March 2002

HRSA Care ACTION

AIDS Vaccines: Flickers of Progress, but a Long Way to Go

In the United States, significant resources, both public and private, have been dedicated to developing an AIDS vaccine. Although progress has been made, tremendous scientific, ethical, and logistical challenges must be overcome before the hope for a vaccine can become a reality. The vaccine development landscape changes almost daily, and the nation’s leading newspapers and AIDS-related websites are replete with news of breakthroughs, setbacks, and opportunities. Yet the reports do not always relay the fundamental principles that can give individuals a broader, more contextual understanding of where we stand in the fight to develop an AIDS vaccine. In this article, we seek to give the CARE Act community a framework for understanding the AIDS vaccine landscape. For individuals and organizations struggling to allocate scarce resources while grappling with growing HIV prevalence, such a framework is critical. And for securing access to up-to-the minute information, we provide a list of Web-based resources (see box, page 2), which can apprise readers of the most recent developments. o

Given the number of people infected with HIV—58 million worldwide since the disease was detected—and the rate at which it continues to spread, a vaccine may be the only practical and cost-effective way to bring the epidemic to an end. No true cure has been found for AIDS, and the drugs currently available, although somewhat effective, are expensive, toxic, and difficult to take. Moreover, they are out of reach for the majority of individuals living with HIV disease. Traditional prevention efforts based on education and behavior change have had limited results. The consequence is that every day, more than 16,000 people become infected with HIV, primarily in the developing world. AIDS is cutting the life expectancy in some African countries nearly in half. Insufficient resources and imperfect tools make it impossible to prevent new infections or to treat the millions of people who are living with HIV/AIDS.

A vaccine is a drug that mimics a dangerous organism, or pathogen, and creates immune-system memory concerning that specific pathogen. Vaccines prepare the body’s immune system to defend against infectious organisms—usually either bacteria or viruses—so that the first time a pathogen invades the body, the immune system is ready for it. Vaccines are disease specific: A vaccine against polio protects only against polio, and a vaccine against HIV infection will protect only against HIV infection.

Vaccines may be made from inactivated pathogens, weakened pathogens, or manufactured fragments of pathogens. Vaccines do not fight a pathogen directly; rather, they teach the immune system to recognize an organism as foreign and to mount a faster and more vigorous response than it would without a vaccine. Vaccines can be either prophylactic (i.e., preventative) or therapeutic (i.e., used in treatment). In the latter case, the vaccine is given to stimulate the immune system to modulate or eliminate the disease after it has begun to take hold.  Two key parts of the immune system are involved in vaccines: cellular immunity, which is organized primarily by T-cells, and humoral immunity, which is largely the work of B-cells. T- and B-cells are specialized types of white blood cells. T-cells largely work to kill the body’s own cells when they become infected with a pathogen. B-cells produce antibodies—proteins that stick to free-floating foreign invaders in the bloodstream to disable them and mark them for destruction.

Ideally, someone who has been vaccinated against a particular organism will generate "memory cells." Memory cells help mount a strong and rapid immune system mediated defense and thereby give the body a head start when exposed to the pathogen covered by the vaccine. The goal for an AIDS vaccine would be to involve both the cellular and the humoral components of the immune system.  T-cells would recognize and destroy human cells that have been infected with HIV, and antibodies generated by B-cells would attack free virus in the bloodstream. 

Other bacteria and viruses that have been successfully countered by vaccines have proven to be much easier targets than HIV. Most other pathogens have relatively few subtypes that cause disease. HIV, however, is different. Worldwide, researchers have found at least 10 different HIV subtypes, which are divided into two major classes: HIV-1, which is most prevalent in North America and Europe, and HIV-2, which is found primarily in Africa and Asia. The genetic sequences of different virus subtypes vary widely. In addition, HIV continues to mutate the sites where destructive antibodies might attach, meaning that a vaccine effective against one subtype may have no activity against the others and that new strains can develop that might be able to escape the effects of a vaccine. In fact, the variation found in the HIV virus in just one infected person dwarfs the total variation seen in influenza viruses from all over the world.¹ Moreover, during much of the HIV life cycle, potential points of attack are covered in a protective armor made of sugar compounds and, as a result, are not vulnerable to the immune system. 

