Industrial Strength Research
Collaborative efforts in AIDS vaccine research are adopting some characteristics common in the biopharmaceutical industry
By Catherine Zandonella, MPH*
When President John F. Kennedy vowed to put a man on the moon by the end of the 1960s, he mobilized the nation's top scientists and engineers to the task. The Manhattan Project in the 1940s and the Human Genome Project in the 1990s—each of these projects succeeded on the back of huge sums of money, the best scientific expertise, and an unprecedented level of collaboration among scientists.
Despite significant gains in basic knowledge, twenty years of research have yet to yield an effective preventive vaccine against HIV. Like landing a man on the moon, the search for an AIDS vaccine requires money, minds, and collaboration. The field is moving towards a broad consensus as to what are currently the most important scientific questions. And with funding now becoming more available and more interest concentrated on the task, global health leaders are focusing on the need for cooperation and collaboration among research groups to work more effectively. The new collaborative efforts come in the shape of consortia or virtual institutes: they aren't bricks and mortar establishments but rather collectives of independent research groups keen to share ideas and resources.
So a new research model is emerging, one which emphasizes coordination of efforts, rapid sharing of positive and negative results, structured decision making, accountability, and consideration of long-term goals. If this model sounds familiar, it is because it has much in common with the industrial model of research used by biopharmaceutical companies. But precisely what constitutes this industrial template of research, and which particular characteristics should be adopted, is currently a subject of discussion.
Curiosity-driven v. goal-oriented
Generally speaking, industry is very protective of its research and closely guards its intellectual property and expertise. But within a given corporation research has long followed this collaborative model with a single product-oriented goal in mind, where a project is driven through teams with different expertise until completion.
Conversely, academic scientific research has traditionally been a pretty solitary endeavor, heavily reliant on the principal investigator's specific expertise and interests. Researchers at universities and institutes tend to work in small groups, sharing their results at conferences and through publication in scientific journals. This academic model meant that a research group would work on a specific aspect of a scientific endeavor, publish their results, and then another group would take on a related question, adding incrementally to the pool of accumulated knowledge.
While the investigator-initiated, curiosity-driven model has thrown up serendipitous findings in just about every scientific discipline, a mission as vast as developing an AIDS vaccine requires coordination on the level of the great scientific endeavors of the past. "Focused development programs similar to those within industry are needed so that people can make informed decisions about what is working and what is not," says John Shiver of Merck.
Over the last few years, support for an industry-like research environment for AIDS vaccines has gained momentum. In 2002 IAVI teamed with a number of academic and government research groups to establish one of the first such research programs, the Neutralizing Antibody Consortium. A collaborative effort involving investigators from across the US, the consortium members share standardized methods and common reagents. Even more importantly, they share their ideas and discoveries freely and plan some of their experiments collaboratively.
In June 2003 a group of twenty-four scientists, including Nobel laureates Harold Varmus and David Baltimore, proposed the creation of a Global HIV Vaccine Enterprise, an "alliance of independent entities" that brings together many of the key players in AIDS vaccine research and calls for the coordination of efforts to improve vaccine discovery. The Enterprise has consulted widely and published early last year its scientific strategic plan that outlines the key unanswered questions in AIDS vaccine research and has helped build consensus across the whole field.
Last year the US National Institutes of Health (NIH) awarded funds to start the Center for HIV/AIDS Vaccine Immunology (CHAVI), a consortium of largely academic research groups with leadership at Duke University, North Carolina (see A new virtual Center, IAVI Report 9, 4, 2005). Additionally, the Bill & Melinda Gates Foundation will grant up to $360 million over the next five years for the creation of research centers that function as a network of collaborating institutions. Part of the goal is to get people working across disciplines, says José Esparza, who is coordinating the effort. "We would like to bring together complementary expertise that otherwise would not be available."
Taking stock of industry
The ability to bring together that expertise is just one of the strengths of the industrial approach. Perhaps the most important aspect of an industry approach, and where it differs most from the investigator-led academic model, is in the decision-making process, management, and oversight of a project. Instead of relying on the typically academic decision-making by consensus and committee, industry cultivates accountability by adopting an organizational structure that gives authority to individuals. As the late, eminent vaccinologist Maurice Hilleman put it, "there must be a point where authority prevails and the buck stops."
Vaccine candidates are stewarded from research to development by an experienced project manager or team. This management structure ensures that researchers are communicating and milestones are being met, which are important throughout the project. "The project manager provides the discipline to march the product through all the phases of its development," says Gary Nabel, director of the Vaccine Research Center (VRC) at the NIH.
