An Enterprising Solution Takes One Step Forward

Global plan for HIV vaccines welcomed with endorsements and questions

By Philip Cohen, PhD

The grand idea of forging a global partnership to accelerate the development of an effective AIDS vaccine took a step closer to reality with the publication of a scientific strategic plan identifying scientific roadblocks currently impeding progress. The plan from the Global HIV/AIDS Vaccine Enterprise, described as “an alliance of independent entities,” calls for a near doubling of worldwide investment in vaccine research and the coordination of an unprecedented network of researchers and labs between which reagents, data and intellectual property will freely flow.

The plan was announced in January by the Enterprise in the Public Library of Science journal PLoS Medicine, after more than a year of work and input from more than 140 participants from 17 countries, including representatives from many of the key players in AIDS vaccine research and development: the Bill & Melinda Gates Foundation, the International AIDS Vaccine Initiative (IAVI), the National Agency for Research on AIDS (ANRS) of France, the US National Institutes of Health (NIH), the United Nations Joint Programme on HIV/AIDS (UNAIDS), the World Health Organization, and the Wellcome Trust.

The document was greeted with endorsements and tough questions over the many remaining details of the plan that have yet to be resolved. Whether the Enterprise reaches these aspirations, experts say, will depend on how the plan is implemented and whether Enterprise members, outside scientists, funders, and other stakeholders rise to the many challenges that lie ahead.

The Enterprise began as the brainchild of the Bill & Melinda Gates Foundation, which was looking for ways to further accelerate AIDS vaccine research and development. They solicited input from a broad range of vaccine experts, including members of the Foundation, the NIH and IAVI, resulting in a 2003 policy paper in the journalScience (300, 2036, 2003 [PubMed]). That paper argued that a more systematic and efficient way to feed more promising vaccine candidates into the development pipeline was to forge a global “enterprise” to attack the problem, defined as “a high-quality collaborative research system that goes well beyond the high-quality but separate research projects that we have today.”

While collaborative efforts between independent labs are already underway, the hope is that the Enterprise will be a galvanizing force to encourage new collaborations and strengthen existing ones. However, the Enterprise is not intended to encompass all AIDS vaccine research, act as a managing bureaucracy, nor serve as a funding agency. Instead, its coordinating committee will help to shape and evaluate goals—the first of which was to draft the strategic plan—and establish a secretariat to provide logistical support and facilitate collaborations.

In its global collaborative vision, the Enterprise is often compared to the Human Genome Project, a network of public labs that divided the task of sequencing the three billion or so DNA bases in our chromosomes. The important lesson, according to Jose Esparza, senior advisor, HIV/AIDS at the Gates Foundation is to think big. “People now realize that no individual institution can do this. Unless we think bigger and better we are not going to develop an effective vaccine in the near future.”

While the genome project provides a rough analogy, it is dwarfed by the ambitions of the Enterprise. For starters, even at current levels of funding AIDS vaccine research will spend in the next five years more than the US$3 billion price tag of the public genome sequencing. And while the elucidation of our genetic sequence was a technical tour de force, essentially no breakthroughs in scientific understanding were required and progress was easy to measure. The way forward for AIDS vaccine design is much less clear.

It’s not surprising then that while the strategic plan of the Enterprise acknowledges that many practical and organizational problems complicate AIDS vaccine development, they pinpoint the major barriers as scientific. So job number one the Enterprise set for itself was to prioritize the scientific issues to be tackled.

The PLoS Medicine paper provides this scientific strategic plan, identifying four major gaps in current knowledge that pose obstacles to vaccine development and would benefit from a comprehensive, coordinated research plan of attack.

The first area concerns questions about recently-transmitted viruses. A 2004 study (Science, 303, 2019, 2004 [PubMed]) has suggested, for instance, that sexually-transmitted viral strains are not typical, but may be unusually sensitive to antibody neutralization in vitro. The aim is to establish a panel of virus isolates that better represents these recently transmitted viruses, which are by definition the ones a preventive vaccine must fight, so learning more about this first line of viral invaders is crucial.

The next missing link identified by the plan are the elusive immune factors that account for protection in some animal models of the disease, particularly infection of rhesus macaque monkeys with simian immunodeficiency virus (SIV) or hybrid simian/human immunodeficiency viruses (SHIVs). When animals are vaccinated with live-attenuated viruses they attain a very impressive level of immune protection against later virus challenge. Safety concerns prohibit this type of approach to protection being attempted in humans but it will be very instructive for researchers to understand what constitutes an effective immunity against viruses closely related to HIV in a model system.