Perhaps most challenging, HIV—unlike most viruses—attacks some of the very immune cells that are needed to combat it. When HIV enters the body, it infects a particular type of T-cell, CD4+ cells, which play an important role in organizing the body’s immune response. Because HIV attacks the immune system, only vaccines that provide less than "sterilizing immunity" (i.e., complete protection) may be possible.

Instead of complete protection (which, of course, is the "Holy Grail" of AIDS vaccine research), a vaccine might be able to prevent infection only in some people or simply block continued infection, reduce the amount of virus in an individual, or delay the onset of symptoms following HIV infection. Although a "perfect" vaccine (see box) certainly is the goal, a vaccine that confers less than complete protection still could have a major impact on reducing the incidence of HIV disease. Combined with prevention efforts and treatment, even a partially effective vaccine could be an important weapon in reducing the number of new cases of AIDS. More must be learned about the interaction between HIV and the immune system and how the virus eventually overwhelms the ability of the immune system to root it out. 

Once a promising vaccine approach is identified, the vaccine candidate must be studied in the test tube, then in small animals, and then, finally, in nonhuman primates before human trials can begin. Testing AIDS vaccines, however, requires human subjects—no perfect animal model of the disease has been developed.

Each vaccine candidate thought promising enough to be studied in a human efficacy trial (also called a Phase III trial; see box, page 4) requires thousands of participants who must be followed for at least 3 or 4 years. Ideally, for the trials to determine whether a vaccine is effective, they should include people whose behavior puts them at risk for infection. In the United States and Europe, people at high risk for infection include men who have sex with men, sex workers, intravenous drug users, and people with multiple sex partners. Often these groups of people have reason to be distrustful of government and other institutions; as a result, they are difficult to identify and recruit into trials.

Similarly, many people in developing countries who could  participate in vaccine trials are poorly educated about medical science. Special care must be taken to obtain truly informed consent when recruiting such participants into trials: Unproven vaccines offer potential dangers as well as potential benefits. Both recruitment and the trials themselves must be conducted in a culturally appropriate manner. Developing countries, where AIDS is epidemic, generally lack the indigenous medical personnel and scientific infrastructure needed to support clinical trials and to distribute a vaccine once it is available. Those challenges must be addressed as well.

Many vaccine candidates can result in volunteers testing positive on an HIV test—even if they have not been infected. A positive test may result in employment, housing, or other discrimination, which is not prohibited by law in many parts of the world. It is important to find ways to prevent discrimination and avoid conferring a stigma on people who enter trials if the trials are to attract a sufficient number of volunteers.

Wherever a vaccine is tested, it needs the support of the community. A trial cannot go forward without widespread community involvement, simply because of the number of volunteers any trial would need. Moreover, should an effective vaccine be found, it is unlikely to find a receptive audience without widespread community involvement and support.

Once a vaccine is developed, it will be important to ensure that it is made available to people most in need. Unfortunately, the countries with the greatest HIV infection rates generally are among those with the fewest resources and most rudimentary public health systems. At the same time as scientific challenges are being addressed, it is critical that ways be found to pay for and distribute the vaccine to all areas of the world where HIV is a threat. It is instructive to keep in mind that some two decades after the development of an effective hepatitis B vaccine, 1 million people each year die from hepatitis B, mostly in the developing world, where the vaccine generally is not available. In fact, the only disease that has been eliminated worldwide through vaccination is smallpox.

More than 60 human clinical trials of some 30 vaccine candidates have been conducted to date. Most have focused on protein targets—primarily glycoproteins gp120 and gp160—located on the outer layer of the HIV virus, or the envelope. Generally, the vaccine candidates have stimulated the immune system to produce antibodies, but the antibodies have not reacted against the HIV virus itself.  The only vaccine to reach Phase III clinical trials is AIDSVax, a genetically engineered vaccine developed by VaxGen.

AIDSVax contains synthetic gp120, an antigen found on the outer layer of HIV. An antigen is a molecule on an organism that is seen as foreign by the immune system. When it comes into contact with an immune-system cell, it stimulates  the immune system to attack it. The function of gp120 in HIV is to help the virus attach to human cells so that it can enter the cells and cause disease. Scientists studying AIDSVax hope that people who are vaccinated and later exposed to HIV will develop a rapid antibody response that will coat the gp120 antigen and stop it from attaching to and entering human cells, thereby preventing HIV from causing disease. Results from the trials, which are taking place in the United States, Canada, the Netherlands, and Thailand, are expected late this year. One additional vaccine candidate, ALVAC, is scheduled to enter Phase III trials in Thailand this year in a study sponsored by the pharmaceutical company Aventis Pasteur and the U.S. Department of Defense.

