Health Affairs, 24, no. 3 (2005): 643-651 doi: 10.1377/hlthaff.24.3.643 © 2005 by Project HOPE	New Online   Pay Cuts For Medicare Docs   Access To Care Woes   Public Coverage More Efficient   Empowering Consumers

This Article Abstract Reprint (PDF) Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to Citation Manager Reprints & Permissions Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by McCluskey, M. M. Articles by Wakefield, S. Search for Related Content PubMed PubMed Citation Articles by McCluskey, M. M. Articles by Wakefield, S. Related Collections AIDS/HIV Consumer Issues Health Promotion/Disease Prevention International Issues Vaccines Public Health Research And Technology

Infrastructure

An HIV Vaccine: As We Build It, Will They Come?

Abstract

 
Early researchers accurately predicted that AIDS would have a globally destructive impact. However, other experts erroneously believed that they would be able to develop a vaccine against the virus in a relatively short period. More than twenty years later, scientists continue to work to achieve this goal. This paper addresses the unique obstacles faced by HIV vaccine researchers. It concludes with recommendations for how policymakers and public health officials could collaborate with researchers to overcome these obstacles and contribute to the discovery of an HIV vaccine that would save millions of lives.

Although some were able to anticipate the destructive impact of HIV, others erroneously predicted the speedy development of a vaccine. Following its emergence, two years passed before researchers identified the actual pathogen, HIV.⁴ More than twenty years later, scientists continue to seek effective human immunity against HIV infection. The initial desire to be optimistic is understandable. The disease was killing young, vibrant people and was not amenable to available therapies. Creating an expectation for an imminent vaccine, however, may have added undue pressure to the process of vaccine discovery.

This paper examines the purpose and goals of an HIV vaccine, the obstacles to developing it, and what policymakers can do to strengthen trust in the vaccine development process and to ensure a supply of volunteers to test the vaccine.

An HIV Vaccine: Goals And Timeline

Top An HIV Vaccine: Goals... A Further Step: Engaging... NOTES

 
Arguably, vaccines are the most effective and affordable means of diminishing the spread of infectious diseases. According to the World Health Organization (WHO), an HIV vaccine would complement other preventive interventions and could reach populations where other efforts (such as the "ABC" method—"Abstinence, Be faithful, and use Condoms") have been insufficient. The WHO also suggests that a vaccine may serve as a therapeutic intervention in association with antiretroviral therapies (ARVs), the current treatment for slowing the progression of HIV. This approach could lead to a decrease in the cost of treatment and an increase in its long-term efficacy.⁵

Long-term protection. In general, vaccines provide dependable and long-term protection against infectious agents. Vaccinations induce immunity to prevent infection or to keep an infection from persisting and causing disease. However, it is probable that the first licensable HIV vaccines will provide only partial protection. More specifically, HIV vaccines may initially create an immune response that cannot protect every cell from infection but instead slows the pace of infection enough to allow natural host defenses to rapidly clear virus-infected cells. The disease would progress more slowly, thereby reducing and delaying the need for ARV treatment. The vaccine could also augment conventional therapies by requiring the virus to mutate both the immunologically sensitive sequences and the active sites of ARVs in order to escape. Thus, despite persistent infection, the disease burden and the need for treatment would be diminished.⁶

Reduce transmission to others. An additional goal of HIV vaccine development is to create immunity that reduces transmission to others by decreasing a person’s viral load. Realizing this goal would benefit the population at large by slowing the pandemic over time.⁷ Many infections occur through contact with a person who has high levels of virus in the blood during the initial phases of infection.⁸ The infected person may be unaware of his or her HIV-positive status and may not have begun to receive treatment. Independently, these approaches cannot reverse the impact of the AIDS pandemic. Collectively, however, they have the capacity to mitigate the spread of HIV.⁹

Vaccine timeline: "How long will it take?" Although the value of an HIV vaccine is not in question, it remains unclear when such a vaccine will be available. It is common for effective vaccine development to take decades, but the development of an HIV vaccine has been particularly complicated because of its unique biological characteristics and its dependence on public participation in clinical trials.¹⁰

According to the International AIDS Vaccine Initiative (IAVI), twenty-five Phase I, four Phase I/II, two Phase II, and one Phase III trials (the final phase) are under way worldwide.¹¹ Many current trials are being conducted in countries where the general population is at greater risk for infection.

