PrEPVacc, the only current large HIV vaccine study, has been halted ahead of schedule because “there is little or no chance of the trial demonstrating vaccine efficacy in preventing HIV acquisition,” according to a December 6 announcement. Trial leaders shared the news at the International Conference on AIDS and STIs in Africa, underway this week in Zimbabwe.

“We have come so far in our HIV prevention journey, but we must look to a new generation of vaccine approaches and technology to take us forward again,” said PrEPVacc chief investigator Pontiano Kaleebu, MD, PhD, of the MRC/UVRI and LSHTM Uganda Research Unit.

The PrEPVacc trial, testing two vaccine regimens along with oral pre-exposure prophylaxis (PrEP), enrolled more than 1,500 men and women at risk for HIV in South Africa, Tanzania and Uganda. Participants will not receive any further vaccine doses, but they will be informed about the interim findings, followed for additional safety data collection and offered HIV testing and referral for ongoing care. The oral PrEP component of the trial will continue.

Only one large vaccine study—the RV144 trial in Thailand—has shown any effectiveness for HIV prevention. That trial tested a vaccine containing HIV’s gp120 envelope protein (AIDSVAX) plus a second vaccine that delivered DNA instructions for HIV proteins. In 2009, researchers reported that this prime-boost regimen reduced new infections by 31%.

PrEPVacc used a similar approach. Participants were randomly assigned to receive AIDSVAX plus a DNA vaccine; these two vaccines plus a third vaccine (CN54gp140) that uses a modified poxvirus vector (MVA) to deliver HIV DNA; or saline placebo injections.

In addition, the study compared two PrEP pills, Descovy (tenofovir alafenamide/emtricitabine) and Truvada (tenofovir disoproxil fumarate/emtricitabine). Truvada is approved as an HIV prevention option for all populations, but Descovy is not yet approved for cisgender women and others exposed to HIV via vaginal sex due to inadequate data. PrEPVacc, which enrolled nearly 90% women, aims to fill this research gap.

“It is important to remember that PrEPVacc is three studies in one, and the PrEP part is continuing,” said PrEPVacc project lead Sheena McCormack, MD, of University College London. “We hope that we will have valuable insights from the quantitative and qualitative findings to guide the use of oral PrEP beyond the trial.”

As of October, more than 1,000 participants had received the full vaccine regimen, and most of them also received one of the PrEP pills. Reviewing interim data in November, the study’s independent data monitoring committee found no safety concerns. However, based on the early findings, they determined that trial will likely be unable to show that the vaccine can prevent HIV. Full study results are expected in the second half of 2024.

Some experts and advocates think this is not surprising because PrEP pills alone are so effective for HIV prevention that it’s difficult to show that vaccines provide additional protection. Today, the widespread availability of oral PrEP makes large vaccine trials much more challenging, as ethics require study investigators to offer participants the best existing prevention tools—experimental vaccines can no longer be pitted against just a placebo.

But some researchers and advocates remain optimistic. One of PrEPVacc’s accomplishments was developing the capacity of local researchers to conduct clinical trials in Africa, which still bears the brunt of the HIV epidemic.

“The scientific hurdles are high, but I have equally high hopes that an HIV vaccine will be developed one day,” said PrEPVacc trial director Eugene Ruzagira, PhD, MPH, of the MRC/UVRI and LSHTM Uganda Research Unit. “Every day, all around the world, important research like PrEPVacc is moving us forward, and participants are willing to step forward with us and make a difference to the health of their communities.”

New Vaccine Approaches Needed
Today’s announcement adds to a long string of disappointments in HIV vaccine research.

The Uhambo trial tested a DNA vaccine plus another vaccine containing gp120 proteins from the HIV subtype most common in southern Africa. It was halted ahead of schedule in 2020 after early results showed that it did not prevent HIV acquisition.

Two large Phase III vaccine trials, Imbokodo and Mosaico, tested a vaccine (Ad26.Mos4.HIV) that uses an adenovirus vector to deliver antigens from multiple HIV strains plus different booster vaccines. Imbokodo was stopped early in August 2021 after the vaccine regimen failed to protect young women in Africa. Likewise, Mosaico was discontinued in January 2023 because it did not reduce the risk of HIV acquisition for gay and bisexual men and transgender women in North and South America and Europe.

PrEPVacc appears to be “the last roll of the dice” for traditional HIV vaccines, study coordinator Jonathan Weber, MD, of Imperial College London, told CNN earlier this year.

“We do clinical trials because we don’t know the answer to questions. It was important to find out whether the combination vaccine regimens in PrEPVacc, developed over 20 years, should be ruled out or further developed for preventing HIV,” Weber added in today’s announcement. “While we await the final results and analysis of individual products, I believe that our interim result puts this generation of putative HIV vaccines to bed.”

But that doesn’t mean HIV vaccine research has come to an end.

Some experts think a successful prevention vaccine will need to trigger the production of broadly neutralizing antibodies (bnAbs) that can recognize multiple strains of HIV. The germline targeting approach uses a series of vaccines in a stepwise manner to encourage the development of specialized B cells that can produce bnAbs. Researchers hope to speed up the process by employing the same messenger RNA (mRNA) technology used for COVID-19 vaccines. Taking a different approach, Vir Biotechnology is testing an experimental vaccine (VIR-1388) designed to help the immune system produce T cells that recognize HIV.

Early results from small studies of these and other strategies look promising, but much work remains to be done before they can be tested in large human trials.

While expressing disappointment about the PrEPVacc outcome, the International AIDS Society (IAS) urged stepping up HIV vaccine research and development.

“We cannot and will not lose hope that the world will have an effective HIV vaccine that is accessible by all who need it, anywhere,” said IAS executive director Birgit Poniatowski. “A vaccine remains one of our most powerful tools to reach and change the lives of vulnerable communities and key populations in the most affected parts of the world.” 

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