The View from the Mothership

Global HIV Vaccine Enterprise Director William Snow reflects on the past and ponders the future course for the organization, and the field of HIV vaccine research overall.

By Mary Rushton

Fifteen years into the AIDS pandemic, the world got a triple-dose of good news. Highly active antiretroviral therapy (HAART)—the combination of drugs to treat HIV infection—was incredibly effective. It rescued millions of HIV-infected people from the brink of death. The success with HIV treatment continues today with newer classes of drugs and drug combinations that are highly effective and less burdensome than the earliest therapies.

The search for a safe and effective vaccine is not so easy. HIV is a complex virus that outruns and outmaneuvers the immune response and presents a great challenge to vaccine developers. Almost all of the vaccine candidates tested to date have failed. The only trial to show any protection against HIV was the RV144 trial in Thailand and the regimen tested in this trial was only modestly effective (31.2%).

No candidate thus far has been capable of inducing antibodies against most circulating HIV strains, the so-called broadly neutralizing antibodies (bNAbs) that most researchers think would be necessary for an ideal vaccine. But scientists have been making remarkable progress toward developing antibody-based vaccine candidates. Hundreds of bNAbs have been identified and this, along with the recent stabilization of the notoriously shape-shifting HIV Envelope protein, are fueling vaccine design and development efforts. Meanwhile, scientists are building on what they learned from the RV144 trial and are developing modified candidates to test in future efficacy trials.

Amidst all of this, the Global HIV Vaccine Enterprise, headquartered in New York City and led by long-time AIDS vaccine advocate William Snow, is trying to accelerate the pace of research, priBill-Snowmarily through increasing dialogue and facilitating collaborations among the major players in the field. The Enterprise doesn’t fund research, sponsor trials, or develop candidates, rather it troubleshoots issues and provides forums for the field to reach consensus on critical issues. The Enterprise’s Timely Topics in HIV Vaccine Research, launched in 2012, regularly convenes expert panels to analyze and respond to unresolved questions that encroach upon vaccine development. The series kicked off with a session on the ethics of pediatric clinical trials (Science 300, 2036, 2003). Another recent topic was therapeutic vaccines, which figure prominently in the emerging field of HIV cure research. Lately, innovation and product development issues are at the forefront. A boot camp held last year by the Enterprise for vaccine researchers and product development experts looked at different ways to incorporate a more industrial-like approach in the vaccine discovery process (see In BriefIAVI Report, Vol. 19, No. 4).

The Enterprise’s Secretariat also meets regularly with funders and industry leaders and organizes the bi-annual HIV Research for Prevention (HIVR4P) meeting, which replaced the annual AIDS Vaccine meeting that ended in 2013. HIVR4P is the only meeting focusing solely on HIV prevention—the next one will occur this October in Chicago.

Like HIV vaccine researchers themselves, the Enterprise has struggled over the years. Before Snow took the helm as director in 2012, there were questions about how the organization could stay focused and remain relevant (seeThe Enterprise Changes CourseIAVI Report, Sep.-Oct. 2011). The Enterprise was conceived in 2003 by an alliance of organizations that wanted to speed up the search for an HIV vaccine through mutual coordination, collaboration, and the sharing of knowledge (Science 530, 2036, 2003). This lofty premise gave way to six working groups that developed roadmaps and recommendations for the field and an interim Enterprise Secretariat, led by José Esparza, was established and housed at the Bill & Melinda Gates Foundation. Esparza at the time served as the Gates Foundation’s Senior Advisor on HIV Vaccines.

Some were critical then that the Enterprise was primarily led by the Gates Foundation. The Enterprise’s Board of Directors also had a hard time finding a permanent director to lead the Secretariat. There were doubts whether the Enterprise would be able to meet the challenge of its first Scientific Strategic Plan, published in 2005 (Nature Medicine 16, 981, 2010), that called for a doubling of research dollars and unprecedented coordination among independent researchers to allow intellectual property and data to flow freely. Then in 2007, Alan Bernstein, the founding president of the Canadian Institutes of Health Research, became the Enterprise’s first director. He led the organization from 2007-2011 and during this time many still questioned the role of the Enterprise.

In 2009, the New York City-based HIV prevention advocacy organization AVAC, which was co-founded by Snow, published a report that was critical of the Enterprise. In the report, Piecing Together the HIV Prevention Puzzle, the advocacy organization questioned whether the Enterprise still has the “influence to accelerate and activate conversations between funders and scientists that will lead to swift action in critical directions.” A year later, and just weeks shy of the publication of the Enterprise’s second Scientific Strategic Plan (Nature Medicine 16, 981, 2010), AVAC once again took a critical look at the Enterprise’s role. In AVAC’s 2010 Report, Turning the Page, the organization said it was the job of the Enterprise secretariat to hold donors, scientists, and organizations accountable for matching their work to the priorities outlined in the Enterprise’s Strategic Plan. “Whether this will happen is, to be frank, an open question,” the AVAC report noted.