Of course knowing how macaques fight the virus will be of little use if vaccinologists can’t find a way to elicit an effective response in humans. This leads to the last two areas that the Enterprise highlights as in dire need of illumination: strategies to induce antibodies that will neutralize genetically-diverse strains of the virus, and identifying vaccine candidates that elicit robust cellular immunity. Both arms of immunity have been targeted by past or existing vaccine candidates but have so far yielded disappointing results in clinical trials.

The plan doesn’t include any novel insights to crack these barriers but argues that its vision for a new level of global collaboration and coordination should help answer the questions more rapidly. For example, studies of newly-transmitted viruses would benefit from rapid and frequent communication between epidemiologists and clinicians who identify recently-infected people and laboratory researchers probing viral genetics and immune responses. Similarly, solving the mystery of protection in animal models would be sped along by coupling facilities with the resources to study large numbers of animals to generate statistically significant data and laboratories specializing in sophisticated immunological analysis. The plan proposes that consortia be formed to focus on these issues that, in turn, would be supported by a new infrastructure of labs providing a common stock of reagents and standardized assays across all efforts.

Dennis Burton of the Scripps Institute says this synchronization would immensely benefit the entire field. “With a free-for-all, it’s difficult to compare results from different labs,” he says. “You have two researchers with different assays, different read-outs and they can’t tell whose experiment is working better.” In contrast, central labs could guarantee that all researchers have access to the same panels of virus isolates to characterize antibodies or provide validated assays to assess immune responses in clinical trials. As a result, all the research efforts become part of a larger, consistent data set, giving every experiment more bang for the buck.

Many of the plan’s key scientific issues echo what AIDS vaccine researchers have been advocating for years and calls for steps that have already been incorporated within some ongoing research efforts. So it represents the current consensus of the field. But the Enterprise also represents a new commitment by many of those groups to strive for a higher level of coordination. The hope is that protocols could be broadly standardized, allowing wasteful overlap between projects to be eliminated and pushing researchers to study important areas that have formerly been neglected because they were too difficult for individual groups to tackle on their own.

“More resources can make a huge difference,” says Gary Nabel, director of the Vaccine Research Center (VRC) at the NIH. “There are experiments that never get done and things that aren’t attempted when resources are limited.” As an example, he cites hunting through crystallization conditions for HIV proteins. “This is extremely dull work,” he says. “There’s a practical limit to how much of it anyone can do day after day.” That’s why the VRC and IAVI’s Neutralizing Antibody Consortium are among the groups that have invested in untiring—but expensive—robots that can analyze as many conditions in one day as labs were formerly able to test in months.

Further downstream from the research laboratory, the plan finds a need to enlarge the capacity to manufacture vaccines and increase the number of clinical professionals to test them in human populations, particularly in developing countries where the toll of the virus is the greatest but clinical expertise lags far behind.

The plan was endorsed immediately by US senator Richard Lugar, chairman of the US Senate Foreign Relations committee, in a Washington Post editorial he co-authored with Patty Stonesifer, president of the Bill & Melinda Gates Foundation. Bill Gates and Bono, U2 singer and co-founder of the advocacy group DATA (Debt, AIDS, Trade, Africa), used the opinion page of the UK newspaper The Daily Telegraph to express their hopes that leaders of developed nations would fund the activities of the Enterprise as part of a four-step plan to prioritize international development over the next year.

Figure 1. The scientific strategic plan of the Enterprise identifies six key challenges to the development of an effective AIDS vaccine, and proposes the formation of consortia or centers to further accelerate vaccine research. Adapted with permission from a figure created by the Bill & Melinda Gates Foundation..
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The Enterprise also seems to be part of a wider zeitgeist in which combating AIDS is on many politicians’ lips. The Group of Eight (G8) leading industrialized nations endorsed the goals of the Enterprise as far back as June 2004. In the United Kingdom, Prime Minister Tony Blair has vowed to use Britain’s presidency of both the G8 and the European Union this year to focus attention on African poverty and health issues, including HIV. British Chancellor of the Exchequer Gordon Brown has even gone as far as proposing a mechanism for raising $50 billion in development funding with an International Finance Facility that would sell bonds on the global capital market. And at the recent annual meeting of the World Economic Forum, French President Jacques Chirac proposed his own revenue mechanism: new taxes on international financial transactions, jet and shipping fuel, and air plane travel tickets to fund the fight against AIDS.

