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Clinical Trial

Neutralizing Antibody Immune Correlates for a Recombinant Protein Vaccine in the COVAIL Trial

Youyi Fong et al. Clin Infect Dis. .

Abstract

For COVAIL recipients of a coronavirus disease 2019 (COVID-19) Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

Trial registration: ClinicalTrials.gov NCT05289037.

Keywords: COVID-19 booster; Omicron; correlate of risk; exposure-proximal titer; variant vaccine booster.

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Conflict of interest statement

Potential conflicts of interest . L. D. received support from Novo Nordisk (NN) via a philanthropic gift to UC Berkeley that supported conference/meeting-related travel she took in 2021 and 2022, as well as supported her tuition during her PhD from 9/2020 to 5/2023. S. C. reports grant support to her institution from NIH/NIAID for the present manuscript. N. G. R. received NIH funding to her institution for the present manuscript and her institution received funds for her to conduct research in the past 36 months from Merck, Sanofi, Pfizer, Vaccine Company, Immorna, Quidel and Lilly. In the past 36 months, N. G. R. received consulting fees from Krog; payment for virology education; support from Sanofi and Moderna to attend meetings and/or travel; participated on Moderna, Sanofi, Seqirus, Pfizer advisory boards; served on EMMES, ICON, BARDA, CyanVac Micron Safety Committees; served in advisory roles on ARLG, TMRC, CDC-Pertussis challenge, served (and is currently) an Associate Editor at Clinical Infectious Diseases; and her institution received equipment, materials, drugs, medical writing, gifts or other services from the Georgia Research Alliance. A. R. B. received support for the present manuscript from Merck, and received grants or contracts from Moderna, Pfizer, Cyanvac, and Vaccitech in the past 36 months. In the past 36 months, she also received consulting fees from GSK, Moderna, Sanofi, and Novavax; and payment for a speaker role at learning lounges for IDWeek from Moderna and Sanofi.

D. J. D. received an award to his institution from Leidos Biomed/NIH to conduct the clinical trial reported in the manuscript. A. R. F. reports in the past 36 months research grants to her institution from Janssen, Merck, CyanVac, VaxCo, BioFire Diagnostics, Moderna, Pfizer, and AstraZeneca; consulting fees from ADMA Biologics, GSK, Sanofi Pasteur, and Merck; support for attending meetings and/or travel from GSK, Moderna, and Sanofi Pasteur; and participation on a Novavax Data Safety Monitoring Board or Advisory Board. L. R. B received an NIH grant to his institution for the present manuscript; reports grants from NIH, Harvard Medical School, Wellcome Trust, and the Gates Foundation to his institution in the past 36 months; and participated in an NIH DSMB meeting in the past 36 months and an FDA AMDAC Committee in the past 36 months. L. R. B. is involved in human immunodeficiency virus (HIV) and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), COVID Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School.

Figures

Figure 1.
Figure 1.
A, Covariate-adjusted cumulative incidence of COVID-19 from 7 through 188 d post D15 (last COVID-19 endpoint) for each booster arm (Beta, Prototype, Beta + Prototype) and for the three booster arms pooled. B, Violin box plots of D15 levels for the 6 nAb titer markers (D614G, Delta, Beta, BA.1, BA.4/BA.5, weighted average), shown by non-cases and COVID-19 endpoint cases (stratified by booster-proximal cases, booster-distal-cases, and proximal + distal cases). Non-cases: No evidence of SARS-CoV-2 infection after D1 through to the first event of (1) reaching 188 d post D15 visit without a COVID-19 event, (2) early termination, and (3) receiving an out-of-study boost. Booster-proximal cases: COVID-19 endpoint between 7 and 91 d post D15 visit; booster-distal cases: COVID-19 endpoint between 92 and 188 d post D15 visit; cases (proximal + distal): COVID-19 endpoint between 7 and 188 d post D15 visit. Rate: Percent with nAb titer above the limit of detection (LoD) = 40 AU/mL. C, Cox model covariate-adjusted hazard ratios of COVID-19 per 10-fold increase in each of the 6 nAb titer markers at D15 and exposure-proximal. Point estimates, 95% CIs, and 2-sided P values are shown. D, Covariate-adjusted controlled risk of COVID-19 by nAb ID50 titer against BA.4/BA.5 estimated using a Cox model (orange line) or a nonparametric method (turquoise line). Both curves were restricted to the middle 95% of the marker distribution. Shaded regions represent 95% CIs. The green shaded region is a kernel density estimate of log10 D15 nAb-ID50 BA.4/BA.5 titer (AU/mL). Panels B–D pool over the 3 booster arms. All analyses adjust for baseline factors defined in the text, where adjustment for FOI score had no influence on results. Wt. Avg. = Maximum diversity weighted geometric mean of the 5 nAb titers D614G reference, Beta, Delta, Omicron BA.1, and Omicron BA.4/BA.5. Abbreviations: AU/mL, arbitrary units/mL; CI, confidence interval; COVID-19, coronavirus disease 2019; FOI, force of infection, nAb, neutralizing antibody; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ULOQ, upper limit of quantitation.
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References

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