Clinical trial volunteers and scientists around the globe who have been working without success to find an HIV vaccine since the mid-1980s face a new dilemma as we mark World AIDS Day 2020.
Now that daily antiviral pills have been shown to protect people from infection with HIV, will volunteers still sign up for a vaccine trial where chances are 50-50 they would get a placebo?
In recent years, evidence has built that pre-exposure prophylaxis, or PrEP — drugs such as Truvada that protect against infection — can be as much as 99% effective in preventing HIV if taken daily. Meanwhile, trials have shown that new and longer-lasting injectable antivirals show promise of working even better over time.
Yet developing an effective vaccine is just as important today as it was 35 years ago, when the effort began. To date, HIV/AIDS has claimed nearly 33 million lives, and more than 1.7 million new infections were recorded in 2019 alone, before global attention shifted to the more immediate threat of COVID-19.
PrEP is expensive — Truvada retails in the U.S. for $2,000 per month — and new injectable antivirals such as bimonthly shots of cabotegravir, if eventually approved by the Food and Drug Administration, could be even more costly
So, despite the complexities of designing clinical trials in the age of oral PrEP, researchers are charting pathways to conduct trials that can accurately and ethically test the latest generation of candidate vaccines.
“I for one believe that we won’t end the epidemic without a vaccine, so the question is really how we do these complex trials in the face of all these new interventions,” said Dr. Carol Weiss, laboratory chief for the Food and Drug Administration's Office of Vaccines Research and Review.
She was speaking last month at a public workshop about the future of vaccine trial design, the third in a series of top vaccine expert discussions organized with the help of Hutch HIV prevention researchers and hosted by the International AIDS Society.
Much of the focus is on a large trial of a new HIV vaccine candidate that has recently begun to roll out in the U.S., Latin America and Europe. The trial is called Mosaico, and its goal is to enroll 3,800 participants who have a high risk of contracting HIV, including men and transgender people who have sex with men.
Mosaico will be a case study in how an HIV vaccine trial can be carried out in the age of PrEP. The difficulty, of course, is that if PrEP is available, it would be ethically untenable to deny it to participants. However, were all trial participants taking an effective drug for preventing HIV, it would be almost impossible to prove that the unproven vaccine is also effectively stopping viral transmission.
Use of PrEP in HIV prevention trials has been increasing. In a trial of a vaccine candidate that began in 2008 and completed in 2013, only 5% of participants took newly available PrEP drugs. But in newly completed trials testing whether infusions of broadly neutralizing antibodies prevented HV infection, 40% of participants in the trial took PrEP.
“We have to find ways to make these studies work,” said Dr. Susan Buchbinder, protocol leader for the Mosaico trial.
A professor at the University of California, San Francisco and director of an HIV clinical trials unit in that city’s Department of Public Health, she has collaborated for decades with the Hutch-based HIV Vaccine Trials Network, or HVTN, which is managing four major global HIV prevention trials.
After weighing the ethics and practicality of various trial designs, Buchbinder and the HVTN team landed on a solution: enroll in Mosaico only participants for whom taking daily PrEP was problematic.
“Some people don’t want to take a daily pill. It is difficult to adhere to something requiring daily or frequent dosing. Or they don’t like the way it makes them feel. Some people don’t like the idea of taking an antiviral drug; some people just prefer getting a vaccine,” Buchbinder said.
To assure the trial is ethically sound, all potential enrollees are offered an opportunity to obtain PrEP. It would be a win for prevention if they opt for the drugs, because they will access a proven way to stop HIV transmission. However, that decision would exclude them from participating in the vaccine trial.
The remaining candidates will be counseled to be certain they genuinely understand their decision. Critically, they also will have the option to begin taking PrEP during and throughout the trial if they change their mind. The trial was designed to anticipate later decisions to start PrEP, so uptake of the drug will not compromise the study. Because the trial is randomized and “blinded” — participants do not know whether they were assigned at random to the half given the vaccine or the half receiving a placebo — the impact of a later decision to take PrEP is minimized.
