New Challenges of HIV Vaccine Research

The search for a vaccine for HIV promises to require decades of work by researchers and sustained optimism on the part of trial volunteers and the public. The virus presents daunting scientific obstacles: no perfect animal model of HIV disease exists; recovery from HIV infection has not been documented; the "correlates of protection" (immune responses which would protect people from infection) are not known; the virus is highly variable so a vaccine for one "clade" (or type of HIV) may not protect against a different HIV-1 clade; and the virus mutates rapidly and may be able to elude a vaccine.

Traditional approaches to vaccine development, such as "whole killed" or attenuated virus methods raise special safety concerns with HIV, since a faulty vaccine which actually infects a recipient could have lethal consequences. Finally, it may be impossible to find a vaccine which prevents actual infection (also called "sterilizing immunity"). Instead, research goals may focus on a product which can inhibit progression to disease, or lower viral load in infected persons. Assessing a vaccine's ability to meet these post-infection goals may add years to human trials.

These obstacles may translate into a product development and human trial timeline measured in decades. When many people think of a vaccine trial, they picture one large trial that proves efficacy in a few years. Progress will probably be more incremental in the case of HIV vaccines.3 It is likely that a series of human trials will continue for many years and require tens of thousands of volunteers in several countries.

Vaccines for HIV are not the first to require multiple human trials over many years. The vaccine for haemophilus influenzae type B (HIB) was developed over a 17-year period and involved hundreds of thousands of individuals in human trials.4 The HIB vaccine may have limited application as a model of the social dynamics of HIV vaccine research, however. Like HIB, HIV has a relatively low annual infection rate in the United States, meaning that efficacy trials will likely be lengthy, expensive, and generate results which are sometimes difficult to interpret. Unlike HIB, human trials for HIV will take place under intense media scrutiny and political activity, and involve adults in stigmatized risk groups, rather than children in the general population.

During the extended testing timeline for HIV vaccines, results from efficacy trials may create controversy even as they advance research. NIAID is now developing the concept of "Intermediate Sized Trials" to test early vaccine candidates. Unlike standard large-scale ("Phase III") human trials, intermediate trials would involve fewer volunteers and be less expensive, allowing researchers to test several different products and pursue only the most promising with full-scale efficacy trials. The drawback of intermediate trials is that their results have lower "statistical power" and may provide ambiguous results. For each intermediate sized trial, public health officials and researchers will need to decide whether the results justify expanding to a full-scale Phase III trial.

The three "phases" of human (clinical) trials

Phase I: Involves small numbers of low risk volunteers and is designed to test the safety, acceptability and appropriate dosage of a product.

Phase II: Involves larger numbers of volunteers (usually several hundred) and is designed to test safety and immunogenicity (the ability of the product to induce responses from the immune system).

Phase III: Large scale trials, usually involving several thousand volunteers designed to test the safety and efficacy (effectiveness) of a product.

Intermediate Sized Trials are intended to give an indication of whether or not product may be efficacious. These trials involve smaller numbers of volunteers than Phase III trials and can be expanded to full-scale efficacy trials if the product being tested shows promise.

If, in the early 21st century, trials have not succeeded in identifying a broadly licensable vaccine, thousands of new volunteers will be needed to sustain HIV vaccine research. Scientists will still be making difficult decisions about the threshold for advancing to full scale trials, and each of these decisions may be an occasion for renewed public debate. Recent history suggests that the public perception of this process - its ethical conduct, its use of resources, its hope for success - will have a powerful impact on the successful development and distribution of vaccines for HIV.

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