HIV Vaccine Trial Halted After No Efficacy Observed

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has announced that HVTN 702, an experimental HIV vaccine phase 2b/3 study clinical trial has been halted. During an interim review an independent data and safety monitoring board found that the vaccine regimen did not prevent HIV.

As a result, NIAID and partner organizations have discontinued vaccination in the South Africa based study, which was initiated in 2016. The monitoring board did not express concerns regarding participant safety.

The HVTN 702 clinical trial was testing an investigational prime-boost vaccine regimen which had previously shown potential in the RV144 clinical trial in Thailand. The regimen used in the RV144 trial was adapted for use in HVTN 702, for the HIV subtype clade C which is most common in southern Africa.

According to Carl W. Dieffenbach, PhD, Director of the Division of AIDS at NIAID, the variability of HIV may have been responsible for the difference in results.

“There’s something about Clade C HIV, there's a reason that strain is the predominant global strain,” Dieffenbach told Contagion®.

"In Thailand they have a mixed epidemic of clade B and clade AE. HIV is HIV but they're all significant variations on a theme."

The HVTN 702 vaccine regimen consisted of the canarypox vector-based vaccine ALVAC-HIV combined with a 2-component gp120 protein subunit vaccine with an adjuvant.

The study enrolled 5407 HIV-negative volunteers across 14 locations in South Africa. Sexually active men and women between 18 and 35 years of age were eligible for enrollment.

Volunteers were randomized to receive either a placebo or the investigational vaccine regimen. All study participants received 6 injections over a period of 18 months. Participants in both groups were offered HIV prevention standard of care such as oral pre-exposure prophylaxis.

In an interim analysis conducted in mid-January, the data and safety monitoring board reviewed data from 2694 volunteers who received the investigational vaccine and 2689 who had received the placebo. At least 60% of participants had been in the study for more than 18 months at the time of interim analysis.

The analysis found that 129 HIV infections occurred among the vaccine recipients, compared with 123 HIV infections which occurred among the placebo recipients.

The interim report pointed out that there was no significant increase or decrease in rates of infection with vaccination. On these grounds, the data and safety monitoring board concluded that the vaccine had not shown efficacy. It was then recommended that no further vaccinations be administered.

"The bottom line is this vaccine did not work. It had no biological activity that in any way, shape, or form that prevented HIV acquisition. Because it was placebo controlled, I can make that fairly bold statement," Dieffenbach said.

"It induced immune responses that we had specifically sought...we needed to test this in a clade C environment. Are we inducing the right antibodies that we think we need to induce? The answer was yes, and it had no effect."

NIAID agreed with the data and safety monitoring board’s recommendations and halted vaccination. Participants will continue to be monitored over time.

Dieffenbach did not think much of the vaccine design seen in HVTN 702 would be preserved in future efforts to vaccinate against HIV where clade C is circulating.

"For clade C, this vaccine will not carry almost anything forward. We're going to need different targets, the epitopes need to be different, the nature of the antibodies will need to be much better at neutralizing the viruses...But I think we'll continue down that path of being able to elicit broad neutralizing antibodies in people by vaccination, it's an active area of research and will only grow in importance," Dieffenbach explained.

Other ongoing efforts to develop an HIV vaccine include Mosaico and Imbokodo, both late-stage multinational vaccine trials testing a novel mosaic vaccine regimen. The trials are testing a different vaccine concept than the one investigated in HVTN 702. These designs focus on T cell epitopes.

Ultimately, the results are troubling, given the seemingly indelible quality of HIV in endemic areas. But those working to control the virus believe HIV need not be a natural fact of life in such regions.

"One critical point that this vaccine trial brought home is that we absolutely need high quality, durable protection strategies for HIV for these populations. The incidence seen at the trial was the same as there has been for a decade or more in South Africa, which is highly problematic," Dieffenbach said.

"PrEP [pre-exposure prophylaxis] is available, people have tried to roll it out. We need prevention strategies that young men and women are going to use to really help get this epidemic under control. And whether it's going to be injectable antibodies or antiretrovirals or topical agents, we just don't know. But it really calls into question: what is going to work and how soon can we get it through trials, licensed, and delivered to these tremendously at-risk populations?"