American Foundation for AIDS Research, May 2003
Kristen Kresge

This year's Retrovirus conference introduced a surprisingly robust list of HIV vaccine candidates, both still in the lab or already in human trials. Scott Hammer from Columbia University had the daunting task of providing an overview of the many vaccine trials. Beyond the multitude of trials, Hammer's talk zeroed in on a crucial obstacle that current vaccine candidates have yet to counter: viral escape.

Cellular Immunity Vaccines Face a Roadblock
Most recent vaccine research has focused on establishing cellular immunity, one of the two approaches that the immune system takes in fighting infection. Vaccines aimed at inducing cellular immunity produce killer T-cells in the body, which eliminate HIV-infected cells. This is a new strategy for vaccine development. Vaccines that trigger killer T-cells may not be able to completely prevent HIV transmission (by producing "sterilizing immunity"), but they the immunity they provoke may so suppress viral replication that the infection remains under control with no evident disease. New research indicates that cellular immunity ultimately fails to manage HIV. Viral replication appears over time, and so does disease progression.

Vaccine protection eventually fails because the virus can mutate to become unrecognizable to the immune response, which focuses on a few specific HIV protein sequences. Even while the vaccine-induced immunity is effectively keeping the virus in check, a small amount of HIV replication is still occurring in the cells. This replication is enough to allow the virus to mutate. Once mutated, the virus eludes the immune response mounted by the vaccine and the disease progresses rapidly.

From the start of the conference, studies stressed this viral escape. Dr. Dan Barouch of Harvard Medical School presented results of a monkey experiment that illustrates the ability of the virus to evade a DNA-based vaccine developed by Merck. This vaccine triggers an immune response by inducing cells that take up HIV-derived genetic extracts to provide a mock HIV infection. In this study, four rhesus monkeys were immunized with a simian version of the Merck vaccine and then challenged with a virulent form of simian immunodeficiency virus (SIV). Five control monkeys were given an inactive vaccine. All nine animals were followed over a three-year period.

The four DNA-immunized monkeys showed initial control of virus replication and remained healthy. But eventually three of the four animals lost immune control and became sick or even died. One monkey became sick within the first year after being injected with the virus. Two additional animals experienced an increase in viral replication and became sick after three years of maintaining an undetectable virus level in their blood. The increased viral replication occurred simultaneously with a killer T-cell decline in the animals and the emergence of the same two dominant mutations in the virus.

The slightly mutated virus appeared impervious to the monkey's immune defense but the vaccine was not a complete failure. The vaccinated monkeys were able to slow disease progression much more effectively than the control monkeys. Three of the five control monkeys sickened quickly after exposure to the challenge virus. Another one maintained immune control for at least one year after exposure and then eventually experienced a viral breakthrough. These four animals had the same virus mutations as the three vaccinated monkeys that became sick, indicating that these mutations are pivotal for viral escape.

One vaccinated monkey and one control monkey are still staving off infection effectively. Although these results are discouraging, Barouch warned against making broad generalizations about cellular immunity-based vaccines. He explained that this study intentionally involved a weak vaccine and a potent virus to more easily detect viral escape.

Barouch strongly cautioned against interpreting these results as the death of the vaccines that elicit cellular immunity. "We're still very enthusiastic about this approach. The glass is still half full and it still shows tremendous promise," he said. "This is not a completely negative message."

Animal experiments utilizing more potent vaccine candidates described at the conference, support Barouch's comments. John Shiver, Director of Vaccine Research at Merck, offered a latebreaker report on encouraging results from monkey experiments that administered an initial DNA-based vaccine followed by a "booster" comprised of a recombinant virus that enter cells and produces HIV proteins but does not replicate. These prime and boost vaccinations were more effective together than either given alone against two virulent viruses in monkeys. The vaccine plus the boost also provided a 10 to 35-fold reduced viral load compared with control animals up to 136 days after exposure to the test virus.

Merck will present more data on this two-phase vaccine at an April vaccine symposium. In the meantime, research will continue to evaluate the protective effect afforded by cellular immunity-based vaccines.

The Return to Antibody Research
Despite some encouraging results from both clinical and preclinical vaccine candidates, an obvious paradigm shift in vaccine research took place at the conference. Dr. David Ho, Director of the Aaron Diamond AIDS Research Center and Chair of the Retrovirus Conference's Scientific Program Committee, declared that recent experiments show the need for researchers to reopen their efforts to develop a different class of vaccines – those that produce antibodies to fight off HIV.

Vaccine research in the early 1990's took this approach, the traditional one for vaccines, but they quickly ran into difficulties. As opposed to vaccines that rely on killer T-cells, an antibody vaccine would introduced HIV proteins into the body to stimulate the production of neutralizing antibodies. These would latch onto free HIV in the body, blocking its ability to enter cells while flagging it for destruction.

Work on neutralizing antibodies went out of fashion because the surface of HIV is covered with several sugars. This barrier makes it difficult for antibodies to reach the viral proteins. HIV can easily mutate so that its envelope is impervious to any antibodies that do effectively block it. As a result, promising early antibody vaccines did not prove protective enough. This failure triggered the shift to cellular immunity.

"People said this is going to be hard," said Dr. Susan Zolla-Pazner, referring to antibody-based vaccines. But Zolla-Pazner, Director of the Immunology Research Laboratory at the Veterans Affairs Medical Center in New York, has been a longtime champion of the need for a vaccine that induces broadly neutralizing antibodies against HIV. Her research has continued to focus on this approach because although cellular immunity may be able to control infection, it never held hope for preventing infection.

Zolla-Pazner's presentation at the Retrovirus conference concentrated on antibodies that can bind with a section of HIV envelope protein known as the V3 loop. This loop plays an important role in aiding virus entry into cells. Antibodies isolated from HIV-positive individuals are able to interfere with this part of the viral protein and stop HIV from entering cells. The V3 loop protein can easily change its structure, but the antibodies are able to neutralize HIV with variant V3 loop sequences.

The question then becomes, What substance can serve as a vaccine to evoke such antibodies in the body? Zolla-Pazner called this question reverse immunology. She began her talk with a reference to Johnny Carson's popular character, Karnac the Magnificent. Much as Karnac already knew the answer but had to come up with the question, researchers like Zolla-Pazner are working backwards.

Neither Zolla-Pazner nor Karnac know what substance could be used to produce such broadly neutralizing antibodies, but they will be working to find out. Zolla-Pazner observed that this is an exciting time for vaccine research because now researchers can focus on rational design of vaccines in the same way that rational drug design produces effective anti-HIV drugs. Her main message about neutralizing antibodies: "Put it back on the table again. It's important."

And that seems to be just what is happening. Many researchers "took the cellular fork in the road," said Zolla-Pazner, but "we're going to have to have a vaccine that induces both antibodies and a cellular response."

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