Understanding Clinical Research Studies

What information can clinical research studies provide?

AIDS vaccine candidates must go through pre-clinical, Phase I, and Phase II testing before advancing into large-scale Phase III efficacy trials, which test the ability of a vaccine to protect against HIV infection or slow disease progression. But before Phase III trials begin, researchers use clinical research studies to determine the practicality of conducting research in a given community and ready a trial site and community for future vaccine (and other HIV) research trials. Such studies provide critical information about how to design efficacy trials and in which populations it is most appropriate to test vaccine candidates.

Efficacy trials enroll thousands of volunteers who are followed for several years. Running clinical research studies prepares the site for the recruitment and retention of a large number of volunteers. These studies also encourage the development of local scientific research centers, which provide the critical infrastructure for future trials. These centers must be able to meet the technical demands of running large trials, including the capacity to collect data, perform a large volume of laboratory tests, evaluate study procedures like physical exams, as well as to provide general healthcare for the many volunteers.

Clinical research studies also help strengthen the local health care system in order to support future trials. Any volunteers that become HIV infected during clinical research studies through exposure in the community are referred to local clinics for evaluation, care, and treatment. Pregnant women are referred to programs for the prevention of mother-to-child transmission of HIV.

Many groups that are interested in conducting preventive AIDS vaccine trials first conduct clinical research studies. The HIV Prevention Trials Network, the Botswana-Harvard AIDS Institute Partnership, IAVI, and others are engaged in research studies in different communities, many in eastern and southern Africa.

Prevalence and incidence studies

Determining the prevalence of HIV infection in a community is one important type of research study. Prevalence is the percentage of people infected in a population at a specific time, calculated based on results from a sample of the population. All volunteers in prevalence studies are provided with comprehensive voluntary counseling and testing (VCT) for HIV.

The process of VCT in clinical research studies includes gathering relevant background information as well as information on sexual practices, condom use, and history of sexually-transmitted disease. This comprehensive VCT process prepares healthcare workers and counselors at each site for the management of large groups of volunteers. Over 20 times more people may need to receive VCT than are actually eligible for a vaccine trial. Many participants may not be willing to participate, while others may not qualify for the study.

Volunteers who are at risk of HIV infection but are not already infected can enroll in HIV incidence studies. HIV incidence is the rate of new infections per year, measured by determining the number of new infections in a specific population over a given period of time. Researchers need to know the incidence in a community to calculate how many volunteers to enroll in an efficacy trial in order to show if a vaccine prevents HIV infection or slows disease progression. Previous research studies have shown that HIV incidence often declines in areas where extensive VCT and public health campaigns promoting HIV education take place.

Incidence studies may include several thousand volunteers per site and last 2-4 years. Participants receive VCT at least every three months. The Botswana-Harvard AIDS Institute Partnership is currently conducting a research study in Botswana in collaboration with the HIV Vaccine Trials Network to evaluate HIV incidence.

Studying early infection

Another type of research study follows a subset of volunteers from incidence studies that recently became infected with HIV through exposure in the community. This allows researchers to learn the characteristics of the virus strain that establishes an infection and the immune system’s early response to HIV infection. Vaccine researchers hope to learn how to design AIDS vaccines from these studies.

Monitoring volunteers that are newly infected with HIV also provides a general picture of the natural course of infection in the community. Understanding how HIV infection normally progresses will help researchers evaluate if a candidate is effective at slowing disease progression in vaccine trials. Most of the knowledge on HIV infection has come from studying populations in North America, Europe, and Thailand. This is less relevant to African populations where different strains of HIV are present and the general health of the community may vary. IAVI is currently seeking approval to start this type of research study at six sites in Kenya, Uganda, Rwanda, and Zambia.

Laboratory reference ranges

Clinical research studies can also help scientists understand the existing health of a local population through laboratory results. This type of study includes healthy, HIV-uninfected volunteers. It is important for researchers to understand the community’s background health profile so that when a vaccine trial takes place they can correctly differentiate naturally-occurring diseases and not attribute their symptoms to side effects of the vaccine candidate. Much of the existing data on laboratory results were produced from populations in North America and Europe and might not apply to African populations.

To understand the general health of a population, researchers conduct medical histories and physical exams and analyze the results of a number of laboratory tests. Researchers then establish a reference range for HIV-uninfected volunteers for each individual test result. Genetics, nutritional factors, and the presence of diseases common in the community can affect the laboratory results. Once established these reference ranges will help determine if a volunteer can be included in a vaccine trial and can help researchers assess the health of volunteers during the trial.

Other types of research studies are also looking at the levels of pre-existing immunity to different viruses that are being developed as vectors for AIDS vaccine candidates (see the February Primer on Understanding Pre-existing Immunity). It is important for researchers to know the level of pre-existing immunity to viruses that may be used as vectors since this might limit the immune response to a candidate vaccine.