Modern Drug Discovery Magazine: Thailand on the Eve of an Aids Vaccine Trial
A man sits before a television watching Thai soap operas in a hospital waiting room. He looks on, occasionally glancing at a nurse’s table where another patient is receiving an injection. When asked his age, he must think for a minute. He is 39 years old and heroin user for the past 24years and the telltale signs of his addiction, needle tracks, scar his forearms. He lives in Bangkok as a social pariah. He has no family, and his only human contact is with other addicts. When he lost a friend to AIDS a few years ago, he became afraid for his life. As a hard-core intravenous drug user at high risk for AIDS infection, he realized he had to quit. His plan is simple. First, he wants to quit; then he hopes for a normal life to become an auto mechanic and start a family.
Another patient, reluctant to speak, lives with his father. He is 26years old, a recovering heroin addict who, after making a commitment to quit drugs, felt forced to abandon his friends who all were addicts. He depends on his family for his needs: food, shelter, clothes, and money. He came to the clinic to seek help after the endless pursuit of money for drugs and the accompanying suffering became intolerable.
During their recovery, both men found out about an AIDS study from asocial worker at the methadone clinic. Because the two men were at high risk for HIV infection, the Thai Ministry of Public Health has found that30-40% of intravenous drug users have HIV. They decided to take part in the trial of a vaccine to prevent the further spread of a disease that has ravaged their country. After years of drug use and joblessness, both men say they now feel connected to something larger than themselves.
This scene is repeating itself across Bangkok in 17 methadone clinics. American and Thai scientists have begun the first efficacy trial of an HIV vaccine in Thailand. VaxGen hopes for a silver bullet. Many hurdles must be leapt before a potent HIV vaccine hits the market (see sidebar, A massive challenge). But researchers at VaxGen, Inc. (Brisbane, CA), a biotechnology company spun off from pharmaceutical giant Genentech, think understanding what works and what doesn’t in conferring immunity to AIDS requires clinical trials of vaccine candidates. To that end, VaxGen has recruited 2500 Thais at high risk for AIDS for a trial of its so-called AIDSVAX vaccine. The study, launched in March, costs $9 million and uses proteins tailored to elicit antibodies against the strains of HIV most common in Asia (see sidebar, The innards of a vaccine candidate). The tests represent the first large-scale AIDS vaccine project featuring full cooperation between Western and Asian scientists.
In this era of international travel, you cannot view infectious diseases in a bubble as HIV is now spread across international borders, says William Heyward of the Centers for Disease Control and Prevention (CDC) in Atlanta, GA, and a collaborator with VaxGen. It is now more important than ever that AIDS vaccine trials be collaborative in nature between host governments, scientists, and pharmaceutical manufacturers.
This is the next step for AIDS research around the world, says Donald Francis, president and co-founder of VaxGen and former director of the CDC’s AIDS Laboratory, in a prepared statement. No one can ignore16, 000 new infections a day of a virus that has essentially 100 percent mortality, and the only way it is going to be stopped is a vaccine. Everyone in the world should be rooting not just for us but also for the whole process of vaccine development.
A vaccine candidate emerges Francis has traveled a difficult road developing AIDSVAX. A major setback came in 1994 when, after Genentech had invested 10 years and $50 million in research, the National Institute of Allergy and Infectious Diseases (NIAID) declined to fund phase III trials to determine whether the vaccine provided immunity to HIV infection. Undeterred, Francis spun off a new company, VaxGen, from Genentech and raised $60 million to develop the vaccine. With funding and further research results in hand; Francis convinced both the Thai government and NIAID to join VaxGen in the first AIDS vaccine efficacy trials on both sides of the Pacific.
VaxGen is phasing I and II clinical trials found that the vaccine induces an immune response in more than 90% of recipients. The most common side effect of early trials in the United States was soreness in the arm at the site of injection. In the third phase of trials, researchers will follow 2500 Thai volunteers, who are currently not infected, for three years. VaxGen began phase III clinical trials on 5000 volunteers in the United States in the summer of 1998, making it the first of more than 40AIDS vaccines currently in trials to make it to the final stage of clinical testing.
