Nov 24, 2010
Irreverent humor aside, there is a substantial vein of truth to this joke. In developed countries, where patients are able to afford expensive cocktails of antiretroviral drugs, HIV has become a manageable chronic condition. For much of the world, however, HIV inevitably leads to AIDS and continues to be a death sentence. An estimated 33 million people currently live with HIV and 2 million die from AIDS annually. In some countries in Sub-Saharan Africa more than 15% of adults are infected with the virus and the region accounts for more than 70% of AIDS-related deaths (). Public health measures such as sex education, needle exchanges and condom distribution can contain the epidemic, but only a vaccine has the potential to cure the disease.
It has been nearly a quarter century since HIV was identified and yet, despite the money and effort directed at the problem, there is no vaccine. Why has it been so difficult? The simple answer is that HIV is unlike any other pathogen we have ever encountered. To evade immune system defenses, the virus mutates at an incredible rate. Amazingly, there is as much viral genetic variability in a single HIV infected individual as is found in a year of influenza worldwide (). This renders static vaccines nearly useless, as protection generated against the immunization strain generally fails to stop mutated viruses from establishing an infectious foothold.
HIV’s unique pathology also hinders vaccine development. The virus resides and replicates in CD4+ T cells, a type of white blood cell that plays a crucial role in directing many of the complex elements involved in a healthy immune response. Infected CD4+ T cells are destroyed in a well-meaning but fratricidal attempt at damage control by killer T cells, until so few remain that the body becomes susceptible to opportunistic infections. Though the progression from initial viral infection to full-blown immunodeficiency can take years, there is not a single documented case of an individual who has developed immunity to HIV. Historically, the immune defense mounted by survivors provides important insights for developing a vaccine, but there are no such clues for HIV.
Moreover, because the virus destroys the immune system, the elements of the immune response that might postpone the inexorable decline – what immunologists term correlates of protection – have not been identified. Without correlates of protection it is unclear what type of immune response will be most effective against the virus, and therefore scientists lack an obvious roadmap for designing a successful vaccine. Not surprisingly then, in large phase III efficacy trials over the past two decades, vaccine candidates have ranged in efficacy from moderately protective to apparently neutral to downright harmful ().
Despite this history, a few recent developments in HIV research have brightened the forecast in the field. The first is the discovery of a rare class of HIV-infected individuals who are able to maintain low viral levels for decades without antiretroviral therapy. These fortunate few, known as elite controllers, are the closest thing to survivors of the AIDS epidemic and studies of their genetic makeup have generated both biological insights and interesting therapeutic candidates (,,). Elsewhere in the field, improved technologies for screening large numbers of biological samples from new patient cohorts have shed light on antibodies present in patient sera that are able to neutralize many subtypes of HIV (,,). Crystallographers and immunologists are working to elucidate the structures and mechanisms of these antibodies in order to design vaccines that will elicit a similar protective response.
For the interested entrepreneur, there are compelling arguments both for and against entering the HIV vaccine arena. On one hand, there is tremendous scientific excitement surrounding HIV research, an emphasis on opening of the field to engineers and others in non-traditional disciplines, and ample opportunity to apply innovative new technologies that in other fields might be seen as too risky or experimental. On the other hand, history is littered with failed HIV vaccine development attempts by even the most well-funded biopharma efforts including Chiron, VaxGen, Merck and others.
Much of the current funding for HIV vaccine research and development comes from public-private partnerships such as the International AIDS Vaccine Initiative (IAVI) (). IAVI channels money from governments, private foundations and industry players to vaccine researchers worldwide. Fruitful partnerships with over 50 academic, industrial and government institutions have resulted in seven international clinical trials of IAVI-supported vaccine candidates in the last decade ().
IAVI also manages the IAVI Innovation Fund – jointly sponsored by the Bill & Melinda Gates Foundation – which provides grants to small- and medium-sized biotech companies to advance emerging technologies (). Recent recipients include VaxDesign (Orlando, FL), whose artificial human immune system is designed to rapidly analyze potential vaccine candidates; Theraclone (Seattle, WA), whose technology can screen B cells from HIV infected patients to identify new neutralizing antibodies; and Lipoxen (London, UK), whose novel lipid-based formulations are designed to improve the performance of anti-HIV antibodies.
Thanks to support from IAVI and other public-private partnerships, there is a market for companies with novel tools and innovative perspectives to get involved in HIV vaccine research and development. However, it is still not known how the market will react to a successful vaccine, provided one is discovered and approved. The number of HIV-infected individuals increases annually, but more than 95% of them live in the developing world (1). In such a system, return on research and development expense is offset by the moral imperative to provide life-saving treatment to the world’s poor.
A number of innovative financing mechanisms have emerged in the quest to balance financial reward with public health. The Global Alliance for Vaccines and Immunisations (GAVI), a partnerships primarily between wealthy countries and the Gates Foundation, donates money to purchase vaccines for developing countries (). Other models that are less dependent on the tides of the global economy include differential pricing schemes, advanced market commitments and creative licensing agreements to secure low-cost vaccines for the neediest patients (,, ). Merck and GlaxoSmithKline have begun to test new financing mechanisms as they distribute their human papilloma virus vaccines worldwide, including to self-pay populations that cannot afford the several-hundred-dollar shelf price in the United States market where reimbursement is common (). It is reasonable to expect that efficient systems for profitable and equitable vaccine distribution will be in place within the next decade.
There are inherent scientific and economic risks to any technology venture. For the entrepreneur interested in tackling the AIDS crisis, these risks take the form of two questions: Can we make a vaccine? And, can we make money doing it? There are no definitive answers but the current pace of scientific discovery and level of enthusiasm in the HIV vaccine field, coupled with a global network of agencies committed to fostering innovation and promoting fair distribution, suggests that the answer to both questions is a resounding yes.
 McElrath and Haynes, Immunity 2010, 33.
 Migueles et. al., Proc. Nat. Acad. Sci. 2000, 97.
 Baker et. al., Expert Opin. Biol. Ther. 2009, 9.
 Kosmrlj et. al., Nature 2010, 465.
 Walker et. al., Science 2009, 326.
 Wu et. al., Science 2010, 329.
 Walker and Burton, Curr. Opin. Immunol. 2010.
 IAVI Insights, Innovative financing mechanisms to advance global health. Policy Brief 21, June 2009. 23% of global R&D spending for neglected diseases comes from product development partnerships.
 IAVI Innovation Fund: http://www.iavi.org/research-development/IAVI-RD-Programs/Pages/innovation-fund.aspx
 Spurring innovation for the development of HIV and AIDS technologies, IAVI Focus 2009.
 Outterson and Kesselheim, Market-based licensing for HPV vaccines in developing countries, Health Affairs 2008, 27.
 IAVI Insights, Procurement and pricing of new vaccines for developing countries. Policy Brief 16, August 2008.
A highly enlightening and entertaining review of the history of the HIV vaccine effort is Jon Cohen’s text, Shots in the Dark: The Wayward Search for an AIDS Vaccine (W. W. Norton, 2001).