The Enterprise Changes Course

Eight years after researchers outlined their vision for an HIV vaccine enterprise, the organization is streamlining its focus

By Regina McEnery

About 10 years ago, a handful of leaders in the field of AIDS vaccine research began considering the idea of creating an organization that would bring greater coordination, collaboration, and transparency to the field. Developing a safe and effective AIDS vaccine had proven to be a hugely difficult task, and scientists were in agreement that research and development needed to be accelerated.

Out of this idea for an organization that could serve as a guiding force for the field came the Global HIV Vaccine Enterprise—a concept officially proposed in Science in 2003 by 24 players in AIDS vaccine research. The following year, six working groups were created to make recommendations on key areas highlighted in the Science article. This led to the establishment of an interim Enterprise Secretariat that was housed at the Bill & Melinda Gates Foundation, and the publication of a scientific strategic plan for the field the following year.

The Enterprise was a grand metaphor, invoking the image of a spaceship boldly steering the HIV vaccine field. But now, after both the organization and the field have undergone many changes, the future direction of the Enterprise has been reconsidered. A seven-person board of directors, after a concerted review, released a letter on October 26th describing a re-envisioned Enterprise that “will both complement the efforts of stakeholders and address the collective needs of the field.”

The Enterprise will now focus on three key priorities: coordination, collaboration, and resource optimization. The main activities of the Enterprise will now include organizing the annual AIDS Vaccine Conference, convening relevant parties on strategic issues, and organizing an annual funders’ forum to optimize current resources and mobilize new funding. A small Secretariat led by a to-be-named director will oversee implementation of these activities. “The board is working very hard to rejuvenate the Enterprise with a model that is more agile, focused, streamlined, and relevant to the field,” says Jose Esparza, senior advisor on vaccines for the Bill & Melinda Gates Foundation, who has served as interim president of the Enterprise board since late 2010 when Peter Piot, director of the London School of Hygiene & Tropical Medicine, resigned the post.

While scientists and advocates support greater collaboration and coordination within the field, there has always been a lack of consensus on how the Enterprise should be structured, what its role should be, and what kind of leader would best suit the organization’s needs, as well as those of the field. These questions have intensified since the departure of its first executive director, Alan Bernstein, in June.

Indeed, interviews with 15 researchers, advocates, and policy makers in the field illustrate how difficult it has been to reach consensus on these questions. Esparza acknowledges that there is no shortage of opinions about what the Enterprise should or should not be, and he believes that this collision of ideas has created confusion among people in the field. Still, he says, the dialogue is fruitful and necessary, particularly at a time when research dollars are in short supply and every dollar should be used with maximum efficiency.

The Enterprise is being modified at a time when funding for AIDS vaccine research is on the decline, dropping by 11% since 2007, when it reached a high of US$960 million. By contrast, it is a particularly fruitful time for AIDS vaccine research, fueled by the unexpectedly promising findings from the RV144 trial, the first trial to show any vaccine-induced protection against HIV, and the recent discovery of broadly neutralizing antibodies and the structural elucidation of their targets on the virus.

The genesis of the Enterprise

The Global HIV Vaccine Enterprise was the brainchild of Richard Klausner, who headed the US National Cancer Institute for six years before joining the Gates Foundation as its executive director for global health in 2002. The foundation had recently made a substantial contribution to AIDS vaccine development in January 2001 with a $100 million, five-year challenge grant to IAVI that was announced at the World Economic Forum in Davos, Switzerland, to correct what Bill Gates considered an “unbelievable market failure” in developing an AIDS vaccine (seeGates Foundation Pledges “Challenge Grant” to IAVI, IAVI Report, Dec. 2000-Jan. 2001). The grant—significantly higher than the $25 million grant the foundation had awarded to IAVI in 1999—put IAVI on track to launch clinical trials of three of its most promising vaccines (see Gates Takes On AIDS, Science, Jan. 29, 2001). Klausner joined the foundation 16 months later and felt there was a need for an organization that could provide a more systematic way of developing and evaluating AIDS vaccine candidates.

