By Carey Goldberg
WBUR

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.

“One of the great challenges for development of HIV vaccine is viral diversity,” said Daniel Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston.  Ian Cuming /Getty

By Julia Belluz
Vox.com July 24th, 2017

Developing a vaccine to stop HIV is thought to be among the most daunting challenges in medicine for one big reason: The virus is extraordinarily genetically diverse, even more so than the flu. So it’s difficult to think about how a single shot might work against all the different HIV subtypes circulating around the world.

But scientists may be inching toward a vaccine that could tackle HIV’s genetic diversity and prevent the virus from taking hold in people.

Researchers from the National Institutes of Health and Johnson & Johnson at the International AIDS Society conference in Paris Monday morning presented data on a clinical trial of what’s called the “Ad26-env mosaic vaccine.”

The mosaic vaccine was developed using a computer algorithm to analyze HIV data from around the world and select a range of HIV sequences to include in a shot. It’s called a “mosaic” because it involves taking pieces of different viruses and sticking them together to generate immune responses that can cover a broad range of HIV subtypes.

“One of the great challenges for development of HIV vaccine is viral diversity,” said Dan Barouch, a lead researcher on the vaccine and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. “The mosaic strategy is one way to attempt to deal with the global virus diversity.”

A word of caution, though: We’re only in the early phase of human testing, and the vaccine could ultimately fail to prevent the virus from spreading among people. But so far, the HIV community is carefully watching the Ad26 vaccine research because the approach seems quite promising.

The mosaic approach seems promising in very early clinical research

In the 35 years of the HIV epidemic, only four HIV vaccine concepts have been tested in humans. The mosaic strategy is the fifth concept, and one of only two HIV vaccines that’s currently part of clinical trials of efficacy in humans. (The other is the HVTN 702 HIV vaccine candidate, now underway in Thailand.)

In the study of the Ad26 mosaic vaccine, called the APPROACH trial, 393 volunteers in the United States, Rwanda, Uganda, South Africa, and Thailand were randomly assigned to receive one of seven experimental vaccines or a placebo. The mosaic vaccine was the best tolerated and also capable of generating anti-HIV immune responses in all the people who received the shots.

Before this, studies of the mosaic vaccine in rhesus monkeys showed a 66 percent efficacy rate, meaning 66 percent of monkeys that got the shot were protected from the virus. (With HIV, 50 to 60 percent is about the efficacy range researchers hope for.) Interestingly, in the early human study, the immune response was comparable to the rhesus monkey one, which gave the researchers hope that the vaccine might be similarly effective in people.

We need more human studies of this HIV vaccine

But we still don’t know if the vaccine will protect humans from the virus, since the studies so far have only looked at safety and immune responses, not efficacy. And many medicines that look promising in animals, and safe in humans, don’t pan out in clinical trials focused on efficacy.

“I wouldn’t use the word excited too much,” said Anthony Fauci, director of the NIH’s National Institute of Allergy and Infectious Diseases. “It’s a step forward toward getting another candidate into trial that could have some promise.” It’s too soon to say if and when the mosaic vaccine might work to prevent the virus from spreading in humans, he added.

As for next steps, if the researchers continue to see promising data on the mosaic vaccine from another ongoing study, a larger human efficacy trial will move forward toward the end of the year in southern Africa, involving some 2,600 healthy, HIV-negative women.

Deaths from AIDS have halved since 2005 — but there’s still a ton of work to be done

We’ve made remarkable progress against HIV around the world. In 1996, as HIV prevalencewas peaking around the world, the United Nations established UNAIDS, the first global health body focused on a single disease. In 2000, the UN Security Council convened an unprecedented meeting to address the out-of-control AIDS crisis. This led to a massive concentration of resources into HIV/AIDS research, and triggered global and coordinated efforts to stem the disease.

Researchers and doctors figured out how to get people tested and diagnosed quickly, and uncovered effective treatments that allowed those with HIV to live long, relatively healthy lives. Public health officials also waged awareness campaigns about prevention, reminding people to practice safe sex with condoms and get tested, and that early HIV treatment can save lives. Recently, researchers even discovered a pill to prevent HIV.

