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The Quest for an HIV Vaccine In 2009, twenty-nine years into the HIV/AIDS pandemic, the Centers for Disease Control and Prevention estimated that over 1.1 million people in the U.S. were living with HIV/AIDS.1 The international impact of HIV/AIDS continues to be profound. Two thirds of all adults and children with HIV/AIDS live in sub-Saharan Africa, where the epidemic has drastically reduced life expectancy.2 In 1990, the estimated life expectancy in Zimbabwe was 62.4 years.3 By December 2006, average life expectancy had plummeted to 34 years for women and 37 years for men, among the lowest in the world.4 The International AIDS Vaccine Initiative (IAVI) projects that a vaccine with just 50% efficacy administered to 30% of the population of developing countries between 2015 and 2030 would prevent approximately a quarter of the infections that would otherwise occur.5 Without a vaccine, the number of new infections per year could increase from 6 million to 10 million by 2030.6 Given these discouraging statistics and projections, the development of a safe and effective HIV vaccine remains a critical but elusive goal. Funding and Other Issues In general, significant amounts of time have historically been required for the development of a new vaccine. It took over a century for the typhoid vaccine and nearly 50 years for the polio and measles vaccines to be developed once their causative agents were identified.7 Regarding a potential HIV vaccine, development has been further complicated by a formidable array of biological, political, economic, logistical, and ethical challenges. In the early years of the AIDS pandemic, many politicians downplayed the seriousness and scope of the disease. After gaining momentum in the late-1980s, progress in vaccine research stalled in the mid-1990s, when HIV vaccine research funding constituted only about seven percent of the National Institutes of Health (NIH) AIDS budget. Scientists thought the vaccine effort was "dead," the private sector had condemned vaccines as unprofitable, and AIDS activists pushed successfully for financial resources to be spent on drug treatments instead of vaccine research. The delay in vaccine development can be attributed in part to a lack of private sector funding: AIDS vaccine research is overwhelmingly driven by the public and philanthropic sectors. The HIV Vaccines and Microbicides Resource Tracking Working Group estimates that in 2006 the pharmaceutical industry spent approximately $79 million on AIDS vaccine research, only 8% percent of the total $933 million spent worldwide.8 Dr. Edward Tramont, Director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), has suggested that drug companies lack incentives to create an HIV vaccine and are likely to wait to profit from a government-developed vaccine.9 The industry has compelling reasons to refrain from investment. The process of developing an HIV vaccine has already proven to be extremely difficult, costly, and time-consuming. Conducting clinical trials forces pharmaceutical companies to confront a constellation of ethical, political, and economic complications, and they have no guarantee of profiting from these endeavors, even if research is successful. The projected demand for an HIV vaccine as well as the general nature of the vaccine market suggests slim profit potential. The countries most in need of the vaccine are precisely those which have the least ability to pay: low- to middle-income nations.10 Additionally, most vaccines are administered once or twice in a person's lifetime, while drugs must be taken daily over long periods of time. Accordingly, the best-selling and most profitable pharmaceuticals are generally those that manage cholesterol, asthma and depression, not preventive interventions like vaccines. Pharmaceutical companies, according to president and founder of IAVI Seth Berkley, "are looking for blockbuster drugs, the multi-billion drug, the next big thing." A possible HIV vaccine lacks this revenue potential.11 Weak support from the private sector is part of the larger problem of inadequate global spending. Worldwide, spending on an HIV vaccine from all sources - the government, private industry, and foundations - constitutes only about three percent of global spending on AIDS.12 The bulk of this money has gone toward funding treatment, rather than research. In poor countries with high HIV prevalence, investing in high-tech research - the work crucial to the successful development of an HIV vaccine - is generally not financially feasible.13 The Global HIV Vaccine Enterprise, an international initiative dedicated to coordinating HIV vaccine research directions, predicts that implementing their strategy would require $1.2 billion per year, more than total global spending on HIV/AIDS in recent years.14 Funding from private groups such as the Gates Foundation has partially compensated for funding shortfalls in promoting the kind of research that could lead to a vaccine. Another strategy under consideration for HIV and other vaccines is the "advance