The Thai volunteers, who are all recovering intravenous drug addicts, will receive a series of seven injections over three years; in a double-blind test, half will receive the vaccine while the others will receive a placebo. The volunteers will also receive counseling on how to reduce their risk for infection. According to the CDC, about 6% of intravenous drug users in Thailand become infected every year. The trial will determine if AIDSVAX lowers that percentage.
Benefiting a developing country despite controversy surrounding AIDSVAX is likelihood of success; Thai leaders and the media in Thailand have lauded AIDSVAX for addressing the AIDS crisis in a developing country. According to the Joint United Nations Programmed on HIV/AIDS (UNAIDS), more than 90% of the world AIDS research has focused on subtype B, which is predominant in the West, even though 90% of those infected are from developing nations, where other subtypes are involved. In Thailand, the B subtype exists but most infected people have subtype E. VaxGen trials in Thailand use a vaccine targeted against both B and E subtypes.
Victor Zonama, vice president of the International AIDS Vaccine Initiative, says the study is an important venture into testing vaccines in developing countries. This is very encouraging; thus far there have been few efficacy tests that match the viral strains of developing countries he says. But Zonama also believes that more research on other vaccine candidates should happen before the three-year VaxGen study ends. We believe that many different products should be tested instead of waiting for the results of this study. An overview of the epidemic despite hope that a vaccine may be near, the stark realities of AIDS provide sobering testimony to the horrors of the epidemic. AIDS is among the top 15 killers worldwide. UNAIDS and the World Health Organization (WHO) estimate that at the beginning of 1998, more than 30 million people were infected with HIV, and that 117 million people around the world had already died from the disease.
Unless a cure is found or life-prolonging therapy is made more widely available, the majority of those now living with HIV will die within a decade. These deaths will not be the last. The virus continues to spread, causing nearly 16,000 new infections a day despite prevention efforts.
The UNAIDS/WHO report raises the concern that the most potent weapons against HIV transmission are still underused: knowledge and prevention. In Thailand, for example, new AIDS cases continue to crop up among heterosexuals who practice unsafe sex. Although 2.3% of the population in Thailand lives with HIV, only a fraction knows they are infected. And because people can live for 12 years or longer with HIV before any symptoms of AIDS crop up, the virus continues to spread unobserved.
The Condom King
In the face of other concerns such as poverty and undernourishment, the political, religious, and community leaders of developing countries have often overlooked the significance of AIDS.
Thailand was in deep denial about its AIDS problem when news of the epidemic began to surface in the mid-1980s. At first, the Thai government played down the problem, fearing that negative publicity would hurt the nation’s largest source of foreign capital, the tourist industry. Prostitution, one of the top monetary contributions to Thailand’s gross domestic product, is a major factor in Thailand’s AIDS problem: According to WHO, more than half of the 800,000 people in Thailand infected with HIV are sex workers, their clients, or drug injectors. After a period of claiming the virus was a western disease, the government tried to downplay the AIDS problem by restricting the movement and activities of HIV-infected people, threatening jail for those who did not comply.
In the early 1990s, the Thai government acknowledged the spreading epidemic and instituted a widespread initiative of AIDS education and prevention. Largely credited with bringing AIDS awareness to the forefront of Thai culture is Mechai Viravaidya, a government minister who instituted a radio and television campaign warning against the dangers of AIDS. He popularized the use of condoms and became known as the condom king.
By embracing prevention, Thailand slowed the accelerating spread of HIV infections. A nationwide ì100% condom program has encouraged sex workers to use condoms and has distributed almost 60 million free condoms year. Condom use among prostitutes has increased to about 90% and is credited with a sharp decrease in sexually transmitted disease rates. So successful was the government’s campaign that the HIV infection rate now doubles every two years instead of twice a year, as in the late1980s.
Our prevention efforts started to take off in the late eighties and have helped to stem the tide of HIV infection, says Kachit Choopanya, chairman of the medical advisor committee to the governor of Bangkok. The problem now is the high number of HIV-positive cases of nearly 1million people are infected.
Thailand struggles with AIDS HIV have taken its toll on Thailand despite the success of government initiatives to slow its spread. More than half of all new infections are occurring among those under 25, and the Asian economic crisis is likely to increase the HIV burden borne by the younger population says Peter Piot, executive director of UNAIDS. Children and young people in Asia face enormous hurdles today, growing up in a circumstance of shrinking economies and expanding risks from AIDS.
