Analysis of antibody markers as immune correlates of risk of severe COVID-19 in the PREVENT-19 efficacy trial of the NVX-CoV2373 recombinant protein vaccine

Youyi Fong; Yunda Huang; Ying Huang; Wayne Woo; Alice McGarry; Germán Áñez; Lisa M Dunkle; Iksung Cho; Christopher R Houchens; Karen Martins; Lakshmi Jayashankar; Flora Castellino; Christos J Petropoulos; Andrew Leith; Deanne Haugaard; William Webb; Yiwen Lu; Chenchen Yu; Lindsay N Carpp; April K Randhawa; Michele P Andrasik; James G Kublin; Julia Hutter; Maryam Keshtkar-Jahromi; Tatiana H Beresnev; Carina A Rodriguez; Milagritos Tapia; Christine B Turley; Carmen D Zorrilla; Stuart H Cohen; Susan E Kline; Elizabeth Barranco; Lawrence Corey; Kathleen M Neuzil; Dean Follmann; Julie A Ake; Cynthia L Gay; Karen L Kotloff; Thomas Jones; Richard A Koup; Ruben O Donis; Peter B Gilbert

doi:10.1093/cid/ciaf558

Analysis of antibody markers as immune correlates of risk of severe COVID-19 in the PREVENT-19 efficacy trial of the NVX-CoV2373 recombinant protein vaccine

Clin Infect Dis. 2025 Oct 25:ciaf558. doi: 10.1093/cid/ciaf558. Online ahead of print.

Authors

Youyi Fong^{1

2

3}, Yunda Huang^{1

4}, Ying Huang^{1

2

3}, Wayne Woo⁵, Alice McGarry⁵, Germán Áñez⁵, Lisa M Dunkle⁵, Iksung Cho⁵, Christopher R Houchens⁶, Karen Martins⁶, Lakshmi Jayashankar⁶, Flora Castellino⁶, Christos J Petropoulos⁷, Andrew Leith⁸, Deanne Haugaard⁸, William Webb⁸, Yiwen Lu¹, Chenchen Yu¹, Lindsay N Carpp¹, April K Randhawa¹, Michele P Andrasik¹, James G Kublin¹, Julia Hutter⁹, Maryam Keshtkar-Jahromi¹⁰, Tatiana H Beresnev¹⁰, Carina A Rodriguez¹¹, Milagritos Tapia¹², Christine B Turley¹³, Carmen D Zorrilla¹⁴, Stuart H Cohen¹⁵, Susan E Kline¹⁶, Elizabeth Barranco¹⁷, Lawrence Corey^{1

18}, Kathleen M Neuzil¹², Dean Follmann¹⁹, Julie A Ake²⁰, Cynthia L Gay²¹, Karen L Kotloff¹², Thomas Jones⁶, Richard A Koup²², Ruben O Donis⁶, Peter B Gilbert^{1

2

3}

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center; Seattle, WA, USA.
² Public Health Sciences Division, Fred Hutchinson Cancer Center; Seattle, WA, USA.
³ Department of Biostatistics, University of Washington; Seattle, WA, USA.
⁴ Department of Global Health, University of Washington; Seattle, WA 98195, USA.
⁵ Novavax, Inc.; Gaithersburg, MD, USA.
⁶ Biomedical Advanced Research and Development Authority; Washington, DC, USA.
⁷ LabCorp-Monogram Biosciences; South San Francisco, CA, USA.
⁸ Nexelis; Seattle, WA, USA.
⁹ Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH; Rockville, MD, USA.
¹⁰ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH; Rockville, MD, USA.
¹¹ Division of Pediatric Infectious Diseases, University of South Florida, Morsani College of Medicine; Tampa, FL, USA.
¹² Center for Vaccine Development and Global Health, University of Maryland School of Medicine; Baltimore, MD, USA.
¹³ Atrium Health Wake Forest School of Medicine; Charlotte, NC, USA.
¹⁴ Obstetrics and Gynecology Department, School of Medicine, University of Puerto Rico, Medical Sciences Campus; San Juan, Puerto Rico.
¹⁵ University of California Davis Medical Center, Department of Internal Medicine, Division of Infectious Diseases; Sacramento, CA, USA.
¹⁶ University of Minnesota Medical School, Department of Medicine, Division of Infectious Diseases and International Medicine; Minneapolis, Minnesota, USA.
¹⁷ Ponce Health Sciences University; Ponce, Puerto Rico.
¹⁸ Department of Laboratory Medicine and Pathology, University of Washington; Seattle, WA, USA.
¹⁹ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD, USA.
²⁰ U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research; Silver Spring, MD, USA.
²¹ University of North Carolina School of Medicine; Chapel Hill, NC, USA.
²² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD, USA.

Abstract

Background: We previously showed that ancestral-specific anti-Spike binding IgG concentration and 50% inhibitory dilution neutralizing antibody titer (nAb-ID50) measured at 2 weeks post-dose 2 (∼peak) were inverse correlates of risk (CoRs) of COVID-19 over 2 months post ∼peak in the PREVENT-19 trial of the NVX-CoV2373 vaccine; there were not sufficient data to assess CoRs of severe COVID-19.

Methods: Here we assessed, in the same vaccinated cohort, Delta- and ancestral-specific Spike IgG and nAb-ID50 at ∼peak and over time as CoRs of severe COVID-19 and of Delta COVID-19 over 3.5-10 months post ∼peak (287 breakthrough Delta cases, including 8 severe; 446 non-cases).

Results: ∼Peak antibody levels were much higher for non-cases vs. severe cases (all inferred Delta), with nAb-ID50 Delta geometric mean 209.5 arbitrary units (AU)/mL (95% CI: 176.1, 249.1) vs. 9.6 AU/mL (95% CI: 2.4, 38.6), respectively. Frequency of detectable nAb-ID50 titer was 98.3% (97.2, 99.0) for non-cases vs. 62.5% (22.3, 93.9) for severe cases. All markers were inverse CoRs of severe COVID-19, with a ∼peak hazard ratio (HR) of 0.13 (95% CI: 0.03, 0.57) per 10-fold nAb-ID50 Delta increase. Severe COVID-19 risk through 305 days post-Day 35 was 0.0338 (0.0043, 0.206) at the nAb-ID50 Delta 2.5th percentile (8.4 AU/ml), and 0.002 (0.0000, 0.0108) and 0.0002 (0.0000, 0.0035) at the 50th and 95th percentiles (210, 2522 AU/ml).

Conclusions: Post-vaccination NVX-CoV2373 antibody levels are stronger predictors of severe COVID-19 than any-severity Delta COVID-19. Low antibody responses indicate vulnerability to severe COVID-19.

Keywords: COVID-19 vaccine efficacy trial; IgG binding antibodies; case-cohort sampling; exposure-proximal correlates analysis; immune correlates; neutralizing antibodies; severe COVID-19.

Abstract

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