Those interviewed for this article who were part of the earliest discussions about the Enterprise model say it was Klausner who coined the term “Enterprise” and who suggested that it be modeled after the $3 billion Human Genome Project, a collaboration of more than 2,000 scientists from academia, industry, and government sectors begun in 1990 by the US National Institutes of Health and the US Department of Energy. A hallmark of the government-led Human Genome Project and its network of collaborators, which included the Broad Institute in Cambridge and the Sanger Centre at Washington University in St. Louis, was a call to share data openly.

Deciphering the human genome, however, was essentially an engineering problem, while the development of a successful AIDS vaccine candidate was, and remains, a more basic science challenge. Researchers still lacked understanding about which immunological mechanisms correlated with protection and how to induce these HIV-specific immune responses with a vaccine. “We’re basically talking about defining the black box of the human immune system and a virus that has defeated it 59 million times or more,” says Carl Dieffenbach, director of the Division of AIDS (DAIDS) at the US National Institute of Allergy and Infectious Diseases (NIAID) and an honorary board member of the Enterprise.

IAVI’s founder and former chief executive officer Seth Berkley, who was involved in some of the earliest discussions about the Enterprise, felt a better model might have been the Atlanta-based Task Force for Child Survival and Development, which was formed in 1984 as a collaboration between the World Health Organization (WHO), the United Nations Children’s Fund, the United Nations Development Program, the World Bank, and the Rockefeller Foundation, to achieve universal child immunizations by 1990.

“These groups met quarterly to talk about how they were going to improve immunizations in the world,” says Berkley, who left IAVI in June to head up the GAVI Alliance, a Geneva-based global partnership launched in 2000 to increase access to immunizations that evolved from the Task Force. “They coordinated rather than competed, they worked together,” says Berkley, who recalls pushing for the task-force model. But the idea never gained traction among those involved in creating the Enterprise.

Lawrence Corey, who was principle investigator of the Seattle-based HIV Vaccine Trials Network (HVTN) when Klausner first approached him about the concept of the Enterprise, thinks the analogy to the Human Genome Project may have been a “bit overblown.” But, he says, scientists involved in the creation of the Enterprise were largely in agreement that the field needed to change in some ways.

“There was recognition that the pipeline was not very robust,” says Corey, who is now president and director of the Fred Hutchinson Cancer Research Center in Seattle. “The people we had worked in traditional ways, in individual groups, trying to do it all. There was an egocentric aspect to the programs, such that ‘I would invent an HIV vaccine.’ There was no sense of sharing of data and no sense of saying I tried that, don’t walk down that path,” Corey says.

Some of this sentiment arose in 2003 after VaxGen’s vaccine candidate AIDSVAX proved to be ineffective in men who have sex with men, injection drug users, and women in two large Phase III efficacy trials, VAX003 and VAX004, enrolling nearly 8,000 volunteers total. It was with these results still fresh that scientists published the article in June 2003 laying out the need for a Global HIV Vaccine Enterprise (1). The concept of the Enterprise outlined in Science was an amalgamation of suggestions from various players who had signed on to the article. The article described the need for creative, new public and public-private partnerships to drive the vaccine discovery effort, the creation of HIV vaccine development centers to increase the diversity of approaches and types of vaccines entering clinical trials, HIV vaccine consortia to address some of the basic immunological questions impeding the development of a vaccine, and more standardized approaches to pre-clinical and clinical laboratory assessment.

The publication in Science was followed by a meeting in August 2003 at the Airlie House in Virginia, where about 60 AIDS vaccine scientists, funders, advocates, and policy makers laid out a vision for an alliance of independent agencies and research groups that would participate in the implementation of a shared strategic plan. This alliance was to consist of representatives from government research agencies like the US National Institutes of Health, HIV vaccine research groups like IAVI, the pharmaceutical and biotech industries, developing countries, and international organizations such as the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS). A year later, six working groups were formed to evaluate and make recommendations for the field. That same year, the Group of Eight (G8) countries endorsed the idea of the Enterprise at their annual summit.

“I think there was a sense there wasn’t a place for the basic research entities to come together,” says Chris Collins, who as AVAC’s executive director in 2003 co-authored the Science paper. “They wanted to try to find ways to have discussion about standardized measures and a forum to share information, to have a place to have a discussion about rational research. It wasn’t clear how that would happen without creating a new entity,” he adds.

