Potholes in road to vaccine against HIV

As promising vaccine fails test, other researchers aim at different targets

by Tom Valeo

November 16, 2007

Despite two decades of trying, the development of a vaccine against HIV remains an elusive goal.

Just recently, for example, one of the most promising vaccines ever developed failed to block or even slow down HIV infections when tested in a "test of concept" trial, which was halted prematurely. The trial was sponsored by Merck & Co. and the federally funded HIV Vaccine Trials Network (HVTN).

The vaccine, known as V520, attempted to stimulate the immune system’s killer T cells, which search out and destroy cells in the body that have been infiltrated by a virus. The vaccine used a weakened form of human adenovirus, one of the viruses that cause the common cold, to transport three genes from HIV into the body, thereby stimulating an immune response.

More than 3,000 uninfected people in North and South America and Australia were enrolled. Those receiving the vaccine and those receiving a placebo later contracted HIV at approximately the same rate, showing the vaccine to be totally ineffective. A similar trial of V520 in South Africa also was halted.

Trying 'retrovaccinology'

A different and still promising approach to an HIV vaccine is a method called "retrovaccinology." An example was reported in the Sept. 6 issue of Nature. Researchers at the Scripps Research Institute focused on the b12 antibody, identified in 1992 in a 31-year-old man who had been HIV-positive for six years without developing AIDS. By creating a mutated version of b12, the researchers hoped to identify the changes it produced in the immune system to confer immunity.

The researchers believe that to be effective, a vaccine against HIV must stimulate the production of neutralizing antibodies such as b12, which attach to the HIV virus and prevent it from entering host cells. The Scripps researchers tested b12 as well as two mutated versions of the antibody, known as K322A and LALA, on female monkeys who were infected with simian HIV. The normal b12 antibody as well as K322A protected eight out of nine animals, while LALA protected five of nine.

“Hopefully, we can work backwards towards a vaccine using b12 and the very few other really great, broadly neutralizing antibodies against HIV that have been found,” said Ann Hessell, Scripps Research Senior Research Associate and the first author of the Nature paper.

Dennis Burton, a professor at Scripps and another author of the paper, hopes to use the process, which he refers to be the newish word "retrovaccinology," to work backward from an antibody called 2G12, also isolated from an infected patient whose immune system apparently neutralized the HIV virus. At an HIV symposium held last spring in Canada, Burton revealed that 2G12 actually consists of two antibodies joined together, which recognize the unique coating of sugars that normally hides the HIV virus from the immune system.

“This study is part of the effort to understand how protection against HIV occurs,” Burton said. “If we really understand this, then we can design tailor-made vaccines in a way that has never been done before.”

However, in a comment in the same issue of Nature in which this paper appeared, John R. Mascola of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID), one of the NIH Institutes, urged caution.

“Clearly, there is much we don’t know about how protective antibodies work and the level of antibodies required for maximal protection,” he wrote. “As Hessell and colleagues’ findings indicate, antibodies against HIV-1 are likely to exert a protective effect through more than one mechanism. So continued research should seek to elucidate and measure alternative biological functions of protective antibodies.”