Ebola Vaccine Safe, Immunogenic in Phase I Trials

Janis C. Kelly

April 03, 2015

A vaccine that uses a genetically engineered recombinant vesicular stomatitis virus (rVSV) to present Ebola virus glycoprotein to the immune system appeared safe and immunogenic enough in phase 1 studies to warrant further development, researchers from the United States and Europe report. The research groups reported the trial results in two articles published April 1 in the New England Journal of Medicine.

Both research teams tested the Zaire ebolavirus (ZEBOV) rVSV-based vaccine developed by the Canadian National Microbiological Laboratory, licensed to BioProtection Systems (NewLink Genetics), and sublicensed to Merck for research and development. The Canadian government donated 800 vials of the vaccine to the World Health Organization for testing.

In the US study, Jason A. Regules, MD, from the Walter Reed Army Institute of Research, Silver Spring, Maryland, and colleagues from the rVSVΔG-ZABOV-GP Study Group tested the vaccine in a phase 1, placebo-controlled, double-blind, dose-escalation trials in 52 healthy volunteers at the Walter Reed Army Institute of Research and the National Institutes of Health Clinical Center, Bethesda, Maryland.

They randomly assigned three volunteers in each group of 13 subjects to receive an intramuscular injection of placebo, and the other 10 volunteers to receive an intermuscular injection of rVSV-ZEBOV at either 3 million plaque-forming units (PFU) or 20 million PFU. They followed the patients for 28 days postinjection.

All participants who received the vaccine, which uses a live virus vector, developed transient VSV viremia. The most common adverse events were injection-site pain, myalgia, and fatigue.

At day 28, all subjects who received the vaccine had antibodies against the ZEBOV glycoprotein, and the response was stronger after the 20 million PFU dose than after the 3 million PFU dose. Similarly, the ability to neutralize the Zaire-Kikwit glycoprotein in a pseudovirion assay was stronger after the higher vaccine dose.

Meanwhile, in the other paper, Selidji T. Agnandji, MD, from the Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon, and colleagues from the VSV Ebola Consortium (VEBCON), organized by the World Health Organization, report on three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial. The researchers recruited healthy adults in Lambaréné, Gabon; Kilifi, Kenya; Hamburg, Germany; and Geneva, Switzerland.

In the three open-label, dose-ranging trials, 114 subjects received doses of 300,000 PFU to 3 million PFU, and 24 healthy adults received doses between 10 million PFU and 50 million PFU in the randomized controlled trial.

As in the study by Dr Regules and colleagues, most subjects (103 of 114) who received at least 3 million PFU of the vaccine developed transient viremia, but no rVSV was detected in saliva or urine. About 35% of vaccinated subjects developed fever, and the authors warn that vaccine-induced fever should be anticipated, especially if the vaccine is administered to contacts of patients infected with Ebola virus disease in whom an unexpected fever could be worrisome. The most common adverse effects were mild injection site reactions.

More concerning was the confirmed arthritis observed in 22% of participants in one cohort of the study by Dr Agnandji and colleagues, as well as viral seeding of joints and skin. "It showed that viral dissemination and replication can occur and persist for up to 2 to 3 weeks after immunization — in other words, that early innate responses may not always be sufficient for complete viral control," the authors write.

All subjects in the study by Dr Agnandji and colleagues who received vaccine produced ZEBOV-glycoprotein-specific antibody responses, and as in the study by Dr Regules and colleagues, neutralizing antibody titers were higher after higher doses of vaccine.

The authors comment, "The viral dissemination in skin and joints that was observed in some participants needs to be balanced with the possible benefit offered by this vaccine in the potential control of outbreaks of Ebola virus disease."

Based in part on the data from these studies, researchers have selected a dose of 20 million PFU for a phase 3 efficacy study recently initiated in Guinea by the Partnership for Research on Ebola Vaccines in Liberia trial (sponsored by the World Health Organization, the Ministry of Health of Guinea, Médecins sans Frontières, Epicentre, and the Norwegian Institute of Public Health), and for a phase 3 trial that will be conducted in Sierra Leone (sponsored by the Centers for Disease Control and Prevention and the Ministry of Health of Sierra Leone).

One coauthor of the first study holds a patent related to the rVSVΔG-ZEBOV-GP vaccine. Four coauthors have various relationships with NewLink Genetics. Another coauthor reports a pending patent related to chimpanzee adenoviral vector-based filovirus vaccines, a patent related to optimized vaccines to provide protection against Ebola and other viruses (licensed to Crucell), a patent related to the development of a preventive vaccine for filovirus infection in primates (licensed to Crucell), a patent related to immunization for Ebola virus infection (licensed to Crucell and GlaxoSmithKline), and a patent related to accelerated vaccination (licensed to Crucell and GlaxoSmithKline). One coauthor of the second study reported receiving lecture fees from Gilead, Merck Sharp & Dohme, and Bristol-Myers Squibb. Another coauthor reported receiving research funding from GlaxoSmithKline and from Sanaria. Another coauthor reported receiving research funding from GlaxoSmithKline. The other authors have disclosed no relevant financial relationships.

N Engl J Med. Published online April 1, 2015. Regules full text, Agnandji full text

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