 1.19-1.94). In the first six months of follow-up in the three-dose analysis, the aHR was 0.31 (95% CI: 0.20-0.50); however, the combined analysis of all subsequent periods showed an aHR of 1.37 (95% CI: 1.02-1.85). The overall effectiveness of the primary series and third-dose vaccinations against severe, critical, or fatal COVID-19 was 95.9% (95% CI: 94.0-97.1) and 34.1% (95% CI: −46.4-76.7), respectively. Subgroup analyses showed that the healthy vaccinee effect is pronounced among those aged 50 years and older and among those more clinically vulnerable to severe COVID-19.Conclusion A strong healthy vaccinee effect was observed in the first six months following vaccination. This effect may have stemmed from a lower likelihood of vaccination among seriously ill, end-of-life individuals, and less mobile elderly populations.

RR\ID 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.

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Review: The paper adds to the literature on the healthy vaccinee effect by utilising the well-known Qatar nationwide surveillance system. They also analysed stratification by age group, which I don't recall seeing before. I only have one concern about the analysis, which is the validity of the results.

The follow-up until a positive SARS-CoV-2 test does not appear to be necessary to investigate outcomes unrelated to Covid-19. It can induce informative censoring because unvaccinated individuals will have a higher rate of censoring as a result of SARS-CoV-2 infection, and because it is not matched pair censoring, it can also cause unbalancing in the cohort.

General comments:

The study is overly reliant on self-citation, with 27 out of 57 (47%) of the references being self-citations. This is significantly higher than the average for any paper. Recent studies on this same subject are not cited in the paper (e.g. https://www.tandfonline.com/doi/full/10.2147/CLEP.S468572 or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9520345/)

Methods:

I have a concern about the analysis that could affect the validity of the reported results. The authors follow-up the research subjects until they have a positive SARS-CoV-2 test. It is not clear why they are doing that when investigating outcomes unrelated to COVID-19. This could introduce informative censoring because unvaccinated individuals will have a higher rate of censoring (being removed from the sample) as a result of SARS-CoV-2 infection (because they are more likely to be infected or more likely to have their infection detected). Additionally, because it is not matched pair censoring (in other words, if an infected person is removed, the matched uninfected person is not also removed from the sample), this approach could also unbalance the cohort as infected persons are removed. This concern should be addressed in the manuscript.

Discussion:

It would be helpful to move the background on Qatar during COVID either to background or to supplementary materials.

One point worth discussing is why the results between 3-doses vs. 2-doses and 2-doses vs. unvaccinated were very similar during the first 6 months. The reader is likely to expect that unvaccinated individuals would be very different from vaccinated ones so it would be useful to explain this finding.

Minor Comment:

Please include the number at risk in the KM curves.

Review 1: "Assessing Healthy Vaccinee Bias in COVID-19 Vaccine Effectiveness Studies: A National Cohort Study in Qatar"

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