Understanding the Costs and Benefits of AIDS Vaccine Efficacy Trials
Why are late-stage trials so expensive and why is it important to invest in them?
During the earliest stages of AIDS vaccine development, researchers use animal models to evaluate the safety and efficacy of various vaccine candidates. The most promising AIDS vaccine candidates are then evaluated in early-stage clinical trials that are specifically designed to determine whether the candidates are safe, and whether they are capable of eliciting immune responses against HIV, what is known as immunogenicity. Such early-stage clinical trials are classified as Phase I or II trials and are generally small, involving approximately 300 volunteers per study.
It is the larger Phase IIb test-of-concept or Phase III trials that are specifically designed to evaluate whether an AIDS vaccine candidate is effective in preventing HIV transmission. Or, in the case of some studies, whether the candidate is capable of slowing progression of HIV disease in individuals who become HIV infected despite vaccination (seeVAX March 2005 Primer on Understanding Clinical Research Studies). These so-called efficacy trials determine whether a vaccine can be approved and licensed for use by the public. Phase IIb and III trials are much larger, involving several thousands of volunteers, and are often conducted at multiple clinical research centers. Because of their size and complexity, vaccine efficacy trials are both expensive and difficult to execute. However, because these trials can provide surprising results that may inform the design of improved vaccine candidates, they are also widely viewed by researchers as an important way to advance AIDS vaccine research.
Factors that influence trial cost
One major factor influencing the cost of efficacy trials is the HIV incidence rate—the number of new HIV diagnoses in a given population during a set period of time. The lower the HIV incidence rate in a population, the more volunteers that have to be screened and recruited into a clinical trial for researchers to determine if the vaccine is effective in preventing or controlling HIV. For the RV144 trial in Thailand, which provided the first evidence of efficacy for an AIDS vaccine candidate, investigators had to recruit 16,000 volunteers because the HIV incidence was so low in the trial population.
The criteria that are used to determine if an individual is eligible to join a trial can also increase the number of volunteers that must be screened, and therefore add to the costs. For example, researchers involved in the HVTN 505 trial are seeking to enroll HIV-uninfected men who have sex with men who are circumcised and who have not been previously exposed to a common cold virus known as adenovirus serotype 5 (Ad5), which is used in the vaccine candidate being tested in this trial to deliver non-infectious fragments of HIV to the immune system to try to induce immune responses against HIV. The additional criteria (being circumcised and having no pre-existing immunity to Ad5) were added to the HVTN 505 study after the results of the STEP trial. This trial, which tested a similar Ad5-based vaccine candidate, showed that male volunteers who received the vaccine had a higher risk of acquiring HIV if they were uncircumcised and had been previously exposed to the Ad5 virus (see VAX July 2009 Primer on Understanding Inclusion/Exclusion Criteria).
The collection and storage of laboratory specimens can also contribute to the cost of conducting efficacy trials. Blood, cell, and tissue samples must be taken periodically during a clinical trial so researchers can compare both the types and levels of immune responses among volunteers who receive the vaccine candidate with those who receive an inactive placebo, and hopefully glean information that will be useful in determining what is required for vaccine-induced protection against HIV. Both the volume and types of samples collected can add substantially to the cost of a trial because some specimens, including tissue samples, are difficult and time-consuming to procure and analyze. Once these specimens are collected, researchers also must store and preserve them properly in freezers, sometimes for years, for future analysis, which is also quite expensive.
Additionally, the process of manufacturing vaccine candidates can also add to the costs of conducting a clinical trial.
In the nearly 30 years since the AIDS pandemic began, scientists have evaluated just three AIDS vaccine candidates in efficacy trials. Two recently conducted clinical trials, STEP and RV144, yielded surprising results. While many scientists agree that basic research is necessary to advance AIDS vaccine development, more recently, many researchers are extolling the unique power of clinical trials to provide clues that can inform design of future vaccine candidates.
A well-designed, well-executed AIDS vaccine efficacy trial, even one where the vaccine candidates fail to prevent transmission or lower disease progression, can provide clues to what triggers vaccine-induced protection against HIV. Researchers are still mining the data collected in the STEP trial to gain information that will be useful in developing better vaccine candidates. Meanwhile, teams of researchers are carefully analyzing samples from RV144 in an attempt to understand what led to the modest efficacy of the vaccine candidates tested in that trial. Such information would be valuable to advancing the quest for an AIDS vaccine.