Immunity duration of a recombinant adenovirus type-5 vector-based Ebola vaccine and a homologous prime-boost immunisation in healthy adults in China: final report of a randomised, double-blind, placebo-controlled, phase 1 trial

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Jing-Xin Li, PhD a, † et al.

Excerpts below; full text is at http://www.sciencedirect.com/science/article/pii/S2214109X16303679

Summary

Background

The 2013–15 Ebola virus disease epidemic in west Africa greatly accelerated the development of Ebola vaccine. We aimed to analyse the immune persistence induced by one shot of an adenovirus type-5 vector-based Ebola virus vaccine up to 6 months and the effect of boosting with a homologous vector in healthy adults in China.

Methods

In a randomised, double-blind, placebo-controlled, phase 1 clinical trial in one site in Jiangsu Province, China, 120 healthy adults aged 18–60 years received an initial dose of intramuscular adenovirus type-5 Ebola virus vaccine of 4·0 × 1010 viral particles, 1·6 × 1011 viral particles, or placebo, and were followed up to day 168. Participants were subsequently re-recruited to receive a booster dose of the same vaccine or placebo, in the same dose, at month 6. Women who were pregnant, breastfeeding, or planned to become pregnant during the next month were excluded. Randomisation was conducted by computer-generated block randomisation. Randomisation data were unmasked for interim analysis of the data obtained between days 0–28 but not disclosed to participants or site staff. Safety and immunogenicity analysis were done on the intention-to-treat population. We aimed to assess the safety profile of the experimental vaccine and the immunity responses to a single-dose immunisation or a homologous prime-boost regimen. Primary outcomes were Ebola glycoprotein-specific ELISA antibody responses 28 days post-boost and the occurrences of adverse reactions post-boost. The original trial and the extended booster study were registered with ClinicalTrials.gov, numbers NCT02326194 and NCT02533791, respectively.

Findings

Between Dec 28, 2014, and Jan 9, 2015, we enrolled 210 volunteers. 90 participants were not randomised due to not meeting inclusion criteria (61), meeting exclusion criteria (4), or withdrawal of consent (25). 120 people were randomly assigned to receive intramuscular Ebola vaccine at 4·0 × 1010 viral particles (low dose, n=40), Ebola vaccine at 1·6 × 1011 viral particles (high dose, n=40), or placebo (n=40, in two groups of 20). After prime vaccination, the geometric mean titer (GMT) of ELISA EC90 peaked at 682·7 (95% CI 424·3–1098·5) in the low-dose vaccine group and 1305·7 (970·1–1757·2) in the high-dose vaccine group at day 28, and then fell gradually through the next a few months to 575·5 (394·8–838·8) in the high-dose vaccine group and 197·9 (107·9–362·7) in the low-dose vaccine group at day 168. No specific response was recorded in the placebo group with a GMT of 5·0. Of the 120 participants involved in the initial trial, ten participants declined to participate, and 110 were included in the boost immunisation: 38 received the low dose, 35 received the high dose, and 37 received the placebo. At day 28 after boost vaccination, the ELISA EC90 titres rapidly rose to 6110 (95% CI 4705–7935) in the low-dose group and to 11825 (8904–15705) in the high dose group. 78 of 110 participants reported at least one solicited adverse reaction within the first 7 days after booster administration. Both of the groups who received vaccine showed significantly higher incidence of mild or moderate solicited adverse reactions than did the placebo group.

Interpretation

The adenovirus 5-vectored Ebola vaccine of 1·6 × 1011 viral particles was highly immunogenic and safe. The lower dose of 4·0 × 1010 viral particles was also safe, but immunogenicity seemed to be more vulnerable to the pre-existing immunity of adenovirus 5. A homologous priming-boosting regimen with adenovirus type-5 Ebola vaccine at 6 months interval was able to elicit greater antibody responses with longer duration. These results support an immunisation strategy to implement a booster injection for a more durable protection against Ebola virus disease.

