Monkey Vaccine Renews Hope
New approach boosts cellular immunity.
by Larry Schuster

In April, researchers reported promising results involving a new AIDS monkey vaccine, which appears to be a good candidate for human trials if follow-up studies prove equally positive. Researchers at Yerkes Regional Primate Research Center in Atlanta, which is affiliated with Emory University, say their three-year study in macaques found the vaccine was able to substantially contain the AIDS virus in these animals, though it was not able to eradicate it.

"I just couldn't believe the results when I first saw them," said Harriet L. Robinson, chief of Microbiology and Immunology at Yerkes and the project's lead researcher. "I didn't believe we could do this well."

Robinson's study compared eight vaccine approaches against strains of SIV, or simian immunodeficiency virus, the sister virus of HIV. The most effective involved a purified DNA vaccine containing several SIV genes combined with a recombinant fowl-pox vaccine containing the same viral DNA, or HIV genes. This two-pronged strategy allowed the DNA vaccine to "prime," or induce certain immune responses, that were then enhanced by the fowl-pox vaccine, which is derived from a bird virus that does not reproduce in human cells but strengthens or broadens the immune response to HIV.

Robinson reported that the DNA-fowl-pox vaccine reduced the level of virus replication in the monkeys by at least 1,000, and as many as 10 million, viral copies. In humans, up to a billion copies of HIV are generated each day. The vaccine was also able to contain a hybrid SHIV virus, a genetically engineered virus made from an HIV envelope and SIV core, during a 62-week period. Until this point, Robinson said, only vaccines featuring live yet weakened strains of virus that risk causing disease in humans have been able to contain severe viral challenges in monkeys.

How It Works
There are two arms to the body's immune defenses. The first is a cell-mediated immune response that involves a subset of immune CD8 T-cells (also called cytotoxic T-lymphocytes, or CTLs) that target other infected cells. A secondary humoral immune response uses neutralizing antibodies, or immunoglobulins, which are protein molecules that can recognize and bind to the HIV molecule.

Until recently, many scientists felt that a candidate HIV vaccine should try to boost both kinds of defenses, since in some viral diseases, CTL responses control infection while antibodies stop the infection from taking hold. For the most part, HIV vaccine studies solely aimed at neutralizing antibodies haven't worked well, partly because the variable virus mutates every time it reproduces and can escape detection by antibody defenses.

But in the past year, there has been mounting evidence suggesting that CTLs may be the key player in controlling viral activity. Robinson said she believes the heightened immune response involving CTLs seen with her vaccine stopped virus replication within the infected cells but did not necessarily destroy the infected cells. What the Yerkes study showed, added Robinson, was that "both DNA and recombinant pox vaccine can raise CD8 response, and the combination is dynamite, especially if you use the DNA first."

The two key features of the Yerkes vaccine are its potential safety and protective ability. The vaccine contains purified DNA that encodes for several viral proteins including the capsid that surrounds the nucleic acid, or the genetic code of the virus; a protein involved with replication; a protein involved with the envelope; and a protein that cells generate early in the infection process.

Scientists who commented on the work said the approach does represent an important advance. Peggy Johnston, Associate Director for Vaccine and Prevention Research at the National Institute of Allergy and Infectious Diseases, which funded the research, said one of the most exciting aspects of the Yerkes research was the protection the vaccine recorded in the absence of the neutralizing antibodies. "This is one of a short list of what needs to move into human trials," Johnston said, explaining that the short list of such high-priority vaccine candidates totals about three or four.

Robinson said she is very optimistic that when tailored and simplified for use in humans, her approach could be useful as a preventive vaccine for those not infected as well as for people with functioning immune systems who are HIV positive and taking combination drug therapies. "If it works in people the way it works in monkeys, it would keep the level of the incoming virus so low you wouldn't be able to detect the virus using PCR [polymerase chain reaction] assays," Robinson predicted. PCR is a sensitive technology that detects HIV by expanding tiny amounts of the virus' genetic material. Robinson envisions that with her vaccine, the level of the virus would be kept so low it would be rarely transmitted.

Others aren't so sure. Taking a closer look at Robinson's study, David Gold, an editor at the International AIDS Vaccine Initiative, or IAVI, notes that after vaccinating the monkeys, the researchers first challenged them with two weaker strains of SHIV viruses that seemed to protect the animals against those strains, then challenged them with a more virulent virus. In Gold's view, the initial exposure to what he calls "wimpy viruses" may have acted to jump-start immune defenses that helped contain the more virulent virus.

"In a sense, it's almost like a live attenuated boost," says Gold, comparing the use of weak viral challenges to vaccines made of live virus particles that also induce strong immune responses. While he's quick to praise Robinson as a top scientist, Gold wonders if the protective responses would have occurred without using the wimpy virus as a boost. Says Gold: "This combination may be extremely promising even without this [use of weaker virus challenges]. But it just messes up the data a little bit too much for my taste."

Further experiments may give us the answer. Robinson's goal is to test her vaccine in human trials in a year or two. But first she'll carry out a yearlong follow-up study in the monkeys. This new study will compare different methods of inoculation, as well as the number of immunizations needed to elicit optimal immune defenses, and will test more simplified vaccines as well. Researchers hope to determine precisely what immune response the vaccine combination triggered.

Wayne Koff, Vice President for Research and Development at IAVI, also feels that Robinson's approach ought to be tested in humans. Says Koff: "I think it's an advance in the sense that it uses a new combination of vaccines. It's beginning to show what people intuitively have thought: As you use a combination of vaccines and increase the number of genes in the vaccine, you increase the opportunity of getting a protective response." But he cautions, "These are important steps in a long process. Until you begin to evaluate this vaccine concept in clinical trials, the utility of the vaccine remains in doubt. These are steps of a marathon as opposed to leaping from one end of the game to the other."

Maybe so, but there are also new runners in what's become a hot race. In May, a team from the Aaron Diamond AIDS Research Center in New York and the Tulane Regional Primate Research Center reported that it's come up with a new hybrid SHIV virus, which triggers an immune response in monkeys that more closely mimics what occurs in people exposed to HIV, according to the authors of the study.

AIDS vaccine clinical trials began in 1987. Currently, there are only two vaccines in the most advanced phase of human trials, in which vaccines are tested for efficacy. One of the vaccines, AIDSVAX, by VaxGen Inc., of Brisbane, California, is being tested as a preventive vaccine; it induces antibody responses to HIV. The second candidate, Remune, is a therapeutic vaccine being developed by Immune Response Corporation of Carlsbad, California. It induces cellular immune responses. About 20 AIDS vaccines are currently in therapeutic and human-prevention trials worldwide. Altogether, U.S. AIDS researchers estimate that 55 AIDS vaccines have been evaluated in clinical trials worldwide since the start of the epidemic.

Larry Schuster is the Science and Technology Editor at United Press International in Washington, D.C.