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Challenges in HIV Vaccine Development – An Overview In 2007, the United States entered its twenty-sixth year since the beginning of the HIV/AIDS epidemic with approximately 1.2 million people living with HIV/AIDS.1 Internationally, the 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, life expectancy in Zimbabwe was estimated to have been 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 licensed in 2015 could prevent between a tenth and a half of the 150 million new infections expected to occur between 2015 and 2030. Without a vaccine, the number of new infections per year could increase from 6 million today to 10 million by 2030.5 Given these discouraging statistics and projections, the development of a safe and effective HIV vaccine remains an eagerly anticipated, yet 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 about 50 years for the polio and measles vaccines to be developed once their causative agents were identified.6 With the HIV vaccine, development has been further complicated by a formidable array of biological, political, economic, logistical, and ethical issues. The early years of the AIDS pandemic were marked with politicians downplaying or even denying altogether the seriousness and scale of the disease. Progress in vaccine research stalled in the mid-1990s, a time when HIV vaccine research funding constituted only about seven percent of the National Institutes of Health’s (NIH) AIDS budget. Scientists thought the vaccine effort was “dead,” the private sector had condemned vaccines as unprofitable, and AIDS activists pushed successfully for money to be spent on drug treatments instead of vaccines. One hypothesis could attribute the delay in vaccine development in part to a lack of funding, particularly by the private sector. IAVI estimates that in 2005, the pharmaceutical industry spent approximately $75 million on AIDS vaccine research, a number which constituted only 10 percent of the total $759 million spent worldwide.7 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.8 The industry faces some compelling reasons to refrain from greater investment. The process of developing an HIV vaccine has already proven to be extremely difficult, costly, and time-consuming. Conducting clinical trials requires pharmaceutical companies to deal with a constellation of ethical, political, and economic issues, and they have no guarantee of profiting from these endeavors. This potential lack of profit is a result of the likely demand for an HIV vaccine and the nature of vaccines, generally. The countries most in need of the vaccine are precisely those which have the least ability to pay: low- to middle-income nations.9 Additionally, most vaccines are administered once or twice in a person’s lifetime, as opposed to drugs which must be taken daily over long periods of time. Accordingly, among the best-selling and most profitable drugs are those that lower cholesterol and control asthma and depression, not preventive interventions like vaccines. Pharmaceutical companies, as president and founder of IAVI Seth Berkley says, “are looking for blockbuster drugs, the multi-billion drug, the next big thing” – which is unlikely to be, in terms of revenue, the HIV vaccine.10 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.11 The bulk of the money has gone towards treatment, which competes with research funding. In poor countries with high HIV prevalence, investing in high-tech research – the type crucial to the successful development of an HIV vaccine – is a low priority, if not an impossibility.12 The Global HIV Vaccine Enterprise, an international effort at coordinating HIV vaccine research directions, predicts that global spending to implement their strategy would cost $1.2 billion per year. In 2006, global spending from all sources totaled slightly more than 50% of that figure -- $684 million.13 Funding from private groups such as the Gates Foundation has been one response to these funding shortfalls and promote research that could lead to a vaccine. Another strategy being considered for HIV and other vaccines is the “advance market commitment,” a large sum of money governments would guarantee to pharmaceutical companies in order to ensure demand and prices at a profitable level, thus making research and development less of a financial risk for industry.14 That said, some analysts of research funding ask if the problem is not one of enough money being spent bit, instead, existing funds not being allocated appropriately.15 Biological Reasons It may seem difficult to understand why, in an age of gene therapy and miracle drugs, developing an HIV vaccine continues to be so difficult. Part of this attitude may reflect the current outlook on science and medicine from the public and scientific community. As journalist Michael Specter notes, biology is now driven by genomics instead of trial and error.16 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. Seth Berkley critiqued this approach, lamenting that “it cost us at least a decade.”17 However, vaccine development has always been very challenging.18 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. Human immune systems are 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 admitted that “in the strict scientific sense, we don’t know how the [whole-cell] pertussis vaccine works.”19 Much of the difficulty in developing an HIV vaccine can be attributed to the unique