Researchers at Yerkes Regional Primate Research Center at Emory University and the Emory Vaccine Research Center have developed a multiprotein AIDS vaccine that has prevented the development of AIDS in monkeys infected with a highly virulent HIV analogue seven months after vaccination. The study results are reported in the March 9 online version of Science, and will be published in the paper issue of the journal later this month.
The federally funded study indicates that the vaccine, comprised 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 have been really excited about the level of control we have achieved with our memory response," said lead author Harriet L. Robinson, Ph.D., Chief of Microbiology and Immunology at Yerkes and a faculty member of the Emory Vaccine Center. "Even among the groups that received the low-dose vaccine, the infections were controlled."
The vaccine’s greatest strengths are its abilities to cause expression of multiple proteins and to provide memory immune responses months after inoculation. Unlike other AIDS vaccine candidates, this vaccine causes expression of the three major polyproteins, Gag, Pol and Env, that are expressed by HIV. This induces immune responses to all three proteins instead of only one or two, thus increasing the body’s ability to recognize and react to HIV.
"We think the expression of multiple proteins was critical to the success of our vaccine," Robinson said.
Also, the researchers waited seven months after the last of the three inoculations to test the vaccine’s long-term protection — a critical measure of vaccine success.
Another significant advantage of this vaccine is its simple inoculation regimen. Previous studies of HIV vaccine candidates have involved as many as six inoculations, while this vaccine required only three. "Because this is a relatively simple vaccine, it is more consistent with actual human use," Robinson said.
In the two-year study, Robinson and her team of researchers vaccinated a total of 24 monkeys with a series of three inoculations: two DNA-based vaccines delivered eight weeks apart, to prime the immune system, and a single recombinant modified vaccinia Ankara (rMVA) booster administered at 24 weeks. The monkeys were categorized in four groups by vaccine dosage (high versus low) and inoculation method (just under the skin versus deep in the muscle). Researchers compared the 24 vaccinated monkeys to a control group including two mock immunized monkeys and two non-vaccinated animals.
Seven months following the booster, the monkeys were infected with a highly virulent hybrid of simian and human immunodeficiency viruses (SHIV). The SHIV challenge was administered rectally, since most HIV infections in humans occur during sexual activity, via the mucosal membranes of the vagina or the rectum. As expected, all of the monkeys became infected with SHIV.
The researchers found that the vaccine provoked the immune system to generate large numbers of T-cells specific to SHIV and immune system memory cells. The establishment of these memory cells is vital to the success of any vaccine, because these cells are responsible for "remembering" and recognizing a particular pathogen long after vaccination.
After infection, the non-vaccinated monkeys rapidly developed high levels of virus, 100 times that typically found in HIV-infected humans, and progressed to AIDS. By contrast, the vaccinated animals maintained low levels of virus characteristic of people who are infected with HIV but do not develop AIDS over very long periods of time. Similarly, the vaccinated monkeys remained healthy. Infection with SHIV, as with HIV, is characterized by extremely rapid replication of the virus, resulting in high levels of virus soon after infection. Two weeks after infection, the vaccinated monkeys had 10 times less virus in their blood than the non-vaccinated group. Within five weeks after the SHIV challenge, the virus had suppressed the immune systems of all of the non-vaccinated monkeys, whose CD4 cells were profoundly depleted. With a single exception in the low-dose group, the vaccinated monkeys maintained their CD4 cells. At 12 weeks post-challenge, the lymph nodes of the vaccinated animals were intact and responding to the infection, while those of the infected control animals had been functionally destroyed.
By 28 weeks, all four non-vaccinated monkeys developed opportunistic infections associated with AIDS and were euthanized. By contrast, all 24 vaccinated monkeys remained healthy at 28 weeks, and continue to remain healthy.
It is important to note that the vaccine did not prevent infection in the vaccinated monkeys. Instead, the vaccine controlled infection by keeping the virus from replicating in large numbers. Maintaining a chronic, low-level infection prevents progression to AIDS and reduces the risk of virus transmission, since higher viral loads are associated with greater infectiousness. "Dr. Robinson’s exciting results represent a major turning point in our quest for an AIDS vaccine," said Rafi Ahmed, Ph.D., Director of the Emory Vaccine Research Center. "Using the best animal model available, Dr. Robinson has provided the proof of concept that a vaccine can prevent the development of AIDS. The next step, and the most important one, is to determine how effective this vaccine is in humans. This is now the highest priority of the Emory Vaccine Research Center."
The HIV version of this vaccine will move into clinical trials in humans in 2002, primarily funded by the National Institutes of Health with additional support from proceeds from the 2000 Alaska AIDS Vaccine Bike Ride. The Yerkes Research Center sent a team of bicyclists to the ride, which netted over $3 million, of which $1 million has been given to the Emory Vaccine Research Center to fund AIDS vaccine efforts.
The study was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Collaborators include scientists from NIAID, the Centers for Disease Control and Prevention and Duke University Medical Center.
In addition to Robinson, the study’s authors are: Rama Rao Amara, Bernard Moss, James M. Smith, Janet M. McNicholl, Francois Villinger, John D. Altman, Shari L. Lydy, Shawn P. O’Neil, Silvija I. Staprans, David C. Montefiori, Yan Xu, James G. Herndon, Linda S. Wyatt, Maria Angelito Candido, Natalia L. Kozyr, Patricia L. Earl, Hak-Ling Ma, Bennett D. Grimm, Michael L. Hulsey and Harold M. McClure.
Yerkes Regional Primate Research Center is the oldest scientific institution dedicated to primate research. Its programs cover a wide range of biomedical and behavioral sciences.
The above story is based on materials provided by Emory University Health Sciences Center. Note: Materials may be edited for content and length.
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