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[This article was published in 2009 and updated in May 2012. Read the update here.]

Developing an HIV vaccine has proved a very difficult project. The International AIDS Vaccine Initiative (IAVI) has, in response, created a model scientific collaboration to search for breakthroughs. The IAVI AIDS Vaccine Consortia started with a consortium to create a vaccine that would elicit neutralizing antibodies. It has since added two more.

The consortia act as virtual laboratories consisting of geographically distant researchers who readily share their findings across institutional boundaries. A major startup issue was developing an intellectual property master agreement that dovetails with the policies of the researchers’ institutions. The agreement grants IAVI an option to license program inventions while giving all participating organizations a share of any future licensing revenues. IAVI provides secure financing and covers most of the administrative work, thus freeing scientists to focus on their research to an unusual degree.

HIV presents a formidable challenge for vaccine developers. To block the virus’ invasion, immune responses have to target constantly shifting viral proteins. In terms of viral diversity, “If flu is my fist, then HIV is the size of this room,” says Seth Berkley, president of IAVI. In addition, the HIV envelope is wrapped in a mantle of captured human cell membrane material. This mantle protects viral particles from immune recognition and attack. Finally, there is no adequate animal model for HIV infection.

IAVI was founded in 1996 to promote development of a globally affordable and accessible HIV vaccine. It supports HIV vaccine research by partnering with academic, corporate and government institutions. Since 2001, it has also developed its own research facilities.

HIV has proved too complex for the individual investigators trying to develop novel solutions in his or her separate institutions. IAVI emphasizes the use of “industrial-style project management” to prioritize the most promising vaccine strategies and quickly form ad hoc teams to investigate them.
To facilitate this interorganizational collaborative approach, IAVI has created a system known as the AIDS Vaccine Consortia (AVC). By 2009, the AVC network combined the efforts of researchers at 21 organizations across the globe.

Creation of the Neutralizing Antibody Consortium

Traditional vaccines teach the body to produce antibodies against the virus in question. Antibodies are Y-shaped proteins tailored to attach themselves to specific viral proteins. Neutralizing antibodies can block the virus from entering cells and reproducing. HIV researchers in recent years have largely focused instead on “cellmediated immunity.” This part of the body’s immune defense involves white blood cells that eliminate cells already infected by viruses. But vaccines based on cell-mediated immunity, such as the one Merck had to abandon, have had disappointing results so far. The generated immune responses have been too weak, nor could they compensate for the shape-shifting propensity of HIV proteins even if they had been stronger.

At the beginning of this decade, Wayne Koff, IAVI’s senior vice president for research and development, decided to take another look at antibody research. Papers published in 1999 and 2000 showed that administering antibodies completely protected uninfected macaques. Koff says that when IAVI surveyed the ongoing research, “We found many investigator-initiated small grants and no industrial-style, mission-oriented programs.”

In line with Koff ’s critique, IAVI established the Neutralizing Antibody Consortium (NAC) in 2002. The initial consortium included researchers from four institutions: The Scripps Research Institute (La Jolla, Calif.), the University of Pennsylvania School of Medicine (Philadelphia), Weill Medical College of Cornell University (New York City) and the Dana-Farber Cancer Institute (Boston). In addition, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) agreed to support the consortium through its Vaccine Research Center.

IAVI fully funded the consortium startup with its own resources. It has continued to do so over the years, allowing NAC members to spend more time in the lab and less in the office writing grant proposals. Robert Doms, the initial NAC researcher at the University of Pennsylvania, says that he was delighted with the financial freedom the consortium provided. “IAVI has allowed me to concentrate on more risky research,” he says. In contrast, “The NIH tends to put its outside grants into further developed, less speculative projects.”

The NAC became a virtual research center. It provides a means for the scientists to share their thoughts and observations across institutions. “In forming the NAC, groups agreed to several basic principles,” says Koff. “These included early sharing of data, candor around the table and shared intellectual property. We wanted to ensure that all members would benefit from the consortium’s success and that the developing world would have access to a vaccine.”