How much a financial infusion this will ultimately mean for the Enterprise or AIDS vaccine research in general isn’t clear. But the Enterprise strategic plan calls for boosting the yearly investment in vaccine research from the less than $700 million currently spent to $1.2 billion.

Most of that new money has yet to materialize. The NIH has announced it will fund a Center for HIV/AIDS Vaccine Immunology (CHAVI) with a first year grant of $14.4 million, growing to $49 million in subsequent years, to address some of the obstacles. The Gates Foundation has recently issued a Request For Proposals (RFPs) in which consortia or centers can apply for $360 million over the next five years to support vaccine research targeted at priorities laid out in the Enterprise scientific plan. “The proof is in what happens next,” says Anthony Fauci, head of the NIH’s National Institute of Allergy and Infectious Disease. “What new commitments people make, what new funders come in, will decide whether this is real or not.”

However, the budget of the NIH, which next year will include $607 million of the world’s AIDS vaccine research funds, is set to grow only 0.5% next year and less than 2% annually until at least 2009.

While funding is crucial, Esparza says it isn’t surprising that it lags behind at this early point in the Enterprise’s development. “We need to do our homework and provide potential donors with the detail they need to see,” he says. That homework includes a comprehensive business document that will outline exactly where that new money is needed and how each dollar could help build a lab, say, or support a clinic. It will also elaborate the costs of not developing a vaccine and the financial rewards of curbing the epidemic. The Gates Foundation and IAVI are now collaborating to produce a comprehensive report.

“People strongly support the conceptual framework of more resources, more priority for an AIDS vaccine,” says Seth Berkley, president and CEO of IAVI. “The critical thing is that this is implemented in the right way,” he says. “The epidemic is global and so should be the response. We need to bring in the best researchers and companies in the world to work on this problem.”

Indeed, with the plan now published, the discussion and debate seems to have shifted to the best way to implement the plan, motivate those scientists and avoid repeating the mistakes of the past. In an accompanying editorial in PLoS Medicine, for example, a trio of editors, Virginia Barbour, Barbara Cohen and Gavin Yamey, pointed out the current plan contained no timelines, which they argued make it unlikely to light a fire under the vaccine community. Without a set of defined milestones they say “it will be impossible to define success and failure, review progress, and assure internal and external accountability.”

However, even on this simple point of timelines a wide range of opinion can be found. Some vaccine experts think setting a clear list of objectives with timelines is critical for the Enterprise’s success, while others argue the devastation caused by the HIV pandemic is itself a sufficient motivator and that imposing a schedule on research progress is artificial.

This small disagreement demonstrates the greatest challenge the Enterprise faces—keeping far-flung and independently-minded scientists and clinicians working together smoothly and focused on the same goal. Talk to a few members of the Enterprise and the challenge inevitably emerges in a simple phrase: everyone likes the idea of coordination, nobody likes to be coordinated. That will be all the more challenging since the Enterprise aims to link together a massive scientific network without a controlling central authority.

But for now, this loose structure is ideal because there are so many possibilities to be explored, says Jerry Sadoff, president of the Aeras Global TB Vaccine Foundation and co-chair of the Enterprise’s vaccine manufacturing working group. “Early on you want a very egalitarian and open process. You don’t want to strangle anything that’s good,” he says. “But as the candidate number goes lower, the process needs to be more authoritarian, where you have to make tough decisions about what to bring forward and under these circumstances experience rules.” He doesn’t expect that process to break the Enterprise coalition, but he says it’s natural to expect some tensions to develop.

Another natural tension in the vaccine field is between academic and industrial partners. Nonetheless, Burton thinks the AIDS vaccine field could learn from industry’s focus on quickly identifying promising candidates and turning them into usable products. “Pure research projects are great ways to do science, but they are not enough for the HIV vaccine field,” he says. “You need a marriage between innovation and an industry-like vaccine effort to push things forward.” Klaus Cichutek at the Paul Ehrlich-Institut, the German Federal Agency for Sera and Vaccines, thinks another key area where the Enterprise could apply this corporate philosophy is in bridging the gap between basic researchers with promising preclinical vaccine candidates and clinical trials. Making the transition from bench to bedside requires candidates to jump a number of hurdles, including toxicological testing, regulatory review, and scaling up to clinical-grade production. Germany is now experimenting with agencies that provide these services to basic researchers for other vaccines. “It has started. It’s working but would need to be restructured and reorganized to focus on good HIV vaccine candidates,” he says.

