TY - JOUR
T1 - Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA
T2 - a first-in-human, phase 1, open-label, dose-escalation trial
AU - RV 507 Study Team
AU - Hamer, Melinda J.
AU - Houser, Katherine V.
AU - Hofstetter, Amelia R.
AU - Ortega-Villa, Ana M.
AU - Lee, Christine
AU - Preston, Anne
AU - Augustine, Brooke
AU - Andrews, Charla
AU - Yamshchikov, Galina V.
AU - Hickman, Somia
AU - Schech, Steven
AU - Hutter, Jack N.
AU - Scott, Paul T.
AU - Waterman, Paige E.
AU - Amare, Mihret F.
AU - Kioko, Victoria
AU - Storme, Casey
AU - Modjarrad, Kayvon
AU - McCauley, Melanie D.
AU - Robb, Merlin L.
AU - Gaudinski, Martin R.
AU - Gordon, Ingelise J.
AU - Holman, La Sonji A.
AU - Widge, Alicia T.
AU - Strom, Larisa
AU - Happe, Myra
AU - Cox, Josephine H.
AU - Vazquez, Sandra
AU - Stanley, Daphne A.
AU - Murray, Tamar
AU - Dulan, Caitlyn N.M.
AU - Hunegnaw, Ruth
AU - Narpala, Sandeep R.
AU - Swanson, Phillip A.
AU - Basappa, Manjula
AU - Thillainathan, Jagada
AU - Padilla, Marcelino
AU - Flach, Britta
AU - O'Connell, Sarah
AU - Trofymenko, Olga
AU - Morgan, Patricia
AU - Coates, Emily E.
AU - Gall, Jason G.
AU - McDermott, Adrian B.
AU - Koup, Richard A.
AU - Mascola, John R.
AU - Ploquin, Aurélie
AU - Sullivan, Nancy J.
AU - Ake, Julie A.
AU - Ledgerwood, Julie E.
N1 - Funding Information:
The National Institutes of Health funded the study via an interagency agreement with Walter Reed Army Institute of Research. We thank the clinical trial participants who contributed to furthering vaccine research. We acknowledge our Walter Reed Army Institute of Research colleagues James E Moon, the medical monitor for the trial, and Jacqueline Sievers, Yessenia Gomez, and David Wallace for administrative, regulatory, programmatic, and quality assurance support. We also acknowledge our Vaccine Research Center colleague Lesia K Dropulic for her review of the manuscript. We also acknowledge the contributions of the Emmes corporation for assistance with data management and protocol development. The RV 507 Study Team at the Vaccine Research Center included Rebecca Lampley, Brenda Larkin, Pamela Costner, Hope Wilson, and Mike Read. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in Army Regulation 70–25.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2023/1/28
Y1 - 2023/1/28
N2 - 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 × 1010 or 1 × 1011 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 × 1010 pu (n=20) or 1 × 1011 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 × 1010 pu group and 545 [276–1078] in the 1 × 1011 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13–119] in the 1 ×1010 pu group and 27 [95–156] in the 1 ×1011 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.
AB - 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 × 1010 or 1 × 1011 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 × 1010 pu (n=20) or 1 × 1011 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 × 1010 pu group and 545 [276–1078] in the 1 × 1011 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13–119] in the 1 ×1010 pu group and 27 [95–156] in the 1 ×1011 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.
UR - http://www.scopus.com/inward/record.url?scp=85146853540&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(22)02400-X
DO - 10.1016/S0140-6736(22)02400-X
M3 - Article
C2 - 36709074
AN - SCOPUS:85146853540
SN - 0140-6736
VL - 401
SP - 294
EP - 302
JO - The Lancet
JF - The Lancet
IS - 10373
ER -