federally appointed ethics panel has rejected an application from a team of scientists to deliberately infect people with the Zika virus, a decision that threatens to further slow the search for an effective vaccine.
The panel’s report, published without fanfare last week on the website of the National Institutes of Health, said it would not currently be ethical to conduct the study because of the risk to potential volunteers and their sexual partners and because there are other possible study approaches.
It is not uncommon for researchers to deliberately infect study participants with viruses in the course of vaccine research. So-called “human challenge studies” allow scientists to assess a vaccine’s effectiveness more quickly than by traditional means.
But the ethics panel reviewing the proposal for a Zika challenge study advised that it wouldn’t currently be ethical to conduct one.
“The bottom line of the ethics review is right now the way protocols are written and the way people are talking about it, it isn’t ethically sound to do it,” Dr. Anthony Fauci, director of the NIH’s National Institute for Allergy and Infectious Diseases, told STAT.
“But these obstacles can be overcome,” Fauci said, suggesting the scientists can restructure their research proposal.
The nine-member panel, chaired by Seema Shah, an ethicist at the University of Washington School of Medicine, was asked to study the ethics of a proposal to develop a controlled human infection model, in which people would be deliberately infected with Zika. The request to study the plan came from the NIAID and the Walter Reed Army Institute of Research.
The group concluded that a challenge study might be an acceptable way to study the virus and vaccine candidates in future, but for the time being conducting these studies where Zika is spreading is the more ethical approach. The panel raised concerns about the study’s capacity to harm third parties who hadn’t volunteered for the research — for instance, the sexual partners of male volunteers who could conceivably contract Zika after the study. And it raised concerns about the risks to the participants themselves.
Zika infection is so mild in most cases that it’s estimated 4 out of 5 infected people don’t experience symptoms. However, a small portion of people who contract Zika go on to develop Guillain-Barré syndrome, a form of progressive paralysis from which patients normally recover but which can in rare cases be fatal.
“Given the amount that has already been discovered about Zika virus in terms of complications and modes of transmission in the last six months alone, there appear to be alternative ways to develop vaccines with a reasonable probability of being protective,” the group’s report stated.
Dr. Anna Durbin, a vaccine researcher at Johns Hopkins University who was among those proposing the study, said the panel seemed not to understand the rationale for doing the research or the hurdles that will face any group that wants to conduct the large human trials needed to prove that Zika vaccines work.
She and colleagues from the NIH and the University of Vermont College of Medicine — which has a vaccine testing center — were seeking to answer key questions about Zika infection and to figure out which of a number of experimental vaccines is most likely to prevent transmission of the virus from a pregnant woman to her fetus.
“Instead of diluting our resources over many, many different candidates, if we use the controlled human infection model early on, we can really then concentrate those resources to ensure that the best candidates move forward,” Durbin said.
Under their proposal, volunteers would be informed of the risks of infection and would be closely monitored in a controlled, inpatient setting. Durbin and her colleagues have done experimental infection studies for other viruses — including recent research involving a dengue virus vaccine.
Currently there are four experimental Zika vaccines in the earliest stages of human testing; more are on the way. But the pivotal Phase 3 trials that prove whether a vaccine works won’t start for at least another year, in the best-case scenario.
There has long been concern that by the time experimental vaccines are ready to be tested in Phase 3 trials, the outbreak will be receding, making it difficult to prove whether the vaccines are protective.
Trials such as these would involve vaccinating a large number of volunteers and giving a placebo shot to volunteers in a matching group, then watching to see whether there were more infections among the participants who had not been vaccinated.
But if there is little Zika virus circulating, such a trial would not produce results.
Durbin said the epidemic in Latin America already appears to be waning in some areas. Fauci said he told Shah, the lead author of the ethics report, that this argument against challenge studies was not strong and should not stand in the way of ethics approval.
Durbin said one of the crucial reasons for conducting Zika challenge studies is to try to home in on vaccine candidates that can completely block future infection — a phenomenon known as “sterilizing immunity.”
Many vaccines don’t generate sterilizing immunity. They train the immune system to spot and shut down an infection in the early stages, before it can make the infected person sick. For some diseases, that’s all that’s needed from a vaccine.
But given the risk that Zika poses to developing fetuses, a Zika vaccine will need to do more, Durbin said, noting that even low-level infection in a pregnant woman might allow viruses to make their way to the uterus and attack her developing fetus.
“The whole purpose is to eliminate poor [vaccine] candidates,” Durbin said. “If you know that it’s not effective, you’re utilizing resources, you’re enrolling volunteers for a product that is not the best product. To me, it’s a waste of resources.”
“The bottom line of the ethics review is right now the way protocols are written and the way people are talking about it, it isn’t ethically sound to do it.”
Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases
She also questioned the report’s suggestion that more ought to be learned about Zika infection — including how long people are able to transmit the virus sexually — before challenge studies are conducted.
Zika has been spreading in parts of the Americas for two years now, Durbin noted. The fact that there are still no answers to basic questions like how long do men emit infectious virus in their semen points to the difficulty of arriving at the information in uncontrolled settings. “If a longitudinal study to answer these questions has not yet been done,” she said, “I don’t know why they think that they will be done in the future.”
Fauci suggested Durbin and her colleagues could fine-tune their study protocol to limit the risks to participants and the risk that they might infect others, including perhaps by enrolling women who are no longer of reproductive age.
The scientific community continues to learn more about Zika. A paper published last week showed that infection in mice can damage testicles — which, if shown to be the case in men, could also have implications for future fertility. It was the third paper to show this result in mice.
Fauci suggested that a short study looking for post-infection consequences in a couple of hundred people who were previously infected would strengthen the ethical argument for conducting Zika challenge studies. “If someone did that, I likely would approve it to be funded by us,” he said.