Clinical Context

The Ebola virus devastated West Africa from 2013 to 2016, and it is clear that a vaccine is necessary to prevent such a tragedy from ever developing again. The current study by Henao-Restrepo and colleagues describe a recombinant, replication-competent vaccine that demonstrated excellent efficacy in animal models during challenge with the Ebola virus. The vaccine is derived from a vesicular stomatitis that expresses a glycoprotein of the Zaire Ebola virus.

The vaccine is associated with a robust immune response after just 1 dose. In previous preliminary reports of the current study protocol, the vaccine appeared very effective in preventing Ebola virus disease, so much so that the delayed vaccine group of the research protocol was discontinued. Its short-term protection is thought to be a result of activation of innate immunity.

A study by Zhu and colleagues yielded successful results from a phase 2 trial involving a recombinant adenovirus vaccine, but the study by Henao-Restrepo and colleagues, which describes the final results of the Ebola virus vaccine, will be detailed in "Study Highlights."

Study Synopsis and Perspective

An experimental Ebola virus vaccine was 100% effective in preventing the disease after 10 days in the 5837 people who received it in Guinea and Sierra Leone. Meanwhile, 23 of the 4507 people who did not receive the vaccine contracted the virus in the same time frame.

These findings, published online December 22, 2016, in the Lancet,^[1] are the final results from a phase 3 trial of a recombinant, replication-competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein, dubbed rVSV-ZEBOV. The same issue also includes successful results from a phase 2 trial,^[2] led by Feng-Cai Zhu, MSc, from the Jiangsu Provincial Center for Disease Control and Prevention in Nanjing, China, and Alie H. Wurie, MSc, from the Ministry of Health and Sanitation in Freetown, Sierra Leone. This phase 2 trial encompasses another vaccine candidate: recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant.

The rVSV-ZEBOV trial was conducted as the Ebola epidemic in that area was on the decline, so the investigators, led by Ana Maria Henao-Restrepo, MD, from the World Health Organization, Geneva, Switzerland, enrolled participants who were close contacts, as well as contacts of contacts, of people who had contracted the disease.

In this ring vaccination strategy, all of the person's contacts would be randomly assigned, as a group, to be offered the vaccine either immediately or after a 21-day delay. People were eligible to receive the vaccine if they were at least 18 years old and were not pregnant, breastfeeding, or severely ill. After the vaccine began to show effectiveness, an independent safety board recommended offering the vaccine immediately to all eligible contacts and to extend the eligibility criteria to include children 6 years and older.

In total, the researchers randomly assigned 51 clusters containing 4539 people to receive the vaccine immediately, 47 clusters of 4557 people to receive the vaccine after a delay, and 19 clusters of 2745 people to the nonrandomized part of the study. For outcomes, the investigators only considered cases of Ebola virus that occurred 10 days or more after random selection.

By 21 days after vaccination, no cases of Ebola virus occurred in clusters in which some of the people had been vaccinated. The investigators say this suggests that the vaccine "seemed to have contributed to interrupt Ebola transmission" in those groups. The effectiveness of ring vaccination was 70.1%, with 52.1% of people vaccinated.

Adverse events occurred in 53.9% of people within 14 days of vaccination. Most (87.5%) adverse events were mild, 11.0% were moderate, and 1.2% were severe. Children most commonly reported headache (52.6%), fatigue (11.3%), and injection site pain (9.3%) within 3 days of vaccination. Adults reported headache (25.0%), fatigue (19.0%), and muscle pain (13.2%). Of the 80 serious adverse events, half were Ebola virus disease, which was not considered to be caused by the vaccine because it occurred in the first 10 days. Four people were involved in road traffic accidents. Two had serious adverse reactions attributed to the vaccine: 1 febrile reaction and 1 case of anaphylaxis. A third had influenza-like symptoms, which the researchers judged to be possibly related.

In an attempt to keep the clusters as similar as possible, the researchers stratified them according to size (≥20 people counted as a large cluster) and urban vs rural locations. The immediate vaccination group had more high-risk contacts in their clusters. The nonrandomized clusters had higher uptake of vaccine, possibly because of public knowledge of the interim results and possibly because children also could be included.

Because of difficulties in implementing the trial ("[a] devastating outbreak of Ebola virus disease is clearly not the ideal situation for doing a vaccine trial," the authors note), the investigators did not attempt to collect samples from vaccinated people for immunologic analysis. Still, they observe, "The findings...showed that it is feasible to undertake efficacy trials in the challenging circumstances of epidemics."