biological mechanisms of the virus, some of the same characteristics that make it so formidable as a global health threat. HIV is a retrovirus, which means that its genetic information is contained in RNA instead of DNA. Currently, no vaccines against human retrovirus infections exist, so researchers lack prior models to work from.20 Those infected with HIV develop a broad range of immune responses against the virus, but these responses fail to eliminate HIV or prevent progression to AIDS.21 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.22 Those on the quest for an HIV vaccine must overcome the virus’ effectiveness 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 and biological functioning often rely 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.23 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.24 These are not the only issues posed by working against such an intricate virus. For example, most scientists believe that two classical approaches to developing viral vaccines, using whole inactivated or live-attenuated (weakened) viruses, cannot be utilized due to safety and ethical reasons. They have instead turned to more modern and technologically sophisticated techniques, such as developing subunit vaccines, which contain only a part of rather than the whole virus.25 During the mid- to late 1990s, controversy arose over attempts to introduce a live-attenuated HIV vaccine, which would be particularly dangerous due to its potential to cause AIDS or an autoimmune or other malignant disease.26 Experiments with primates showed that some macaques who were given the candidate vaccine eventually developed an AIDS-like syndrome and also suggested that the strains used in the vaccines could be deadly to individuals with immature immune systems.27 In past experience, 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.28 In 1997, the International Association of Physicians in AIDS Care (IAPAC) presented its plan to test a live-attenuated HIV vaccine in people. 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 safety concerns and the need for more data gathering are undeniable, 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.”29 It can be argued that 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 small number of people (in comparison to those saved) were at risk of infection from the vaccine itself.30 While research on live-attenuated vaccines has all but vanished, researchers’ current work is further complicated by a lack of suitable animal models to test the vaccines on before initiating trials with humans. Experiments currently involve chimpanzees infected with HIV and monkeys infected with Simian Immunodeficiency Virus (SIV), a related virus, but vaccine candidates have invoked different responses in each animal model.31 Research is further complicated by HIV’s genetic variability and geographical distribution. The are nine subtypes, or clades, of the virus, and viruses from different subtypes can recombine to create new hybrid viruses, known as circulating recombinant forms (CRFs), which also infect humans.32 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.33 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.34 Conclusion Given the numerous challenges in acquiring research funding and the science in developing 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 progression to AIDS.35 Some scientists are skeptical that a vaccine that fully prevents HIV will ever be created, but many remain optimistic about the prospects for a vaccine that can 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 development of safe, effective, and accessible HIV vaccines. Its research and development (R&D) projects have resulted in six vaccine candidates that have entered 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 cover key issues such as R&D expenditures, future spending needs, vaccine demand, health and economic impacts, and incentives to increase industry participation.36 Proposed by vaccine researchers in 2003, the Global HIV Enterprise focuses on speeding vaccine development through scientific collaboration, mobilizing funding to increase resources, and 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” and having the ability to tackle “major scientific problems that have proven too difficult for any one group to address alone.”37 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 funders by holding an annual Funders’ Forum. Dedicated to facilitating and coordinating HIV research, the Enterprise encourages collaborative, high quality, and timely research.38 CHAVI, which was launched by the NIH, also was created in response to the many obstacles in HIV vaccine development. Founded in July, 2005, the consortium established clinical trial sites, clarified its scientific goals and protocols, and dealt with intellectual property issues in its first year.39 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.40, 41 It is hoped that these and other innovative international partnerships will fulfill their missions and aid researchers in working towards an HIV vaccine. -- By Jessica Ho, University of Pennsylvania (yjho@sas.upenn.edu) For More Information
• Center for HIV/AIDS Vaccine Immunology (CHAVI): http://www.chavi.org/
1 HIV/AIDS Policy Factsheet: the HIV/AIDS Epidemic in the United States. 11 July 2007. The Kaiser Family Foundation. 26 July 2007 <http://www.kff.org/hivaids/upload/3029-071.pdf>. |
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