Jan. 16, 2001 BALTIMORE, Md. -- After more than a decade of targeting steps of the AIDS virus entering human cells, a team of vaccine researchers now with the University of Maryland Biotechnology Institute (UMBI), have designed new vaccines to stop HIV infections before they can occur by sex, blood exchange or other means.
The team has received a new $5.3 million grant from the National Institutes of Health (NIH) to help complete the best of their HIV vaccines, according to David M. Hone, associate research professor at UMBI's Institute of Human Virology (IHV).
The IHV vaccines are carried directly into human cells by a strain of Salmonella bacteria that Hone and colleagues have severely crippled by multiple mutations. The vaccine itself, in each case, is a liquid suspension of the nontoxic bacteria, swallowed by volunteers.
The oral vaccines include bits of DNA from HIV's outer coat, which the researchers have also rendered harmless. The bits of HIV cannot cause AIDS. At IHV, the vaccinating system has been tested successfully for safety in human volunteers.
Racing against still-raging AID pandemic around the world, and an ever increasing number of HIV mutations, the team will apply the NIH funding to make sure at least one of their vaccine candidates soon becomes a clinical success. They will begin clinical trials of the best candidates as soon as late this year.
"One of the unique aspects of our trials is that we have a wide array of vaccines coming down the pipeline because we are fully aware that vaccine development is 99 percent misses with the occasionally one vaccine that stands on its merits," explains Hone.
The method of putting a vaccine into Salmonella or another infectious bacteria species-bactofection--has already been approved in part by the U.S. Food and Drug Administration in previous volunteer studies of nontoxic Salmonella carrying DNA that makes a piece of the HIV protein, says Hone.
Principal investigator of the NIH grant George Lewis, who directs IHV's vaccine division, describes bactofection as a "Trojan horse-like" surprise attack on the elusive AIDS virus. "We have altered the Salmonella so it can no longer cause any intestinal illness, but the bacteria still know all the roadmaps to get inside human cells. The cells themselves use the piece of HIV DNA delivered by the bacteria to then manufacture copies of the HIV antigen."
Four and a half years ago, three independent groups of researchers, including a University of Maryland team at IHV, discovered that certain bacteria could transfect or move bits of DNA into cells of higher organisms and have the DNA express or manufacture the new copies in the cells. The IHV team gained two broad U.S. patents for the system, one in 1999, and one in 2000.
Lewis says that in practical terms of fighting AIDS globally, a vaccine locked into Salmonella bacteria is "extremely transportable." It may not need refrigeration in developing countries. It would also be far less expensive to manufacture than other AIDS vaccines under development, according to Seth Berkeley, president of the International AIDS Vaccine Initiative. The non-profit IAVI, in July pledged to help develop the IHV vaccine delivery system in Africa. The oral vaccines also eliminate the need for sterile needles, meeting a requirement of the World Health Organization for AIDS vaccines.
Biologically, the innovative IHV vaccines provide protection both by whole body immunity as well as in the critically important mucosal tissues, such as the genito-urinary tract and rectum, where HIV often first enters the body during sexual contact with an HIV infected individual. So far, the vaccines have been shown in animals to induce strong reactions by mucosal immune cells that are similar to those known by researchers to stop HIV infection. At the same time, the vaccines also stimulate a strong immune reaction to fight HIV in the blood stream, says Hone.
"If this proves to be both safe and very immunogenic in humans, it will be a total breakthrough in HIV vaccines," says Hone, "because of the way it attacks the virus at its first contact."
[In recent HIV research, scientists have surmised that on mucosal membranes HIV may enter the body by attaching itself to cells called dendritic which act as watchdogs of the immune system. Typically, the dendritic cells capture invading microorganisms then set off an alarm for other immunity cells, such as T-cells which then fight off the invaders. But in the case of an HIV invasion, the virus can hitch a ride into the lymphoid tissues, where it proceeds to infect the T cells and others, thus tending to neutralize the immune system for its own benefit.]
The key to success of the IHV vaccines is that the carrier bacteria immediately infect the dendritic cells on mucous membranes in the digestive tract. The oral HIV DNA vaccine within the disarmed Salmonella, hitchhikes a ride to the mucosal cells, and then stimulates immunity by raising antibody responses throughout the mucosal lymphoid tissues and in the blood.
Previously, the IHV's vaccinating system was tested successfully for safety in human volunteers. The NIH grant will now support comprehensive testing of the best candidates vaccines through three inter-linked projects: 1. More preclinical animal trials of Salmonella-delivered vaccines which are in final building stages at IHV laboratories. 2. Tests to induce vaccine components that give newly enhanced antibody responses to HIV infection. And, 3. clinical trials in Baltimore.
Project one is directed by Hone who has over 15 years of experience in development and evaluation of Salmonella vectored vaccines. In previous studies, Hone developed a strain of Salmonella, which is now the central component of new oral vaccines against typhoid fever. He also led a study that was the first to document that a bacterial HIV-1 vaccine might work.
Hone and colleagues are building on what he calls "the gold standard" of HIV vaccine testing: the gp120 protein on the HIV coat. The virus puts gp120 in charge of directing entry into human cells. During the past few years, several trials at the National Institute of Allergy and Infectious Diseases have shown that using the gp120 is safe and well tolerated by human volunteers. The IHV researchers have genetically engineered two versions of the HIV gp120 protein for delivery in the Salmonella bacteria. Researchers have known about gp120 since 1987. But by itself delivery of gp120 DNA is not enough to raise sufficient antibodies to fight the invading HIV, says Hone who is confident that project two will solve the problem.
Project two is headed by Anthony L. Devico, associate professor, IHV, who has built structural variations of the molecular juncture, or joined complex of gp120 on HIV and a receptor point on human cells called CD4. Under normal circumstances, gp120 changes shape when it binds to CD4. The change exposes a special part of gp120 that allows, and is required for, easier entry into the human cell. In some HIV patients, researchers have detected strong antibodies against HIV that partially covered the special parts of gp120 on HIV thereby blocking entry into human cell.
Devico and the IHV team have formed a vaccination strategy to induce similar types of antibodies to bind to the special surfaces components of gp120.
Project three will be led by Lewis in collaboration with Edmund Tramont, M.D. Lewis has over 25 years of experience in immunology and Tramont has over 30 years experience in the conduct of vaccine trials.
Following a decade of steady progress, Hone says, "The key now is to get the trials finally underway. Of course, we know we will have new generations of these vaccines constantly coming on line. So, as this program proceeds, we will develop more and more sophisticated vaccine designs. In come cases, they will be tailored to each part of the epidemic around the world. Some of these candidate HIV vaccines will soon get into larger scale phase II and III clinical trials."
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