For early stage research the project manager can help the investigator understand factors outside the researcher's area of expertise, such as whether a project has the potential to pass regulatory hurdles. The project manager can advise on the potential for adverse immunological events and other toxicity issues and the ease of scaling up the manufacturing process so that only workable technologies move from the discovery phase into further development, says Nick Jackson, a former vaccine researcher at GlaxoSmithKline Pharmaceuticals and now a project manager for IAVI's collaboration with GSK. "The bottom line is that [project management] adds structure and accountability, while striving to maintain flexibility so that it doesn't stifle the creativity of the researcher," says Jackson.
A project manager is an asset to any research lab, says David Ho, scientific director of the Aaron Diamond AIDS Research Center. "We have come to appreciate how important that is to keep things on track. There are many management stages that are not common in research labs. Even at the formative stage the investigator needs to think about many things in parallel and the timelines involved," he says. "A project manager helps the group follow the timeline they set for themselves, and it draws your attention to the things that need to be done at a certain time."
In academia, the job of project management usually falls to the principle investigator, and becomes one more responsibility on top of supervising graduate students, writing and submitting papers, and applying for grants. "It would serve any lab to have [project managers] around to see that work is done efficiently, but in AIDS vaccine research they are indispensable," says Ho.
Publish or perish
A shift to a more industry-like way of doing research could be tough for some investigators who are accustomed to the relative freedom found in academia. Abandoning investigator-led research completely is not the solution. Curiosity-driven research has provided numerous innovations. Penicillin, for example, was discovered when Alexander Fleming left some moldy culture plates in a drawer. But he would never have realized what he was seeing if not for the incremental work of microbiologists before him.
Yet the academic system has some shortcomings that make it less than ideal for AIDS vaccine development. Of course collaboration in academia does go on, but these relationships are often fluid and informal and may be terminated for reasons that have nothing to do with the research. Formalizing the collaboration with intellectual property agreements can encourage researchers to be more invested.
The lack of oversight inherent in academic freedom means that major questions can go unanswered, simply because nobody sought out that knowledge or someone was refused a grant to study it. Some problems might simply be too difficult or too resource-expensive for a small research group to tackle alone. For example, studying mucosal immunity is prohibitively expensive due to the difficulty in collecting samples from the gut.
Publication of research studies in scientific journals is the lifeblood of academic science. A strong publication record can make a scientist's reputation and is a strong motivator for funding agencies to renew grants. This emphasis on publishing often means that research groups closely guard their own research results to ensure they aren't scooped, and this becomes a strong disincentive to collaborate with other research teams. Also, in the rush to publish proof-of-concept studies researchers may not give sufficient thought to how well the technology will translate to the clinic.
The publish-or-perish mantra may also keep researchers from admitting that a project is not working out as hoped. Few researchers publish negative results, either because they fear it may reflect badly on them or because journals refuse to publish them. Yet publishing negative results keeps other researchers from following blind alleys. "Negative data can be quite useful in this field in terms of rejecting and moving on to the next concept," says Dennis Burton, an immunologist at The Scripps Research Institute in La Jolla, California.
The research grant structure can provide a perverse incentive to continue with mediocre projects, says Burton. If a researcher finds that his or her research isn't returning the hoped-for results, or won't translate well to the clinic, he or she is not likely to immediately call up the funding agency and tell them so. Instead, the researcher might keep that work going through the end of the grant while starting up new projects. "People keep the ball in the air long enough to get the grant renewed," says Burton. "But what you really want to do is reject failed concepts as soon as possible. If something doesn't work, you and all the other people in the field need to know it as soon as possible so that more fruitful avenues can be followed."
Making it happen
The new industrial-style collaborations are meant to sidestep these pitfalls. CHAVI contains some aspects of the industrial model but retains the committee ethos commonplace in academia. Their strategic plan includes both a discovery phase and a product development phase, each of which has a team leader, and the teams are organized according to the unanswered questions posed by the Enterprise's scientific strategic plan. An internal committee evaluates whether the discovery phase is producing viable approaches. Meanwhile, a product development evaluation committee looks at what comes out of the discovery teams and decides if a project is ready to be subjected to timeline management pursuant to moving forward with clinical trials. "We hope that by organizing in this manner we can have both a discovery phase where serendipity is clearly needed and a product development phase where we rapidly evaluate and optimize the vaccine candidate," says Barton Haynes, director of CHAVI.
CHAVI is essentially a not-for-profit company in an academic setting. It has a chief scientific officer and chief medical officer, much like a corporation. The challenge is to give the scientist enough freedom, while at the same time keeping the science focused, says Haynes. "It is a grand experiment and the key is the interdisciplinary approach using components of the corporate model to focus the firepower to solve a very hard problem."