market commitment," a program in which governments guarantee money to pharmaceutical companies in order to ensure that demand and prices will remain at a profitable level for a new product. Advance market commitments are thought to make research and development less of a financial risk for industry.15 Some analysts suggest, however, that current funds are adequate but that they are simply not being allocated appropriately.16 Biological Reasons It may seem difficult to understand why, in an age of synthetic biology and 'miracle' drugs, developing an HIV vaccine continues to be so difficult. This attitude may reflect changes in the character of biomedical research. As journalist Michael Specter notes, biology is now driven by genomics instead of trial and error.17 Earlier in the HIV/AIDS pandemic, the task of developing a vaccine fell primarily to molecular biologists who attempted to reduce the virus to its smallest components. IAVI's Seth Berkley has critiqued this approach, lamenting that "it cost us at least a decade."18 Vaccine development has always been extremely challenging.19 Vaccines rely on the ability of the immune system to identify certain particles, such as the entire virus (usually attenuated, inactivated, or killed) or parts of the virus (i.e. proteins) as foreign to the body. Subsequently, the immune system must destroy these foreign particles and be able to invoke the same response if the body encounters that particular virus again. The human immune system is extremely complex, and scientists are still working to fully understand its structure and function. Additionally, even the mechanisms of successful vaccines are not always completely understood. As late as 1998, scientists acknowledged that "in the strict scientific sense, we don't know how the [whole-cell] pertussis vaccine worked," despite it being widely and safely used for decades.20 Much of the difficulty in developing an HIV vaccine can be attributed to the unique biological mechanisms of the virus, the very characteristics that make it so formidable a global health threat. HIV is a retrovirus; its genetic information is contained in RNA instead of DNA. Currently, no vaccines against human retroviruses exist, so researchers lack prior models from which to work.21 Those infected with HIV develop a broad range of immune responses towards the virus, but these responses fail to eliminate HIV or prevent eventual progression to AIDS.22 Antiretroviral drugs, the most effective treatment strategy currently available, decrease a patient's viral load and delay the development of AIDS, but they do not eliminate HIV from the body. As a result, scientists have no examples of successful immune responses to guide them in vaccine development.23 Those on the quest for an HIV vaccine must overcome the effectiveness of the virus in evading immune responses. Once the virus enters a human cell, it will continue to mutate throughout the period of infection. This is important because the immune system often relies on the body's ability to recognize the exact 'shape' of a particular particle. Furthermore, HIV can conceal itself by incorporating into the host DNA and becoming a provirus.24 An HIV vaccine would only have a few days or weeks to prevent the virus from establishing a permanent foothold in the body, researchers suggest. The vaccine would also need to be constantly monitored and modified to keep pace with the steady stream of new HIV variants, since the virus mutates very rapidly.25 These are not the only issues posed by the intricacy of the virus. For example, most scientists believe that two classical approaches to developing viral vaccines, using whole inactivated or live-attenuated (weakened) viruses, cannot be employed for safety and ethical reasons. They have instead turned to more modern and technologically sophisticated techniques, such as developing subunit vaccines, agents contain a part of the virus rather than the whole virus.26 During the mid- to late 1990s, controversy arose over attempts to introduce a live-attenuated HIV vaccine, thought to be particularly dangerous due to its potential to mutate and cause AIDS or other diseases.27 Experiments with primates showed that some macaques who were given the candidate vaccine eventually developed an AIDS-like syndrome. This work also suggested that the strains used in the vaccines could be deadly to individuals with immature immune systems.28 In trials of other vaccines, however, live-attenuated vaccines against other infections have provided better protection of those immunized because they can stimulate a more substantial and broad-based immune response.29 In 1997, the International Association of Physicians in AIDS Care (IAPAC) presented its plan to test a live-attenuated HIV vaccine in human subjects. More than 300 clinicians volunteered, but the Division of AIDS at the NIAID concluded that there was insufficient evidence of the safety and efficacy of a live-attenuated HIV vaccine. While there are undeniable safety concerns and more data is certainly needed, proponents of the live-attenuated vaccine