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. Issue 10373 (28th January 2023)

• Record Type: Journal Article
• Authors: Hamer, Melinda J; Houser, Katherine V; Hofstetter, Amelia R; Ortega-Villa, Ana M; Lee, Christine; Preston, Anne; Augustine, Brooke; Andrews, Charla; Yamshchikov, Galina V; Hickman, Somia; Schech, Steven; Hutter, Jack N; Scott, Paul T; Waterman, Paige E; Amare, Mihret F; Kioko, Victoria; Storme, Casey; Modjarrad, Kayvon; McCauley, Melanie D; Robb, Merlin L; Gaudinski, Martin R; Gordon, Ingelise J; Holman, LaSonji A; Widge, Alicia T; Strom, Larisa; Happe, Myra; Cox, Josephine H; Vazquez, Sandra; Stanley, Daphne A; Murray, Tamar; Dulan, Caitlyn N M; Hunegnaw, Ruth; Narpala, Sandeep R; Swanson, Phillip A; Basappa, Manjula; Thillainathan, Jagada; Padilla, Marcelino; Flach, Britta; O'Connell, Sarah; Trofymenko, Olga; Morgan, Patricia; Coates, Emily E; Gall, Jason G; McDermott, Adrian B; Koup, Richard A; Mascola, John R; Ploquin, Aurélie; Sullivan, Nancy J; Ake, Julie A; Ledgerwood, Julie E; Lampley, Rebecca; Larkin, Brenda; Costner, Pamela; Wilson, Hope; Read, Mike;
• Is Part Of: Lancet. Volume 401:Issue 10373(2023)
• Page Start: 294
• Page End: 302
• Publication Date: 2023-01-28
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Medicine; Electronic journals; Periodicals; 610.5
• DOI: 10.1016/S0140-6736(22)02400-X
• Languages: English
• ISSNs: 0140-6736

Abstract

Summary: 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 10 or 1 × 10 11 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 10 pu (n=20) or 1 × 10 11 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 10 pu group and 545 [276–1078] in the 1 × 10 11 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13–119] in the 1 ×10 10 pu group and 27 [95–156] in the 1 ×10 11 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.