‘Mosaic’ HIV Vaccine Looks Good In Early Trial, Boston Researcher Tells AIDS Conference

By Carey Goldberg

At a major international AIDS conference in Paris this week, researchers presented findings on a new HIV vaccine that look promising enough to launch a big clinical trial by the end of this year. That means it’s still several years before the vaccine could come into widespread use, and that’s in a best-case scenario. But still, in the monumentally frustrating world of HIV vaccines — or rather, the lack thereof — any good news is excellent news.

I spoke with Dr. Dan Barouch, professor of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, who is leading the research. Our conversation, edited:

How would you sum up what you’re presenting?

We are presenting the phase 1 and phase 2a clinical data on a new HIV vaccine concept. We’ve been working on this vaccine together with [the company] Janssen as well as multiple other partners, and our goal is to create a global HIV vaccine, using optimized, so-called ‘mosaic’ HIV sequences, delivered by a common cold virus, and then boosted by a purified protein to augment antibody titers.

In pre-clinical studies in rhesus monkeys, this vaccine provided 66 percent protection against a series of virus challenges. We’ve now advanced this vaccine into clinical trials, and in the phase 2a clinical study, called APPROACH, we enrolled 393 participants in the United States, East Africa, South Africa and Thailand. To date, the vaccine has been shown to be safe, and has induced robust immune responses in human volunteers, including 100 percent of vaccine recipients developing antibody responses.

Importantly, the responses induced in humans were essentially comparable with the responses that we believe were protective in animals. So these findings support the advancement of this vaccine candidate into a larger phase 2b efficacy trial, which we hope will begin before the end of 2017.

What is the difference between a phase 2a and 2b study?

A phase 2a study is a study typically in several hundred people, and the goal is to evaluate the safety of the vaccine as well as whether the vaccine induces immune responses that were intended. A phase 2b study is the first study to actually look at the efficacy of the vaccine: Does the vaccine actually prevent HIV infection in humans? That is a much larger study, typically several thousand people. It will probably take about three years.

What do you what do you mean by ‘mosaic’ and why does that seem to be the approach to take?

In a collaboration between our group and Los Alamos National Labs, we developed synthetic HIV sequences that are not the full sequences found in any virus in real life, but rather are computer-optimized sequences that encode the sequences that we believe will raise immune responses that are most relevant for globally circulating viruses.

HIV is a hugely diverse virus, and one of the big challenges in the development of an HIV vaccine is the diversity of the virus worldwide. We believe that these sequences will likely raise immune responses that are the best we can do now to cover this global diversity of the virus.

How effective would you expect this vaccine to be in humans?

That’s an incredibly important question. We don’t yet know whether this vaccine will be effective in humans, and if so, we don’t know the extent. That’s the goal of the next phase of testing. So it’s really not possible to predict at this time how effective it will be in humans. But I would say that the pre-clinical and early-phase clinical data to date are promising, and contribute, I think, to a new sense of optimism that the development of a safe and effective HIV vaccine might in fact be possible.

Is this a ‘first’ or a ‘most’?

There have only been four HIV vaccine concepts that have been tested for clinical efficacy in humans to date. There have been many other vaccines that have been tested in small studies or animal studies, but only four concepts have advanced to the point of testing for whether they actually prevent HIV infection in humans.

So assuming that further data generated this fall continues to look good, then we’ll be in a position to start the efficacy trial of this vaccine concept before the end of this calendar year. So it is a test of a new vaccine concept. And in animal models, the data looks promising. And in the early phase clinical trials, the data also looks promising.

Where will the efficacy trial be conducted?

The trial will be conducted in sub-Saharan Africa: in South Africa as well as a number of other countries in sub-Saharan Africa.

Why has developing an HIV vaccine been so very, very hard, and how might this be an answer that could address that difficulty?

The challenges in the development of an HIV vaccine are unprecedented in the history of vaccineology. Never before has a vaccine had to handle the challenges posed to it by HIV. I’ll just give you two examples. The first example is virus diversity. We need a new flu vaccine every year. The diversity for HIV is vastly more than influenza. So if you need a different flu vaccine every year, how are you going to make an HIV vaccine that covers the genetic diversity of the virus worldwide? So, an attempt to solve that problem is the generation of these synthetic, so-called mosaic sequences that aim to expand the breadth of immune responses that are induced by the vaccine.

A second major problem is that HIV integrates into host chromosomes very quickly and creates long-lived latent reservoirs; essentially, the viruses quickly go into some cells and go to sleep. Those are exceedingly difficult to eradicate. So for a vaccine to be successful, the virus has to be blocked before it can establish latency. So not only would a vaccine have to induce a broad variety of immune responses that can handle the genetic diversity of the virus, but those immune responses have to be potent and powerful enough to act very, very quickly upon exposure to the virus.

And could you explain a little more the joint effort to computer-generate the sequences that you that you needed?

In a collaboration with Bette Korber at Los Alamos National Labs, we looked at virus sequences from all over the world. And those were used to create synthetic antigens that are not found in nature but rather are computer-based approximation of the sequences that would give the optimal coverage of global viruses. And so these antigens — we showed first in monkeys as well as in humans now — can raise robust immune responses to HIV.

I should emphasize that we do not yet know whether this vaccine will protect humans but I think the data to date are encouraging enough to advance this vaccine candidate forward into larger scale testing.

If this pans out, will this be the first vaccine developed in that way?

Yes. This would be the first vaccine developed in that way that will have advanced into efficacy trials.

Are there other applications for this approach if it works?

There could be lessons for the generation of vaccines for other diverse pathogens as well.