Association between COVID-19 vaccine efficacy and epidemic force of infection

Jing Xu¹, M Elizabeth Halloran^{1

2}, Mia Moore¹, Lily Zhang¹, Ollivier Hyrien¹, Alex Luedtke³, Hana M El Sahly⁴, Lindsey R Baden^{5

6}, Paul A Goepfert⁷, Glenda Gray⁸, Beatriz Grinsztejn⁹, Magdalena E Sobieszczyk¹⁰, Ann R Falsey¹¹, Samuel T Robinson¹, Nina Marie G Garcia¹, Honghong Zhou¹², Ilse van Dromme¹³, Carla Truyers¹³, Ian Hirsch¹⁴, Kathleen M Neuzil¹⁵, Lawrence Corey¹, James G Kublin¹, Dean Follmann¹⁶, Holly E Janes¹, Peter B Gilbert¹, Yunda Huang¹⁷

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
² Department of Biostatistics, University of Washington, Seattle, WA, USA.
³ Department of Statistics, University of Washington, Seattle, WA, USA.
⁴ Department of Molecular Virology and Microbiology, Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁵ Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ The University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ South African Medical Research Council, Cape Town, South Africa.
⁹ Evandro Chagas National Institute of Infectious Diseases-Fiocruz, Rio de Janeiro, Brazil.
¹⁰ Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
¹¹ Division of Infectious Diseases, Department of Medicine, University of Rochester, Rochester, NY, USA.
¹² Biostatistics, Moderna, Cambridge, MA, USA.
¹³ Johnson & Johnson, Beerse, Belgium.
¹⁴ Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹⁵ Fogarty International Center, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Biostatistics Research Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. yunda@fredhutch.org.

PMID: 41547989
PMCID: PMC12921246
DOI: 10.1038/s41541-026-01374-3

Association between COVID-19 vaccine efficacy and epidemic force of infection

Jing Xu et al. NPJ Vaccines. 2026.

. 2026 Jan 17;11(1):54.

doi: 10.1038/s41541-026-01374-3.

Authors

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
² Department of Biostatistics, University of Washington, Seattle, WA, USA.
³ Department of Statistics, University of Washington, Seattle, WA, USA.
⁴ Department of Molecular Virology and Microbiology, Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁵ Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ The University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ South African Medical Research Council, Cape Town, South Africa.
⁹ Evandro Chagas National Institute of Infectious Diseases-Fiocruz, Rio de Janeiro, Brazil.
¹⁰ Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
¹¹ Division of Infectious Diseases, Department of Medicine, University of Rochester, Rochester, NY, USA.
¹² Biostatistics, Moderna, Cambridge, MA, USA.
¹³ Johnson & Johnson, Beerse, Belgium.
¹⁴ Biometrics, Vaccines & Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
¹⁵ Fogarty International Center, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Biostatistics Research Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. yunda@fredhutch.org.

PMID: 41547989
PMCID: PMC12921246
DOI: 10.1038/s41541-026-01374-3

Abstract

The association between vaccine efficacy (VE) and force of infection (FoI) remains incompletely understood. Previous analyses have been primarily based on trial-level summary data-not accounting for the effect of time and constrained by the number of trials. Here, we leverage individual-level data from three phase 3 randomized, placebo-controlled COVID-19 vaccine trials-the COVE trial (Moderna, CoVPN3001), the AZD1222 trial (AstraZeneca, CoVPN3002), and the ENSEMBLE trial (Janssen/Johnson & Johnson, CoVPN3003)-and contemporaneous geographic-location-specific SARS-CoV-2 surveillance data from the start of the pandemic through November 14, 2021 (including the blinded follow-up periods of the trials) to conduct five cohort- and vaccine-specific analyses: COVE (U.S.), AZD1222 overall (U.S. + non-U.S.), AZD1222 U.S., ENSEMBLE overall (U.S. + non-U.S.), and ENSEMBLE U.S. In AZD1222 U.S., higher VE was associated with higher FoI (p = 0.01). In ENSEMBLE overall, lower VE was marginally associated with higher FoI (p = 0.21), further supported by a region-specific analysis. In COVE, AZD1222 overall, and ENSEMBLE U.S., no VE-FoI association was found. These findings highlighted a new perspective: the VE-FoI association appears complex, potentially influenced by FoI levels, with patterns suggesting an inverted U-shaped relationship, showing a positive association at low FoI levels and a negative association at high levels.

