In December 2003, the Chiron Corporation began its first trial of a preventive AIDS vaccine strategy. Chiron is co-sponsoring the trial with the US National Institute of Allergy and Infectious Diseases. The trial will be conducted by the US HIV Vaccine Trials Network (HVTN) and will enroll 168 volunteers at 10 sites in the US. The trial will test the safety and immunogenicity of a combination of two vaccines given at different times. This is called a "prime-boost" strategy; it is hoped that this strategy will produce a broader range of immune responses than either of the vaccines used alone. The first vaccine is called DNA/PLG and it contains synthetic fragments of clade B HIV genetic material. The second vaccine is called gp140. It is a copy of a part of the "envelope" or outer coating of HIV. Neither vaccine contains material that can cause HIV infection.

The 11th Conference on Retroviruses and Opportunistic Infections took place in San Francisco from 8-11 February and was attended by over 3,500 researchers and activists from around the world. The main focus of the annual meeting is basic science of retroviruses (a family of viruses that includes HIV) and HIV treatment and care, but this year there were also several sessions that looked at the current state of AIDS vaccine research. Researchers presented data on a variety of topics including challenges to developing vaccines that will strongly produceneutralizing antibodies (see Primer) against HIV; lessons learned from the large-scale AIDS vaccine trials to date; and how to best use the funds available for AIDS vaccine research.

Stephen Lewis, United Nations special envoy to Africa, gave a keynote address in which he said, "It is important to note that there are more potential vaccines in the pipeline than ever before." Lewis went on to say that "an AIDS vaccine is also a women's issue" since an effective vaccine would give to women "the ultimate protection from HIV infection without the male partner...having any involvement." Lewis singled out the work of IAVI and said that "much more" activity was needed from the pharmaceutical industry and government-sponsored research.

In February the Bill and Melinda Gates Foundation announced a US$82.9 million grant to fund the search for a vaccine to prevent tuberculosis (TB). The grant is the largest ever for TB vaccine research. It was given to the Aeras Global TB Vaccine Foundation, a US-based research organization that is developing two TB vaccine candidates. Currently, the only available vaccine against TB, called BCG, primarily protects infants and young children against severe TB; it does not work as well in adults. The search for a TB vaccine has been slow due to lack of funding and lack of involvement on the part of major pharmaceutical companies—some of the same factors which have also slowed AIDS vaccine research. TB is one of the leading causes of death in people infected with HIV, and an effective TB vaccine is urgently needed. Dr. Jerald Sadoff, president of Aeras, says that it will take eight to ten years to evaluate these vaccine candidates and make them available, if they prove effective.

AIDS is the single most serious health threat in the world today. But at the same time, there are many other illnesses that pose major problems in several regions that also have severe AIDS epidemics including sub-Saharan Africa, Asia and Latin America. Other widespread diseases include worms (also known as helminthic infections or intestinal parasites), tuberculosis, malaria and sexually transmitted diseases other than HIV. To be effective, an AIDS vaccine will have to provide protection to people who are (or have been) infected with other diseases. This is one reason why AIDS vaccine trials are being conducted in these regions of the developing world. These trials will provide valuable information about how other diseases might affect AIDS vaccine trials.

This is a relatively new focus for any field of vaccine research. Many of today’s vaccines, including those against polio and measles, were approved based on the results of large trials in the US and Europe where healthcare systems are generally effective and diseases like tuberculosis are relatively uncommon. After approval, these vaccines were eventually distributed worldwide and reached people living in resource-poor settings. It was only at this stage that researchers began to gather information on how people in developing countries respond to the vaccines.

