Safety and immunogenicity of a next-generation live-attenuated yellow fever vaccine produced in a Vero cell line in the USA: a phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial

Kayvon Modjarrad, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Paul T. Scott, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Melanie McCauley, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Brittany Ober-Shepherd, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Erica Sondergaard, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Mihret F. Amare, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Ajay P. Parikh, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Badryah Omar, Emerging Infectious Diseases Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Ada-Marie Minutello, Sanofi, Marcy L'Etoile, France.
Haritha Adhikarla, Sanofi, Swiftwater, PA, USA.
Yukun Wu, Sanofi, Swiftwater, PA, USA.
Andrey Rojas P, Sanofi, Bogotá, Colombia.
Valentine Delore, Sanofi, Marcy L'Etoile, France.
Nathalie Mantel, Sanofi, Marcy L'Etoile, France.
Meshell N. Morrison, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Kamila S. Kourbanova, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Melissa E. Martinez, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Ivelese Guzman, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Melissa E. Greenleaf, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Janice M. Darden, Diagnostics and Countermeasures Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Michael A. Koren, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Melinda J. Hamer, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA; Department of Military and Emergency Medicine, Uniformed Services University, Bethesda, MD, USA; Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Christine E. Lee, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Jack N. Hutter, Clinical Trials Center, Walter Reed Army Institute of Research, Bethesda, MD, USA.
Sheila A. Peel, Diagnostics and Countermeasures Branch, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Merlin L. Robb, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Manuel Vangelisti, Sanofi, Marcy L'Etoile, France.
Emmanuel Feroldi, Sanofi, Marcy L'Etoile, France. Electronic address: emmanuel.feroldi@sanofi.com.

Document Type

Journal Article

Publication Date

8-14-2024

Journal

The Lancet. Infectious diseases

DOI

10.1016/S1473-3099(24)00406-7

Abstract

BACKGROUND: Recent outbreaks between 2015-17 and production delays have led to a yellow fever vaccine shortage. Therefore, there is an urgent need for new yellow fever vaccines with improved production scalability. A next-generation live-attenuated yellow fever vaccine candidate (vYF), produced in a Vero cell line has shown similar immunogenicity to licensed yellow fever vaccines in preclinical studies. In this study, we aimed to report the safety and immunogenicity of vYF in human clinical trial participants. METHODS: In this first in-human, phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial conducted at a single centre in the USA (Walter Reed Army Institute of Research, Silver Spring, MD, USA), 72 healthy adults (aged 18-60 years), without a known history of flavivirus infection or vaccination were randomly assigned (1:1:1:1) using interactive response technology to receive one dose of either vYF at 4, 5 or 6 Log CCID or the licensed YF-VAX (18 individuals per group). The primary outcomes were safety, neutralising antibody (NAb) titres through D180 post-vaccination in the per-protocol analysis set (comprised of yellow fever-naive participants who received their intended vaccine and provided a valid post-vaccination blood sample), and occurrence, and level of yellow fever viraemia in each vaccine group through D14 post-vaccination. FINDINGS: All vYF doses had a safety and tolerability profile similar to YF-VAX. The most frequently reported solicited injection site reactions (vYF groups vs YF-VAX group) were pain (22% [12 of 54 participants, 95% CI 12-36] vs 28% [five of 18 participants, 10-54]), and erythema (13% [seven of 54 participants, 5-25] vs 39% [seven of 18 participants, 17-64]), with headache (32% [17 of 54 participants, 20-46] vs 44% [eight of 18 participants, 22-69]) and malaise (26% [14 of 54 participants, 15-40] vs 33% [six of 18 participants, 13-59]) as the most frequently reported solicited systemic reactions. One grade 3 solicited reaction (erythema) reported in the YF-VAX group resolved spontaneously. No serious unsolicited adverse events or deaths were reported. Viraemia was transiently detected in 50 participants between D4 and D10 in all groups and was observed in more participants or for a longer time in the vYF 6 Log CCID and YF-VAX groups. All yellow fever-naive vaccine recipients across the study groups seroconverted yielding four-fold increase from baseline in yellow fever NAb titres measured by yellow fever microneutralisation assay by D28 and were seroprotected with yellow fever NAb titres of at least 10 [1/dil]). Overall, 100% (18 of 18 participants, 95% CI 82-100), 89% (16 participants, 65-99), 100% (18 participants, 82-100), and 94% (17 participants, 73-100) of participants in the vYF 4 Log, vYF 5 Log, vYF 6 Log CCID groups, and YF-VAX group, respectively, remained seroprotected through D180. INTERPRETATION: vYF has a similar safety and immunogenicity profile to YF-VAX. In general, the vYF 5 Log CCID dose appeared to show optimal viraemia, safety, and immunogenicity, and was chosen for subsequent development. FUNDING: Sanofi.

Department

Emergency Medicine

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