Important note: Information in this article was accurate in March 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, March 15, 1999
Daniel J. DeNoon, Senior Editor
University of North Carolina, Chapel Hill researchers have developed recombinant proviral genomes - known to virologists as replicons - from Venezuelan equine encephalitis virus (VEE; see Vaccine Weekly, June 23, 1997). A year ago they announced that a prototype VEE-vectored AIDS vaccine was safe and immunogenic in monkeys, and they had just challenged the immunized animals with pathogenic SIV (see Vaccine Weekly, March 23, 1998).
At this year's 6th Conference on Retroviruses and Opportunistic Infections, held January 31-February 4, 1999, in Chicago, Illinois, they reported that all four vaccinated monkeys had far lower viral titers than controls during acute infection and remain disease free. Two of the animals continue to have undetectable viral loads, although viral titers have increased to high titers in the other two.
Even as work continues on optimizing the vaccine, a human version based on the African clade C HIV is being developed with an eye to clinical trials in cooperation with the International AIDS Vaccine Initiative (IAVI).
"We hope to get that into human trials within three years," said UNC researcher Robert Johnston in a symposium presentation to the Retrovirus Conference.
VEE - an alphavirus of the family Togaviridae - is spread by mosquitoes and can cause fatal human infections during epizootics among horses. The virus also has abortifacient effects. A 1995 outbreak in Columbia, spread by heavy mosquito infestation after record-setting rainfall, led to an estimated 75,000 human infections. Three hundred people died and 3,000 developed neurologic complications.
Nevertheless, humans are only an incidental host for VEE. There already is a live, attenuated VEE vaccine; new highly attenuating mutations have been incorporated into a genetically engineered live attenuated vaccine.
Several factors make VEE an attractive vaccine vector:
The VEE replicon particles, or VRP, contain nonstructural VEE genes encoding replicase, the viral subgenomic RNA promoter sequence, and the 5' and 3' cis-acting ends. Foreign genes (up to an estimated 5 kilobase pairs) inserted downstream of the promoter achieve high- level expression.
"These are suicide particles: they go in, they express, and then they do nothing because they can't reproduce," Johnston said. "No ill effects have ever been seen in a vaccinated animal ... including direct injection into a mouse brain."
In the macaque monkey studies, animals received four escalating doses of a VRP cocktail with particles encoding SIV envelope, matrix, and capsid antigens. The animals then received another two booster immunizations with a gp140 VRP.
"Instead of boosting with soluble protein we are giving replicons which should produce proteins in vivo," Johnston noted. Three of the four monkeys developed neutralizing antibodies and - even more impressively - strong SIV Gag- and Env-specific cytotoxic lymphocyte (CTL) responses.
Upon challenge with the highly pathogenic E660 strain of SIV, the vaccinated animals had viral loads two orders of magnitude lower than those seen in control animals. Two of the controls had to be euthanized at 16 weeks postchallenge, and the other two had high viral loads.
The vaccinated animal that failed to generate antibody and CTL responses eventually developed a the high viral load seen in the two surviving control animals (10(6) copies/mL). A second vaccinated animal developed a viral load of 10(5) copies/mL, but the other two animals have persistently undetectable virus. These animals remain healthy despite persistent evidence of infection.
"Our goal is to increase the antigens in the cocktail to use most of the gag and pol genes," Johnston said.
The VRP approach is also being used to develop an influenza vaccine and a vaccine against the hemorrhagic Marburg and Ebola viruses. A prototype Ebola vaccine already has been protective in the Guinea pig model (Hevey et al., Virology, 1998;251(1):28-37).
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