A huge increase in death rates among younger adults has inevitably led to an increase in the number of orphans. According to UNAIDS, by the start of 1998, about 8.2 million children around the world had lost their mothers to AIDS, many of whom had lost their fathers as well. Thailand has one of the highest proportions of AIDS orphans in Asia. Another widespread problem in Thailand is discrimination against people with HIV infection. A 1994 Thai Red Cross study of 116 households in Northern Thailand found that some parents beat their children for playing with a neighborhood child who is HIV-positive, and that many communities believe that children with HIV should not be allowed in schools. Patients have been thrown out of hospitals after revealing their HIV status. The Asian economic crisis, which took hold in 1997, has exacerbated the AIDS problem in Thailand. Many people lead more migratory lifestyles, often leaving rural homes for the cities. Some people are also returning to their rural districts, and such reverse migration may bring HIV into previously untouched areas. Many unemployed women in the cities wind up in prostitution through coercion, trafficking, or economic need.
As the economic hard times hit, many schools have experienced falling enrollments and higher dropout rates, reducing the opportunities to teach children about HIV and AIDS. Many unschooled young people enter adulthood lacking employable skills, making them more likely to drift into high-risk behaviors, such as drug use and prostitution.
Governments in Asia must compensate for lost revenue [due to the economic crisis], but the great danger is that health and education programs will be sacrificed, Piot says. Families must be encouraged to keep their children in school, and communities must give children and young people the support, skills, and information they need in order to avoid or cope with situations that will make them vulnerable to HIV infection. Investments today in HIV prevention will continue to pay off or generations to come.
Finally, cost limits access to drugs and therapies that the West takes for granted most are out of reach for Thais. Choopanya explains in the U.S., for example, there might be five drug combinations available for HIV sufferers. In Thailand, we have only two or three. What’s more, Choopanya says, the costs of those drugs make them accessible only to the very wealthy.
In Thailand, a country with limited money and a high infection rate post infection therapy is not the answer. They are smart to explore nipping the problem in the bud, says Heyward. Prevention and the search for a vaccine are the only ways they can get out of their situation. A massive challenge expert agrees: Developing a vaccine against HIV is an extremely difficult task. But most researchers hold out hope that a vaccine is possible.
The challenge arises partially because correlates of immunity for HIV have not been pinned down. However, some people have been exposed to HIV numerous times but remain uninfected. If these people represent a natural protective state, a vaccine could be modeled on them. Also, some people’s immune systems are capable of at least controlling HIV infection, if not eliminating it. Some people can live with HIV for a long period of time even in the absence of therapy. But it’s not forever, says Margaret Johnston, Naiadâs assistant director for HIV/AIDS vaccines and associate director of the vaccine prevention and research program in the division of AIDS.
Another factor making vaccine development difficult is that HIV mutates with such speed that new viruses can escape immune recognition. The 10 major genetic subtypes, or clades, of HIV differ from each other by around 30%. Each subtype may require a different vaccine. A third factor is that neutralizing antibodies, which prevent HIV from infecting cells, may not be enough to confer immunity. HIV exists in the body not only as a free virus, which antibodies can kill, but also hidden within cells. Cellular immunity may be required as well, which occurs when white blood cells called cytotoxic T lymphocytes (CTLs, or killer Tcells) destroy any cells already infected with the virus. To prevent sexual transmission, an HIV vaccine may even have to stimulate mucosalimmunity from the mucous membranes of the genital tract.
Finally, researchers have not found a perfect animal model to test vaccine candidates on. The best candidate is the chimpanzee, which can be infected with HIV. However, chimps do not develop AIDS. Also, because chimps are endangered, they are expensive to use in laboratory tests.
