[NOTE: This is an UPDATE to a case study initially published in 2009. Read the original case study for appropriate context.]
Testing the efficacy of HIV candidate vaccines requires extensive human trials in every region where the virus is prevalent. This is because genetic, environmental and viral differences may require adjustments in vaccine strategy. The International AIDS Vaccine Initiative (IAVI) for this reason has developed a network of clinical research centers (CRCs) in Africa and India, two focal points of the epidemic with limited scientific resources. Working with in-country researchers, IAVI has helped strengthen local facilities’ physical and human resources.
The last two years have seen incremental progress on the HIV vaccine front. The major prevention breakthroughs have occurred with other biomedical prevention strategies. And while the steps forward in vaccine research have helped to clarify IAVI’s path, the progress with other strategies have ironically complicated it.
Two years ago, IAVI’s protocol G was just commencing. This study involved the Clinical Research Centers in a hunt for naturally occurring broadly neutralizing antibodies. It enrolled about 1,800 HIV-positive volunteers from Côte d’Ivoire, Kenya, South Africa, Rwanda, Australia, United Kingdom, Thailand and the United States. Only one percent exhibited “elite” neutralizing activity. Further analysis by IAVI-associated laboratories discovered 17 antibodies able to block HIV across subtype with unprecedented potency. The researchers are now investigating how to design a highly protective vaccine that elicits these antibodies in the general population.
IAVI is not waiting for these hoped-for vaccines to begin new trials. The CRCs are currently participating in three preliminary vaccine trials with a total enrollment of 427 (including an IAVI-monitored site in Boston, Massachusetts). “This is the largest number we have ever enrolled,” comments Pat Fast, IAVI’s Chief Medical Officer. These trials involve candidate vaccines with promising results in monkey or earlier human trials. Notably, one element in each trial is a strain of adenovirus (Ad35) modified to produce HIV proteins. A similar adenovirus 5-based vaccine failed in a 2007 trial amid indications that it actually made recipients more susceptible to HIV. IAVI, whose research led to the new Ad35 vaccines, expects that they will avoid the immune issues raised by Ad5.
Based on the preclinical results, the different CRCs have expressed an interest in going forward with the Ad35 vaccines, which are given some months before or after another innovative vaccine (one of which involves a different adenovirus strain). Fast recounts, “IAVI’s R&D group chose the vaccines, with advice from external advisers and the approval of IAVI management. We then asked particular CRCs whether they wanted to participate. It was the local investigators’ decision to go forward.”
Previous CRC studies were generally considered “preparatory” in that they investigated the epidemiologic and immune variables affecting trial design. One of these checked how vaccine immune responses might differ in an African population. This investigation, the Yellow Fever DNA Microarray Assay Study, produced a picture of immune responses after yellow fever vaccination.
The study was an opportunity to introduce a new technology, DNA microarray analysis, to the Ugandan CRC. DNA microarray assays are a quick, relatively inexpensive and comprehensive way to measure genetic activation. It will be quite useful in understanding HIV vaccine responses in future studies. The current study compared the genetic responses to yellow fever vaccine in healthy Ugandan adults to those in North and South Americans. The results, as yet unpublished, indicated differences in Africans due to past infections, which in itself is a valuable lesson.
“Even though the orientation was capacity building, the research was novel and cutting edge,” Fast noted.
The Yellow Fever DNA Microarray investigation forms part of a larger vaccine preparatory study conducted among Ugandan fishing communities on the shores of Lake Victoria. This overall study, largely funded by the European and Developing Countries Clinical Trials Partnership (EDCTP), is documenting HIV epidemiology and risk factors, including the contributing social and behavioral conditions, in three lakeside districts. Some of the study results were published in August 2011. The researchers (from the Uganda Virus Research Institute, including its IAVI-associated HIV program) found that the communities have a very high HIV prevalence (29 percent among teens and adults or 4.5 times the national average). Active syphilis, at 4.3 percent prevalence, was elevated by a similar proportion.
