AIDS vaccine researchers provide clinical updates and details on planned trials
The projected number of individuals participating in a Phase I AIDS vaccine trial in Kenya and Rwanda, conducted by IAVI in partnership with the VRC, will be increased after approval was granted recently from the local institutional review boards in the countries. Project San Francisco began enrolling volunteers at the site in Kigali, Rwanda late last year—marking the start of the first AIDS vaccine trial in the country—and the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi began recruitment in January. Total enrollment for both sites was initially set at 64 volunteers but will now be increased to 104.
This trial is one of three closely coordinated trials testing the safety and immunogenicity of a "prime-boost" vaccination regimen with the VRC's DNA plasmid and adenovirus serotype 5 (Ad5) vaccine candidates (see Spotlight, this issue).
Other developments in Kenya include the opening of two new community clinics in Kilifi by the Kenya Medical Research Institute (KEMRI), with support from IAVI. One of these clinics, the Comprehensive Care and Research Clinic, will offer HIV testing and counseling services that can help facilitate future AIDS vaccine trials in the country, as well as house a clinical trials laboratory. Part of this building has also been reserved for provision of HIV treatment and care through the District Hospital, including a program for the prevention of mother-to-child transmission that tests over 4000 pregnant women each year.
The other newly-established clinic will focus mainly on couples voluntary counseling and testing that can help identify individuals in serodiscordant relationships, where one partner is HIV infected and the other is not. This type of counseling will help identify HIV-uninfected individuals who are therefore at high risk for HIV infection within their marriage or partnership and can possibly be volunteers for future AIDS vaccine trials (see VAX October 2005 Primeron Understanding Couples Voluntary Counseling and Testing). Couples counseling is an established practice at sites in Rwanda and Zambia, but this clinic is one of only a few to utilize this approach in Kenya.
KEMRI also opened a new drop-in center and clinic in Mtwapa for HIV-uninfected individuals who are at high risk for HIV infection. Over 300 uninfected volunteers have already been enrolled in a study to help promote an understanding of HIV infection and identify ways they can lower their risk. Collaborators from the University of Washington will treat volunteers for sexually-transmitted diseases, including offering antiretroviral (ARV) treatment to those who become infected with HIV from exposure in their community during the course of the study.
The African Union in partnership with the Joint United Nations Programme on HIV/AIDS (UNAIDS) initiated a unified call from leaders of many African nations to increase and improve HIV prevention services on the continent. On April 11 government leaders from several countries kicked off this initiative. Among these was Meles Zenawi, the Primer Minister of Ethiopia, who emphasized how the scale up of prevention services can have profound effects in dealing with the epidemic.
Elements of this comprehensive prevention plan include addressing the root causes of HIV transmission, improving the availability of and access to HIV testing and counseling services to increase knowledge about the virus and help prevent transmission, and developing strategies specifically targeting women and youth with important messages on HIV prevention. At the launch, First Lady Jeannette Kagame of Rwanda spoke about the disproportionate number of women in Africa who are HIV infected. Other components of the effort include the need to strengthen and expand existing healthcare systems and programs to prevent mother-to-child transmission of HIV.
Of the 5 million new HIV infections in 2003, 3.2 million occurred in sub-Saharan Africa, according the latest UNAIDS statistics. And although access to HIV treatment and care has increased in recent years, the huge number of new infections can cause a significant burden on existing programs.
The World Health Organization (WHO) and UNAIDS predict that implementation of broad prevention programs such as these could help avert 63% of new HIV infections that are expected to occur in the next 6 years. This initiative was launched in advance of a Special Summit on HIV/AIDS, tuberculosis, and malaria that will convene next month in Abuja, Nigeria involving African Union heads of state.
Active recruitment and enrollment of volunteers has now started at research sites in Lusaka, Zambia; Masaka, Uganda; Kigali, Rwanda; and Kangemi, Kenya for a multi-centre, epidemiological study of newly HIV-infected individuals being conducted by IAVI. Volunteers who were recently infected with HIV through incidental exposure were identified through participation in incidence studies where they were counseled on risk-reduction practices and tested for HIV at least four times a year.
This new study will track these HIV-infected individuals for up to five years to follow the natural course of HIV infection in these cohorts. All volunteers will receive counseling and care and will be referred to a program offering antiretroviral (ARV) treatment when needed. Investigators will analyze samples of the newly-transmitted virus and evaluate early disease progression. Data from this study could help AIDS vaccine researchers in the design of new preventive vaccine candidates (see Primer, this issue).