The NAC has since grown to 15 member institutions, including organizations in the U.S., Europe and Asia. It has established four priorities based on the research gaps members noticed. These are: understanding antibodies’ molecular activity, elucidating the interaction between HIV proteins and antibodies at the atomic level, developing technology to assist in vaccine design, and screening HIV protein sequences for use in a vaccine. The order of these priorities shifts from year to year as research proceeds.

Two New Consortia

Building on the NAC model, IAVI has added two new consortia in recent years. Members of each consortium include different subsets of the NAC membership plus several new organizations.
In 2006, IAVI established the Vector Consortium (VEC), which now has eight institutional members including IAVI. Like the NAC, the VEC covers a neglected aspect of HIV vaccine research. In the interests of safety, HIV vaccines under development generally utilize genetically engineered viruses (viral vectors) that do not cause major disease in humans. These viruses are altered to carry HIV proteins and to be nonreplicating. Their ability to provoke a protective immune response has turned out to be rather weak. The VEC’s purpose is to investigate replicating viral vectors. “We are looking at most stimulating kinds of vectors, the live vector ones and work on how we would create a useful vaccine,” says Koff.

If replicating viral vectors pose some danger of causing disease, an attenuated HIV vaccine causes even more shivers. Such a vaccine might turn out to be not so attenuated in some people, resulting in HIV disease. This problem occurs with the live polio vaccine. Yet the only vaccine that has proved protective in a monkey model is an attenuated virus. (That vaccine was fully protective only against the same strain of virus as was in the vaccine. It also caused immune deficiency in some monkeys.) IAVI initiated its Live Attenuated Consortium in 2007 to study the immune response to this type of vaccine. The consortium hopes to learn what the key elements are that make the attenuated virus vaccines protective. Researchers could then apply the lessons learned when designing safer candidate vaccines.

A New Regime for Intellectual Property

Intellectual property (IP) rights are critical to IAVI’s goal of ensuring that an HIV vaccine reaches developing countries at a reasonable price. Achieving this goal required considerable ingenuity when drawing up the consortia’s master agreement. IAVI and the other founding institutions constructed a durable IP arrangement that grants IAVI the option to license any AVC inventions including enabling background technology. Revenues resulting from development of these inventions will be shared within each consortium according to an agreed-upon formula.

“It took two years of negotiations to hammer out the IP details before executing the master agreement,” Lita Nelsen, director of the Technology Transfer Office at the Massachusetts Institute of Technology, advised the nascent NAC. The agreement went through 10 or 12 preliminary drafts. Nelsen says, “Traditionally, universities collaborate but recognize that they have competing interests: what’s mine is mine and what’s yours is yours. But here, the researchers just wanted to end a world scourge. Good will can accomplish a lot.” The consortium concept offered a number of financial and organizational benefits, so the researchers pushed to make it work.

IAVI receives an exclusive licensing option for any discoveries in return for funding the research. If IAVI decides to exercise its option, it pays the patent application fee and gets the rights in the area of HIV vaccines. The inventing institution receives the largest share of any royalties that result, and IAVI receives a smaller share. The remaining royalties are split among the other consortium members.

“The agreement keeps people at the table, sharing their ideas. If anyone makes an invention, well, they likely would not have gotten there without the team brainstorming,” says Koff. The issue becomes more complicated if multiple institutions contributed concretely to a particular invention. If that is the case, all the contributing organizations share in the major inventor’s portion of the revenues. IAVI’s patent counsel is available to help resolve patent issues.

All new consortia members have to make a commitment to the AVC research program and the set IP procedure. As agreed by the founding members, participation requires accepting the master agreement on a take-it-or-leave-it basis. A separate Cooperative Research and Development Agreement (CRADA) governs the research contributions of the NIH, NIAID’s Vaccine Research Center. The CRADA states the U.S. government’s standard technology transfer and licensing terms. In 2007, IAVI signed another supplementary agreement with the Indian government’s Department of Biotechnology (DBT). This agreement allows the Neutralizing Antibody Consortium to work with two Department of Biotechnology-funded institutes. It also envisions using Indian manufacturers to produce reagents for vaccine design.

