The World Health Organization (WHO) and the United Nations Joint Programme on HIV/AIDS (UNAIDS) recently sponsored a technical consultation with experts in the AIDS vaccine field to discuss the design and use of Phase IIb "test of concept" trials in evaluating AIDS vaccine candidates and their implications for approval and licensure (seeVAX September 2005 Primer on Understanding Test-of-Concept Trials).

This meeting, hosted by IAVI, was held from January 31 to February 2 in New York City and brought together a diverse range of organizations to consider both the design of test of concept trials and how they should be viewed by vaccine approval agencies in developing countries. Attendees included representatives from the Botswana Harvard AIDS Institute Partnership, Medical Research Council of South Africa, Chinese Center for Disease Control and Prevention, Project San Francisco in Rwanda, HIV Vaccine Trials Network (HVTN), US National Institutes of Health (NIH), US Centers for Disease Control and Prevention, US Food and Drug Administration, IAVI, Johns Hopkins University, as well as other representatives from India, Thailand, and Zambia. The recommendations of this group will be presented as a position paper to the WHO/UNAIDS Vaccine Advisory Committee and will be used to help these organizations develop a set of guidelines on test of concept trials for AIDS vaccines.

The Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi began enrolling volunteers in a Phase I AIDS vaccine trial in January. The trial, IAVI V001, is sponsored by IAVI in collaboration with the Vaccine Research Center (VRC) at the National Institute of Allergies and Infectious Diseases (NIAID). It was initially started in Rwanda and was expected to enroll a total of 64 volunteers in these countries. However after early success in recruiting volunteers the target number for both countries will be increased, pending regulatory approval by the local Institutional Review Boards in Kigali and Nairobi.

Sabina Wakasiaka, a nurse counselor from KAVI, credits the successful enrollment rates to outreach programs conducted in the last few years, which have helped to increase the vaccine literacy among many community organizations. The trial staff at KAVI is promoting initiatives to recruit more women for this trial, including holding community seminars within homes or offices targeting only women.

This is one of many ongoing trials testing the safety and immunogenicty induced by a "prime-boost" vaccination regimen with a DNA plasmid vaccine and an adenovirus serotype 5 (Ad5) vector that was developed at the VRC (seeVAX November 2005 Global News, First AIDS vaccine trial starts in Rwanda).

Almost a dozen clinical trials are now ongoing to see if drugs to suppress herpes simplex virus-2 (HSV-2) can reduce the risk of HIV transmission and infection (see VAX November 2005 Spotlight article, HIV prevention in a pill?). These studies were initiated because of mounting evidence that there is an association between HSV-2 and HIV infection. Researchers have long thought that HSV-2 infection could increase the amount of HIV in the genital tract and therefore increase both sexual transmission of and infection with HIV. But a relationship between these infections has not been firmly established in a controlled, clinical trial until now. At the 13th Conference on Retroviruses and Opportunistic Infections (CROI) held this February in the US, Nicolas Nagot from the London School of Hygiene and Tropical Medicine (LSHTM) in the UK in collaboration with the Centre Muraz in Bob-Dioulasso, Burkina Faso, presented data from the first "proof of concept" trial verifying the association between HSV-2 infection and HIV.

This study enrolled 140 women infected with both HIV and HSV-2 in Burkina Faso and randomly assigned them to either the treatment or placebo group. Those on treatment received the anti-herpes drug valacyclovir once a day for three months, while those in the placebo group received an inactive substance. The women were followed for a total of nine months, three months prior to and for three months following treatment. Over 12 visits, researchers measured the levels of HIV and HSV-2 in the genital tract of these women and found that those taking valacyclovir had significantly lower quantities of HIV than those that received placebo. Valacyclovir also significantly reduced the level of HSV-2 in the genital tract of women compared to those in the placebo group.

Although this study does not show a direct link between HSV-2 suppression and HIV transmission, this is the next step for researchers. Several trials are currently ongoing to see if HSV-2 suppressive therapy can lower HIV infection rates.

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All articles written by Kristen Jill Kresge

How can AIDS vaccine trials help build infrastructure and capacity in developing countries?

