What are some of the complications in designing trials to study partially effective AIDS vaccine candidates?
Most vaccines against viruses such as polio and smallpox effectively prevent the pathogen from ever causing disease or making people sick. This makes the process of evaluating their efficacy rather direct. Unfortunately, the nature of HIV presents a number of challenges to the classic approach of developing and testing vaccine candidates.
Many researchers think that a preventive AIDS vaccine that protects against HIV infection entirely would need to induce broadly neutralizing antibodies against the virus. These Y-shaped proteins latch on to the virus and effectively neutralize it so it can no longer wreak havoc. But designing an AIDS vaccine candidate capable of inducing broadly neutralizing antibodies is a difficult challenge.
Many AIDS vaccine candidates that are currently being tested induce only cellular immune responses and not neutralizing antibodies, so they are not expected to block HIV infection from occurring. Instead, it is hoped that a candidate that induces cellular immune responses may help slow disease progression in individuals who subsequently become HIV infected. Such vaccine candidates are often referred to as being partially effective (seeVAX May 2007 Primer on Understanding Partially Effective AIDS Vaccines).
Evaluating partial efficacy
HIV is a persistent infection that can linger quietly for years before causing disease—typically, it takes an average of eight to 10 years for someone who is HIV infected to develop AIDS. Because it is impractical to follow volunteers in a vaccine trial for a decade, researchers use markers of disease progression in volunteers who become HIV infected instead to evaluate partially effective vaccine candidates.
One marker for disease progression is viral load, which is the amount of HIV that circulates in blood. Viral load is considered a good predictor of how quickly a person with HIV progresses to AIDS.
Soon after a person first becomes infected with HIV, during what is called acute infection, viral load is typically very high. Once the body’s immune responses against HIV are activated, the viral load typically drops to a much lower level—referred to by researchers as set point viral load. In most individuals, viral load remains at this lower set point level for many years. Over time, as the immune system becomes incapable of controlling HIV, viral load eventually increases, usually accompanied by a loss of CD4+ T cells that marks the progression to AIDS.
Generally, the lower the set point viral load, the longer it will take for a person to progress to AIDS. Researchers speculate that a partially effective vaccine candidate could help lower the set point viral load further, and therefore delay the time to onset of AIDS—perhaps allowing a vaccinated person to control HIV effectively for longer than a decade without the aid of antiretrovirals (ARVs).
Viral load as an endpoint
Several trials of current AIDS vaccine candidates are designed to evaluate viral load as a marker of the candidate’s efficacy. The recent STEP trial of more than 3,000 participants, which evaluated Merck’s vaccine candidate MRKAd5, was designed to look at whether the candidate could prevent HIV infection entirely, or lower viral load in individuals who became HIV infected during the trial through natural exposure. Vaccine candidates themselves cannot cause HIV infection.
Results of this trial showed that the candidate was ineffective in preventing HIV infection. It also showed that there was no difference in viral load between vaccinated volunteers and placebo recipients. Some trials, including STEP, also monitor the time until initiation of antiretroviral therapy following HIV infection as another marker of the vaccine candidate’s efficacy.
Using viral load as a marker to evaluate the efficacy of a vaccine candidate becomes more difficult if volunteers who acquire HIV infection during the trial begin taking ARVs. Once people begin taking ARVs, which are highly successful at reducing viral load, it limits the ability of researchers to tease out any effect of the vaccine candidate. This has become increasingly relevant as more people start ARV therapy earlier, often during the period of acute infection. This could impact the design of future trials of partially effective vaccine candidates.
Current guidelines about when to start therapy vary greatly. Earlier treatment for HIV infection is now recommended in Europe and the US, but in wealthy countries, it is often up to the discretion of an individual’s doctor. Many developing countries follow guidelines set by the World Health Organization, which doesn’t recommend treatment until a person develops AIDS defined as a CD4+ T cell count below 200 cells in one ml of blood). But the International AIDS Society recently altered its recommendation, and now suggests starting treatment when the level of CD4+ T cells drops below 350. A number of African countries are considering revising their treatment guidelines based on this recommendation.
The move to earlier initiation of treatment stems from research that indicates starting treatment earlier significantly reduced the risk of illness and death associated with AIDS. Researchers are now considering how these shifting guidelines may alter the evaluation of partially effective vaccine candidates.