Nelson Michael, director of the US Military HIV Research Program and a member of the Enterprise’s Board of Directors, said following Bernstein’s departure in 2011 there was a serious discussion about whether the Enterprise should even exist. “There was a very strong voice within this relatively small board that maybe we had done the experiment, that it had failed, and that it was time to move on,” Michael recalls. “The view was that the Enterprise, for better or for worse, had become expensive and was not particularly well connected with its primary mission.”

Enterprise logoBut the Enterprise found its footing with Snow, a self-proclaimed gadfly with enormous credibility in the field. Snow’s passion for ending the epidemic is matched only by his willingness to ask tough questions without apology. Though not a scientist, his roots in AIDS vaccine research run deeper than many. In what he calls a “personal journey,” Snow’s involvement in the famous activist group ACT-UP and with community advisory boards for clinical trials led him to co-found AVAC in 1995. He also sits on the AIDS Vaccine Research Subcommittee of the US National Institute of Allergy and Infectious Diseases (NIAID), and the US National Institutes of Health’s (NIH) Vaccine Research Center Scientific Advisory Working Group. Snow also served on the Enterprise’s original council and as treasurer of its board when it received its first round of funding.

Michael believes that were it not for Snow’s appointment as director of the Enterprise Secretariat in 2012, the Enterprise would have been disbanded. “He worked in partnership with the board and the funders to carve out why the Enterprise should exist,” says Michael. “And for a guy without formal scientific training, he really has an intuitive understanding of the disease and the epidemic, from scientific to psychosocial. At meetings we have attended he’d often say, ‘If we were to ask this question and get this answer, how would it really help us to move the ball forward to make a vaccine for HIV?’ He was masterful at that.”

But Esparza worries that the Enterprise and the field of AIDS vaccine research in general is still losing momentum. “The Enterprise is an example of the ‘big science’ approach that 10 years ago we thought would result in an HIV vaccine,” recalls Esparza, one of the early framers of the Enterprise and now the president of the Baltimore-based Global Virus Network, an international coalition comprised of virologists from more than 20 countries. “My major concern now is that the field of HIV vaccines does not seem to have the necessary sense of urgency. Basically, the HIV vaccine people are making themselves irrelevant for the current global HIV prevention effort. That is sad because we are convinced that without a vaccine the HIV epidemic will not be controlled, not even in the US.”

But there is no question that the pace of discovery has picked up in recent years. The world in which the Enterprise is operating is much different from when the concept was launched in 2003, and so is the organization itself. IAVI Report recently spoke with Snow about the early days of the Enterprise, where it is heading, and his views on the current HIV prevention landscape.

Why did you take on the responsibility of running the Enterprise?

I saw it as a golden opportunity to try to do some of the things that I always thought ought to be, and could be done. I had always played the role of the gadfly, so this was almost like it was meant to be. I think the partners knew they needed someone who knew the field, who got along well with people, had the history and the background, and who could promote the principles and ideals of the Enterprise. I had never run a non-profit organization before or been a senior manager of one, but I am proud to have been representing the Enterprise for this period of time. It really is a collaboration of organizations that don’t necessarily have to collaborate with each other and it is our job to facilitate that.

How did you first become involved with the Enterprise?

AVAC was one of the signatories of the original article proposing the creation of a Global HIV Vaccine Enterprise (Science 300, 2036, 2003). At the time, Chris Collins was the executive director of AVAC, and he was the person who signed on to the article and went to the original retreat. After that I was asked to join the board of the Enterprise as it was being formed.

Were you always a supporter of the Enterprise concept?

Yes. I thought that there was a need for more organization, high-level participation, and strategic thinking, so it sounded like an incredible opportunity from the beginning. And the individuals who signed on to that and stuck with it through the formation of the Enterprise were exactly the right people to lead that effort—top leaders in the field with the ability to influence change.

Weren’t there some who wanted the Enterprise modeled after the Human Genome Project?

Yes, there was a lot of talk about that when I was on the steering committee, but it turned out that that [Human Genome Project] was really more of an engineering, heavy lifting, big numbers kind of thing. I think of the Enterprise as more ambitious, really, and less certain.

Was there much disagreement at first on the role of the Enterprise?

The initial proposal [described in 2003] proposed creating centers of excellence. But, early on, people began to realize that was unrealistic. So the idea evolved to be a more virtual network. The ultimate intention was to create a Scientific Strategic Plan for the field. That was done before the Enterprise Board started looking for a director. The strategic plan really laid the foundation for the NIH to create CHAVI [The Center for HIV/AIDS Vaccine Immunology] and for the Gates Foundation to create the CAVD [Collaboration for AIDS Vaccine Discovery].

Who was involved in shaping the Enterprise in the early days?

