TY - JOUR
T1 - Safety, tolerability, and immunogenicity of the Ebola Sudan chimpanzee adenovirus vector vaccine (cAd3-EBO S) in healthy Ugandan adults
T2 - a phase 1, open-label, dose-escalation clinical trial
AU - RV 508 Study Team
AU - Mwesigwa, Betty
AU - Houser, Katherine V.
AU - Hofstetter, Amelia R.
AU - Ortega-Villa, Ana M.
AU - Naluyima, Prossy
AU - Kiweewa, Francis
AU - Nakabuye, Immaculate
AU - Yamshchikov, Galina V.
AU - Andrews, Charla
AU - O'Callahan, Mark
AU - Strom, Larisa
AU - Schech, Steven
AU - Anne Eller, Leigh
AU - Sondergaard, Erica L.
AU - Scott, Paul T.
AU - Amare, Mihret F.
AU - Modjarrad, Kayvon
AU - Wamala, Amir
AU - Tindikahwa, Allan
AU - Musingye, Ezra
AU - Nanyondo, Jauhara
AU - Gaudinski, Martin R.
AU - Gordon, Ingelise J.
AU - Holman, La Sonji A.
AU - Saunders, Jamie G.
AU - Costner, Pamela J.M.
AU - Mendoza, Floreliz H.
AU - Happe, Myra
AU - Morgan, Patricia
AU - Plummer, Sarah H.
AU - Hickman, Somia P.
AU - Vazquez, Sandra
AU - Murray, Tamar
AU - Cordon, Jamilet
AU - Dulan, Caitlyn N.M.
AU - Hunegnaw, Ruth
AU - Basappa, Manjula
AU - Padilla, Marcelino
AU - Gajjala, Suprabhath R.
AU - Swanson, Phillip A.
AU - Lin, Bob C.
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 - Kibuuka, Hannah
AU - Ake, Julie A.
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/12
Y1 - 2023/12
N2 - Background: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available. Methods: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 1010 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed. Findings: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41–75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30–73) to 4 weeks after vaccination (196, 125–308). Interpretation: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks. Funding: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.
AB - Background: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available. Methods: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 1010 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed. Findings: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41–75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30–73) to 4 weeks after vaccination (196, 125–308). Interpretation: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks. Funding: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.
UR - http://www.scopus.com/inward/record.url?scp=85169831577&partnerID=8YFLogxK
U2 - 10.1016/S1473-3099(23)00344-4
DO - 10.1016/S1473-3099(23)00344-4
M3 - Article
C2 - 37544326
AN - SCOPUS:85169831577
SN - 1473-3099
VL - 23
SP - 1408
EP - 1417
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 12
ER -