One Step Forward, Two Steps Back — Will There Ever Be an AIDS Vaccine?

In April 1984, when the human immunodeficiency virus (HIV) and AIDS were just beginning to be understood, a senior official in the Department of Health and Human Services stated at a press conference that there would be a marketable vaccine within "a minimum of two years, probably more like three years."1 This prediction has haunted the search for an AIDS vaccine, whose most recent setback was the announcement that a promising vaccine candidate, Merck's V520, was not effective and may actually have increased some subjects' risk of acquiring HIV. Unfortunately, about a quarter-century after the discovery of HIV, there is neither a marketable vaccine nor a credible expectation about when there will be one.

A successful HIV vaccine would either prevent infection or reduce the viral load in persons who became infected, helping them to remain healthy and perhaps reducing their likelihood of transmitting the virus to others. But vaccine developers face many scientific challenges, including those posed by the genetic diversity and rapid changes of the viral envelope proteins and other features that allow HIV to elude immune control.2 Critical immunologic responses that would prevent infection or control the virus are incompletely understood. Nonetheless, there has been considerable interest in vaccines, such as V520, that induce primarily T-cell responses, because numerous studies have provided evidence of the role of T-cell immunity in controlling HIV infection.

The V520 vaccine consists of three injections of a recombinant, replication-defective adenovirus type 5 vector that carries three HIV genes and was designed to elicit HIV-specific T-cell immune responses (see diagram). Adenovirus type 5 is a common cold virus and is generally considered harmless. The vaccine was evaluated in two trials involving volunteers who were HIV-negative but at high risk for infection. The HIV Vaccine Trials Network, which is funded by the National Institute for Allergy and Infectious Diseases (NIAID), in conjunction with the vaccine developer, Merck, conducted the STEP trial in the United States and abroad; the Phambili trial was conducted in South Africa. In September 2007, the STEP trial, which had enrolled 3000 subjects, was stopped after the data and safety monitoring board, at its first interim analysis, concluded that the vaccine neither prevented HIV infection nor reduced the amount of virus in those who became infected. In October, the Phambili trial, which had enrolled only 801 subjects, was also stopped; the trial's monitoring board concluded that there was no reason to anticipate more favorable results. Participants in both studies were told whether they received vaccine or placebo.

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