First human trial of NIH-GSK Ebola vaccine shows promise

Researchers from the National Institutes of Health (NIH) and GSK today reported promising initial findings from early human tests for one of two Ebola vaccines destined for West Africa, the first in a flurry of results expected by the end of the year.

The vaccine, called ChAD3, uses a modified chimpanzee adenovirus and was developed by the US National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, and GSK.

Researchers reported findings from a 20-person trial today in an early online edition of the New England Journal of Medicine (NEJM). Experts not involved in the trial expressed optimism about the results but raised some potential issues.

Trials of various vaccines

Investigators are studying two versions of the vaccine. The bivalent version reported in today's NEJM report contains genetic material from Zaire and Sudan Ebola species, the two most lethal strains. The Zaire strain is responsible for West Africa's outbreak. The phase 1 trial launched in early September at the NIH Clinical Center in Bethesda. Md.

The bivalent version of the vaccine is also being tested at Emory University in Atlanta to collect more safety and immunogenicity data, the NIH said today in a backgrounder on its Ebola vaccine trials.

Tests of a monovalent version that contains genetic material only from the Zaire strain began in October at the University of Maryland in Baltimore, with results expected by the end of 2014. Trials of the monovalent vaccine are also under way in the United Kingdom, Mali, and Switzerland, with initial safety and immunogenicity results also expected by the end of the year.

Two phase 1 studies of the Canadian-developed vaccine—also a monovalent version—launched in the United States in October. That vaccine uses an Ebola virus protein spliced into a vesicular stomatitis virus (VSV-EBOV). A trial of the vaccine at the NIH Clinical Center involves a prime-boost strategy at three different antigen levels and another trial, conducted at the Walter Reed Army Institute of Research, is testing a single dose of the vaccine at the same three antigen levels.

Early results for the VSV-EBOV vaccine are also expected by the end of the year, according to an Oct 22 NIAID statement.

Immunogenicity and safety results

The trial of the bivalent ChAD3 vaccine involved 20 healthy adults. Half received a lower dose of 2 X 1010 particle units (PUs), and half received a higher dose of 2 X 1011 PUs. Researchers tested their blood 2 weeks and 4 weeks after vaccination to assess antibody levels.

Antibodies were detected in all 20 study participants within 4 weeks of vaccination, but levels were higher in those who received the higher dose.

Based on earlier studies of the vaccine in nonhuman primates, the investigators looked at the T-cell immune response and found that the vaccine did induce a T-cell response, including CD8, 4 weeks after immunization in many of the volunteers: 2 of 10 who received the smaller dose and 7 of 10 who received the larger dose.

Julie Ledgerwood, DO, chief of the clinical trials program at the NIAID Vaccine Research Center and the study's primary investigator, said in an NIAID statement that earlier studies suggested that CD8 T cells played a key role in protecting vaccinated animals who received a lethal Ebola dose. "The size and quality of the CD8 T cell response we saw in this trial are similar to that observed in non-human primates vaccinated with the candidate vaccine."

When they looked at tolerability, the study team found no serious adverse events, though two people who received the higher dose developed a brief fever within a day of vaccination. The fevers resolved within 24 hours with fever-reducing medication.

Anthony Fauci, MD, NIAID's director, said in the statement today that safe and effective vaccines could play a role in shutting down the current outbreak and preventing large ones in the future. "Based on these positive results from the first human trial of this candidate vaccine, we are continuing our accelerated plan for larger trials to determine if the vaccine is efficacious in preventing Ebola infection."

Based on early encouraging results for the bivalent vaccine, NIAID said it is in active discussions with Liberian health officials and other partners about the next steps for testing the vaccine in West Africa. It said goals of the phase 2/3 tests are to reveal more about whether the vaccine works, adding that plans for those trials hinge on the results of other phase 1 studies  under way.

The agency said it doesn't expect to make any announcements on larger-scale testing until early 2015.

Experts welcome results, air remaining questions

Fauci told CIDRAP News that the study was a success, showing that the vaccine is safe and produces a response that researchers predict will be protective. He said the few fevers participants had were easily managed and that the response at the higher of the two doses was comparable to the protection seen in monkeys that were subjected to a lethal Ebola challenge.

Daniel Bausch, MD, MPH, of Tulane School of Public Health and Tropical Medicine in New Orleans, wrote today in an NEJM editorial that both of the vaccines furthest along in the developmental pipeline have shown to be 100% protective in nonhuman primates 4 to 5 weeks after a single dose, offering hope that their help in stemming West Africa's outbreak is more than theoretical.

Though the results described in today's study are promising, several questions remain, he pointed out. For example, the better immune response that came with the larger dose was also associated with minor adverse events, which included fever and leucopenia. Bausch said that although no serious adverse events were seen, the sample size was too small to draw firm conclusions.

Squeezing the maximum number of doses from the vaccine supply is also important to consider when gauging the results of Ebola vaccine studies, he said.

Bausch wrote that two issues that cloud the analysis of the new study, and those that will follow, are lack of knowledge about correlates of immunity—the antibody levels that actually signify protection from disease—and lack of standardization of stock viruses. He added that until more is known about immune correlates, it's tough to say if the response to the lower dose described in today's NEJM report is "good enough."

Other key question are the length of protection and the possible need for a booster and if the vaccine is effective in West African settings, and the results from other ongoing studies will shed light on the issues, Bausch said.

Researchers face stiff headwinds in the months ahead, with tough decisions hanging in the balance about dosage, whether traditional phase 2 and 3 trials can be done ethically in West Africa's outbreak region, and if the two top vaccine candidates should be compared head to head, he wrote. "The road is still long and there are many challenges, but we are nevertheless one step closer to a solution."

Michael T. Osterholm, PhD, MPH, director of the University of Minnesota's Center for Infectious Disease Research and Policy, publisher of CIDRAP News, said the first study results are welcome news, as health groups move forward with the Ebola vaccine. "It's critical to get these studies done," he said.

He said a key issue will be determining the dose, which will factor in to how much vaccine can be made and how quickly production could be scaled up. He said the dose that was most effective in the study was a substantial one. "It gives you pause," he said.

For comparison, the multiple-dose VSV-EBOV trial involves doses of 3 X 106, 2 X 107, and 1 X 108 PUs, which are orders of magnitude smaller.

Fauci said he's not too concerned about the dose issue. He said that other studies that are under way on the vaccine, especially the one in the United Kingdom, are exploring lower doses. He added that he's confident that there won't be any problems scaling up enough doses to proceed with additional clinical trials that are planned.

See also:

Nov 26 NEJM study

Nov 26 NEJM editorial

Nov 26 NIAID press release

Nov 26 NIAID Q and A

Oct 22 NIAID statement

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