approach argue that given the proportions of the HIV/AIDS epidemic and the promising results from animal studies, "it is wrong to require a vaccine to meet U.S. safety and efficacy standards, [and] further delay is unethical."30 It can be argued from an ethical standpoint that it would be permissible to use a live-attenuated HIV vaccine with the potential to save millions of lives worldwide, even if a comparatively small number of people were at risk of infection from the vaccine itself.31 While research on live-attenuated vaccines has largely ceased, current research is further complicated by a lack of suitable animal models on which to test vaccines before initiating trials with humans. Experiments currently involve chimpanzees infected with HIV and monkeys infected with Simian Immunodeficiency Virus (SIV), a related virus. However, vaccine candidates have invoked different responses in each animal model.32 Research is further complicated by HIV's genetic variability and geographical distribution. There are nine subtypes, or clades, of the virus. Viruses from different subtypes can recombine to create new hybrid viruses, known as circulating recombinant forms (CRFs), which also infect humans.33 Subtypes and CRFs have different geographical distributions. For example, subtype B is most prevalent in the Americas, whereas subtypes C and E are the major causes of HIV/AIDS in Africa and Thailand, respectively.34 Scientists are not yet certain of the significance of this genetic diversity, but it could mean that different vaccines would be needed for different clades of the virus.35 Conclusion Given the numerous challenges both in acquiring funding and in conducting research for development of the HIV vaccine, it is important to realize that the first generation of HIV vaccines will most likely be, at best, moderately successful in preventing the disease or its progression into AIDS.36 Some scientists are skeptical that a vaccine that fully prevents HIV will ever be created, but many remain optimistic about the prospect for a vaccine that might have a significant impact on the HIV/AIDS epidemic in the hardest-hit countries. The scientific community's efforts to overcome the economic and biological barriers to developing an HIV vaccine have resulted in several noteworthy collaborations. These include the International AIDS Vaccine Initiative (IAVI), the Global HIV Vaccine Enterprise, and the Center for HIV/AIDS Vaccine Immunology (CHAVI). IAVI was founded in 1996 as a global not-for-profit, public-private partnership working to accelerate the development of safe, effective, and accessible HIV vaccines. Its research and development (R&D) projects have resulted in six vaccine candidates that have been tested in human trials in 11 countries. IAVI also links HIV vaccine laboratories in different parts of the world, provides training and support to field laboratory and staff performing clinical trials, and partners with local institutions. The initiative's publications analyze how public policy could accelerate vaccine development and address key issues such as R&D expenditures, future spending needs, vaccine demand, health and economic impacts, and incentives to increase industry participation.37 Proposed by vaccine researchers in 2003, the Global HIV Enterprise focuses on speeding vaccine development through scientific collaboration, the mobilization of funding, and the development of a strategic plan focusing on discovery, clinical trials, and product development and manufacturing. The Enterprise describes itself as representing "a new way of doing business", claiming the ability to tackle "major scientific problems that have proven too difficult for any one group to address alone."38 It seeks to accomplish its goals through rapid information sharing, monitoring the status of HIV research, and engaging donor governments, private philanthropies, and other potential sources of funding through an annual Funders' Forum. The Enterprise aims to encourages collaborative, high quality, and timely research.39 CHAVI, which was launched by the NIH, was also created in response to the many obstacles in HIV vaccine development. Founded in July 2005, the consortium has established clinical trial sites, clarified its scientific goals and protocols, and dealt with intellectual property issues in its first year.40 Its research goals focus on studying immune responses at the earliest stages of infection, examining SIV infection and mucosal protection in primates, and designing and testing new vaccines.41, 42 It is hoped that these and other innovative international partnerships will aid researchers in working towards an HIV vaccine. -- By Jessica Ho, University of Pennsylvania (yjho@sas.upenn.edu); Updated July 2010. For More Information • Center for HIV/AIDS Vaccine Immunology (CHAVI): http://www.chavi.org/ Continue to II. Logistical and Ethical Considerations in HIV Vaccine Clinical Trials
1 HIV/AIDS Policy Factsheet: the HIV/AIDS Epidemic in the United States. Sept 2009. The Kaiser Family Foundation. |
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