More recent vaccines, such as those targeting Streptococcus pneumoniae (which causes pneumonia and meningitis) and hepatitis B, were evaluated in developing countries including South Africa and Thailand. But the AIDS vaccine field is the first to include developing countries at every stage of vaccine testing—from small safety studies to large-scale efficacy trials. There are several reasons for this focus. First, some of the highest rates of new HIV infections per year are found in the developing world. AIDS vaccine efficacy trials need to be conducted in places with high rates of HIV infection if they are to provide rapid answers about whether or not a vaccine provides protection. These trials test a vaccine by comparing the number of HIV infections (through high-risk contact such as unprotected sex) in a group of volunteers who are given the vaccine with the number of infections in a group given an inactive substance called aplacebo. This comparison can be made most rapidly in communities where there are high numbers of new HIV infections each year.

Second, these trials will provide information about how AIDS vaccine candidates will work in the places where they are most urgently needed: developing countries where poverty, poor healthcare and high rates of other diseases are part of many people’s daily lives.

This is important information to collect since there is evidence that some vaccines work differently in people in developing countries when compared to people in developed countries. In some small studies of cholera vaccine, BCG vaccine (which protects against tuberculosis), tetanus toxoid, and oral polio vaccine, people living in developing countries had lower immune responses to these vaccines when compared to people in the industrialized world who received the same vaccine. One possible explanation for these differences lies in the fact the immune systemmounts specific responses to every infection that occurs in the body (see Primer). Pre-existing immune responses to other infections might affect people’s ability to mount responses to these vaccines.

This does not mean that these vaccines do not work in developing countries. According to these studies, increasing the vaccine dose given to people in the developing world usually boosts their immune responses. However it does mean that AIDS vaccine trials must learn about other pre-existing infections in people who participate in trials or will someday use a licensed vaccine.

The Soweto Vaccine Evaluation Unit at Chris Hani Baragwanath Hospital in South Africa recently conducted a study in which they tested over 100 potential AIDS vaccine trial volunteers for helminthic infection. Some studies have shown a connection between infection with these and other worms and reduced responses to vaccines such as tetanus toxoid, BCG and oral cholera.

"Helminth infection and exposure to other types of worms occurs more commonly in Africa than in developed countries. We are interested in how many adults from Soweto have such infections," says Guy De Bruyn, one of the South African scientists conducting the study.

De Bruyn says that if the Soweto study finds high levels of helminthic infections, the site may test future AIDS vaccine trial participants for worms and, if necessary, provide anti-worm medication before administering the AIDS vaccine candidate.

Health and trial participation

All volunteers for all preventive AIDS vaccine trials receive an HIV test before enrollment, since volunteers must be uninfected with HIV when the trial begins. The other components of the health screening process vary depending in the type of trial. Small Phase I safety studies are designed to confirm that the vaccine is completely safe for use in humans.

These trials also measure volunteers’ immune responses to vaccines. All Phase I trial volunteers undergo a lengthy health screening process. This includes an analysis of volunteers’ blood samples, so that trial staff have a good understanding of volunteers’ immune responses and general health status before the trial starts. Phase I participants are closely monitored throughout the study and trial staff make precise diagnoses of any health problems that occur among volunteers. For example, a feverish patient from a community with high rates of malaria would have his or her blood tested to confirm malaria infection—even though a doctor might ordinarily prescribe anti-malarial medications based on the symptoms alone. By pinpointing the cause of all health complaints in Phase I trials, vaccine developers can make reliable statements about the safety of the candidate vaccine.

In the next stage of larger trials (Phase II and Phase III) volunteers undergo a shorter health screening process. Volunteers are still tested for HIV and other severe illnesses, but they may not be screened for mild conditions or "asymptomatic" conditions that they may be unaware of, such as low-grade malaria, worms or anemia. By testing the vaccine in this population, vaccine developers get a better idea of whether or not some common conditions will impact on how the vaccine works.

If a vaccine shows efficacy in Phase II and Phase III trials then vaccine developers will conduct follow-up studies to learn even more about how the vaccine works in people with more complex health issues. Vaccine developers will only seek approval for the vaccine after this lengthy but important process has been completed. So far, no AIDS vaccine candidate has reached this stage of development.

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All articles written by Emily Bass