Chapel Hill - Scientists at the University of North Carolina at Chapel Hill have won a five-year federal grant totaling more than $12 million to develop a safe and effective vaccine against HIV, the virus that causes AIDS.
The grant from the National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS, in Bethesda, Md., is one of only three large HIV Vaccine Research and Design grants awarded by the agency this year.
Over the next five years, a team led by Dr. Robert E. Johnston, professor of Microbiology and Immunology at the UNC-CH School of Medicine, will apply $12.35 million to study a novel vaccine method that is showing promise in early tests on monkeys.
The vaccine approach under study at UNC is built around a disabled, safe version of the Venezuelan equine encephalitis virus (VEE). In the wild, the tropical microbe infects horses and is sometimes carried to humans via mosquitoes.
Johnston and Microbiology/Immunology research associate professor Dr. Nancy Davis studied VEE for about a dozen years, developing candidate vaccines against the virus. Their work led them to believe it might be modified for use as a safe vaccine vector. Now it appears that their notion is correct.
Johnston and his colleagues are using a cocktail of VEE replicon particles (VRP) as a vector to carry the vaccine's molecular payload into the immune system. First, they modified the virus by removing about one-third of its genes. They then inserted genetic material taken from a pathogen, using as a test case simian immunodeficiency virus (SIV). In rhesus macaque monkeys, SIV causes a disease that is similar to AIDS in humans.
"The idea behind vaccination is to trick the body into thinking it's already had the disease once before. That's what vaccines do," Johnston explains. "They present the body with proteins from a disease organism and induce the body to respond immunologically in various ways to these antigens. Then when the individual is subsequently exposed to the real pathogen, they're immune."
According to Johnston, the VRP vaccine targets cells in lymph nodes, the critical tissue of the immune system. "The vector will produce the immunizing protein in the heart of the immune system. And we think some of its effectiveness derives from that biological feature," Johnston says.
In their most recent studies, the researchers have immunized four rhesus macaques using the SIV-VRP vaccine. The animals were then challenged with an intravenous injection of the real virus.
"And we've shown that, in fact, these modified vaccine vectors do induce both significant cellular and humoral [antibody] immunity in the vaccinated macaques and that some protection is demonstrated upon challenge," Johnston says. "All of the vaccinated animals were infected with SIV, but due to having been vaccinated, their maximum virus load was reduced by 99 percent, and they didn't show signs of disease. In one of the animals, virus was not detectable one year after challenge."
Under three research projects, the grant will fund continued efforts to optimize the vaccine system and improve protection.
"The three research projects will examine fundamental issues of vector and immunogen design for an HIV vaccine based on the VEE vector system," Johnston says. One project will conduct basic research into lymph node targeting and immunogenicity - the ability of vectors to induce an immune response. Another project will explore the role of protein structure in immunity induction. The third project will expand on previous experiments, combining the vector improvements derived from the first two.
"We feel these three research projects will provide clear direction for the construction of a second generation HIV vaccine candidate based on an improved VEE vector system," Johnston says. A first-generation HIV vaccine is being constructed now using the current system.
This project is being funded by a $4.6 million grant from the International AIDS Vaccine Initiative (IAVI) and is led by Robert Olmsted, director of research at AlphaVax, Inc., a Durham, N.C.-based biotechnology company which holds the commercial license for the VEE technology from UNC. AlphaVax, the UNC group and scientists from South Africa are working to have a prototype vaccine ready for human safety testing by the end of 2000.
Collaborators under the NIAID grant include Dr. Ron Swanstrom, professor of Biochemistry and Biophysics and director of UNC Center for AIDS Research; Dr. Jeffrey A. Frelinger, chairman of Microbiology and Immunology at UNC; Dr. Phil Johnson of Children's Hospital Research Foundation, Columbus, Ohio; and Dr. David Montefiore of Duke University Medical Center.
Note to media: Dr. Robert Johnston can be contacted at 919-966-3507; email: rjohnst@med.unc.edu. UNC-CH School of Medicine media contact is Lynn Wooten, 919-966-6046 or email LWooten@unch.unc.edu.