“The reason we do research is to get answers to questions. We got an answer, and it is definitive,” said Carl Dieffenbach, Ph.D., of the National Institutes of Health, about the early termination of the HVTN 702 HIV vaccine trial. The trial, also called Uhambo, began in 2016 and enrolled 5,407 HIV-negative participants at 14 sites in South Africa. During a January 2020 interim analysis, a data and safety monitoring board found that the rate of HIV acquisition did not differ substantially between the vaccine and placebo arms (129 versus 123 seroconversions) and recommended stopping the trial early. Participants will continue to be followed, and HIV-negative participants will be offered pre-exposure prophylaxis (PrEP) during the follow-up. No safety concerns about the vaccine itself were raised.
While the early termination of HVTN 702 is disappointing, there is hope for the future, said Mitchell Warren of AVAC: “The good news is the vaccine and broader prevention pipeline is diverse and promising, with a large number of different strategies being tested in efficacy trials and earlier stage research, including in three vaccine efficacy trials,” he said. In a press release, he called on trial data to be shared quickly so the lessons from this failure can be promptly fed back into the research pipeline.. “The HIV vaccine field is more coordinated than ever before, which means it can take the answers this trial has provided and move the research agenda forward in new directions.”
HVTN 702 was based on the prime-boost approach first tested on a large scale in Thailand in the RV144 trial. Some components of the vaccine used in Thailand were redesigned for the South African trial to adjust for a different clade of HIV common in South Africa and to improve the vaccine’s effectiveness and durability. Neither version of this vaccine achieved the desired 50% effectiveness threshold.
This probably means that using a canarypox vector and two proteins is not a useful approach, said Dieffenbach. However, “as a concept, prime-boost, I’m not ready to throw it out,” he added. We may just need to find a different combination of vector and active components. “The immune landscape that you can induce looks like the colors of the rainbow,” he elaborated. The current vaccine may have only covered a portion of the rainbow, the yellows and reds, for example. “We want to make sure the next vaccine induces all the colors of the spectrum.”
The two other HIV vaccine trials currently underway—Imbokodo, among women in southern Africa, and Mosaico, among men and transgender people who have sex with men in the U.S., Latin America, and Europe—try to cover all the colors of the rainbow. Different from HVTN 702 and RV144, they use a “mosaic” approach that is active against a variety of different HIV strains. Both trials are still in the early stages, with results expected in 2021 and 2023, respectively. Neither is affected by the early termination of HVTN 702.
Another vaccine efficacy trial, PrEPVac, is slated to start soon in Africa, Warren explained. It will test two vaccines and two PrEP options, and results are expected in 2023. Other studies are testing antibody infusions as a step toward developing a vaccine based on the results of these infusions. “Despite the setback of HVTN 702, these trials represent a necessary diversity in the pipeline,” Warren noted.
“There is a third approach, inducing broadly neutralizing antibodies, but it is not close to prime time to be ready for large-scale trials,” explained Dieffenbach. Other options include antiretrovirals or antibodies in the form of proteins that could be injected or implanted.
Further down the line could be a “Star Wars” option, gene therapy. “The idea that we use gene therapy on healthy people, so they don’t get a disease down the line, is futuristic,” said Dieffenbach. However, if successful, it could provide protection for life. While this may not become the next childhood vaccine due to safety concerns, the goal would be to inoculate young people before they start to have sex.
“Safety concerns” also drive some of the opposition to longstanding, highly effective vaccines, such as the one against measles. Would people be willing to try a new HIV vaccine that is 50% effective? “Each country and population is going to have to make that determination for themselves,” said Dieffenbach. “No prevention strategy may be 100%, like the measles vaccine. We may need combination strategies.”
However, voluntary male circumcision has been shown to be 65% effective in preventing HIV acquisition during heterosexual sex. To date, 20 million such procedures have been performed in Africa, even though circumcision is more invasive than vaccination, he explained. “There will be uptake at even 50%,” Dieffenbach predicted. Warren is similarly optimistic: “We’re confident that with the right planning, clear information sharing, and active, ongoing community engagement, a partially effective vaccine could be successfully rolled out where it is needed most.”
Before uptake becomes a relevant question, we will need an effective HIV vaccine. To that end, research continues. However, to continue this and other prevention research, funding for such work also must be continued, Warren noted.