Biological factors affecting the timeline. HIV-1, the virus that leads to the vast majority of AIDS cases worldwide, is unique in its ability to elude the body’s attempts to create natural immunity. HIV not only mutates frequently, it has also developed other mechanisms to become immunologically silent and to hide its vulnerable sites from immune responses. In particular, it has been difficult to produce vaccine antigens that can induce broadly neutralizing antibodies to HIV. There is no known lasting natural immunity against HIV; virtually all who are infected with HIV eventually succumb to AIDS.¹²

If researchers clearly understood what the immune system must produce to prevent HIV from infecting the very cells that otherwise prevent infection, a safe vaccine could be developed to mimic this immunity. However, while there is temporal variability, HIV acts to defeat the immune systems of the infected person by entering the T-cells, the white blood cells that are part of the immune system. Indeed, no one has cleared infection naturally.¹³

Social barriers to ensuring participation in clinical trials. With aggressive HIV vaccine research efforts under way worldwide, tens of thousands of people—the majority in countries with high HIV prevalence rates—will be needed as clinical trial volunteers. These otherwise healthy people will have to make sacrifices for the sake of research. They will have to commit time, respond to invasive questions, and potentially face negative reactions from their family and friends. The vaccines they receive may not provide any level of protection or confer any immediate or long-term benefits. Because the vaccines are being given to human subjects for the first time, there are inherent risks, even if theoretical.

Unfortunately, HIV vaccine research is burdened by inherent public mistrust based on misinformation, erroneous assumptions, and unrealistic expectations. Many do not presume that HIV vaccine research is being conducted for the greater good. The erroneous assumption that trial participants are at risk for HIV infection can preempt effective communication between researchers and the public. And it is feasible that principles of paternalism can play a role in the explanations of these investigational products. Some less experienced researchers may be tempted to sidestep difficult explanations of the vaccine product and trial procedures, despite strict ethical and regulatory mechanisms that are in place worldwide. In general, however, HIV vaccine researchers go to great lengths during the informed consent process to present a plethora of understandable materials and information, devoid of any coercive overtones, that emphasize volunteering as a personal choice.

Nevertheless, the public’s knowledge about HIV vaccine research may be limited and erroneous and its trust of the process, impaired. For example, a 2001–2002 survey conducted by the National Institute of Allergy and Infectious Diseases (NIAID) indicates that more than 72 percent of African Americans, 49 percent of Latinos, 33 percent of men who have sex with men (MSM), and 46 percent of the general population either strongly agreed, somewhat agreed, or stated they did not know when asked if there was already a vaccine for HIV that was being kept secret. When asked whether the vaccines being tested could give a person HIV, 65 percent of African Americans, 71 percent of Latinos, 70 percent of MSM, and 69 percent of the general population either strongly or somewhat agreed that it could, or said they did not know.¹⁴

These answers also reflect a number of other community concerns with HIV vaccine research: general knowledge of HIV/AIDS, the frequency of messages targeting the community, general understanding of and interest in available research, the level of stigma associated with HIV/AIDS, denial of the existence and impact of HIV/AIDS, and the priority given to HIV/AIDS amid the myriad of other issues affecting the community (such as education, housing, and employment).

As indicated by the NIAID survey, mistrust is particularly strong among people of color. This mistrust has led to their relatively low representation in preventive HIV vaccine trials in the United States, despite their relatively high HIV prevalence rates. According to the 2000 census, African Americans represent 12.3 percent of the U.S. population. However, according to the U.S. Centers for Disease Control and Prevention (CDC), more than half of new HIV infections in 2003 occurred among African Americans. Women of color represented almost 85 percent of new infections, and African American women had a rate of AIDS diagnosis more than twenty-five times the rate of white (non-Hispanic) women.¹⁵ Poverty, social stigma, lack of access to care and prevention, substance abuse, and exposure to sexually transmitted diseases (STDs) are all factors in this imbalance. Although U.S. recruitment and education initiatives are in progress to improve statistical validity across all racial and ethnic groups, more resources are required to recruit diverse study populations.

