Safety and Immunogenicity of Novel Adenovirus Type 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines

Abstract

IMPORTANCE Developing effective vaccines against Ebola virus is a global priority. OBJECTIVE To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo). DESIGN, SETTING, AND PARTICIPANTS Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18-to 50-year-olds from December 2014; 8-month follow-up was completed October 2015. INTERVENTIONS Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 10 10 viral particles) or MVA-BN-Filo (1 × 10 8 median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later. MAIN OUTCOMES AND MEASURES The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations. RESULTS Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%-99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses. CONCLUSIONS AND RELEVANCE In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies.

Post-exposure treatments for Ebola and Marburg virus infections

“…Vaccines that were assessed in phase I and/or II studies during the 2013-2016 EBOV epidemic include rVSV-EBOV [268][269][270][271][272] , Ad5-EBOV [273][274][275] , rVSV-EBOV combined with rAd5-EBOV 276 , ChAd3-EBOV with or without MVA-EBOV [277][278][279][280] , Ad26-EBOV combined with MVA-EBOV 281 , and DNA encoding multiple filovirus GPs 282,283 . These EBOV vaccines generally elicited good immunogenicity against EBOV GP, and no serious adverse events were described.…”

Ebola vaccines in clinical trial: The promising candidates

“…Moreover, boosting with the heterologous vaccine could prolong durability of protective immunity and induce stronger immune response to antigens than using homogeneous vaccination, which was shown in different clinical trials and suggested as a prospective approach of vaccination by WHO experts. 30,33,37 In the past decade, we have witnessed impressive progress in the development of viral vectored vaccine. Recombinant viral vectors are good at delivering heterologous antigens that combine the different favorable features of other vaccine modalities, with minimal disadvantages.…”

“…A single-center, randomized, placebocontrolled, observer-blind, phase I trial adopting prime-boost regimen (prime with Ad26-EBOV or MVA-BN Filo and boost with the alternative vaccine 28 or 56 d later) enrolled 87 participants to evaluate the safety and immunogenicity of the Ad26-EBOV (Table 4). 30 Mild to moderate injection-site pain was the 31 Two outstanding advantages of this Ad5-EBOV was noticed: first, the Ad5-EBOV is the first Ebola vaccine developed according to the 2014 epidemic strain, which was considered to be a new epidemic strain, with 96.7% homology of the nucleotide sequence and 97.6% homology of amino acid sequence 31 compared to the GP gene of the strain in 1976 which was based on by other vaccines; 32,33 Second, the Ad5-EBOV is lyophilized white powder (can be stored at 2-8 C), which may be more suitable for the areas where the cold chain system is incomplete than those liquid formulations. After a preliminary efficacy was observed in the pre-clinical animal studies, the Ad5-EBOV was quickly put into the clinical trials at the end of 2014 ( Table 1).…”

Development of Vaccines Based on Adenoviral Vectors: A Review of Foreign Clinical Studies (Part 2)

“…Contains antigen АМА-1 (apical membrane antigen -1) [16]. Для данного типа вакцин заявлены уже 3 и 4 фаза исследова-ний, которые планируется проводить не только на здоровых добровольцах, но и людях с ВИЧ-инфекцией, пожилых людях, детях, в том чис-ле рожденных у участников предыдущих этапов исследований.…”