The fishing populations are remarkable for the dangers inherent in their highly mobile occupation. Income is insufficient, and women are pressured to engage in transactional sex for favors to feed themselves and their families. Alcohol use is very high in the villages; condom use is low and public health services nearly nonexistent.
The investigators concluded, “Our data suggest that a holistic approach is required, which combines good health services with well-designed locally appropriate educational and community development efforts tailored to the entire fishing community.”
The Uganda/IAVI HIV program has responded by holding a number of health fairs and HIV counseling sessions while lobbying to get government clinics involved. (This is a regional issue—the Kenyan government has recognized similar problems on its side of the lake.)
Another neglected, high-risk group is “men having sex with men” (MSM). An IAVI-supported clinical center run by the Kenya Medical Research Institute (KEMRI) in coastal Kenya has been instrumental in the study of this group’s role in the HIV epidemic as part of its vaccine preparatory studies that also include female sex workers. Homosexual sex is highly stigmatized and heavily penalized in Kenya, but the study site provided a friendly, protected place where this hidden population could be open about its sexual preferences.
According to a paper published in February 2012, the researchers found an HIV incidence of 6.8 percent in MSM, which was 2.5 times higher than the incidence in female sex workers. Total prevalence in the MSM cohort is about 20 percent, about 2.5 times the prevalence for the region as a whole. An examination of HIV strains infecting MSM found that they were largely the same as in the broader Kenyan epidemic. The number of men infected with novel hybrid strains, however, suggested that they formed a special closed sexual network.
The publicity generated by these HIV studies has helped the KEMRI researchers increase the government’s awareness of MSM’s unmet needs for treatment and prevention of HIV and other sexually transmitted diseases. The current Kenya National AIDS Control Council (KNACC) estimates that MSM (including prisoners), and their female partners account for 15 percent of new infections. Its 2010-13 National Strategic AIDS Plan singles out MSM as a one of the groups most at-risk for HIV. It plans a six-fold increase in the number of MSM reached by HIV prevention programs. As with programs targeting other at-risk groups, the Plan states that the atmosphere will be one of “mutual accountability, gender equality and human rights.” In contrast, the previous Strategic Plan barely mentioned MSM.
IAVI conversely has had to cut back its activities among some high-risk groups. Most conspicuously, it ended its pioneering study of discordant couples in Zambia and Rwanda, plus a newer Ugandan cohort. Discordant couples, in which one partner is HIV-infected and the other not, obviously represent a population in desperate need for HIV prevention. The KNACC notes that 44 percent of HIV transmissions in Kenya occur within such couples.
However, a recent African study funded by the National Institutes of Health, HPTN 052, found that treating the infected partner reduced HIV transmission within these couples by 96 percent. (It also reduced disease events in the infected partner by 41 percent). Given these results, it is clearly no longer acceptable to include discordant couples in vaccine trials. In the aftermath of HPTN 052, cohort members were transferred to couples counseling program at government clinics.
A similar transition occurred at the Rustenburg, South Africa research center, which had a small MSM cohort but was concentrating on a group of impoverished migrant women. The women had high HIV incidence without obvious risk factors aside from poor health services. This cohort has become the basis for a microbicide trial utilizing tenofovir-containing gel. A previous study with this antiviral medication found a reduction in HIV acquisition by as much as 54 percent. The Rustenburg group is now shifting its observational efforts to high-risk, mostly heterosexual men.
Fast says, “We made major changes based on the developments in medical prevention. You have to keep following the course of science.” The failures as well as the successes are important here: A number of prevention trials have failed to produce meaningful results because the recruited populations had very low HIV rates. IAVI’s own preliminary studies in the general population Uganda and Kenya also found that low HIV incidence made vaccine trials unfeasible.
Even as early vaccine trials are enrolling, the documentation of HIV’s spread needs to continue, for the good of the high-risk groups as well as to ensure the ability to prove vaccine efficacy.
By David Gilden