The Dale and Betty Bumpers Vaccine Research Center (NIAID, intramural) and the HIV Vaccine Trials Network (NIAID, extramural) have gathered the most frequently asked questions from potential HIV vaccine trial participants. The issues addressed by these questions are not unique to any one trial (Exhibit 1). Providing easily understood information is the first step in overcoming the obstacles of adequate clinical trial participation.

Creating allies. Trust building also includes reaching out to those who may feel threatened by the vaccine research to explain how it will benefit them. For example, the development of an HIV vaccine requires the engagement of prevention and care/treatment providers and advocates who may be concerned that funding for their programs could be slighted in the effort to fund vaccine research. An HIV prevention provider may be the first person to be asked about vaccine research by someone who has just tested negative for HIV and could serve as an excellent referral for vaccine prevention trials. For HIV care/treatment providers, the partner in a serodiscordant couple (only one partner is infected) may ask about vaccine research, and, again, the provider could serve as an excellent referral source.

Members of the media are also invaluable allies in educating the public. Vaccines often only receive media attention when there are product shortages or when lawsuits arise. HIV vaccines are particularly vulnerable to media misinformation because of complexities in their product and protocol design. Accurate media coverage is essential to the success of future HIV vaccine trials.

A Further Step: Engaging Policymakers

Top An HIV Vaccine: Goals... A Further Step: Engaging... NOTES

 
Policymakers and public health professionals can play a pivotal role in assisting HIV vaccine researchers to educate the public as to why a vaccine against HIV is not yet available, what an initial vaccine might be able to accomplish, and what role the public might play in developing the vaccine. They can contribute to explicitly educating communities of color to alleviate their mistrust of HIV vaccine research and increase their participation in clinical trials.

Policymakers also can develop policies that help to eliminate the stigma that may prevent some people from participating in clinical trials. Finally, they have the ability to guarantee that, once available, the vaccine reaches those who are in greatest need of immunization.

Accelerating research. Although the threat of bioterrorism rapidly moved a package of incentives for anthrax and smallpox vaccines (direct funding for research, liability protections, accelerated regulatory review, and guaranteed fast-track licensure and purchase of new products), this same level of urgency has not been applied to developing a vaccine for HIV.

Financial investment. Private investment in such research is very low, perhaps because of the high risk and uncertain returns on investment in an HIV vaccine in contrast to many other pharmaceutical products. National scientific research institutions and other public-sector sources—such as international development agencies—account for the majority of funds invested in HIV vaccine research. The largest financial commitment to HIV vaccine research, by far, has come from the United States. The U.S. government spent well over $400 million on this research in fiscal year 2004 through its National Institutes of Health (NIH).¹⁶ Forging public/private-sector partnerships can bring together the strengths of these entities to accelerate the development of HIV vaccine.

Global efforts. The NIH has worked creatively to harness private-sector expertise by supporting companies that are designing novel vaccine approaches and conducting HIV vaccine research. IAVI has also facilitated public/private-sector partnerships, concentrating its efforts in developing countries. IAVI’s partnerships have paved the way for projected success in developing nations such as Rwanda and Kenya, where multiple public-sector agencies understand and endorse HIV vaccine research. One key result of this involvement is the establishment of prepared cohorts, ready and waiting for the next worthy HIV vaccine candidate to begin in expanded-phase clinical trials later in 2005. The South African Group and the United States Military HIV Research Program in Thailand and in East Africa are other examples of successful partnerships resulting in a responsive, edified, and prepared public, willing and eligible to participate in these HIV vaccine trials.¹⁷

During the summer of 2004, under the auspices of the Bill and Melinda Gates Foundation, the G8 countries endorsed the Global HIV Vaccine Enterprise, a coordinated plan to tackle scientific and infrastructural obstacles to the development of an HIV vaccine. These efforts could lead to a more cooperative marketplace with limited regulatory or trade barriers to HIV prevention and treatment.

