Discussion of HIV prevention technologies tops the bill at international meeting
The first AIDS vaccine candidate developed by Russian scientists, known as Vichrepol, is now in Phase I clinical trials. Descriptions of this candidate and the ongoing study were presented in posters at both the International AIDS Conference in Toronto (see Spotlight article) and the AIDS Vaccine 06 conference held from August 29 to September 1 in Amsterdam. Vichrepol is a recombinant protein vaccine comprised of fragments of HIV proteins administered with an adjuvant known as polyoxidonium, which is already used with a licensed influenza vaccine.
The ongoing clinical trial involves 15 volunteers who receive 3 intramuscular injections of the vaccine candidate at 5 different doses. The dose is only escalated once the safety and tolerability of the lower dose is established. So far two of the five doses have been evaluated and no side effects or safety issues have been reported. The poster presented at the AIDS Vaccine 06 conference reported that the vaccine candidate induced antibody responses and suggested that subsequent studies will be needed to fully evaluate its safety and immunogenicity.
By the end of last year there were 350,000 documented HIV infections in Russia and the epidemic continues to expand at an alarming pace. As in many other countries in Eastern Europe and Central Asia, the majority of new HIV infections in Russia are occurring amongst injection drug users. Russia recently announced plans to create a vaccine research center for Eastern Europe and Central Asia to work on developing and testing other AIDS vaccine candidates (see VAX July 2006 Global News)
IAVI's flagship publication, the AIDS Vaccine Blueprint 2006: Actions to Strengthen Global Research and Development, was released on August 15 during the International AIDS Conference in Toronto. This biennial publication outlines a series of new scientific and policy initiatives to accelerate the development of an AIDS vaccine through the involvement of industry, building research and clinical trials capacity in developing countries, and a new vaccine development model that will promote the rational design of vaccine candidates as well as an accelerated approach to clinical trials. "The challenges to developing an AIDS vaccine are enormous," said Seth Berkley, Chief Executive Officer and President of IAVI. "We're trying to accelerate every component."
Industry's involvement in the development of an AIDS vaccine is seen by many in the field as imperative since much of the expertise in testing and manufacturing licensed vaccines is found within large pharmaceutical companies. Although several companies are actively engaged in AIDS vaccine research and development, the Blueprint calls for an increased level of commitment.
Another area highlighted in the document is the continued need to enhance the ability of developing countries to conduct AIDS vaccine clinical trials, including the development of networks of excellence for both research and clinical trials in the countries hardest hit by the epidemic. "We need more clinical trial capacity and we also hope that more vaccine research will be done in developing countries," says Pontiano Kaleebu, Assistant Director of the Uganda Virus Research Institute.
The Blueprint also recommends that the AIDS vaccine field implement an accelerated approach to clinical trials that will provide researchers with preliminary data about a candidate's efficacy earlier in development. The proposal would entail running several Phase II trials involving around 500 volunteers in parallel, rather than a single Phase IIb test-of-concept trial with up to 3000 volunteers. Only those candidates that show some degree of efficacy and improve upon the best current products would then go into more advanced trials.
All articles written by Kristen Jill Kresge
What can AIDS vaccine researchers learn from studying people who are HIV infected but progress more slowly to AIDS?
It takes, on average, about a decade for an HIV-infected individual to develop AIDS. This progression occurs gradually as the virus attacks and destroys CD4+ T cells, a subset of immune cells that are an essential component of the body's immune response to pathogens such as viruses and bacteria. Other mechanisms are also implicated in the gradual depletion of these cells. Many CD4+ T cells are initially replenished by the immune system and as a result most HIV-infected individuals remain healthy with few, if any, symptoms for several years. But eventually the immune system begins to fail and the number of CD4+ T cells slowly declines. This is often accompanied by an increase in the HIV viral load, which physicians measure by quantifying the number of copies of virus in a sample of blood.
A person with a healthy immune system has between 600-1200 CD4+ T cells in a milliliter of blood. When the number of CD4+ T cells falls below 200, a person is clinically defined as having AIDS. At this point it is recommended that individuals begin taking antiretrovirals (ARVs) that can suppress the virus. Typically a person's CD4+ T cell count begins to rebound soon after starting ARV therapy and their viral load drops dramatically, often falling below the limit detectable by routine tests.
But some HIV-infected individuals are able to control the virus for much longer than a decade without ever taking ARVs. Researchers have even identified people who have been HIV infected for as long as 28 years and have never progressed to AIDS. These individuals are known as long-term nonprogressors, and they maintain very low viral loads and either don't progress to AIDS or do so much more slowly. Researchers estimate that 1% of all people who are HIV infected are long-term nonprogressors.
Just what makes these individuals able to control HIV for longer than others is still something of a mystery, and it is further complicated because it could be due to different factors in different people. Several characteristics of the virus or the individual's genetic makeup could be partly responsible for this difference and researchers are actively studying long-term nonprogressors to determine exactly what enables them to control their HIV infection. AIDS vaccine researchers are particularly interested in determining the type of immune responses that are responsible for slowing disease progression because mimicking these responses might be the key to producing an effective vaccine.
This could be especially true for a partially-effective vaccine (see Spotlight article), one that would most likely not prevent HIV infection entirely but could lower viral load in people who do become infected. This lowered viral load would reduce the risk of them transmitting the virus to others, so a partially-effective vaccine could significantly reduce the number of new HIV infections. Long-term nonprogressors may hold important clues about what type of immune responses an AIDS vaccine would have to induce to keep HIV viral load under control.
Researchers began studying long-term nonprogressors more than 15 years ago and they have identified several possible explanations for why some people have the ability to control HIV more effectively than others. One is that the virus that these individuals are infected with is weaker and therefore less able to infect and kill CD4+ T cells. Some people are infected with a strain of HIV that is missing a key viral protein, known as Vpr, which limits its ability to infect cells.
Another possible explanation is that people have CD4+ T cells that are resistant to HIV infection. Individuals have been identified who lack a receptor on the surface of these immune cells that is normally used by HIV to gain entry into and subsequently infect the cell. Researchers think there are probably also other genetic properties that allow a person's immune cells to target and kill HIV more effectively.
But there are also many individuals who are long-term nonprogressors who are not infected with a weakened version of HIV or who do not have any of the known genetic properties that bolster their resistance to the virus. Researchers have studied these individuals to see if their immune systems are somehow able to mount more effective immune responses against HIV. So far none of the immune responses they've studied in long-term nonprogressors are any different than in people who progress to AIDS more quickly.
To try to solve this puzzle and identify the particular immune response that might be important in controlling HIV infection, a team of scientists are now collaborating on a project to study specific subsets of long-term nonprogressors known as elite or viremic controllers. Elite controllers are HIV-infected individuals not taking ARVs who maintain viral loads that are considered undetectable (<50 copies of virus per ml of blood). About 1 in every 300 HIV-infected people is considered an elite controller. Viremic controllers are infected people not taking ARVs whose viral load remains below 2000 copies/ml of blood.
Bruce Walker and colleagues at the Harvard Medical School are now working with other AIDS vaccine researchers to identify a group of 1000 elite and viremic controllers around the world—they estimate there are about 2000 in the US alone, most of whom don't know it. They plan to analyze the immunologic and genetic characteristics of these individuals utilizing the information collected by the Human Genome Project that successfully mapped the thousands of human genes. By comparing this information across a larger cohort of controllers, researchers are hopeful that they will be able to identify the specific genes or immune responses that allow some people to control their HIV infection. Hopefully this will yield important clues for the future design of AIDS vaccines.