Funding

Chinese Ministry of Science and Technology and The National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.

Evidence before this study

We searched PubMed for clinical trial reports with the terms “Ebola” or “Ebolavirus”, and “vaccine”, and ClinicalTrials.gov for unpublished randomised trials with no date or language restrictions, up to Aug 17, 2016. Since the 2014 Ebola outbreak, a total of 46 clinical trials with various Ebola vaccines candidates were launched according to the registration on Clinicaltrial.gov and Pan African Clinical Trials Registry. Up to now, only three heterologous prime-boost studies have been reported. Results from these trials indicated that some of the heterologous prime-boost combinations could be powerfully immunogenic in elicitation of both anamnestic antibody responses and robust T-cell responses, but some of them were not. An open-label, cluster-randomised ring vaccination trial with a rVSV-ZEBOV in Guinea showed a high efficacy in preventing Ebola virus disease.

A novel adenovirus type-5 Ebola virus vaccine expressing the glycoprotein of the 2014 epidemic strain was assessed in a phase 1 clinical trial in China, of which safety and immunogenicity data up to day 28 after injection was published in a preliminary report. However, the durability of a single dose recombinant adenovirus type-5 vaccination is still unknown, and assessment of whether subsequent boosts will be necessary to maintain or establish sufficient long-term immunity will be important.

Added value of this study

This report includes the follow-up data from the first phase 1 study of the adenovirus type-5 Ebola virus vaccine in Chinese adults up to day 168, and an extra boosting study with a homologous vaccine at a prime-boost interval of 6 months. The humoral responses were followed up to month 12 after boost vaccination. Although strong immune responses were noted after the one-short regimen of adenovirus type-5 Ebola virus vaccine, especially with the high dose, a quick waning of the antibodies were observed during day 56–168. The homologous prime-boost regimen at month 6 was safe and highly immunogenic. We observed superior antibodies responses induced by the homologous prime-boost regimen to those induced by prime dose alone. However, the boosting effects of specific T-cell responses by the homologous prime-boost regimen seemed small in this study.

Implications of all the available evidence

Adenovirus type-5 Ebola virus vaccine is safe and immunogenic, but the short duration of antibodies raised a need for prime-boost immunisation. A priming-boosting regimen with homologous adenovirus type-5 vector-based Ebola virus vaccine could elicit greater humoral responses, but little cellular immunity response. In future studies, other boosting schedules with a booster vaccination at other prime-boost intervals or with a heterologous Ebola vaccine should be investigated, to provide a longer duration of high protection against Ebola virus.

Introduction

The 2013–15 Ebola virus disease epidemic in west Africa caused by subtype Zaire was the largest in history, spreading across borders and causing a total of 28 616 Ebola cases in Guinea, Liberia, and Sierra Leone, with 11 310 deaths.1 Ebola virus disease used to be deemed regional, and with few cases, the development of a vaccine did not get enough attention and progressed slowly. Since this recent outbreak, development of Ebola vaccine accelerated greatly, and clinical trials with various Ebola vaccine candidates were launched as an emergency response to this crisis.2, 3, 4, 5, 6 and 7 Most of these studies focused on introducing a quick protective response with a rapidly acting immunisation regimen.8 However, following the end of the epidemic, more attention must be put in the durability of the vaccine-elicited protection and the potential benefits of a booster injection.

In October, 2014, we launched a first-in-human trial with a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of Ebola.7 In the preliminary report of this trial, antibody responses elicited by the experimental adenovirus type-5 Ebola virus vaccine have been assessed up to day 28 after vaccination. However, the durability of a single-dose recombinant adenovirus type-5 Ebola virus vaccine immunisation is still unknown, and we must assess whether subsequent boosts will be necessary to maintain or establish sufficient long-term immunity.9 In this Article, we describe the immune dynamics induced by one dose of the adenovirus type-5 Ebola virus vaccine up to 6 months and the boosting responses to a homologous vector vaccine in healthy adults in China.