AIDSWEEKLY Plus; Monday, March 19, 2001
This article was prepared by AIDS Weekly editors from staff and other reports.

This vaccination strategy kept an HIV-like virus in check in monkeys, even when the animals were exposed to very high virus doses months after immunization. The study appeared March 9, 2001, in Science Express, an online publication of the journal Science.

The study indicates that the vaccine, composed of two DNA priming vaccines followed by a modified poxvirus booster, successfully primes the immune system's "memory" and provokes a strong immune response. This relatively simple vaccine regimen has achieved better protection than any other HIV vaccine candidate to date, placing this vaccine among the most promising candidates moving toward human clinical trials.

"We think the expression of multiple proteins was critical to the success of our vaccine," said study director and lead author Harriet Robinson, PhD, chief of the division of microbiology and immunology at Emory University's Yerkes Regional Primate Research Center, Atlanta, Georgia, and a faculty member of the Emory Vaccine Center.

"We have been really excited about the level of control we have achieved with our memory response," said Robinson. "Even among the groups that received the low-dose vaccine, the infections were controlled."

Scientists from Emory University and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) combined two vaccines in a strategy they hoped might be effective and then evaluated that strategy in monkeys. Both vaccines were designed against SHIV, a virus containing components of HIV and the related monkey virus, simian immunodeficiency virus (SIV). SHIV mimics HIV infection and causes serious illness in macaque monkeys. The hybrid virus allows researchers to study the reactions of the immune system to the vaccines and the virus.

The researchers reported 23 of 24 vaccinated monkeys suppressed the virus to nearly undetectable levels during the 20-week follow-up. Virus levels in the one animal were intermittently higher but still more than 100 times lower than those in four control animals that had not received the vaccine. By 28 weeks, all four control animals had developed AIDS-related opportunistic infections and were euthanized, whereas all 24 animals receiving vaccine remain alive and healthy.

The Emory team developed the first component of the vaccine strategy, a circular piece of DNA designed to carry genes for both SIV and HIV proteins. When this DNA is injected into monkeys, an immune response against SHIV is triggered. The scientists then boosted the immune response with a second vaccine, developed by NIAID's Bernard Moss, MD, PhD, and his colleagues. To construct the second vaccine, the researchers added the same genes to a virus called MVA. This virus, a modified version of vaccinia virus that cannot reproduce in human cells, was first produced in the 1960s as a safe, effective smallpox vaccine. Later research led by Moss, who is chief of NIAID's Laboratory of Viral Diseases, further developed the virus for use as a vehicle to ferry genes into the body.

Both vaccines lack certain HIV genes to ensure against formation of HIV itself, so there is no chance of HIV infection due to vaccination. "Our results show that we can protect monkeys against an HIV-like virus using an immunization scheme that is practical for use in people," explained Robinson.

In the current study, researchers combined the DNA and MVA vaccines in a prime-boost fashion. In theory, the DNA vaccine primes the immune response, alerting the body's defenses to a SHIV invasion and preparing against subsequent attacks. The MVA booster then kicks the immune system into high gear by mimicking a viral infection. The researchers hoped a combination regimen of the two vaccines would strengthen the immune system's ability to remember how SHIV looks and launch a rapid defense if infection occurred.

The investigators vaccinated four groups of Rhesus macaque monkeys; each group receiving different dosages of vaccines or different routes of injection. The monkeys were compared with four unvaccinated animals. The researchers waited seven months after vaccination and then infected all the macaques with a high dose of SHIV.

"Most other studies challenge after several weeks," noted Moss, "but a vaccine that only protects for a short time is not very helpful. We extended the post-vaccination time to check long-term efficacy."

He also stressed another important feature of their vaccine strategy: the monkeys were infected by applying the virus in the rectum. "The majority of HIV infections occur when the virus crosses mucous membranes, so we needed to see if our vaccine would work against this route of infection."

Although all 28 monkeys were infected, the vaccinated monkeys showed lower initial SHIV levels and quickly began to suppress the virus further. Twenty weeks after infection, the amount of virus in the bloodstream of the vaccinated monkeys was on average 2,000 times lower than controls. The researchers continue to monitor virus levels in these animals.

"These are among the very best outcomes we have seen in an animal model," says Peggy Johnston, PhD, NIAID's assistant director for HIV vaccines, "and we are using NIH's developmental resources and the HIV Vaccine Trials Network (HVTN) to move these and other promising vaccines into human trials in the United States and elsewhere as quickly as possible."

Both teams have already constructed HIV versions of the DNA and MVA vaccines, and human clinical trials are currently planned for the coming year. The rapid progress of these products and their future entry into clinical trials is being supported by NIAID through a range of programs put into place to fast-track HIV vaccines through the various stages of basic and preclinical research, product development and production, and clinical trials.

The study was funded by NIAID, a branch of the U.S. National Institutes of Health. Collaborators included scientists from the U.S. Centers for Disease Control and Prevention, and Duke University Medical Center. This article was prepared by AIDS Weekly editors from staff and other reports.

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