[NOTE: This is an UPDATE to a case study initially published in 2009. Read the original case study for appropriate context.]
As a means of overcoming the obstacles to an HIV vaccine, the International AIDS Vaccine Initiative (IAVI) created several model research collaborations. These cross-institutional consortia act as virtual research centers that unite scientists who share their findings despite the traditional barriers posed by geography, organizational culture and patent rights. IAVI makes collaboration attractive by soliciting funding for the research and providing administrative support. The scientists are then free to focus on their investigations. In return, IAVI receives first option on exploiting any discoveries. IAVI’s original initiative was the IAVI Neutralizing Antibody Consortium that focused on the “broadly” neutralizing antibodies that occur naturally in a few HIV-positive patients with exceptional resistance to the virus. IAVI also formed two smaller consortia, the Vectors Consortium and the Live Attenuated Consortium.
Neutralizing Antibodies: An Effective Shield Against HIV
In the past two years, IAVI’s Neutralizing Antibody Consortium, the NAC, has remained the main mover of the research agenda. Discovery of the structure and mechanism of broadly neutralizing antibodies, which block most or all HIV variants from infecting cells, could guide the way to a protective vaccine.
Prior to 2009, only four broadly neutralizing antibodies had been described. Rapid progress in testing technology has led to the identification of additional highly potent neutralizing antibodies. These target six different areas on HIV surface protein. NAC researchers have identified dozens of highly potent, novel broadly neutralizing antibodies from HIV-positive individuals. The antibody donors were part of Protocol G, a study spearheaded by IAVI’s Clinical Research Centers. Protocol G attempted to isolate broadly neutralizing antibodies in the blood of nearly 1,800 HIV-positive volunteers mainly from Côte d’Ivoire, Kenya, South Africa, the UK and Thailand. Only one percent of the Protocol G population proved to have the sought-after “elite” neutralizing activity.
The NAC’s work in this field has been crucial—a renaissance in neutralizing antibody-based HIV vaccine development. The science of anti-HIV neutralizing antibodies has advanced rapidly, revealing promise for new vaccines. Meanwhile other vaccine types have shown little to no protective value against HIV during advanced human testing. Much of the latest antibody work has taken place at the IAVI Neutralizing Antibody Center at The Scripps Research Institute in La Jolla, California. Founded in 2009, the Center’s laboratories include about 25 IAVI staff working closely with other NAC laboratories at Scripps.
Aside from laboratory technology, the surge in antibody research arose because, according IAVI Chief Scientific Officer Wayne Koff, “The consortium reached a critical mass. New investigators were brought in by expanding the number of external partnerships and by creating the IAVI Center at Scripps, which became the hub of activity.” Koff quickly noted, “As the consortium has grown, the challenge continues to be the fostering of communication across the multiple partners to facilitate its work.”
The Vaccine Research Center (VRC), part of the National Institutes of Health, has been another key NAC collaborator through a long-term CRADA (Cooperative Research and Development Agreement). Beyond characterizing neutralizing antibodies and their anti-HIV effects, the VRC scientists are helping to explain the basic biology leading to such antibodies’ development in the body. The VRC has engaged in studies on stimulating protective antibodies in humans, with the goal of applying their findings to HIV vaccine development.
IAVI’s AIDS Vaccine Design and Development Laboratory in Brooklyn, New York, is supposed to follow-up on the discoveries by the Scripps Center and others by designing vaccines that would trigger creation of broadly neutralizing antibodies to HIV in the general uninfected population. But we are still far from such vaccines. IAVI is now looking at reconfiguring its research consortia to accelerate vaccine design and screening through the addition of industrial partners. For example, the study that isolated the 17 broadly neutralizing antibodies involved collaboration with Theraclone Sciences of Seattle, Washington. The company has developed proprietary “high throughput” antibody assays that simultaneously test large numbers of antibodies to rapidly identify the few with the potential for medical application.
Part of IAVI’s renewed effort is the deepening of the NAC partnership with the Indian government’s Department of Biotechnology. In March 2011, IAVI and one of the Department’s institutes, the Translational Health Sciences and Technology Institute (THSTI), announced the establishment of a joint HIV Vaccine Design Program. The program will be housed in a new laboratory on the THSTI campus in New Delhi.
“We expect the India lab to be functional later in 2012 and to complement the activities of other partners in the consortium,” says Koff. The laboratory’s work initially will center on high throughput screening of vaccine components that might induce broadly neutralizing antibodies against HIV. Although Protocol G has concluded in other countries, the Indian laboratory will launch a site for this study in an effort to increase the range of known broadly neutralizing antibodies.
Exposed and Protected: Safe Vaccine Vectors That Simulate HIV
Through 2009, IAVI supported two other consortia, the Vector Consortium and the Live Attenuated Consortium. The Live Attenuated Consortium studied the potential for creating a potent, traditional type vaccine from weakened live HIV. The Consortium studied the mechanism of protection conferred by live attenuated vaccines in monkey models of HIV. Its work sparked the interest of several well-resourced organizations. In particular, the NIH and the Gates Foundation have taken up the field. IAVI in response has refocused its funds on other research priorities and terminated the Live Attenuated Consortium.
The Vectors Consortium investigates standard replicating viruses hybridized to exhibit some HIV-like features. In a vaccine, these chimeras promise to have safety advantages over live attenuated HIV. IAVI’s Design and Development Lab has taken up early development of two of the vectors under study and is working with partners (the Japanese company DNAVEC and the Oregon Health & Science University) on two others.
In May 2011, the Oregon collaborators published a paper reporting that an adapted vaccine version of the common virus CMV (cytomegalovirus) conferred 50 percent protection in a monkey HIV model. This demonstration was a good proof of principle, but CMV sometimes causes serious disease in humans. (Interestingly, the protection afforded by the vaccine was not related to neutralizing antibody production.)
Much research obviously remains to creating a safe, effective HIV vaccine. Even basic understanding is lacking about the role of neutralizing antibodies and other immune responses. However, the IAVI strategy of creating global collaborations of experts in immunology and vaccine development is accumulating a series of primary breakthroughs. These could push the field rapidly forward once they reach their own “critical mass.”
By David Gilden