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Conflict of interest statement

Competing interests: Dr Sobieszczyk reported receiving grant support to the institution from the NIH during the conduct of the study and grant support to the institution from the Gates Foundation, Sanofi SA, Merck, Sharpe and Dohme, and Gilead Sciences Inc. outside the submitted work. Dr El Sahly reported receiving grant support from the NIAID during the conduct of the study. Dr Baden reported receiving grant support from the NIH during the conduct of the study. Dr Falsey reported receiving grant support from AstraZeneca during the conduct of the study and grant support from AstraZeneca, Pfizer Inc., and CyanVac LLC, and personal fees for serving on an advisory board from Merck & Co. Inc., GSK, ADMA Biologics Inc., and Moderna Inc. outside the submitted work. Dr Hirsch reported holding stock or stock options in AstraZeneca. Dr Neuzil reported receiving grant support from Pfizer Inc. and the National Institutes of Health (NIH) during the conduct of the study. Dr Janes reported receiving grant support from the NIH during the conduct of the study. Dr Gilbert reported receiving grant support to the institution from the NIAID and NIH during the conduct of the study and serving on the vaccine scientific advisory boards for Moderna Inc. and AstraZeneca. Dr Huang reported receiving grant support from the NIH during the conduct of the study. All other authors declare no competing interests.

Figures

**Fig. 1. Estimated VE at Specific *FoI*_S Levels and Time Since Vaccination.**
Panels a–e corresponds to results from the COVE, AZD1222 (overall and U.S.), and ENSEMBLE (overall and U.S.) Trials. The values of *FoI*_S in the figure are expressed in units of infections per 1000 person-days. In each panel, from left to right, the values represent the 1st quantile, median, mean, and 3rd quantile. The mean and quantiles were calculated based on daily variations across all participants included in the models. VE was assessed at 45 days since vaccination (post–second dose in COVE and AZD1222 or post–single dose in ENSEMBLE).

**Fig. 2. Estimated VE and Placebo Incidence Across Regions in the ENSEMBLE Trial.**
VE was estimated using a Cox proportional hazards model without covariates, with confidence intervals calculated via the delta method. Placebo incidence was defined as the number of cases divided by the total person-years of follow-up in the placebo group.

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References

1. World Health Organization. Status of COVID-19 Vaccines within WHO EUL/PQ evaluation process, https://extranet.who.int/prequal/sites/default/files/document_files/Stat... (2023).
1. Rapaka, R. R., Hammershaimb, E. A. & Neuzil, K. M. Are Some COVID-19 Vaccines Better Than Others? Interpreting and Comparing Estimates of Efficacy in Vaccine Trials. Clin. Infect. Dis.74, 352–358 (2022). - DOI - PMC - PubMed
1. Sharma, R. & Anand, A. The effect of pandemic prevalence on the reported efficacy of SARS-CoV-2 vaccines. PLoS One17, e0266271 (2022). - DOI - PMC - PubMed
1. Xu, S. et al. Real-world effectiveness and factors associated with effectiveness of inactivated SARS-CoV-2 vaccines: a systematic review and meta-regression analysis. BMC Med.21, 160 (2023). - DOI - PMC - PubMed
1. Halloran M. E., Longini I. M. & Struchiner C. J. Design and Analysis of Vaccine Studies. (Springer New York, NY, 2010).

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Association between COVID-19 vaccine efficacy and epidemic force of infection

Affiliations

Association between COVID-19 vaccine efficacy and epidemic force of infection

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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