Deaths from AIDS have halved to 1 million since 2005, and UNAIDS estimates almost 20 million people now have access to treatment. (Some of that access is now in jeopardy, however, given that President Donald Trump has proposed cutting $800 million from a key US government AIDS program called PEPFAR in the 2018 budget.)

An HIV vaccine has long been elusive. The other HIV vaccine in human testing, the HVTN 702 candidate, is a newer version of the only other HIV vaccine to show any efficacy in humans, called RV144. In a trial on the RV144, 31 percent of people who got the vaccine did not develop HIV — too small a number to be useful. But with the new HVTN trial, researchers hope some tweaks to the vaccine might boost the efficacy rate.

“A safe and effective HIV vaccine would be a powerful tool to reduce new HIV infections worldwide and help bring about a durable end to the HIV/AIDS pandemic,” Fauci said in a statement. “By exploring multiple promising avenues of vaccine development research, we expand our opportunities to achieve these goals.”

Beth Israel Deaconess Medical Center Press Release

BOSTON – An investigational preventative HIV vaccine being developed by researchers at Beth Israel Deaconess Medical Center (BIDMC) in collaboration with Janssen Vaccines & Prevention B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, and others has cleared an important hurdle in human clinical trials. In a large Phase 1/2a clinical trial, the vaccine was both well-tolerated and triggered the desired antibody response in 100 percent of the healthy volunteers. The results were announced by Dan H. Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at BIDMC together with colleagues from Janssen at the 9th International AIDS Society Conference on HIV Science in Paris.

“The genetic diversity of HIV presents an unprecedented challenge for designing an effective vaccine,” said Barouch, who is also Professor of Medicine at Harvard Medical School. “A successful preventative vaccine for HIV will need to provide broad protection against a wide range of viral strains. The positive, early-stage results of our ‘mosaic-based’ vaccines suggest the potential to achieve this goal.”

The mosaic-based vaccine regimen contains a patchwork of genetic sequences found in several strains of HIV that are prevalent worldwide. These snippets of genetic information are delivered to the body embedded within a non-replicating human cold virus. Including sequences from various different strains of HIV is intended to provide broad protection from the many strains of the virus.

Representing an early stage of clinical development, the Phase 1/2a APPROACH study evaluated several mosaic-based vaccines for their safety, tolerability and the ability to elicit an immune response against strains of HIV-1 in uninfected adults. As part of the multi-site trial, researchers evaluated the experimental vaccines among 393 uninfected volunteers in the United States, Rwanda, Uganda, South Africa and Thailand. They also tested various vaccine regimens by giving them as a series of four shots at different dosages and/or at different intervals of time.

The double-blind, placebo-controlled randomized APPROACH study demonstrated that all vaccine regimens were well-tolerated, with local pain and headache being the most frequently reported adverse effects. Additionally, the APPROACH study showed that certain vaccine regimens stimulated stronger immune system responses than others. The most promising regimen triggered an antibody response in 100 percent of study participants.

With a death toll of more than one million people each year, HIV/AIDS remains among the deadliest of infectious diseases. While anti-retroviral therapies currently available offer people with HIV hope of a close-to-average life expectancy, the cost and complexity of the drug regime puts it out of reach for the majority of the 37 million people living with HIV worldwide. 

“Despite the benefits of lifesaving antiretroviral treatment, it is unlikely that drugs alone will end the HIV epidemic,” said Barouch. “History is on the side of vaccines.” 

The study is the result of a major collaboration by researchers at BIDMC, Harvard Medical School and the Ragon Institute of Massachusetts General Hospital, MIT and Harvard; the United States Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research (WRAIR), with the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF); the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health (NIH); the International AIDS Vaccine Initiative; the HIV Vaccine Trials Network (HVTN), and Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson. 

This work has been funded by grants from the Bill & Melinda Gates Foundation; the Ragon Institute of Massachusetts General Hospital, MIT and Harvard; the National Institutes of Health (NIH) Integrated Preclinical/Clinical AIDS Vaccine Development (IPCAVD) program grants AI066305, AI078526 and AI096040; NIH grants AI060354; AI078526; AI0080280; AI084794; AI095985; AI096040; AI102660; AI102691; OD011170; HHSN261200300001E.