Rick Klausner of the Gates Foundation and Larry Corey of the HIV Vaccine Trials Network were the lead authors of that first article in Science. They and a lot of other heavy hitters in the field got together for the meetings. The people who took this idea and really fleshed it out were at the Gates Foundation. Helene Gayle, who was running the Foundation’s HIV program, hired José Esparza from the Joint United Nations Programme on HIV/AIDS (UNAIDS.) The Enterprise was one of Jose’s major efforts when he first arrived and it remained dear to his heart throughout the whole process. He put his heart and soul and brain into forming it with a huge amount of support from Siobhan Malone.

What do you consider to be the Enterprise’s biggest accomplishment?

I think there is no question that its biggest accomplishment was getting people to work together. To this day its greatest impact has been just changing the way scientists and funders work among themselves. Basically, the funders got the idea early on to create mechanisms and make funds available for investigators and institutions to work together for the common good.

What were the biggest obstacles to all this change?

There was a fair amount of resistance to the notion of giving large amounts of money to big collaborations. That was a real change from the model where people were getting their own funding and working independently at their institution or with a few close collaborators. I think for people working in HIV vaccines, and also for the funders, it was really a new way of doing things. And it took a while for that concept to prove itself. Also, during this time, NIAID opened its Vaccine Research Center, so there were big tectonic shifts on how we were working. And like any shift, there was a lot of adjustment over what I would say was a period of six to seven years. Let me also say that there was the issue of shared samples, shared data, and confidentiality agreements. That added a whole lot of infrastructure to each consortia and required a lot of heavy lifting.

Did this slow down the pace of research?

No, it really spurred people on. Once these groups got together they were just all over it. All of a sudden there were people from different institutions talking to each other, there was data coming in from a variety of different directions, and scientists were meeting frequently. It was, I think, a very positive experience for them.

Were vaccine advocates pleased with the Enterprise’s work in the early days?

Every year AVAC was pushing the Enterprise to move faster and to do more. The Enterprise didn’t show much in the way of accomplishments after that first Scientific Strategic Plan. It took a lot of time to get the organization going and an equal amount of time to get the collaborations started. During that time, the project spun off from the Gates Foundation, a director was hired, and the Secretariat was moved to New York and staffed.

What are the biggest achievements of this greater collaboration?

Without a doubt the whole area of identifying a transmitted/founder virus [the virus that initially establishes an infection] was one of the first things that came out of this. It showed us that the notion of making a vaccine was going to require more understanding of infection and understanding of the immune system’s reaction to HIV rather than just using a vaccine platform that had worked for something else. Any vaccine should work against transmissible viruses. If only one or a few invaders infiltrate your system, they’re the ones to repel and destroy.

What impact did the RV144 results have on the Enterprise?

It was a major surprise for the Enterprise. They had just drafted a second Strategic Plan—the ink was drying and then RV144 happened, and the [vaccine] search turned on a dime to follow up on the results. The Enterprise’s board met to figure out how to make the Enterprise more flexible and contribute to this effort rather than focus on a strategic plan. The notion was that there were more discrete areas that you could work on in real time. I think that the effect on the Enterprise was very much reactive and prompted it to change direction.

 What’s come out of the Timely Topics events?

Certainly, the focus we have had on industry has been important and valuable. People are realizing more and more that there are good reasons why industry isn’t involved extensively in HIV vaccine research, and good reasons why some of the things they know and techniques that they use are important to the field, so the field is going to have to learn to access them another way. In the end, however, industry’s knowledge is still going to be essential to making a deployable vaccine. There is no easy away around this because the only organization, outside of product development companies, that ever developed its own vaccines used to be the Army.

What’s in store for the Enterprise going forward?

In the near future, we are looking at doing more work in Africa, where we’re trying to help set up a virtual network for African scientists. We’re focusing a bit more on the clinical side, and we’re also looking a little bit more at animal models. I believe we’ve proven our worth, but remember, the Enterprise is the collective of organizations and their achievements. Longer term, we want to stay current, which means anticipating the needs of the field. We can’t be US-centric. Our focus will always be strategic rather than strictly scientific, and the prospects for a rich product pipeline have never been better. Everything an Enterprise partner accomplishes is, to some degree, an achievement for the field at large and for the Enterprise ideal.

Where is the field of AIDS vaccines headed?

I think there is no question that we are on a path where we will get answers to certain questions in the foreseeable future that will be hugely important. That will help us to narrow down the directions we want to go in and help us to better understand what is going on with neutralizing antibodies and the RV144 model. Also, some new approaches and platforms may be transformative. The biggest handicap has always been how long it takes to do certain things—to get animal studies done, to get human endpoints and samples, etc. The field is really paying attention and trying to speed up the iterative process and I think that it is going to bear fruit.

Mary Rushton is a freelance writer based in Cambridge, Massachusetts.