From the start, the Gates Foundation was the biggest benefactor of the Enterprise. Prior to 2007, the Foundation provided in-kind support for the small administrative management needs of the Enterprise Secretariat and funding for the meetings of the working groups. Since 2007, when Bernstein took up the reins at the Enterprise, the Gates Foundation contributed approximately $20 million. DAIDS, the Enterprise’s second-largest funder, has given almost a million dollars per year to the Enterprise since 2007. The Canadian government has also contributed some funding.

“In truth, I think the Gates Foundation was clearly interested in this area and this was one way to help channel their potential involvement in addition to what they were already doing, which was primarily funding IAVI,” added Collins, who is now vice president and director of public policy at amFAR, the Foundation for AIDS Research, in Washington, D.C.

Global HIV Vaccine Enterprise Timeline   


Article in Science calling for greater collaboration in HIV vaccine research

Meeting held to develop vision for the Global HIV Vaccine Enterprise


Six working groups (140 participants from 17 countries) develop roadmaps and recommendations for the field

Interim Enterprise Secretariat established and housed at the Bill & Melinda Gates Foundation


First scientific strategic plan published calling for a near doubling of worldwide investment in vaccine research and coordination among researchers

NIAID awards seven-year, US$300 million grant establishing CHAVI


Adel Mahmoud selected to head Enterprise but withdraws before assuming post

Gates Foundation awards $287 million to the CAVD 


The Enterprise takes on organizing annual AIDS Vaccine Conference

Alan Bernstein becomes first director of the Enterprise and establishes Secretariat in New York City

Enterprise establishes Young and Early-Career Investigators Committee


Enterprise releases 2010 Scientific Strategic Plan


Bernstein steps down as director of the Enterprise; new vision for Enterprise released

NIAID: National Institute of Allergy and Infectious Diseases; CHAVI: Center for HIV/AIDS Vaccine Immunology; CAVD: The Collaboration for AIDS Vaccine Discovery

The Enterprise takes root

The initial planning for the Global HIV Vaccine Enterprise was swiftly followed by release of its inaugural Scientific Strategic Plan (see An Enterprising Solution Takes One Step Forward, IAVI Report, Dec. 2004-March 2005; 2). The plan called for a near doubling of the annual investment in vaccine research. The strategic plan also called for the standardization of assays, including greater access to clinical trial specimens for immunological analysis, common reagents, and for assays to be validated for studying vaccine technologies. It highlighted the need for new tools to detect rare, broadly neutralizing antibodies through the large-scale screening of human blood and the pursuit of novel T-cell inducing candidate vaccines. The plan also emphasized the need to attract new talent to the field by creating new funding opportunities, and to bring new funders on board whose missions and plans were aligned with those of the Enterprise.

“The Enterprise was never going to have grant-making or research decision-making authority,” recalls longtime AIDS vaccine activist Bill Snow, a founding member of AVAC who was not involved with the writing of the plan but later served on the Global HIV Vaccine Enterprise Coordinating Committee. “Its main goal was to create this shared plan that people could work off of and identify areas that weren’t getting enough attention.”

But Giuseppe Pantaleo, executive director of the Swiss Vaccine Research Institute, believes the decision to not give the Enterprise the authority to award grants and fund research limited its influence. “Since the Global HIV Vaccine Enterprise was not intended to be a funding agency, a lot of people at the beginning had limited interest,” says Pantaleo. “You attract a lot of attention if you have a lot of funding.”

Pantaleo says the Enterprise, as it was structured, was also potentially interfering with the established role and leadership of other governmental and non-governmental institutions and organizations that made their own decisions on funding allocations and research priorities.

Still, many researchers credit the Enterprise discussions and strategic plan with spurring a groundswell of financial support for AIDS vaccine R&D. The same year the Enterprise released its strategic plan, NIAID announced it would provide $300 million over seven years to fund the Center for HIV/AIDS Vaccine Immunology (CHAVI). A year later, the Gates Foundation awarded the initial round of grants totaling $287 million through its newly created Collaboration for AIDS Vaccine Discovery (CAVD).

