Findings from three studies conducted by the Partnership for Research on Ebola Virus in Liberia (PREVAIL) were presented on Tuesday evening at a special session on Ebola during the 2016 Annual Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, Massachusetts, USA Feb. 22-25.
Initial results from PREVAIL I, a pioneering placebo-controlled clinical trial of two candidate Ebola vaccines launched in Monrovia in Feb. 2015, indicate that both vaccines stimulate a good immune response in the early weeks after vaccination and are well tolerated, even among people infected with HIV.
The study also found that a number of participants had evidence of a past Ebola virus infection, although none reported being aware of having been infected or of being sick. These and other findings from PREVAIL I, were presented by co-principal investigators on the study, Fatorma Bolay, Ph.D., Director of the Liberian Institute for Biomedical Research (LIBR).
PREVAIL I was initially designed as a Phase 2/3 randomized, placebo-controlled trial that would enroll approximately 28,000 people at risk of Ebola virus disease (EVD) in Liberia to evaluate whether two experimental Ebola vaccines—ChAd3-EBO-Z (GlaxoSmithKline) and VSV-ZEBOV (Merck)—could prevent Ebola virus disease.
However, by March 2015, successful Ebola control efforts had greatly reduced the population at risk of Ebola in Liberia, so the study was scaled back to a Phase 2 trial comparing the safety and immune responses of the two experimental vaccines to placebo.
The site chosen for PREVAIL I was the Redemption Hospital, located near the epicenter of the outbreak in Monrovia. From Feb. 2 to April 30, 2015, 1,500 volunteers age (18 years or older) without fever or history of Ebola virus disease joined the study. The participants were assigned by chance to receive a single injection of either a saltwater placebo or one of the experimental vaccines.
The study excluded women who were pregnant or breastfeeding, but otherwise, men and women with a variety of health conditions, including high blood pressure, diabetes, cancer, and arthritis, were welcome to enroll. PREVAIL I deliberately cast a wide net in order to determine how safe and immunogenic the vaccines are in a range of adults who represent Liberia’s general population. The median age of participants was 30 years old, and 37 percent were women.
Among all participants, initial blood screening tests revealed that 6.3 percent had evidence of a past Ebola virus infection—that is, they had Ebola antibodies—although none reported having been sick. This surprising finding has potentially important public health implications.
“We hope to better understand the implications of this finding as we learn much more about Ebola survivors and their close contacts during the ongoing, long-term study known as PREVAIL III,” noted Dr. Bolay.
The findings said excluding individuals with pre-existing antibodies to Ebola in their analysis, the study team found that 87 percent of those given the ChAd3-EBOV-Z vaccine and 94 percent of the VSV-ZEBOV recipients had measurable anti-Ebola antibodies one month after vaccination.
“The antibody responses measured at 6 and 12 months after vaccination, which will provide important information about how long these immune responses last, are still being collected for analysis,” it said.
The PREVAIL team also screened the study volunteers for HIV and syphilis. The frequency of each in the study population was found to be about 5 percent. This rate of HIV infection is considerably higher than what has previously been reported for Liberia as a whole (1.9 percent in the general population). However, the study team found that being infected with HIV had at best only a modest effect on the immune responses produced to either one of the vaccines.
The participants were asked to return to Redemption Hospital for follow-up visits at week 1, months 1 and 2, and then every 2 months thereafter for 12 months. Approximately 20 percent came in for a special visit at week 2 to be evaluated for any joint problems. Overall, the vaccines were well tolerated, and no significant differences in reported side effects were found between those who received either of the vaccines or the placebo.
Among its successes, the trial achieved a near perfect—98.6 percent—record of attendance at follow-up visits, an unusually high rate for a clinical study conducted anywhere, noted H. Clifford Lane, M.D., Deputy Director for Clinical Research at the National Institute of Allergy and Infectious Diseases (NIAID) at the U.S. National Institutes of Health (NIH), and the lead U.S. scientist on the study. NIAID/NIH and the Liberian Ministry of Health are co-sponsoring the study.
