Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial

Milagritos D Tapia, Samba O Sow, Kirsten E Lyke, Fadima Cheick Haidara, Fatoumata Diallo, Moussa Doumbia, Awa Traore, Flanon Coulibaly, Mamoudou Kodio, Uma Onwuchekwa, Marcelo B Sztein, Rezwanul Wahid, James D Campbell, Marie-Paule Kieny, Vasee Moorthy, Egeruan B Imoukhuede, Tommy Rampling, Francois Roman, Iris De Ryck, Abbie R Bellamy, Len Dally, Olivier Tshiani Mbaya, Aurélie Ploquin, Yan Zhou, Daphne A Stanley, Robert Bailer, Richard A Koup, Mario Roederer, Julie Ledgerwood, Adrian V S Hill, W Ripley Ballou, Nancy Sullivan, Barney Graham, Myron M Levine, Milagritos D Tapia, Samba O Sow, Kirsten E Lyke, Fadima Cheick Haidara, Fatoumata Diallo, Moussa Doumbia, Awa Traore, Flanon Coulibaly, Mamoudou Kodio, Uma Onwuchekwa, Marcelo B Sztein, Rezwanul Wahid, James D Campbell, Marie-Paule Kieny, Vasee Moorthy, Egeruan B Imoukhuede, Tommy Rampling, Francois Roman, Iris De Ryck, Abbie R Bellamy, Len Dally, Olivier Tshiani Mbaya, Aurélie Ploquin, Yan Zhou, Daphne A Stanley, Robert Bailer, Richard A Koup, Mario Roederer, Julie Ledgerwood, Adrian V S Hill, W Ripley Ballou, Nancy Sullivan, Barney Graham, Myron M Levine

Abstract

Background: The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo).

Methods: In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18-65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18-50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 10(10) viral particle units (pu), 2·5 × 10(10) pu, 5 × 10(10) pu, or 1 × 10(11) pu; US participants received 1 × 10(10) pu or 1 × 10(11) pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 10(8) plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov, numbers NCT02231866 (US) and NCT02267109 (Malian).

Findings: Between Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 10(10) pu, 35 [38%] to 2·5 × 10(10) pu, 35 [38%] to 5 × 10(10) pu, and 11 [12%] to 1 × 10(11) pu) and 20 in the USA (ten [50%] to 1 × 10(10) pu and ten [50%] to 1 × 10(11) pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 10(10) and two [2%] received 1 × 10(11) pu) and four (20%) of 20 in the USA (all received 1 × 10(11) pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness.

Interpretation: 1 × 10(11) pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers).

Funding: Wellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases.

Copyright © 2016 Tapia et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile (A) Malian trial. (B) US trial. ChAd3-EBO-Z=replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein. MVA-BN-Filo=modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens. pu=particle units.
Figure 2
Figure 2
Anti-Zaire Ebola virus glycoprotein ELISA titres (background subtracted) for the Malian participants in the nested MVA-BN-Filo booster trial Titres of individual participants are plotted as open circles at the actual week after priming immunisation with ChAd3-EBO-Z vaccine. GMTs are plotted as filled circles with associated 95% CIs. For participants in the booster study, their boost visits ranged from 11·2 weeks to 15·8 weeks after priming; the GMT for the boost visit is plotted at the median of 13 weeks, and the GMTs for postboost visits are plotted at the subsequent target intervals (ie, 1 week, 2 weeks, and 4 weeks after boosting). (A) Participants primed with ChAd3-EBO-Z and then boosted with saline placebo are compared with those primed with ChAd3-EBO-Z and then boosted with MVA-BN-Filo. (B) The longevity of the antiglycoprotein response in participants vaccinated with the 1 × 1011 pu high dose of ChAd3-EBO-Z and boosted with saline placebo is shown and compared with the magnitude of response of the participants who received low doses (1 × 1010 pu, 2·5 × 1010 pu, or 5 × 1010 pu) of ChAd3-EBO-Z, followed by a saline booster. ChAd3-EBO-Z=replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein. GMT=geometric mean titre. MVA-BN-Filo=modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens. pu=particle units.

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Source: PubMed

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