Opinions are mixed on how much CHAVI or the CAVD owe their existence to the early work of the Enterprise. Corey believes the Enterprise did give rise to CHAVI and CAVD and says “anyone who thinks otherwise is not part of the history.” Snow agrees. “There is no question in my mind that neither CHAVI nor the CAVD would have happened in quite that way without this sense of agreement that individual grants were not big enough to solve some of these complex problems.” Others believe the field was already moving in a more collaborative direction by the time the Enterprise was taking root.

Even so, the push for greater coordination and communication among scientists, while widely viewed as important, wasn’t always easy or welcome. “Everyone wants coordination and no one wants to be coordinated, at times not even Larry,” says Corey.

Berkley feels too much coordination in the field could have sidelined good projects that at the time seem like outliers but later on prove to be game-changers, such as RV144 trial. “Different approaches and different ideas are needed,” he says. Dieffenbach agrees. He wonders where the field would be had scientists not pushed forward with RV144. “History has proven them correct but at the time there was this feeling that the only thing we have in the field is this pox-protein component that doesn’t induce immunity in people,” says Dieffenbach. “The field needs to continue to accept scientific risk and pursue the full range of HIV vaccine concepts, including broadly neutralizing antibodies and novel immunogens that may elicit their production, as well as follow-up on RV144.”

Trying to find its niche

Though the field was attracting new funding and working more collaboratively, the Global HIV Vaccine Enterprise had difficulty finding its feet. People familiar with its history say the Enterprise’s mission was hampered by a lack of leadership, a growing lack of respect among some scientists and advocates, and ongoing struggles to identify niches that other stakeholders hadn’t filled but were nonetheless important to the field. Some people had difficulty distinguishing the difference between the Enterprise concept that 15 organizations had signed on to in 2003 and the Enterprise Secretariat.

The organizational structure of the Enterprise was also criticized by participants as being overly bureaucratic. The Secretariat—which consisted of the executive director and a small staff that at its peak reached 10 people—initially reported to a small three-person board of directors. There was also a larger Enterprise Council, containing nearly two dozen members from the alliance of organizations that made up the Enterprise, which served as a venue for information exchange and coordination among the key parties, according to Esparza.

Richard Jefferys, basic science, vaccines and prevention project coordinator for the Treatment Action Group in New York City likened the Enterprise’s role to that of “herding cats,” and says the Enterprise’s attempts at getting laboratories to adopt standardized assays, while welcome, nonetheless duplicated efforts already taken up by the DAIDS-sponsored Partnership for AIDS Vaccine Evaluation (PAVE).

There was also confusion over the ideal qualifications for the leader of the Enterprise. Adel Mahmoud, former head of Merck’s vaccine program, had accepted the executive directorship of the Enterprise in 2006, but several months later, before assuming his new role, changed his mind amid confusion among the Enterprise’s Steering Committee over whether the organization needed a scientific leader, a scientific administrator, or an ambassador (3).

A year later, Bernstein, the founding president of the Canadian Institutes of Health Research, became the first executive director of the Enterprise, and under his direction the Enterprise established its Secretariat in New York City (see Vaccine Briefs, IAVI Report, Sep.-Dec. 2007).

Pantaleo thought Bernstein’s scientific background in oncology, as opposed to immunology, presented challenges for the Enterprise when it came time to write and launch its updated 2010 Scientific Strategic Plan. “He was a great scientist in the cancer field but he was not an immunologist,” said Pantaleo. “That to me created a little bit of difficulty.”

But Bernstein believes the Enterprise was wise to consider recruiting someone outside the HIV vaccine field. “Fresh perspectives, new ideas and opportunities, and new ways of looking at an old problem are always good in science,” he says. And the Enterprise under Bernstein made important inroads in a number of key areas. For instance, the Enterprise made the concerns of young and early career investigators (YECI) a primary area of focus, creating the YECI committee in 2008 and launching the electronic clearinghouse of AIDS vaccine information HIVe that is primarily for young investigators.

Jacques Fellay, a YECI co-chair, says other groups like CHAVI and CAVD have now started to more actively promote junior scientists. “Young investigators need more visibility and exposure and the Enterprise, I think, made it fashionable to do this,” says Fellay, adding that he believes the work of YECI through the Enterprise should go forward. “No one is doing it in such a structured and vocal way.”