Still, vaccination has been highly successful for halting the spread of other infectious diseases, which gives researchers optimism, according to Johnston. Against many viruses, it’s possible to give someone something that looks like the virus and gives them a head start so they are capable of fighting it off, she tells Modern Drug Discovery. Experimental vaccines have protected chimpanzees against HIV infection. And because sexual transmission the predominant way people get infected is relatively ineffective, maybe even a little bit of a head start could be enough to protect someone from infection
Because candidate HIV vaccines in trials have been safe and have induced immune responses, Johnston thinks further research, trials, and refinement of vaccine strategies could lead to an effective vaccine. We may not have to have a vaccine that’s 100% effective to have a significant impact on the progression of HIV around the world, she says. It might still have a significant public health benefit and protect a lot of people. The innards of a vaccine candidate VaxGen’s controversial vaccine, AIDSVAX, elicits an immune response through a protein called glycoprotein 120 (gp120) from the surface of HIV. This protein is part of the outer coat of the virus and binds toso-called CD4 receptors on HIV’s target, helper T cells. Researchers found that gp120 stimulates antibodies that neutralize HIV, according to Phillip Berman, VaxGen’s vice president of research.
VaxGen researchers hope these antibodies will prevent the virus from causing infections. The idea behind the vaccine is that if you have antibodies to gp120, those antibodies block the attachment of the virus to the target cells, Berman says. Researchers at VaxGen have isolated and produced gp120 recombinant proteins from two different strains of HIV. In Thailand, the AIDS VAX formulation uses HIV subtypes E and B. It shouldn’t be difficult to make the vaccine with gp120 proteins from other clades, according to VaxGen.
The form of AIDSVAX that VaxGen is testing in the US also uses gp120from two different strains of virus, but both from subtype B. One of the reasons that the government did not support large-scale trials of the earlier Genentech gp120 vaccine was that some people involved in the early clinical trials became infected with HIV, presumably because the vaccine had only one gp120 protein. The first vaccine could neutralize viruses only that were grown for a long period of time in the lab, but it didn’t neutralize HIV as it came out from the patient, explains NIAID’s Johnston. The discovery two years ago that there were two types of viruses helped VaxGen solve that problem.
The two strains of virus infect different types of cells, T cells and macrophages. Genentech’s gp120 vaccine only worked against viruses that infected T cells. Vaccine strategies against viruses that infect macrophages are probably the most important ones for preventing infection, says Berman, whereas stopping the T cell viruses is probably more important for preventing disease progression. Now, AIDSVAX contains envelope proteins from both strains.
VaxGen makes the vaccine by transferring the gene encoding gp120 into Chinese hamster ovary cells. Those cells secrete gp120, and then researchers harvest the cell culture medium and purify the protein. They then combine it with alum, Al, an additive common to many vaccines that stimulates the immune response.
We don’t expect the vaccines to be 100% successful. We may have to add other strains Berman says. But I’m hopeful that we will have a positive outcome and this will be a product that can be used for a significant portion of the at-risk population… [to] significantly lower people’s level of infection. Berman cites test-tube studies that show that the antibodies can kill HIV viruses, as well as protection the vaccine gives chimpanzees against a viral challenge, as key to VaxGen’s optimism.
Still, critics abound. Many AIDS researchers believe that the immune system cytotoxic T lymphocyte (CTL) response must be triggered to fully protect against AIDS. Immunization with gp120 does not elicit CTLs. I personally believe people should be able to try what they want to try, but it’s a very, very long shot to expect anything that’s measurable from VaxGen’s efficacy trials, David Baltimore told the Wall Street Journal. Baltimore, the president of the California Institute of Technology (Pasadena, CA), heads a government advisory committee on AIDS vaccines.
No one has demonstrated whether antibodies are enough. That’s why this trial is so useful, according to Johnston. The urgency of getting an AIDS vaccine is such that even a good answer is worth going after, she says. That would mean researchers should pursue other strategies. If we get an answer that it works, or it works partially, or it doesn’t work in my mind, it will have been worth doing. Further information on AIDS vaccines abounds online. The following URLs are some of the most informative:
http://www.niaid.nih.gov/daids/vaccine
http://www.niaid.nih.gov/daids/vaccine
http://www.niaid.nih.gov/publications/aids.htm
http://www.niaid.nih.gov/publications/aids.htm
http://www.cdc.gov/nchstp/hiv_aids/vaccine.htm
http://www.cdc.gov/nchstp/hiv_aids/vaccine.htm