Ethan Ashby, Holly Janes, Dean Follmann, Peter B Gilbert, Honghong Zhou, Xiaowei Wang, Bethany Girard, Frances Priddy, James G Kublin, Lawrence Corey, Kathleen M Neuzil, Lindsey R Baden, Hana M El Sahly, Bo Zhang, On Behalf Of Cove Study Group
{"title":"验证和利用非sars - cov -2呼吸道感染作为阴性对照结果的3期COVID-19疫苗试验与延长观察随访。","authors":"Ethan Ashby, Holly Janes, Dean Follmann, Peter B Gilbert, Honghong Zhou, Xiaowei Wang, Bethany Girard, Frances Priddy, James G Kublin, Lawrence Corey, Kathleen M Neuzil, Lindsey R Baden, Hana M El Sahly, Bo Zhang, On Behalf Of Cove Study Group","doi":"10.1093/aje/kwaf176","DOIUrl":null,"url":null,"abstract":"<p><p>Negative control outcomes (NCOs) are useful tools for hidden bias detection, but empirical evidence validating NCOs for COVID-19 is lacking. To address this gap, we examined the blinded phase of the randomized, placebo-controlled Coronavirus Vaccine Efficacy (COVE; NCT04470427) trial of the mRNA-1273 COVID-19 vaccine. We confirmed that acute respiratory illness with a positive test for a non-SARS-CoV-2 respiratory pathogen on a multiplex PCR panel was a valid NCO for COVID-19, considering that it was unaffected by vaccination (vaccine efficacy, VE=3.3% (95% CI, -22.3-23.6)) yet strongly associated with COVID-19 (odds ratio=2.95 (95% CI, 2.00-4.24)). Subsequently, we leveraged non-SARS-CoV-2 infections to detect bias in time-varying VE estimates from COVE's blinded and booster phases. Balanced incidence of non-SARS-CoV-2 infection between vaccinated and unvaccinated COVID-19-free risk sets suggested low selection bias in VE estimates of two-dose mRNA-1273 against COVID-19 during the blinded phase (VE=92.5% (95% CI, 88.8-94.9) 14 days post-dose-two, stable for 5 months). In COVE's booster phase, higher non-SARS-CoV-2 incidence was observed after the single booster (intensity ratio, IR=2.38 (95% CI, 1.75-3.25) 14 days post-boost), suggesting that booster VE estimates may underestimate the true VE against COVID-19. Our findings demonstrate the potential of off-target infections for unraveling complex biases in COVID-19 vaccine studies.</p>","PeriodicalId":7472,"journal":{"name":"American journal of epidemiology","volume":" ","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448673/pdf/","citationCount":"0","resultStr":"{\"title\":\"Validating and leveraging non-SARS-CoV-2 respiratory infection as a negative control outcome in a phase 3 COVID-19 vaccine trial with extended observational follow-up.\",\"authors\":\"Ethan Ashby, Holly Janes, Dean Follmann, Peter B Gilbert, Honghong Zhou, Xiaowei Wang, Bethany Girard, Frances Priddy, James G Kublin, Lawrence Corey, Kathleen M Neuzil, Lindsey R Baden, Hana M El Sahly, Bo Zhang, On Behalf Of Cove Study Group\",\"doi\":\"10.1093/aje/kwaf176\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Negative control outcomes (NCOs) are useful tools for hidden bias detection, but empirical evidence validating NCOs for COVID-19 is lacking. To address this gap, we examined the blinded phase of the randomized, placebo-controlled Coronavirus Vaccine Efficacy (COVE; NCT04470427) trial of the mRNA-1273 COVID-19 vaccine. We confirmed that acute respiratory illness with a positive test for a non-SARS-CoV-2 respiratory pathogen on a multiplex PCR panel was a valid NCO for COVID-19, considering that it was unaffected by vaccination (vaccine efficacy, VE=3.3% (95% CI, -22.3-23.6)) yet strongly associated with COVID-19 (odds ratio=2.95 (95% CI, 2.00-4.24)). Subsequently, we leveraged non-SARS-CoV-2 infections to detect bias in time-varying VE estimates from COVE's blinded and booster phases. Balanced incidence of non-SARS-CoV-2 infection between vaccinated and unvaccinated COVID-19-free risk sets suggested low selection bias in VE estimates of two-dose mRNA-1273 against COVID-19 during the blinded phase (VE=92.5% (95% CI, 88.8-94.9) 14 days post-dose-two, stable for 5 months). In COVE's booster phase, higher non-SARS-CoV-2 incidence was observed after the single booster (intensity ratio, IR=2.38 (95% CI, 1.75-3.25) 14 days post-boost), suggesting that booster VE estimates may underestimate the true VE against COVID-19. Our findings demonstrate the potential of off-target infections for unraveling complex biases in COVID-19 vaccine studies.</p>\",\"PeriodicalId\":7472,\"journal\":{\"name\":\"American journal of epidemiology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448673/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of epidemiology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/aje/kwaf176\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of epidemiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/aje/kwaf176","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH","Score":null,"Total":0}
Validating and leveraging non-SARS-CoV-2 respiratory infection as a negative control outcome in a phase 3 COVID-19 vaccine trial with extended observational follow-up.
Negative control outcomes (NCOs) are useful tools for hidden bias detection, but empirical evidence validating NCOs for COVID-19 is lacking. To address this gap, we examined the blinded phase of the randomized, placebo-controlled Coronavirus Vaccine Efficacy (COVE; NCT04470427) trial of the mRNA-1273 COVID-19 vaccine. We confirmed that acute respiratory illness with a positive test for a non-SARS-CoV-2 respiratory pathogen on a multiplex PCR panel was a valid NCO for COVID-19, considering that it was unaffected by vaccination (vaccine efficacy, VE=3.3% (95% CI, -22.3-23.6)) yet strongly associated with COVID-19 (odds ratio=2.95 (95% CI, 2.00-4.24)). Subsequently, we leveraged non-SARS-CoV-2 infections to detect bias in time-varying VE estimates from COVE's blinded and booster phases. Balanced incidence of non-SARS-CoV-2 infection between vaccinated and unvaccinated COVID-19-free risk sets suggested low selection bias in VE estimates of two-dose mRNA-1273 against COVID-19 during the blinded phase (VE=92.5% (95% CI, 88.8-94.9) 14 days post-dose-two, stable for 5 months). In COVE's booster phase, higher non-SARS-CoV-2 incidence was observed after the single booster (intensity ratio, IR=2.38 (95% CI, 1.75-3.25) 14 days post-boost), suggesting that booster VE estimates may underestimate the true VE against COVID-19. Our findings demonstrate the potential of off-target infections for unraveling complex biases in COVID-19 vaccine studies.
期刊介绍:
The American Journal of Epidemiology is the oldest and one of the premier epidemiologic journals devoted to the publication of empirical research findings, opinion pieces, and methodological developments in the field of epidemiologic research.
It is a peer-reviewed journal aimed at both fellow epidemiologists and those who use epidemiologic data, including public health workers and clinicians.