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Genius Delayed: HIV Vaccines Still in the Works

Genius Delayed: HIV Vaccines Still in the Works

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In February, mixed results were reported from a small trial with a candidate HIV vaccine, but researchers nevertheless said they were encouraged that they were on the right track. Click here to read MedPage Today’s report on that presentation. In this follow-up article, we examine what has happened since with the efforts to bring an HIV vaccine into clinical use.

In retrospect, you have to forgive Margaret Heckler’s optimism.

In 1984, Heckler — then secretary of Health And Human Services — told reporters that the cause of AIDS had been pinned down and that a blood test for the virus, then dubbed HTLV-III, had been developed.

A vaccine, she expected, would follow in the next couple of years. “Yet another terrible disease is about to yield to patience, persistence, and outright genius,” Heckler said.

What Heckler could not know, in those early years, is exactly how much patience, persistence, and genius would be needed. There is still no vaccine for HIV 33 years later and counting — but 2017 was a year of renewed optimism and clinical endeavor.

The search for a vaccine is now more nuanced. Two large randomized trials are investigating drugs that would bar the door to HIV infection in the first place — pretty much the layman’s understanding of what a vaccine does. Those trials are what HIV vaccine research has been about from the beginning — big studies with a potential for a big pay-off.

But other studies are looking at “therapeutic” vaccines, which would boost the immune systems of people already infected so they could control the virus without the need for daily antiviral medications.

On the latter front, there is now some optimism. In February, Beatriz Mothe, MD, PhD, of the Spanish AIS research institute IrsiCaixa in Barcelona, reported early details of a small study that gave, for the first time, a positive signal for a therapeutic vaccine strategy.

At the annual Conference on Retroviruses and Opportunistic Infections (CROI), Mothe reported that five people in a 15-patient trial had been able to keep the virus under control after stopping anti-HIV medications.

“They go up, they go down” but their HIV viral load remains relatively low, she told MedPage Today at the time. That’s a contrast to what usually happens when HIV patients stop taking their drugs — an almost immediate and precipitous increase in HIV.

The study has just finished, Mothe told MedPage Today recently, and the investigators are in the midst of finalizing and analyzing the data.

The viral control she reported at CROI was sustained in four patients throughout the 8-month trial and she and colleagues are now studying the virology and immunology of the participants to try to generate a hypothesis to explain the effect.

“As you can imagine, with such a small non-controlled trial, it is challenging to decipher the exact mechanisms that may explain the observed effect,” she said in an email. The researchers hope to publish their data in the next few months.

Outside experts said they were excited by the report, but cautioned it was early days. Mothe said she and colleagues are starting new trials with novel vaccine candidates that they hope will have even more of an effect.

As Mothe pointed out, the lack of a control group is a challenge for such studies. Exactly how much of a challenge was made clear later in the year.

In December, investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues reported the null outcome of a placebo-controlled trial of another therapeutic vaccine strategy.

Placebo-controlled trials have been rare on the therapeutic vaccine front, largely because — by definition — participants are already infected and there is a risk associated with stopping anti-HIV drugs.

But in the NIAID trial, the researchers found it was possible to use a placebo control group safely. And they re-learned the important lesson that a control group yields valuable information about efficacy.

Many participants treated with the vaccine candidate stopped their anti-HIV medicines and did quite well for some time but so did those given a placebo. Indeed, had the trial simply compared treated patients with historical controls, the researchers might have concluded — wrongly — that they had something that worked.

The investigators pointed out that the effect they saw was very similar to what Mothe and colleagues observed.

On the preventive front, of course, placebo control is the rule. But here again, it has been a challenge to demonstrate efficacy: Only one study has shown any benefit from a vaccine candidate.

In 2009, investigators showed that a vaccine strategy tested in Thailand yielded some protection against infection — an estimated 31%. But the estimate had a wide confidence interval, from 1.1% to 52.1%, and in any case it wasn’t a strong enough result to justify using the strategy clinically.

But the approach used in that trial, dubbed RV-144, is being tested again — after some tweaks. Researchers first pored over the RV-144 data looking for clues to even that small efficacy. Then, using those clues, they re-engineered the vaccines and re-designed the way they would be used.

Late last year, a new trial, dubbed HVTN 702, kicked off in South Africa, with the goal of enrolling 5,400 people and delivering at least 50% vaccine efficacy. A spokesperson for the trial said more than 2,200 participants have already enrolled.

One reason the new trial took a long time to get under way is that the vaccines — there are actually two substances, used in a prime-boost fashion — had to be modified so they were aimed at the HIV clade that circulates in South Africa.

If it proves to be effective when results are available in 2020, variants would be needed for each HIV clade around the world.

That’s why there is some excitement about the second trial now under way — the so-called Imbokodo trial, a phase IIb proof-of-concept study, has just started enrolling 2,600 HIV-negative women in sub-Saharan Africa. The study will look at safety and efficacy.

The vaccine candidate under study is based on what are called “mosaic” immunogens — vaccine components designed to induce immune responses against a wide variety of HIV clades. In other words, if it proves to work, there would be no need to tweak the vaccine for different regions.

Results from Imbokodo (also known as HPTN 705) should be available in about 4 years.


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