Of course, the Enterprise is born partly from the fact that market forces don’t make vaccine development a priority for companies. One proposed solution is for the public sector to take on the unusual role of vaccine production. “In abstract that sounds like a good idea,” says Stanley Plotkin, consultant to Sanofi Pasteur. But he adds that, however difficult, it would be much more efficient and economical to bring industry along for the ride, a route he thinks hasn’t yet been sufficiently explored. “Industry needs to be put on the spot early to determine if they are going to meet these requirements and provide that manufacturing capacity,” he says. He also thinks the Enterprise has a great deal to offer industrial partners by serving as a selection process for the best vaccine candidates to be brought to market.

Including a number of Enterprise partners with obvious financial interests also raises the sticky question of intellectual property (IP) ownership. The strategic plan points out it will be crucial to create an “enabling environment” for IP and data to flow between groups. The benefits of such arrangements are obvious; if groups can readily exchange data and expertise a great deal of time and expense could be eliminated from vaccine discovery and production. Patent rights are often central in these IP discussions, but Lita Nelsen, director of the Technology Licensing Office at the Massachusetts Institute of Technology says there are potentially more troublesome issues when it comes to manufacturing vaccines.

She points out that patents are publicly disclosed, patent licenses frequently negotiated and infringement can be litigated. But other types of intellectual property are just as highly prized by companies: know-how and trade secrets. “For example, think about the unpatented recipe for Coca Cola,” she says. Asking companies to cooperate to make a vaccine may mean they need to share secrets that they traditionally protect only by keeping them in-house. “We’d be asking them to share their crown jewels with their historic competitors,” she says. These issues will need to be dealt with, says Nelsen. “But this isn’t a bogeyman that should drive anyone away from the Enterprise.”

However, some Enterprise members may find they can’t afford to stay. This is an issue for clinical staff in developing countries for whom the Enterprise envisions a considerable clinical training program. Similar programs in the past have often been plagued by brain drain as workers take advantage of their new skills and seek better paying jobs in other countries. This seems like a particular risk for existing and proposed AIDS vaccine trial sites which may not be put to use for some years.

But Pascoal Mocumbi of the European and Developing Countries Clinical Trials Partnership and former prime minister of Mozambique believes these poverty-stricken countries, with the right support, could use this new pool of labor as an opportunity. “If they take advantage of this new human capital it could be used as a launching point for studying broader health care issues in Africa,” he says. The Enterprise plan suggests such sites could be used to study other HIV interventions, such as the use of microbicides or even other diseases. IAVI has already partnered with clinical sites in Africa to study HIV incidence and prevalence, pre-existing immunity to potential vaccine vectors, and to gather baseline physiological measurements in the local population that will be extremely valuable in any future clinical research.

Even if the Enterprise achieves internal harmony, it will still face challenges, argues David Ho of the Aaron Diamond AIDS Research Center in New York City. He points out that the apparent strengths of the proposed Enterprise—its huge community of researchers and their coordination—could also be its Achilles heel if it encourages a type of “group think” that stifles creative approaches. “We are still at a point in AIDS vaccine research where what we don’t know is greater than what we do know,” he says. “Therefore the conventional wisdom may not be correct. You need to keep fresh ideas percolating.” For AIDS vaccine research to succeed, he argues, it will be important that researchers outside the Enterprise are listened to and, just as crucially, funded. The plan seems to acknowledge this danger. “‘Small science’ should not be replaced with ‘big science’. Both approaches must be taken,” it states.

Mitchell Warren from the AIDS Vaccine Advocacy Coalition believes that for the Enterprise to have global legitimacy, it will also need steady outside input from non-scientists such as experts in policy, public health and community leaders. “The challenge is that the Enterprise isn’t an elected body and you can’t give everyone with an interest a seat at the table,” he says. “But people will live with that if they can see who’s doing what, who’s funding it and how they ensure that the ball keeps moving forward.” The plan does propose annual stakeholders forums as one way to keep the Enterprise attuned to these outside voices.

As the Enterprise takes shape it is bound to face many challenges and questions. But Esparza says the greatest will always remain HIV itself. “We have been predicting a vaccine within ten years, for the last twenty years, because HIV has proven to be more complex than we ever thought,” he says. “The scientific community now realizes that working collaboratively is the only chance we have. This realization made the Enterprise possible.”