The IAVI research study will also begin recruiting recently HIV-infected volunteers at other sites in Entebbe, Uganda; Cape Town, South Africa; and Kilifi, Kenya. Other groups, including the recently established Center for HIV/AIDS Vaccine Immunology (CHAVI), are studying individuals during the earliest stages of acute HIV infection. Links between these efforts and the IAVI-led research studies have already been established.
All articles written by Kristen Jill Kresge
How can studying what happens immediately following HIV infection help researchers design an AIDS vaccine?
There are many reasons why HIV is such a difficult virus to combat. One is that HIV directly attacks the human immune system, the body's defense against pathogens like viruses and bacteria. The primary target of HIV is the CD4+ T cells, an important immune cell that directs the body's response to an infection. During HIV infection huge numbers of these cells are infected and killed each day, but new ones take their place.
Doctors or nurses can monitor the progression of HIV disease by CD4+ T-cell counts, which are a measure of the number of CD4+ T cells circulating in the blood. For many years after initial infection the quantity of these important immune cells can stay the same or drop only slightly, but in most people the virus will eventually take over and the total number of CD4+ T cells will start to dwindle.
A typical definition of AIDS is when the total number of CD4+ T cells in an HIV-infected person dips below 200 in a milliliter of blood (in people with healthy immune systems there are between 600-1200 CD4+ T cells in this same amount of blood) or when a person develops one of several AIDS-associated illnesses. Once the CD4+ T-cell count is dangerously low, the immune system is incapable of defending the body from attack by other pathogens and a person also becomes susceptible to many opportunistic infections, which can be deadly.
Measuring the number of CD4+ T cells in the blood is a convenient way for researchers to estimate the damage HIV is doing to the immune system, since blood samples are easily obtained. But the majority of the body's CD4+ T cells aren't in the blood. Rather they are found in the mucosal tissues, such as those lining the respiratory, gastrointestinal, and genital tracts. Looking only at the blood may paint an inaccurate picture of what is really happening during HIV infection, so researchers have recently focused on studying the immune responses occurring specifically at these mucosal sites.
Looking at the gut
When researchers looked at mucosal tissues they found something very interesting. In both animal models and humans, researchers observed a massive killing of CD4+ T cells at mucosal surfaces in the intestine, or gut, very early in the course of HIV infection. For many years scientists were more concerned with the dynamics of the human immune system much later in HIV infection when it begins to fail. But research now suggests that a critical destruction of immune cells occurs long before a person exhibits symptoms or develops AIDS, and often even before an individual knows they are infected with HIV (see VAX November 2005 Primer on Understanding HIV Testing).
The bulk of CD4+ T-cell death in these tissues actually occurs within a few weeks after a person contracts the virus, during a period referred to as acute infection. Although the number of CD4+ T cells in the blood also decreases during this initial stage of HIV infection, researchers found that the greatest depletion is seen in the mucosal tissues of the gut.
Researchers have also found that the immune system has trouble repairing damage in these mucosal tissues. CD4+ T-cell counts often rebound quickly in the blood once an individual starts taking antiretrovirals (ARVs), but the CD4+ T cells in the gut are restored much more slowly than in blood, even in HIV-infected individuals who have been receiving treatment with ARVs for several years.
This may mean that the loss of CD4+ T cells at the mucosal surfaces is a better predictor of disease progression than monitoring their quantity in the blood.
But it would be difficult to monitor HIV-infected individuals by repeatedly measuring CD4+ T-cell counts at mucosal sites. Testing these tissues requires a procedure known as a biopsy, which is a more invasive process than collecting a blood sample. Researchers are now looking for ways to analyze subtle differences between CD4+ T cells in the blood in order to more easily determine and predict what is happening in the gut.
Implications for vaccines
This research has many implications for AIDS vaccine design and research. If the critical battle between HIV and the immune system takes place in the earliest stages of HIV infection, as this research suggests, it is important to closely study the virus that is transmitted and to characterize the nature of the immune responses in the first weeks and months of infection.
Many organizations involved in developing AIDS vaccine candidates are therefore interested in studying recently HIV-infected individuals. IAVI is one group conducting this type of epidemiological study with recently HIV-infected volunteers at several centers in Africa (see Global News, this issue).
Other research organizations are working with collaborators to identify and follow newly-infected individuals at sites in many countries around the world. Information collected from these studies may offer clues to help better define the target for a preventive vaccine.
Another important implication from this research is the need for AIDS vaccine candidates that induce strong immune responses at mucosal tissues, especially those lining the intestine. Several researchers think this will be necessary for a preventive vaccine to be effective and many methods are now being explored to enhance the mucosal immunity induced by existing AIDS vaccine candidates (see VAX December 2005 Primer on Understanding Mucosal Immunity).