Debiasing hazard-based, time-varying vaccine effects using vaccine-irrelevant infections: An observational extension of a pivotal Phase 3 COVID-19 vaccine efficacy trial

Ethan Ashby; Dean Follmann; Holly Janes; Peter B. Gilbert; Ting Ye; Lindsey R. Baden; Hana M. El Sahly; Bo Zhang

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arXiv · 2511.15099

Debiasing hazard-based, time-varying vaccine effects using vaccine-irrelevant infections: An observational extension of a pivotal Phase 3 COVID-19 vaccine efficacy trial

Ethan Ashby·Dean Follmann·Holly Janes·Peter B. Gilbert·Ting Ye·Lindsey R. Baden·Hana M. El Sahly·Bo Zhang

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Abstract

Understanding how vaccine effectiveness (VE) changes over time can provide evidence-based guidance for public health decision making. While commonly reported by practitioners, time-varying VE estimates obtained using Cox regression are vul- nerable to hidden biases. To address these limitations, we describe how to leverage vaccine-irrelevant infections to identify hazard-based, time-varying VE in the pres- ence of unmeasured confounding and selection bias. We articulate assumptions under which our approach identifies a causal effect of an intervention deferring vaccination and interaction with the community in which infections circulate. We develop sieve and efficient influence curve-based estimators and discuss imposing monotone shape constraints and estimating VE against multiple variants. As a case study, we examine the observational booster phase of the Coronavirus Vaccine Efficacy (COVE) trial of the Moderna mRNA-1273 COVID-19 vaccine which used symptom-triggered multi- plex PCR testing to identify acute respiratory illnesses (ARIs) caused by SARS-CoV-2 and 20 off-target pathogens previously identified as compelling negative controls for COVID-19. Accounting for vaccine-irrelevant ARIs supported that the mRNA-1273 booster was more effective and durable against Omicron COVID-19 than suggested by Cox regression. Our work offers an approach to mitigate bias in hazard-based, time- varying treatment effects in randomized and non-randomized studies using negative controls.

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Ethan Ashby, Dean Follmann, Holly Janes, Peter B. Gilbert, Ting Ye, Lindsey R. Baden, Hana M. El Sahly, Bo Zhang. 2025-11-19. Debiasing hazard-based, time-varying vaccine effects using vaccine-irrelevant infections: An observational extension of a pivotal Phase 3 COVID-19 vaccine efficacy trial. https://arxiv.org/abs/2511.15099

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