The theory underlying therapeutic vaccination is that someone already infected would induce viral suppression and interrupt the progress of the disease. Interest in therapeutic vaccines began early in the course of the AIDS epidemic because HIV-infected people were found to develop immune responses to vaccines. Unfortunately, those responses did not induce a drop in viral load or a delay in disease progression. Now that highly active antiretroviral combination with HAART.  

Given what we have learned about the immune system’s response to HIV infection, many scientists are optimistic about the prospect of developing an effective vaccine.  Soon after infection, HIV reproduces vigorously. Even without medication, however, the immune system usually is able to reduce the number of viral copies in the bloodstream and hold HIV in check for a significant period of time. In addition, some people can be repeatedly exposed to HIV and not become infected; others who are infected become "longterm nonprogressors" and remain healthy for many years without treatment. Experimental vaccines in animals have been shown to be protective; although the evidence is preliminary and its significance unclear, promising immune- system responses have been seen in human vaccine trials.  Most important, the number of vaccine candidates in preclinical studies has increased dramatically. After many lean years, determined attention to AIDS vaccine research is coming not only from the government but also from the pharmaceutical industry, private foundations, researchers, and activists in the United States and in other countries. Vaccine efforts are led at the Federal level by the National Institute of Allergy and Infectious Diseases (NIAID) through its international HIV Vaccine Trials Network, which conducts all phases of vaccine research. NIAID also has established an AIDS Vaccine Research Committee, headed by Nobel laureate David Baltimore, to help coordinate vaccine research. For FY 2002, the Federal Government plans to spend $356 million on vaccine initiatives, a 27- percent increase over FY 2001. The new Dale and Betty Bumpers Center for Vaccine Research at the National Institutes of Health is focused on developing an AIDS vaccine as its first effort.

1. Vastag B. HIV vaccine efforts inch forward. JAMA.2001;286(15):1826-8.

Women and the AIDS Epidemic: An Update

Of the 40 million children and adults living with HIV disease today, approximately 17.6 million are women.¹ In India and Thailand, the rate of infection among women is increasing, and in sub-Saharan Africa, more women are living with the  disease than are men.²  Although a smaller proportion of cases is found among women in the industrialized world, it continues to increase, underscoring the need for improved access to care.

Wherever they live, HIV-infected women share certain characteristics. For example, most women contract HIV through heterosexual contact.³ Isolation and discrimination are pervasive among women with HIV disease, and so is poverty, a constant since the onset of the epidemic. Even in the resource-rich United States, most women with AIDS are unemployed and live in households in which the total income is less than $10,000 per year; many were poor before they became infected.⁴  According to a recent American Journal of Public Health article, "40 percent of AIDS diagnoses [in the United States] were in the nation’s poorest counties, although they contain just 25 percent of the 1998 population," and the poorer an HIV-positive person is, the greater her risk for dying from AIDS.⁵

The AIDS epidemic among women in the United States has received increased attention in recent years. Providers have  become more responsive to the complexity of problems that normally coexist with HIV infection among women, and the specific challenges women face have received more attention in treatment guidelines, in the scientific literature, and in the general media. 

The Ryan White CARE Act provides critical assistance for women living with HIV disease in the United States. Few HIV-positive women in care have private health insurance; approximately 50 percent are covered by Medicaid, the single largest payer for AIDS care in the United States.⁶  Women and their families may also be eligible for a variety of other programs, such as Federal and State maternal and child health initiatives and State Children’s Health Insurance Programs. Yet, those programs do not cover some of the services essential for securing health and well-being. The CARE Act is vital to filling those gaps.

Today, adult and adolescent women account for 20 percent of people living with AIDS in the United States but constitute almost one-third (approximately 31.5 percent) of the 500,000 Ryan White CARE Act clients—and a much higher proportion for some programs.⁷ Paramount among them is the Title IV program, which specifically targets women, adolescents, children, and families, and currently funds 90 grants in both rural and urban areas.

In the context of an epidemic in which women increasingly bear the burden of the disease, special CARE Act and  HIV/AIDS Bureau (HAB) activities that target women are improving access to care. Among those activities are the following initiatives:

The CARE Act Amendments of 2000 require that Title I and II funds be used to serve women in proportion to their representation in the local epidemic.

