While there are reports of various Zika vaccine trials proceeding, one the most promising methods to quickly and accurately measure vaccine efficacy has come to a full stop.
“Human challenge trials,” or “controlled human infection models,” involve exposing research subjects to a pathogen, typically in some attenuated state under rigorous controls and oversight, to test a vaccine candidate.
With regard to Zika virus, a bioethics committee convened by the National Institute of Allergy and Infectious Diseases (NIAID) has concluded at present the risks of this approach outweigh the benefits. Among other reasons, the panel cited the risk to research subjects, possible transmission to others, and the availability of safer vaccine trial approaches.
Though a way forward is described in the panel’s recent report to NIAID, for now a red flag has been raised and human infection trials for Zika vaccines are being reconsidered. A researcher who helped develop a controlled human infection model for dengue virus — which is closely related to Zika — questioned the panel’s decision, saying it thwarts the fastest method to develop safe, effective vaccines.
“There are specific questions with Zika that a controlled human research model could really answer,” says Anna P. Durbin, MD, a professor and researcher in the Johns Hopkins University Vaccine Initiative. “I am not sure the committee had adequate information in making their recommendation. I think they overstepped. There is a pathway forward in the recommendations, but unfortunately it is a very narrow pathway and it does limit the value of the controlled human infection model.” (For more information, see related story in this issue.)
Durbin may pursue one example offered by the panel that could sufficiently mitigate the risk of human controlled research risks: a Zika human research model that only enrolled women who use effective, long-acting contraception. That would mitigate both the risks of subsequent birth defects and concerns about the prolonged presence of Zika in semen, which has resulted in sexual transmission of the virus.
“[The panel] did say you may be able to move forward with women only, on very reliable birth control, and that is something we are considering,” Durbin says. “We would would like to develop a controlled human infection model in parallel as we first begin to evaluate our candidate Zika vaccines. If we have breakthrough viremia in those people that were vaccinated, then we may need to re-evaluate our strategy and shouldn’t necessarily take that vaccine candidate forward, even though we saw good immunogenicity.” (See related story, in this issue.)
This is not an inconsequential decision. The CDC announced at a recent press conference that about 10% of pregnant women with confirmed Zika in the U.S. in 2016 had a baby with one of the well-described horrific birth defects. Zika infection — particularly in the first trimester — can lead to fetal microcephaly and other serious congenital brain abnormalities, limb defects, and vision and hearing problems.
NIAID convened a committee to evaluate the ethical issues of Zika vaccine efficacy trials though the controlled human infection model. The panel was charged with determining whether a Zika virus human challenge trial could be ethically justified, and if so, under what conditions. A writing committee comprised of bioethicists, researchers, and federal agency officials recently issued the panel’s report.1
“Given the potentially devastating effects of Zika infection during pregnancy, the insidious nature of the disease, and the promise of what can be learned from human challenge trials, the writing committee concluded that a Zika virus human challenge trial could be ethically justified if certain conditions were met,” the panel concluded. “However, at this point in time, based on what was heard at the consultation meeting and on our review of the latest scientific and ethics research, the writing committee has determined that these conditions preclude the conduct of a Zika virus human challenge trial.”
Unusual Suspects
In an analysis of risks of a Zika virus challenge study, the panel cited several unresolved issues about the epidemiology of virus, which was first found in a monkey in the eponymous Zika Forest in Uganda in 1947. According to the CDC, Zika is the first mosquito-borne virus that can cause birth defects. It also is the first mosquito-borne virus that can be sexually transmitted. In findings that somewhat validate the committee’s concerns, Zika has surprised public health officials on both counts.
There also have been some secondary transmission incidents that are concerning. These include infection via needlestick to a lab worker, a case of female-to-male sexual transmission, and the strange case of a 73-year-old patient in the U.S. who apparently transmitted Zika to a visiting acquaintance — possibly through tears — before dying with an incredibly high level of circulating virus in the blood.2 The secondary case developed symptomatic Zika infection, but subsequently recovered. It is possible that hormonal treatment for prostate cancer somehow accelerated viral replication in the index case, investigators concluded. In addition, some people infected with Zika have developed a rare paralytic syndrome called Guillain-Barré.
Panel Recommendations
In light of such concerns, the Zika bioethics panel made the following points and recommendations:
- There is substantial uncertainty about the risks to potential volunteers in a Zika virus human challenge study. Although the known risks of a Zika human challenge trial appear comparable to the risks of Phase I research with healthy volunteers, without greater knowledge about outcomes from Zika exposure these risks would require high social benefit to be justified.
- The committee was particularly concerned about possible risks to third parties, i.e., that Zika virus might be transmitted from study volunteers to others, such as fetuses and members of the community. Because these third parties generally cannot know about, protect themselves from, or consent to risks, the risks are only reasonable if they can be reduced to near-zero. However, the mechanisms of transmission of Zika virus and how long individuals with Zika can infect others are not fully understood. Before proceeding with a Zika virus challenge study, researchers should therefore demonstrate that the risks to third parties are not likely to be realized.