The approach will put the focus on successful projects and allow the jettisoning of vaccine candidates before moving to full-scale clinical trials. For candidates that are ready for further testing, vaccine developers are increasingly using the Phase IIb trial, an expanded Phase II trial that incorporates efficacy as an endpoint. Merck is taking this approach with a Phase IIb trial of its adenovirus-based vaccine candidate. The goal of these trials is to get answers sooner on whether a vaccine has the potential to work.
IAVI has been active in maintaining that research must adhere to project guidelines in a timely fashion, as shown in its support for the development of a vaccine using a modified vaccinia Ankara (MVA) vector. In 1993 the NIH had identified MVA as a promising vector for delivering antibody-inducing HIV genes. Over the next five years additional research supported that finding, and at the end of 1998 IAVI made the decision with its Oxford University and University of Nairobi partners to conduct Phase I/II trials to evaluate a DNA/MVA combination vaccine in Africa and elsewhere. "In the course of four years we did trials in five different countries," says Seth Berkley, president and CEO of IAVI. These trials were done in parallel to evaluate the candidate as quickly as possible, trading off time against money.
At the end of the trials, the data showed that the DNA/MVA vaccine did not induce an adequate level of immunogenicity. With so much time and effort invested in a strategy, some institutions might have been reluctant to drop it, but IAVI made a decision to end the project—although IAVI still funds other MVA research. "Products that don't pass the bar are terminated quickly without waste of resources so that funds are used efficiently," says Berkley.
The experiments themselves will always take time, but the idea is to accelerate the other aspects of research and development so that laboratory experiments, such as waiting to see if animals develop an immune response, become the most time-consuming thing. "The challenge would be to have no delays except for the time it takes for experiments to finish," says Berkley.
Orderly exploration could help quickly eliminate dead ends. "There's this finite immunological space," says Nabel, "and testing a vaccine candidate/strategy means that, if it doesn't work, you can close off that space and move on."
Some of the drawbacks in traditional academic research, like the publish-or-perish dilemma, stem from researchers having to constantly compete for grant funding. Contingent upon shifting business priorities, industrial researchers usually know their funding is secure as long at the project is continuing to make progress towards its milestones. One option being discussed is to fund quality academic researchers for longer periods of time and make grant renewal less firmly tied to publishable data. "A degree of independence from current funding mechanisms could foster innovation," says Burton.
Secure funding might have another desired effect: luring experienced researchers into the field of AIDS vaccine research. Especially needed are experts in basic immunology, says Bruce Walker, director of Harvard Medical School's Center for AIDS Research. "In the HIV immunology field," says Walker, "there are very few of the mouse immunologists, those that have helped to define how the immune system works, who have made the transition to HIV research."
It is not easy to attract people who are successful in other areas to change focus and work on HIV, says Walker, and new, secure funding could help, especially if it came with few strings attached and with an attitude that says, "We expect you to not worry about funding and publications, just get the job done." More formal funding arrangements could ensure that groups work in tandem for prolonged periods.
As for providing incentives for new researchers to enter the vaccine field, some young researchers may be concerned that working in large collaborative groups hurts their chances for publication and therefore promotion. Haynes says that he is already talking to the deans at the universities participating in CHAVI about basing promotion and tenure less on publications and more on recognizing productivity and group contributions.
An AIDS vaccine effort will differ from industry practices in significant ways. Rather than keep results close to the vest, AIDS vaccine researchers will share them widely. Intellectual property rights will be protected through patents to enable sharing of ideas, so that biopharmaceutical companies will have incentive to take vaccine candidates into development and manufacturing.
A research model alone won't lead to a vaccine. "No matter how good your industrial model is, you have to have the basic strategy first," says Ho. "The harmonization of practices and assays are good for the field, but we should not be misleading ourselves that those are the true obstacles—the obstacle is a scientific one." Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition, agrees. "We shouldn't forget that no matter what research model is used, much basic research remains to be done," he says. "I would hate to see people stuck debating about what is the correct model."
Harmonizing research practices and assays will help ensure that the search for the vaccine is efficient and takes as little time as possible. Yet in applying the industrial model to AIDS vaccine research, we must take care, says Esparza. "In 1997, President Clinton promised an AIDS vaccine in 10 years, and he compared it to Kennedy's initiative to put a man to the moon. But there is a critical difference. Putting a man on the moon was an engineering problem, whereas an AIDS vaccine is a research problem. We know where the moon is, but we don't know where we will find an AIDS vaccine."
The risk, says Esparza, is that we will invest in the wrong vaccine candidate, before we've had a chance to explore all the options. "Right now the goal is not to build a spaceship to the moon," says Esparza. "It is to develop many probes that we will send to different regions of space."
*Catherine Zandonella, MPH, is a freelance writer whose work has appeared in Nature and New Scientist.