In order to determine whether an AIDS vaccine candidate is effective it must be tested in the populations that are most affected by the disease. Clinical trials have to take place in communities where there is a high enough incidence of HIV infection for researchers to determine positive benefits from the vaccine. This often requires running trials in developing countries, where there is the highest HIV/AIDS burden. It is also essential that vaccines be evaluated in the communities that need them the most.

Many organizations involved in AIDS vaccine research, including the Global HIV Vaccine Enterprise and the European & Developing Countries Clinical Trials Partnership (EDCTP), have recently published reports emphasizing the importance of developing both the physical infrastructure and the human resources at clinical trial sites in developing countries. This is the strategy used by organizations like Walter Reed Army Institute of Research, the US Centers for Disease Control and Prevention, and IAVI that have been running vaccine trials in Africa and Asia. The idea of building trial site capacity involves both establishing clinics and laboratories and training medical professionals. Both of these steps help ensure that the research site is sustainable over the long term and can be used for future clinical trials. Developing these sites also benefits the community by providing career opportunities for healthcare workers that can serve the community long after the trial ends or by attracting other medical services to the area, such as HIV treatment programs (see VAX February 2006 Primer on Understanding the Benefits and Risks of Participating in Clinical Research).

Infrastructure

The first step in building an AIDS vaccine clinical trial site involves constructing the actual buildings that will serve as clinics and laboratories or modifying those that already exist. These facilities are then equipped with the instruments necessary to process laboratory samples obtained from volunteers during the trial and preparing these specimens for storage or shipment. Some sites may even develop sophisticated HIV immunology and virology laboratories that can analyze samples and process the data from the trial in the country where it takes place.

India recently started an AIDS vaccine trial sponsored by IAVI in partnership with the Indian Council of Medical Research and the National AIDS Control Organization at the Tuberculosis Research Center (TRC) in Chennai. The TRC, a newly-established center of excellence for the clinical evaluation of vaccines in the country, features a safety and immunology laboratory where all laboratory tests will be run.

Human capacity

Once the clinics and laboratories are established it is also important to build human capacity at AIDS vaccine trial sites. Sponsor organizations spend significant amounts of time hiring and training medical professionals in developing countries to handle the activities associated with the trial.

This occurs through a series of instructional workshops that cover all aspects of the clinical trial process, from screening and enrolling volunteers to collecting and analyzing data, and are based on a set of work practices developed specifically for each site. All trials are certified according to a set of international guidelines, known as Good Clinical Practice (GCP). Compliance with GCP guidelines ensures that the trial is run properly, that the rights and needs of the volunteers are protected, and that the data collected during the trial is of high quality.

Counselors and nurses are trained to work with potential volunteers and to administer the informed consent process (see VAX June 2005 Primer on Understanding Informed Consent). These individuals may also receive specialized training on enrolling women in AIDS vaccine trials and other gender-related issues.

For the staff working in the laboratories the training includes how to handle and process the laboratory samples and the procedures for data management. All tests run in the laboratories are verified by quality control processes to ensure that the results of the trial are meaningful.

The process of site development continues even after the trial has started. Many organizations continue working to enhance the site's ability to deliver HIV prevention and treatment services and to provide referrals to other clinics in the community. This can involve additional training sessions or meetings arranged with the staff from other AIDS vaccine clinical trial sites in order to learn from shared experiences.

Providing the site staff with such extensive training helps strengthen the human resources in that community. Once the trial is complete, these medical professionals can work in many other areas, including research, nursing, or in conducting other clinical trials.

Sustainable trial sites

Developing both the physical infrastructure and human capacity at a site are necessary steps for conducting an AIDS vaccine clinical trial in developing countries, but once established these sites can continue to function well beyond the end of the current trial. The staff's expertise in HIV could make the site suitable for other types of HIV prevention trials, including trials of microbicides, or for clinical research studies that contribute to the understanding of the HIV/AIDS epidemic in that country. These sites may also attract HIV treatment programs or other healthcare services that can continue adding benefit to the community. Keeping these sites active is also of great interest to organizations sponsoring AIDS vaccine trials, since many vaccine candidates will need to be evaluated in the future and these trials will require experienced sites and surrounding communities that have successfully conducted past trials.