Including young people. There are legal, medical, and ethical hurdles to including adolescents in clinical trials. Because informed parental consent is required, young people may be unduly influenced to participate by a parent or guardian. Nevertheless, because young people’s bodies are still changing, there may be differences in optimal dosage, side effects, and long-term impact that can be answered only by their inclusion in vaccine trials. Policymakers should be prepared to work with HIV vaccine researchers to ensure that these hurdles can be overcome.

Addressing stigma and discrimination. Some experimental vaccines may cause a trial participant to have a positive HIV test even though the person is not infected with the virus. Standard HIV tests look for antibodies that recognize HIV, and the study vaccine may have caused the body to produce these antibodies. A more sensitive test can prove that there is no HIV infection. Despite this, the stigma and discrimination that affect people living with HIV/AIDS might affect those who participate in vaccine trials. People with a positive HIV test, even a false positive, are not allowed to donate blood. They also might have difficulties getting insurance or health care, traveling to other countries, obtaining employment, serving in the military or Peace Corps, or in their relationships with friends and family.

Policymakers are in a position to help alleviate the impact of this stigma. For example, they could compel life insurance companies to amend their laboratory screening protocols. If a potential client has a positive screening ELISA antibody test (the standard initial test given to detect HIV infection), the company could automatically administer the more sensitive and specific Western Blot test to discern between a false-positive vaccine ELISA and a true HIV infection.

Ensuring access. To achieve effective and equitable distribution of the HIV vaccine once it is available, governments and international organizations will require both adequate supplies of the vaccines from manufacturers and the infrastructure to deliver the vaccine quickly. Developing countries now wait an average of twenty years after a vaccine is licensed in industrialized countries before it begins to reach their own populations. Hepatitis B vaccine uptake and policies provide insight into the enormous challenges of adult immunization in industrialized countries. Although the vaccine has been available for more than twenty years, financial barriers—as well as a lack of awareness—have prevented many people at risk for infection from receiving an immunization.

It is difficult to establish comprehensive estimates of potential demand, but this information will be crucial for planning how to finance, produce, and deliver a successful vaccine. Policymakers will need to bring together the stakeholders, including vaccine manufacturers, who can work collectively to generate demand estimates for a range of different AIDS vaccines.

Good science will produce a vaccine against HIV. However, good science in and of itself will not be enough. A promising vaccine candidate without the volunteers needed to test it, or a vaccine that is not trusted by the people it is meant to benefit, will impair long-term success. To succeed, researchers must collaborate with policymakers and public health officials to engage the public in the pursuit of an effective HIV vaccine.

Policymakers and public health officials must educate themselves and their constituencies regarding HIV vaccine research. They must find opportunities to speak publicly about the research and contribute to educating prevention and treatment workers and advocates about its benefits to their work. Policymakers should collaborate with clinical trial staff to dispel myths about the research being conducted. Finally, they should call on the public to do its part to achieve the overwhelmingly important goal of finding a vaccine that will save lives and begin to diminish the devastating impact that HIV/AIDS is having worldwide. The more than 20,000 volunteers who have already participated in clinical trials to find an HIV vaccine deserve the highest praise for their selfless contribution. We encourage others to join their ranks.

Editor's Notes

 
Margaret McCluskey (mmccluskey{at}nih.gov) is clinical operations manager of the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) in Bethesda, Maryland. Sarah Alexander is associate director, Communications and External Relations, of the HIV Vaccine Trials Network of the Fred Hutchinson Cancer Research Center in Seattle, Washington. Brenda Larkin is nurse manager at the VRC. Matthew Murguia is director of the NIH Office of Program Operations and Scientific Information, Division of AIDS. Steven Wakefield is associate director, Community Outreach and Education, at the HIV Vaccine Trials Network in Seattle.

The authors acknowledge Chrispin Kambili of the International AIDS Vaccine Initiative (IAVI/Nairobi) for his contribution in describing the IAVI mission, philosophy, and success in East Africa.

