Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial

Melinda J. Hamer, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Department of Emergency Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Katherine V. Houser, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: katherine.houser@nih.gov.
Amelia R. Hofstetter, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Ana M. Ortega-Villa, Biostatistics Research Branch, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Christine Lee, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Anne Preston, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Brooke Augustine, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Charla Andrews, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Galina V. Yamshchikov, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Somia Hickman, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Steven Schech, Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Jack N. Hutter, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Paul T. Scott, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Paige E. Waterman, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Mihret F. Amare, Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Victoria Kioko, Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Casey Storme, Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Kayvon Modjarrad, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Melanie D. McCauley, Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Merlin L. Robb, Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Martin R. Gaudinski, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Ingelise J. Gordon, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
LaSonji A. Holman, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Alicia T. Widge, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Larisa Strom, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Myra Happe, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Josephine H. Cox, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Sandra Vazquez, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Daphne A. Stanley, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Tamar Murray, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Caitlyn N. Dulan, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Ruth Hunegnaw, Vaccine Research Center, and Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

1-28-2023

Journal

Lancet (London, England)

Volume

401

Issue

10373

DOI

10.1016/S0140-6736(22)02400-X

Abstract

BACKGROUND: WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults. METHODS: We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10 or 1 × 10 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056. FINDINGS: Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10 pu (n=20) or 1 × 10 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 10 pu group and 545 [276-1078] in the 1 × 10 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×10 pu group and 27 [95-156] in the 1 ×10 pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination. INTERPRETATION: This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions. FUNDING: National Institutes of Health.

Department

Emergency Medicine

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