Under Bernstein, the Enterprise also assumed a greater role in the direction of the annual AIDS Vaccine Conference, which will be held next year in Boston and co-chaired by the YECI’s former co-chair Dan Barouch, chief of the Division of Vaccine Research at Beth Israel Deaconess Medical Center.

Bernstein also says that during his reign the Enterprise and its Secretariat played a “catalytic role” in the development of regional HIV vaccine research initiatives in Africa—the African AIDS Vaccine Programme, now based in Uganda, and the AIDS Vaccine for Asia Network that was formed shortly after the RV144 results were released.

The Enterprise also brought the topic of systems biology center stage, which some scientists hoped would become one of the organization’s signature issues. Under Bernstein’s tutelage, the Enterprise tried to encourage the HIV vaccine field to take a more integrative approach to systems biology and its intersection with HIV vaccine research. In 2008, the Enterprise held one of the first meetings to bring together systems biologists and HIV vaccine researchers (see A Systems Approach to Understanding Vaccines, IAVI Report, July-Aug. 2010).

But the Enterprise’s foray into systems biology also seemed to be short-lived, disappointing some scientists. Rafick Sekaly, the scientific director of the Vaccine & Gene Therapy Institute in Florida, attended that meeting and he and others hoped that the Enterprise would push for funding for a globally accessible database where systems biologists could report and share their findings. However, the effort was stalled by delays in the release of the Enterprise’s 2010 Scientific Strategic Plan, which highlighted the importance of systems biology, and then shelved completely following Bernstein’s departure in June. “There was a huge vacuum after Alan left,” said Sekaly.

Bernstein, however, feels the impact of the Enterprise’s initiative to highlight the importance of systems biology will become evident. “I believe we have planted a seed that will increasingly bear fruit in the coming years,” he says.

Esparza thinks the organization could have facilitated other recent initiatives like the Pox-Protein Public Private Partnership (P5), which was formed recently to follow up on the RV144 results and joins NIAID, the Gates Foundation, the HVTN, the US Military HIV Research Program (MHRP), Novartis, and Sanofi Pasteur. “I think the Enterprise could have facilitated more if we had been prepared organizationally to do it,” says Esparza. “To some extent, the tension was between the Secretariat remaining distant and neutral or fully involved supporting the work of the Enterprise partners. I believe that the latter is true, provided that it adds real value to their efforts.”

Looking forward

The Enterprise’s Board of Directors will release a more detailed framework for the organization by the end of this year. But just as there are many opinions about the accomplishments and shortcomings of the Enterprise, there are also many ideas about what it should be. While some of the ideas about the role of the Enterprise align with its updated vision, others are not included in the current list of key activities. Some within the field think the Enterprise Secretariat should be focused on engaging pharmaceutical companies in HIV vaccine research, which with a few exceptions has not invested heavily so far. Others believe the Enterprise should be a kind of scientific conscience for the field, helping it prioritize its goals and objectives and determine how best to utilize resources in a financially constrained environment. Others suggest it should continue to focus on recruiting new, young investigators to the field through its YECI committee. Some even believe that the Enterprise has outlived its usefulness and should be disbanded.

Pantaleo, who is not on the board, hopes the Enterprise will move forward as a less US-centric organization, which he believes would help boost funding for AIDS vaccine research among European donors. “I have been making this point forever. The problem is that with the exception of the UK, I don’t think most of the other European countries or politicians have a really clear impression of what the objectives of the Global HIV Vaccine Enterprise are. They have no clue what it is.”

Meanwhile, Nelson Michael, who directs the MHRP and is a member of the Enterprise’s board, believes the Enterprise will be reborn as a much more efficient organization. “Now this is just Nelson Michael talking, but running an annual vaccine meeting is obviously a core function. Funding in the field is far more uncertain for all of us, so having a sounding board or forum for funders could be a useful function for the Enterprise.” Michael thinks this revamped Enterprise model should be tested. “Let’s test drive it and then make a decision downstream,” he says.

1. Science 300, 2036, 2003
2. PLoS Med. 2, e25, 2005
3. HIV Vaccine Effort Loses Leader, Science, Aug. 15, 2006