HIV researchers around the globe are regrouping after this week’s announcement that a promising new vaccine had failed a critical test, shutting down a major clinical trial in South Africa two years before it was scheduled to end.
Hopes were that the trial would show a significant improvement over the mild, 31% effectiveness of a vaccine tested in Thailand over a decade ago. But the new vaccine — a redesign of the one used in Thailand — showed no effectiveness at all.
The deeply disappointing findings were sobering news for researchers at Seattle’s Fred Hutchinson Cancer Research Center, which leads the HIV Vaccine Trials Network, or HVTN, which coordinated the trials with partners in South Africa.
In his first meeting with employees as the new president and director of Fred Hutch, Dr. Tom Lynch said the results are a call for action.
“It does not mean that we stop. It means we redouble our efforts and learn what we can from that effort,” he said.
Operators of the trial, which was launched in 2016, had expected to unblind the study and reveal the results in 2022. But they called a halt to it on Feb. 3 following a recommendation of an independent data and safety monitoring board.
DSMBs periodically monitor such large-scale trials to see if the vaccine is safe and effective. Findings from their independent review are kept from researchers and participants, unless they discover something unexpected. On January 23, they found that while the vaccine was perfectly safe, it was not working.
“There was no evidence of efficacy, no matter how you cut it,” said Dr. Larry Corey, principal investigator for HVTN, during an afternoon meeting with HVTN staffers who gathered to discuss the decision announced earlier that day.
A pioneering virologist who has led HIV/AIDS research on treatments and vaccines since the early days of the epidemic, Corey is also president and director emeritus of Fred Hutch.
“You did a damn good job,” he told the gathering. “It was a painful answer, but our job is to do these studies, and you did it incredibly well.”
The goal of the trial, designated HVTN 702 and known as Uhambo, was to test in South Africa the improved version of the Thai vaccine, which remains the only one ever shown to reduce HIV infection rates. The so-called RV144 study of that vaccine was carried out by the U.S. Military HIV Research Program and the Thailand Ministry of Public Health, and involved a cohort of more than 16,000 Thai volunteers.
Its findings were a surprise when they came out in 2009, because the Thai vaccine was a combination of two vaccine candidates that had failed in prior clinical trials. Because a vaccine that only protected less than a third of people could give a false sense of security, the Thai vaccine was not approved for use. Instead, the results spurred years of research to improve upon it.
— Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases
Corey said that researchers will closely analyze the new trial data to find out why this vaccine did not work, information that could help in the development of a better one.
The Uhambo trial was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the Bill & Melinda Gates Foundation and the South African Medical Research Council. Along with HVTN and vaccine manufacturers Sanofi Pasteur and GlaxoSmithKline, they formed a coalition that led to the South African trial.
“An HIV vaccine is essential to end the global pandemic, and we hoped this vaccine candidate would work. Regrettably, it did not,” said NIAD Director Dr. Anthony Fauci, in a press release. “Research continues on other approaches to a safe and effective HIV vaccine, which I still believe can be achieved.”
The Uhambo trial vaccine was based on the one used in Thailand but was redesigned with different components based upon strains circulating in sub-Saharan Africa. In addition, the vaccine used a different adjuvant, an ingredient designed to stir the immune response.
In fact, testing of the new vaccine showed many immune responses were better than in the Thai trial. Despite this increased immune response, the new vaccine was not effective.
One possibility being explored is that the newer vaccine simply could not counter the wide diversity of HIV strains in South Africa. The viruses circulating in Thailand show less variability and affect a smaller population. The challenge of prevention is simply greater in South Africa, where the infection rate among women is roughly 14 times higher than that women in Thailand.
“Frankly, at this moment, we don’t know the answer,” Corey said. “But we know we need to make a vaccine for those who need it most, and we know that is a very high bar.”
Participants at 14 sites in South Africa are being notified by text messages of the decision to halt the trial. Their health will continue to be monitored for a year. Those who tested positive during the trial were notified at the time of their tests and directed to local health care providers, but they were not informed until now whether they received the actual vaccine or a placebo.
Launched in 2016, the Uhambo study reached full enrollment last year with 5,407 HIV-negative men and women throughout South Africa. They were aged 18-35, a cohort at highest risk of infection. Half the group was assigned to take six shots of the vaccine over 18 months. The other half received six shots of a placebo. The interim analysis was timed to occur after at least 60% of those enrolled had been in the study for at least 18 months, time enough for the vaccine to produce immunity. It found that there were 129 new infections among those who received the real vaccine, and 123 infections among those given a placebo.
The slightly higher number of infections in the vaccinated group does not suggest it increased risk of infection. The differences were not statistically significant.
Meanwhile, work will continue for three other major trials coordinated by HVTN testing different prevention strategies. These include:
Dr. Thomas Lynch is holder of the Raisbeck Endowed Chair at Fred Hutch.
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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