One alteration to the consortia’s master agreement took place in 2007, when the VEC received a major grant directly from an outside source, the Bill & Melinda Gates Foundation’s Collaboration for AIDS Vaccine Discovery (CAVD). The Gates Foundation requires prompt dissemination of CAVD-funded findings and materials to the broader scientific community so as to speed HIV vaccine research. It also requires that any vaccine arising from CAVD research be accessible to people in developing countries. Since the Gates Foundation requirements are consistent with IAVI’s standard policies, they did not greatly alter the sense of the AVC’s master agreement.

Organizational Structure

IAVI ultimately incorporated the three consortia into a single organizational structure, the AVC. A management committee composed of senior IAVI scientific executives oversees AVC operations. This committee reviews the work of the participating research centers and sets organizational priorities to improve integration and efficiency. It also helps revise the research agenda for each consortium, whose work plan is supervised by each consortium’s individual scientific director (or a consortium
executive committee in the case of the NAC).

These scientific directors are critical to the operation of each consortium. They supervise the science program and consult with consortium members on a daily basis. They also conduct frequent work meetings as well as a larger AVC science update meeting. Researcher recruitment is another task within the scientific directors’ responsibility. The directors put together a coherent group to achieve the consortium’s goals, adding new members to fill any gaps that appear. They are, therefore, in charge of building the critical team spirit for the collaborative effort.

Koff, who is also the AVC executive director, says that, overall, “The idea is to relieve the researchers of the grunt work and free them to do the science.” IAVI’s Business Development Department has developed agreements with contractors to do the standard evaluations to expedite data management. The business team also draws up material transfer and licensing agreements needed for research materials such as antibodies, reagents and delivery systems for animal testing. Finally, it manages the licensing of IP coming from the AVC.

Each consortium has an IAVI-hired project manager, too. These project managers work with the researchers to obtain needed testing and materials outside the consortium. They also complete a lot of the standard paperwork and reports.

Extending the Collaboration

IAVI’s Clinical Protocol G Program is a major ongoing NACrelated project that illustrates how the collaborations within the AVC are branching out. This study is screening antibody samples from 1,200 people with HIV spread across Africa, Thailand and the United States. So far, two new potent broadly neutralizing antibodies have been discovered.

Beyond the NAC, Protocol G involves participation by an international network of Clinical Research Centers organized by IAVI as well as outside research institutions. Neutralizing antibodies uncovered by IAVI and its collaborators will aid vaccine design work at the NAC and elsewhere. In the meantime, the work on Protocol G has further honed the capabilities of the Clinical Research Center’s network during a dry spell in actual vaccine trials.

In a move to expand the NAC’s work, in September 2008 IAVI and The Scripps Research Institute announced the establishment of the IAVI Neutralizing Antibody Center, in La Jolla, Calif. Scripps and IAVI scientists will work together at this laboratory center, and IAVI has committed $30 million in funding over a five-year period. The new facility will complement the capabilities of IAVI’s other two research laboratories, the AIDS Vaccine Design and Development Laboratory (Brooklyn, N.Y.) and the Human Immunology Laboratory (London).

Researchers at these labs have become members of the AVC so that there is a tight connection between the IAVI facilities and the geographically disparate consortia. University of Pennsylvania’s Doms says, “IAVI is moving to a model in which real centers are embedded in virtual centers. This model will bring an appropriate organizational scale to a difficult problem.” The synergy from bringing the new and old AVC components together in this novel multilayer organization can engender shifts in researchers’ perspectives. New approaches to the HIV vaccine puzzle may result. That, at least, is the hope in this period when the way forward is still unclear.

By David Gilden