A National Minority AIDS Education and Training Center is enhancing the quality of care in minority communities.

The SPNS Adherence Initiative is reaching individuals with a history of poor adherence. Simultaneously, new models of adherence support are being evaluated.

A Guide to the Clinical Care of Women with HIV/AIDS, the most comprehensive text on the care of women available, was created by the HIV/AIDS Bureau and distributed throughout the country and, indeed, around the world. (Copies are available through the HRSA Clearinghouse at 1-888-ASK-HRSA.) o

Despite these and other efforts throughout the Nation, women with HIV infection are still more likely than men to enter care long after seroconversion, and the decreases in AIDS morbidity and mortality seen among women through 1998 have slowed dramatically (figures 1 and 2). The change from 10,780 new diagnoses in 1999 to 10,459 in 2000 was a decline of only 2.9 percent (see figure 1).⁸

The Northeast region of the United States is home to more women living with HIV disease than any other part of the country, but the South has the fastest growing rate of new AIDS cases among women. (More than half of those cases are in two States: Texas and Florida.) And among women, the leading HIV exposure category has shifted from injection drug use to heterosexual contact. Nationwide, heterosexual contact continues to be the most significant HIV exposure category—62 percent of cases among women reported in 1999.⁹ 

To say that women of color continue to be disproportionately affected by the AIDS epidemic in the United States significantly understates the problem. African American women, who constitute just 12.8 percent of the U.S. female population age 15 and older, account for a staggering 62.6 percent of AIDS cases among women.¹⁰  Hispanic women— just 11.7 percent of the female population in the United States—account for an additional 17.7 percent of female AIDS cases. The number of AIDS cases per 100,000 individuals (i.e., the AIDS rate) is 45.9 for black women and 13.8 for Hispanic women, compared with 2.2 for whites.  Although American Indian/Alaska Native women constitute a comparatively small proportion of the U.S. population (1 percent), the AIDS rate among this group is 8.3—almost four times the rate among whites; the rate for Asian/Pacific Islanders is 1.7.¹¹

"If we can get women into care, we know how to take care of them," says Dr. José Rafael Morales, chief of the Comprehensive Family Services Branch, Division of Community Based Branch Programs, at HAB. Before coming to lead the CARE Act Title IV program, Morales was medical director at the Migrant Health Clinic, Western Region Inc., in Mayaguez, Puerto Rico. "We know that a comprehensive approach to the problems faced by women  and their families is essential for ensuring that they stay in care, benefit from therapy, and take care of their families," he says.

It is now widely understood that the epidemic among women cannot be separated from women’s disproportionate burden of interrelated problems such as poverty, lack of health insurance, and low levels of educational achievement; issues of poor access to housing, substance abuse, and other mental health disorders also play a significant role. (See "Women and HIV/AIDS," HRSA Care Action, December 1998, at http://hab.hrsa.gov/publications.)  Mistrust of the medical system is known to be a complicating factor, as are poverty- and HIV-related stigma and both the reality and the specter of the race based discrimination minority women face.

Gender alone does not predict adherence to treatment regimens, but ample evidence indicates that trying to meet subsistence needs with limited resources interferes with behavior change and accessing services.¹²  "We’ve said it over and over again," says Morales, "but we have to keep saying it: Providing services like transportation, child care, entitlements counseling, and case management is a must, if women are going to stay in care over time."

Poverty and comorbidity appear to be as common as ever among women entering care for the first time, and other problems are emerging. "We continue to see women living in poverty, and they continue to enter care relatively late in the course of disease," says Jesse Chipps, executive director of BABES, a CARE Act funded social support resource for women in Seattle. She notes that a growing number of HIV-positive women are being diagnosed with hepatitis C; however, she believes that part of the growth is due to increased testing, rather than increased incidence. She also cites a rise in the incidence of mental health problems among the 450 patients currently served by her organization, an increase she suggests may be related in part to treatment failure. Chipps puts it this way: "Treatment failure is occurring in women who came into care after 1996 and have never known AIDS without HAART. They are not prepared for the realities of HIV disease that does not respond to treatment, and providers aren’t always prepared to help them cope."

