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Avoiding biases when estimating effects of COVID-19 vaccination during immune checkpoint inhibitor therapy: Preprint challenges view of overall survival benefit of mRNA vaccination in lung cancer and melanoma patients.

SARS-CoV-2 mRNA vaccination (COVID-19 vaccination) within 100 days of immune checkpoint inhibitor (ICI) treatment was reported to improve survival and prevent disease progression in patients with non-small cell lung cancer (NSCLC) and metastatic melanoma (Grippin et al ., Nature, 2025). However, the clinical evidence, derived from real-world observational data, suffers from methodological limitations. Specifically, the vaccinated and unvaccinated groups differed in subtle ways due to the timing of vaccination, the beginning of follow-up, and the definition of eligibility. These key limitations can be overcome by carefully conducting a target trial emulation analysis. Using the original data from Grippin et al ., we emulated a target trial to estimate the causal effect of COVID-19 vaccination within 100 days of ICI initiation on overall survival and progression-free survival in patients with NSCLC and metastatic melanoma. In contrast to the original analysis, we found no evidence that COVID-19 vaccination improves survival outcomes in these populations. Standfirst Claims that SARS-CoV-2 mRNA vaccination within 100 days of starting immune checkpoint inhibitor therapy improves survival in non-small cell lung cancer and metastatic melanoma led us to reanalyze the original dataset by emulating a target trial that aligns time zero, harmonizes eligibility across treatment arms, and addresses immortal-time and selection bias, and we then found no evidence of benefit in either cancer population. Summary points ### Competing Interest Statement Dr Gougis reports an academic grant from Sanofi. Dr. Spano reports consultant or advisory role fees from Roche, MSD, BMS, Lilly, AstraZeneca, Daiichi-Sankyo, Mylan, Novartis, Pfizer, PFO, LeoPharma, Incyte, and Gilead and a research academic grant for MSDAvenir. Dr Stensrud. reports stock, honoraria, and consulting or advisory role from Novartis. The other authors did not declare competing interests for this work. ### Funding Statement This study was funded by the Swiss National Foundation grant number 207436 (MJS and LG). The funding source had no role in the design of the study, interpretation of the data, or decision to submit results. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We reanalysed the dataset from a previously published paper. The authors made the data publicly available online, and it can be found at: <https://www.nature.com/articles/s41586-025-09655-y> I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data can be reproduced using the code available on Github.

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