- Whether a Zika virus human challenge trial has sufficient social value to proceed depends on the reasons for conducting it and whether there are alternative ways to obtain the information. The most compelling rationale for conducting a Zika human challenge trial, given the risks and uncertainty, would be if field trials were prohibitively difficult to conduct in light of a waning epidemic. This rationale is not currently met, but could come to pass in the future.
- A Zika virus human challenge trial only should enroll individuals with capacity to provide their voluntary informed consent. Such a trial should also take steps to minimize the risks to fetuses to as close to zero as possible.
- Researchers and sponsors of a Zika human challenge trial should use a robust informed consent process. For example, researchers and sponsors could require multiple voluntary steps for individuals to take to enroll, adequate time for discussion, and evaluation of and feedback given to enhance participant understanding about critical issues.
- Volunteers should be paid fairly for their time and inconvenience, but they should demonstrate understanding of the risks and uncertainties involved and be evaluated with objective evidence of their eligibility and compliance wherever possible.
- The right to withdraw should be respected in challenge trials by halting the collection of data for volunteers who want to withdraw even if they will have to remain confined to protect themselves or others.
- In the event a Zika [human challenge] trial proceeds, study sponsors should ensure that sites are adequately insured to cover the costs of care and compensation for research-related injury, to both study participants and third parties, and that insurance policies that are purchased have adequate processes in place to efficiently and fairly evaluate and resolve claims.
- Community engagement with the geographic community surrounding the site(s) of a Zika human challenge trial should be conducted in advance of the research to show respect for the community and its values, obtain community buy-in to the goals of the research, and proceed with transparency.
Committee Concerns
IRB Advisor asked the following questions of Seema K. Shah, JD, Zika committee chair and an associate professor at the Treuman Katz Center for Pediatric Bioethics at the University of Washington and Seattle Children’s Research Institute.
IRB Advisor: Just to clarify, given the current state of the science, does the committee recommend against conducting human trials that involve intentionally infecting subjects with Zika virus?
Shah: The committee concluded that a Zika virus human challenge study should not be conducted at this time, based on what we heard about the state of the science, the risks to volunteers and community members, the reasons for doing this type of research, and the alternatives. The committee was concerned that the full spectrum of disease caused by Zika virus is not yet characterized. However, the committee was impressed by how much has been learned about Zika virus in the past two years.
IRB Advisor: Similarly, the committee was particularly concerned that Zika virus might be transmitted from study volunteers to others, such as fetuses and members of the community.
Shah: The committee was concerned about the possibility of transmission to others outside of the study, and recommended that a Zika virus human challenge study should not proceed until researchers can show that risks to others are unlikely to be realized. Research to learn more about how Zika virus is transmitted and how long individuals with Zika virus are infectious is of high priority.
IRB Advisor: There are some safeguards mentioned in the report, such as “long-lasting reversible contraception.” Could research proceed if these type of safeguards are in place?
Shah: The committee concluded that research could proceed if there was a strong enough rationale to justify the risks and uncertainty, and a number of safeguards were in place. We saw two compelling rationales for doing a Zika virus human challenge study: One, if field trials become impossible to conduct, or two, if human challenge trials could accelerate development of a vaccine that could prevent congenital Zika infection. We did not hear evidence that the conditions we laid out are currently met, but we think they could be met in the future.
For example, although field trials are being conducted now, the epidemic may burn out or become more unpredictable over time, making a human challenge study the only way to move vaccine research forward. Additionally, although we did not hear this evidence at our consultation, regulatory agencies and other key stakeholders might clearly indicate that a Zika virus human challenge study would be an acceptable and important way to speed up the licensure of a Zika virus vaccine.
IRB Advisor: So there are conditions that would meet the committee’s concerns and open a way for this type of vaccine trial?
Shah: With a compelling reason to favor a Zika virus human challenge trial over alternative research designs, we were also open to the possibility that a carefully designed Zika virus human challenge trial could move forward. A Zika virus human challenge trial might be ethically justifiable based on applying the latest scientific information to minimize risks, the small numbers of participants who would be enrolled in a Zika virus human challenge trial, and the use of creative approaches to minimize the risks to others so they are near-zero. In our report, we provided a road map for researchers with concrete ethical issues to address and strategies for protecting volunteers and third parties. We did not review any specific protocols and determine whether these conditions were met. Ultimately, the leadership at NIAID will judge whether protocols they receive can meet the ethical conditions for moving forward.
REFERENCES
- Shah SK, Kimmelman J, Lyerly AD, et al. Ethical Considerations for Zika Virus Human Challenge Trials: Report & Recommendations. February 2017: http://bit.ly/2o6rjfm.
- Swaminathan S, Schlaberg R, Lewis J, et al. Correspondence: Fatal Zika Virus Infection with Secondary Nonsexual Transmission. New Engl Jrl Med 2016;375(19):1907-1909.
While there are reports of various Zika vaccine trials proceeding, one the most promising methods to quickly and accurately measure vaccine efficacy has come to a full stop.
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