July 19, 2001 University of California scientists have developed the first vaccine that protects against vaginal transmission of a virus closely related to HIV. In studies with monkeys, all vaccinated animals remained healthy a year after exposure to virulent Simian Immunodeficiency Virus (SIV) that normally causes AIDS-like disease within a year.
Results have prompted plans for human clinical trials with an HIV version of the vaccine. Like the SIV version, the HIV vaccine will combine elements of the highly successful Sabin oral poliovirus vaccine with genetic fragments of the AIDS virus. The Sabin vaccine triggers a robust immune response which extends to piggybacked AIDS virus particles, the scientists found. While the primate study involved SIV fragments, the human vaccine will use HIV fragments.
Because sexual intercourse is the route of transmission in more than 80 percent of HIV infections worldwide, many experts believe the best chance to prevent the spread of HIV infection is by building up an immunological barrier at the port of entry-the mucosal surface of the genitals or rectum. But most vaccines tested so far don't consistently induce a strong immune response against HIV at this critical line of defense. The new vaccine takes advantage of the Sabin live poliovirus vaccine's trait of triggering a broad, long-lasting immune response at the mucosal surface.
The vaccine, administered by nose drops, was developed at the University of California, San Francisco (UCSF) and tested at UC Davis. Raul Andino, PhD, UCSF associate professor of microbiology and immunology conceived of the recombinant vaccine technology, along with Mark B. Feinberg, MD,PhD, then an assistant professor of medicine at UCSF, now at Emory University. UCSF has recently licensed this technology to a company, Iguazu Biosciences Corp., established by Andino and other scientists to carry out human trials of an HIV vaccine using this approach. Like the Sabin poliovirus vaccine used 40 years ago, the new vaccine will be administered orally, an important advantage over most other proposed AIDS vaccines.
A report on the SIV vaccine success appears in the August 2 issue of the Journal of Virology which goes online today (July 18). Andino is senior author on the paper.
"Worldwide, well over 30 million persons are now living with HIV infections." Andino said. "Only the development of a safe, cheap and effective vaccine to prevent infection has the potential of containing and ultimately eradicating the AIDS pandemic."
Because SIV, like HIV, mutates rapidly and evolves into multiple strains, Andino reasoned that many fragments of the SIV genome must be included in a vaccine to trigger an effective response to a number of potential viral antigenic targets. To generate a broad-based immune response, his team developed the SIV vaccine as a "cocktail" combining Sabin poliovirus vectors with many fragments of the SIV genome, nearly covering its entire length. The vaccine is considered very safe because the SIV genetic information is broken into small pieces, with some essential elements missing. The multiple-part cocktail was also useful because the Sabin vaccine is too small to ferry the bulk of the SIV genome.
"We expect the strong mucosal immune responses we found in the tests with monkeys were important in protecting them from SIV infection, although there's more work ahead to figure out exactly how that protection develops," said Shane Crotty,PhD, lead author on the paper who worked on the vaccine while a graduate student in Andino's lab. He is now a postdoctoral fellow at Emory University.
In the study, seven adult female monkeys known as cynomolgus macaques were given the anti-SIV vaccine with nose drops and then exposed to what is considered a highly virulent strain of SIV. They also received "booster" nose drop inoculations five months later. SIV exposure came through a flexible plastic tube inserted into the vaginal canal, releasing a fluid with a high concentration of the infectious virus two months after the last vaccination. Twelve monkeys served as controls, receiving the SIV but not the vaccine.
SIV infection normally leads to serious signs of disease in monkeys within a year and death within two to three years, Andino said. In this study, 48 weeks after exposure to the SIV virus, half of the control monkeys had developed terminal clinical simian AIDS and the other half were seriously ill with the disease.
In contrast, all seven of the vaccinated monkeys were clinically healthy, and two showed no signs of infection by any measure: no virus isolation and undetectable viral loads. Two additional vaccinated monkeys were nearly free of any sign of infections by these measures. The other three, although infected, did not show any clinical manifestation of disease after a year, by which time all control monkeys were sick or seriously ill. The SIV vaccine was tested at UC Davis in collaboration with the research group led by Christopher J. Miller, DVM, PhD, professor of pathology and of microbiology and immunology, and co-author on the paper.
"This is the first AIDS vaccine to provide full protection -- also called sterilizing immunity--for some individuals against vaginal transmission, and we think that is a big step in the right direction," said Andino. "The vaccine can certainly benefit from further improvements, but all of the animals that received it clearly had strong protective immune responses. We believe that the same approach is also very promising to protect people against AIDS"
The scientists plan now to follow a dual track: expanding primate studies while also participating in development of an HIV vaccine for human clinical trials. Since the Sabin vaccine is already proven safe and the initial primate trial indicates the recombinant approach is effective, the researchers expect to move swiftly to human trials.
Co-authors on the scientific paper with Andino, Crotty and Miller are Martha R. Neagu. MS, a technician in Andino's lab; Laura Compton, BS, Ding Lu, Fabien X.-S. Lu, PhD, Linda Fritts; and Barbara L. Lohman, PhD, all colleagues in Miller's UC Davis laboratory; and Jeffrey D. Lifson, Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, NCI-FCRDC, Frederick, Maryland
The research was funded by the National Institutes of Health, the National Cancer Institute, and the Howard Hughes Medical Institute.
Andino noted both the study's strengths and potential weaknesses in the context of worldwide efforts to develop an AIDS vaccine. The limitations: monkeys are not humans, SIV is not HIV; and the experiment's viral load, dosage and the method used to expose the animals to the virus can not perfectly mimic sexual transmission in humans.
On the other hand, the viruses are quite similar. HIV probably evolved from a particular strain of SIV, and the genome sequences of the two viruses are more than 70 percent homologous. The vaccination experiment demonstrated effective anti-SIV immunity even though the Sabin vaccine does not naturally or readily infect monkeys. The candidate AIDS vaccine may actually be a good deal more effective in humans since Sabin viruses are greater than a thousand times more infectious in people than in cynomolgus macaques, and thus likely to generate a significantly stronger immune response to HIV antigens in people than in monkeys.
Finally, for purposes of the experiment, Andino and his colleagues used a relatively high concentration of SIV infectious units - 100,000 IU's - in order to assure that all unvaccinated monkeys would become infected. The "dose" of HIV encountered through sex is not well known, but is likely to be a hundred to ten thousand times less than what was used in this experiment. The experiment's results might indicate that the vaccine is able to trigger an immune defense against an even greater threat than people normally face from HIV.
The abstract of the Journal of Virology article is available online at: http://jvi.asm.org/cgi/content/abstract/75/16/7435
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