Morales, who continues to provide clinical care, notes another phenomenon—the frequency of which isunknown—now occurring in his practice. "Women are coming to me and saying, 'Dr. Morales, I want to go off my meds.’ These are women who have been on complicated regimens since 1996, and they are tired." Morales believes that such decisions rest solely with the patient, but he cautions that patients do not always understand the implications. "Sometimes," he says, "they go off without telling me, not understanding the concept of resistance."

The problems that HIV-infected women face every day have been much discussed in the literature, but one factor not always fully understood is the lack of emotional support many women endure. For example, of the HIV-infected women ages 15 to 44 in the United States, only 14 percent are married, compared with 50 percent of all women in the same age group. Approximately 23 percent of infected women live without an adult companion, and 50 percent have at least one child younger than 15 years old.¹³  Although marriage and shared-living situations are not panaceas for the problems of HIV/AIDS, the data imply that many women living with the disease may be isolated and living without the kinds of interpersonal supports that are often essential for well-being and even survival.

With no end in sight to the AIDS pandemic, a staggering number of HIV-positive women—no one knows how many—remain undiagnosed and out of care. "We can’t get women into care earlier after seroconversion," says Morales, "unless they are being tested." HIV counseling and testing as part of primary care is critical for reaching these women. "And we are currently treating a chronic disease, not an acute condition," Morales says. "We have to help women learn how to take care of themselves and how to incorporate prevention behaviors into their lives."

HRSA and the care community at large are collaborating to improve access to care for HIV-positive women. The CARE Act Amendments of 2000 broaden access to early intervention services (including outreach and counseling and testing) and enhance coordination between the prevention and care systems. The results are increasing the likelihood that HIV-positive women are being brought into care much earlier in the course of disease. In yet another effort to link women with care, HRSA is preparing to release expansion funds for young women of color ages 13 to 24 through the Title IV program. Current grantees may apply for additional grants of up to $100,000 to meet the needs of this population. The guidance for preparing grant applications will be released in mid-March 2002. For more information, contact José Rafael Morales at 301-443-3650 or rmorales@hrsa.gov.  

References

1. Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDS epidemic update—December 2001. Available at: http://www.unaids.org/epidemic_update/report_dec01/index.htm.  Accessed February 15, 2002.

2. UNAIDS. Report on the global HIV/AIDS epidemic—June 2000.  Available at: http://www.unaids.org/epidemic_update/report/index.html.  Accessed February 15, 2002. p. 124.

3. World Health Organization. Women and HIV/AIDS [fact sheet]. June 2000. Available at: http://www.who.int/inf-fs/en/fact242.html. Accessed February 21, 2002.

4. Hewitt RG, Parsa N, Gugino L. The role of gender in HIV progression. Bulletin of Experimental Treatments for AIDS [serial online]. Spring 2001.  Available at: http://www.thebody.com/sfaf/spring01/gender.html.  Accessed February 21, 2002.

5. Karon JM, Fleming PL, Steketee RW, et al. HIV in the United States at the turn of the century: an epidemic in transition. Am J Public Health. 2001; 91:1060-8.

6. Bozzette SA, Berry SH, Duan N, et al. The care of HIV-infected adults in the United States. HIV Cost and Services Utilization Study Consortium. N Engl J Med. 1998; 339:1897-904.

7. Centers for Disease Control and Prevention (CDC). HIV/AIDS Surveillance Report. 2000;12(2):37. Available at: http://www.cdc.gov/hiv/stats/hasrlink.htm.  Accessed February 21, 2002.

8. CDC. HIV/AIDS Surveillance Report. 1999; 11(2):14; CDC. HIV/AIDS Surveillance Report. 2000; 12(2):20.

9. CDC. HIV/AIDS Surveillance Report. 2000;12(2):32.

10. Index of population. U.S. Census Bureau website. Women in the United States: March 2000. Available at: http://www.census.gov/population/www/socdemo/ppl-121.html.  Accessed February 20, 2002; CDC. HIV/AIDS Surveillance Report. 2000;12(2):20.

11. CDC. HIV/AIDS Surveillance Report. 2000;12(2):28.

12. Hader SL, Smith DK, Moore JS, et al. HIV infection in women in the United States: status at the millennium. JAMA. 2001;285:1186-92; Cunningham WE, Andersen RM, Katz MH, et al. The impact of competing subsistence needs and barriers on access to medical care for persons with human immunodeficiency virus receiving care in the United States. Med Care. 1999;37:1270-81.

13. Hewitt et al. 2001.

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