The results of this trial agree with those of the phase 2 PREVAIL trial, in which 94% of 500 individuals showed seroconversion after 1 month. Previous animal studies also showed what Dr Henao-Restrepo and colleagues deem "consistently high and rapid protection."

"Although rVSV-ZEBOV seems to be highly efficacious and safe in the context of an outbreak, some questions remain," Thomas W. Geisbert, PhD, from the University of Texas Medical Branch at Galveston, writes in a related commentary.^[3] Dr Geisbert was not involved in the trial. He notes that the vaccine's long-term efficacy is unknown, as is whether future formulations could reduce the number of adverse events without reducing efficacy. In a phase 1 trial of a lower dose of this same vaccine, 13 of 51 participants reported oligoarthritis.

Phase 2 Trial Also Promising, but Immunity Short-Lived

Another trial, conducted in healthy volunteers in Sierra Leone, found that a recombinant adenovirus type-5-based vaccine was safe and highly immunogenic. A phase 1 trial had been performed previously in Chinese volunteers. This phase 2 trial involved 500 participants at a single center and was a randomized, double-blind, placebo-controlled trial.

Of those participants, 250 received a high-dose vaccine with 1.6×10¹¹ viral particles, 125 received a low-dose vaccine with 8×10¹⁰ particles, and 125 received a placebo with just vaccine excipients and no viral particles.

Immune responses were similar for both versions of the vaccine. The glycoprotein-specific antibodies peaked at day 28 with a geometric mean titer of 1471.8 (95% confidence interval, 1151.0-1881.8) in the low-dose group and 2043.1 (95% confidence interval, 1762.4-2368.4) in the high-dose group vs 6.0 to 6.8 in the placebo group. This response decreased by 85% at 6 months after the injection. Because of the short duration of the response, the authors suggest that a booster may be needed.

The immune response was similar among both versions of the vaccine, but the lower dose was associated with fewer injection site reactions.

"Taking vaccine profiles, manufacturing costs, and production capacity into consideration, 8.0×10¹⁰ viral particles seem to be an optimal dose, since it could induce a high level of glycoprotein-specific antibody responses and confer substantial protection to vaccinated individuals, at least in the short term," the authors write. They note that vaccine efficacy trials will be difficult to conduct without an ongoing Ebola outbreak.

"Concerns remain about the immunogenicity and the nature and durability of protection when implementing mass vaccination campaigns in future outbreak settings in Africa," Martin P. Grobusch, MD, PhD, and Abraham Goorhuis, MD, PhD, from the Center of Tropical Medicine and Travel Medicine of the University of Amsterdam, Amsterdam, The Netherlands, write in an accompanying comment.^[4] The immune response was not as strong in this study as in the previous trial with Chinese volunteers. Although Dr Zhu and colleagues recommend that a booster vaccine may be necessary, Dr Grobusch and Dr Goorhuis note that we do not know how effective that booster might be.

In the phase 3 study (Henao-Restrepo and colleagues), a coauthor discloses being a coinvestigator on the European Commission Innovative Medicines Initiative-funded EBOVAC trial of the Johnson & Johnson prime-boost Ebola vaccine candidate, for which he has received a grant from the European Commission Innovative Medicines Initiative; his partner is an epidemiologist at GlaxoSmithKline in a role unrelated to the company's development of an Ebola vaccine. Two coauthors have acted as unpaid advisors to the EBOVAC trial, for which one discloses travel and accommodation paid for by the EBOVAC consortium to attend a meeting. Two coauthors have received nonfinancial support from Janssen outside of the submitted work. Dr Geisbert has disclosed 5 US patents in the fields of filovirus and antiviral vaccines, including Ebola virus disease, and 2 provisional US patents. In the phase 2 trial (Zhu and colleagues), 2 coauthors are employees of Tianjin CanSino Biotechnology. All other authors and commentators have disclosed no relevant financial relationships.

Lancet. Published online December 22, 2016.

Clinical Implications

• The current Ebola virus vaccine under study is a recombinant, replication-competent vaccine that demonstrated excellent efficacy in animal models during challenge with the Ebola virus. The vaccine is derived from a vesicular stomatitis virus that expresses a glycoprotein of the Zaire Ebola virus, and it induces a strong immune response after just a single dose.
• The current study by Henao-Restrepo and colleagues finds that the Ebola virus vaccine is highly effective among contacts and contacts of contacts of persons with Ebola virus disease. The vaccine was generally safe and well tolerated for patients.
• Implications for the healthcare team: Members of the healthcare team should be aware that these studies demonstrate strong efficacy of the Ebola vaccine. The healthcare team should follow Ebola control and prevention measures currently espoused by the Centers for Disease Control and Prevention and the World Health Organization.

CME Test