According to Stephen B. Kennedy, M.D., MPH, co-principal investigator on the study and coordinator for Ebola research at the Incident Management System (IMS) in Liberia, “PREVAIL I demonstrates the feasibility of conducting a well-designed, randomized, placebo-controlled vaccine trial during an infectious disease outbreak. Our success can be attributed to the efforts of many dedicated individuals on the PREVAIL team as well as our in-country partners. Of special note, the vigorous program of social mobilization and advocacy carried out by trained community members had played a critical role in overcoming public misconceptions about the study, recruiting trial volunteers, and maintaining the excellent rates of follow-up in this study.”
In January 2016, PREVAIL I began graduating the first volunteers. More than 600 have now completed their year-long commitment. All follow-up visits are expected to be completed in April 2016.
A first look at results from PREVAIL II – the only clinical trial evaluating whether the experimental Ebola therapy known as ZMapp is safe and effective—reveals that the treatment is well tolerated and suggests it may hold some promise as an Ebola treatment. However, the study could not enroll enough patients to prove that ZMapp offers significantly more healing benefits than supportive care alone.
ZMapp, made by Mapp Biopharmaceuticals, Inc. (San Diego, California), is a mixture of three different anti-Ebola antibodies. Antibodies are infection-fighting proteins produced by the body that attach to the surface of the Ebola virus and thereby prevent it from damaging cells.
The randomized, controlled study was designed to enroll up to 200 patients of any age with confirmed Ebola virus infection. During 10 months beginning on March 13, 2015, 72 patients joined the study. On January 29, 2016, the trial leaders closed the study because no more Ebola cases were expected. The 72 participants included 54 from seven clinical sites in Sierra Leone, 12 from one site in Guinea, 5 from two sites in Liberia, and 1 from the United States. Their median age was 24 years; slightly more than half were women.
Each patient was assigned by chance to one of two study groups. One group received the best standard of supportive care for treating Ebola infection available at their treatment site. This included giving intravenous fluids; balancing electrolytes, minerals needed to regulate body functions; maintaining healthy oxygen and blood pressure levels; and treating other infections if they occurred. The second group received the best standard of care available at the site plus three separate infusions of ZMapp spaced three days apart and completed over 7 days. The amount of ZMapp in the infusion was determined by the patient’s weight.
To assess how well ZMapp worked against Ebola, the PREVAIL team compared the number of deaths in each group at 28 days after enrollment. In the study, 21 patients died, a mortality rate of almost 30 percent. The standard-of-care group had 13/35 (37 percent) deaths compared with 8/36 (22 percent) deaths in the ZMapp group. (One patient left the study early and was not included in the analysis.) The difference was not statistically significant.
How much virus the patient had when first enrolled strongly affected mortality: 53 percent (16/30) of those with high virus levels died versus 12 percent (5/41) of those with lower virus levels. Among patients with high virus levels, 60 percent (9/15) receiving standard-of-care only died versus 47 percent (7/15) of those who also received ZMapp. In the group with lower virus levels, 20 percent (4/20) on standard-of-care only died versus 5 percent (1/21) of those also given ZMapp. On the whole, those with high or lower virus levels who received ZMapp appeared to do better, but the differences were not statistically significant.
Side effects occurred with similar frequency in both groups. Fever and low blood pressure were the most common side effects reported with infusions of ZMapp. Antihistamines and fever-reducing agents were often given before infusions to reduce possible side effects.
The findings were presented at the meeting in Boston by Richard T. Davey, Jr., M.D., Deputy Clinical Director in the Division of Clinical Research at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and co-leader on the trial.
“Although the trial needed significantly more patients to answer whether ZMapp plus optimized standard of care is superior to optimized standard of care alone, we collected valuable data on the safety of and patient response to ZMapp,” noted Dr. Davey. “Moreover, we demonstrated that a randomized, controlled, multicenter treatment trial can be designed and successfully implemented in the midst of an outbreak.”
The findings said the clinical picture emerging from PREVAIL III shows that survivors and their contacts suffer from many health problems. People in both groups, however, report subjective symptoms more often than are detected by objective tests performed by physicians or physician assistants. Eye complaints, for example, were reported by 60 percent of survivors and more than 58 percent of contacts when they entered the study. Yet only 25 percent of survivors and 14 percent of contacts had abnormal ocular findings on examination.