NOTES

Top An HIV Vaccine: Goals... A Further Step: Engaging... NOTES

 

1. J.M. Mann, "The Global AIDS Situation," World Health Statistics Quarterly 40, no. 2 (1987): 185–192.[Medline]
2. UNAIDS, 2004 Report on the Global AIDS Epidemic (Geneva: Joint United Nations Programme on HIV/AIDS, June 2004), 10.
3. J. Esparza and N. Bhamarapravati, "Accelerating the Development and Future Availability of HIV-1 Vaccines: Why, When, Where, and How?" Lancet 355, no. 9220 (2000): 2061–2066.[ISI][Medline]
4. R.C. Gallo et al., "Isolation of Human T-Cell Leukemia Virus in Acquired Immune Deficiency Syndrome (AIDS)," Science 220, no. 4599 (1983): 865–867.[Abstract/Free Full Text]
5. World Health Organization, "HIV Vaccines," www.who.int/hiv/topics/vaccines/Vaccines/en/print.html#references (22 January 2005).
6. A.T. Catanzaro and B.S. Graham, "Rationale for Current HIV Clinical Trials," in Recent Advances in HIV Infection Research, ed. G. Buela-Casal and M.P. Bermudez (Granada, Spain: University of Granada, forthcoming).
7. I.M. Longini Jr., S. Datta, and M.E. Halloran, "Measuring Vaccine Efficacy for Both Susceptibility to Infection and Reduction in Infectiousness for Prophylactic HIV-1 Vaccines," Journal of Acquired Immune Deficiency Syndromes 13, no. 5 (1996): 440–447.
8. C.D. Pilcher et al., "Brief but Efficient: Acute HIV Infection and the Sexual Transmission of HIV," Journal of Infectious Diseases 189, no. 10 (2004): 1785–1792.[CrossRef][ISI][Medline]
9. Catanzaro and Graham, "Rationale for Current HIV Clinical Trials."
10. W.L. Heyward, K.M. MacQueen, and K.L. Goldenthal, "HIV Vaccine Development and Evaluation: Realistic Expectations," AIDS Research and Human Retroviruses 14, Supp. 3 (1998): S205–S210.
11. For a regularly updated database of HIV vaccine trials, see International AIDS Vaccine Initiative, "Ongoing Trials of Preventive HIV Vaccines," www.iavireport.org/trialsdb (25 January 2005). Phase I trials answer safety and immune-response questions and generally involve a small number of participants at low risk for infection. Phase I/II trials also answer these questions and involve a midsize group of low-risk participants. Phase II trials continue to address safety and immune-response questions while also evaluating optimal dosing. Phase II trials generally engage a midsize group of participants who are at moderate to high risk for infection. If a Phase II trial is successful, researchers move on to Phase III trials, which generally involve a large group of participants at high risk for infection. The goal of Phase III trials is to determine if the vaccine actually works.
12. Catanzaro and Graham, "Rationale for Current HIV Clinical Trials."
13. J.N. Blankson, D. Persaud, and R.F. Siliciano, "The Challenge of Viral Reservoirs in HIV-1 Infection," Annual Review of Medicine 53 (2002): 557–593.[CrossRef][ISI][Medline]
14. Numbers polled were as follows: 2,000 general population, 500 African Americans, 500 Latinos, and 500 men who have sex with men. National Institute of Allergy and Infectious Diseases (NIAID), unpublished survey, December 2001–February 2002.
15. U.S. Centers for Disease Control and Prevention, HIV Surveillance Report, vol. 15 (Atlanta: CDC, December 2004).
16. National Institutes of Health, Fiscal Year 2004 Plan for HIV-Related Research, May 2002, www.nih.gov/od/oar/public/pubs/fy2004/i_overview.pdf (15 November 2004).
17. International AIDS Vaccine Initiative, "Developing and Delivering an AIDS Vaccine: Issues and Answers," July 2004, www.iavi.org/file.cfm?fid=401 (22 February 2005).

                      What's this?