Fred Hutch biostatistician Dr. Holly Janes has participated in the discussions over design of HIV vaccine trials in the era of oral PrEP. She believes the Mosaico trial has set a standard for navigating the difficult choices required to pass ethical muster while retaining the statistical power to produce meaningful results.
Mosaico “was designed carefully so people can make an informed choice,” she said.
Janes noted that committing to PrEP is not a viable HIV prevention choice for many people. Sustained adherence to daily prevention regimens is challenging when the benefit is in the future and may seem abstract. She also noted that people experiencing social stigma desire discrete methods of HIV prevention. They may fear discovery of a bottle of pills or may have difficulty travelling to pharmacies to get prescriptions refilled.
“There are a lot of people who are interested in PrEP, but cannot sustain that over time,” she said. “One reason has to do with the usual challenges of getting people to change their behaviors when they are healthy. An analogy might be the difficulty in getting people to floss their teeth on a daily basis. It’s difficult for all of us.”
The intended start of the trial was interrupted by the COVID-19 crisis, but this month, it restarted in the U.S., including at a site at Fred Hutch’s Seattle Vaccine Trials Unit, which can enroll up to 50 participants.
Dr. Stephaun Wallace, director of external relations for HVTN, is directly involved in explaining the complexity of these trials to potential participants, and he has played an active role in the design of Mosaico.
“In every place where we are doing the study, the goal is to ensure that PrEP is accessible to those who opt for it over study participation, and for those who join the study and later change their mind about PrEP,” he said. “I believe there are a number of people out there who would be interested in a vaccine over PrEP. The current HIV prevention toolkit does not meet the needs of everyone, so finding an effective HIV vaccine with global application is an important contribution to it.”
In his conversations with men who have sex with men and transgender people, Wallace said the questions are sharp and informed.
“They ask whether the vaccine has been tested in large numbers of people. They ask what the data say from earlier phases of this study. They have questions about side effects. They want to know how safety and participants’ rights will be protected, as well,” he said.
While the long search for an effective HIV vaccine has been a string of disappointments, Wallace said there are sound scientific reasons for testing this new vaccine in the Mosaico trial. The name itself refers to the structure of the vaccine, which contains pieces of surface proteins from multiple strains of HIV — a mosaic of antigens — to stimulate an immune response that is more difficult for virus to evade by mutation. HVTN is conducting a trial of a similar vaccine among 2,600 women in five sub-Saharan African countries. The Imbokodo trial completed its enrollment before the COVID-19 pandemic.
Although COVID-19 disrupted and delayed the start of the Mosaico trial, the issues that emerged in the design of it may help inform decisions being made today over how to structure, or restructure, ongoing clinical trials of vaccines meant to stop COVID-19.
The prospect of having vaccines that are at least 90% effective against the coronavirus — now a possibility after early results from trials of vaccines by Moderna, Pfizer, and AstraZeneca — poses problems of its own.
Among the new questions arising: will participants in these trials who were assigned randomly to placebos be offered an approved vaccine once it is available?
One way to do this is to unblind the trial — so the participants know if they had received the vaccine or placebo — and offer the placebo group the approved vaccine. Another would be to provide all participants with a new round of blinded injections, but only those in the placebo group get vaccine, while those in the vaccine group receive a placebo.
Approval will also complicate trials that have not yet started. Two of the five COVID-19 vaccine candidates slated for large-scale clinical trials have not begun. They may have to start at a time when highly effective alternatives — though not readily available — have been approved. Investigators designing the later trials will have to resolve issues around which populations to recruit, such as those who are not likely to get the immunizations early based on the National Academies of Medicine’s Frameworks for Equitable Distribution of Vaccines.
It is a familiar scenario to those designing HIV vaccine trials in the era of PrEP.
“Having successful vaccines is a good problem to have,” said Hutch biostatistician Janes. “It does pose challenges, however, for achieving the goal of developing multiple effective COVID-19 vaccines, and it is something we are wrestling with currently.”
Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at firstname.lastname@example.org.
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