http://www.rockymountainnews.com/cr/cda/email/article/1,1249,DRMN%5F21%5F154861,00.html

HIV vaccine on trial

20 Coloradans to be among volunteers for 1^st human tests of drug designed to

contain, suppress virus

By Jim Erickson, News Science Writer

Next month, 20 Coloradans will volunteer for the first human trials of an HIV vaccine designed to contain and suppress the AIDS-causing virus after it infects its victims. More than two dozen HIV vaccines have been tested since the first AIDS case was diagnosed in 1981. Most were aimed at preventing people from contracting the virus and, so far, none work. But a new generation of vaccines, including the one to be tested at the University of Colorado Health Sciences Center, takes a different tack. In Denver and several other U.S. cities, pharmaceutical giant Merck & Co. is conducting its first trials of a vaccine that carries HIV genes directly into human cells to provoke an immune-system response. “Right now, in AIDS vaccine research, there is more optimism than there has ever been before,” said Dr. Peggy Johnston, assistant director for AIDS vaccines at the National Institute of Allergy and Infectious Diseases, the world’s largest funder of AIDS vaccine research. “And this Merck vaccine, as well as others in this general category, are why everyone is optimistic. So we need to move on them and test them in humans very quickly.” The new Merck vaccine and others like it, called DNA vaccines, attempt to trigger the immune system’s “killer T-cells.” These assassins track down infected cells and destroy them, along with the invading virus. Most of the earlier vaccines tried to make antibodies to prevent HIV from infecting cells. Merck officials will present their latest results from primate studies during an HIV vaccine conference at Keystone Resort on March 28 through April 1. Recently, researchers in several laboratories have demonstrated that monkeys immunized with DNA vaccines and later infected with the AIDS virus remain healthier and live longer than unvaccinated monkeys. This month, Emory University researchers reported that a DNA vaccine protected all 24 vaccinated monkeys for at least seven months, while all four unvaccinated monkeys developed AIDS-related opportunistic infections and were euthanized. Dr. Robert T. Schooley, head of the division of infectious diseases at the CU Health Sciences Center, said the new Merck DNA vaccines prompt the “briskest” killer T-cell responses ever seen in animal studies. “All of these things actually make you feel much more hopeful that we’re finally getting somewhere in generating immune responses that may be meaningful in helping people control the virus if they get infected,” said Schooley, who will head two Colorado trials of Merck DNA vaccines this spring. “We’re a long way from having a vaccine we know will work, but I think we’re at a point where we have a number of vaccines that we really should be testing.” The two upcoming trials will test the Merck vaccine’s safety and any immune responses it might provoke in 20 uninfected volunteers. Study participants must be between 18 and 50, HIV-free and at low risk for becoming infected during the trial. In the first trial, volunteers will receive a series of three injections over several months. The first two shots will contain a “naked DNA vaccine.” One or two of HIV’s 12 genes are placed inside circular pieces of bacterial DNA called plasmids, then injected directly into the arm muscle. Naked DNA vaccines have been tried before, but they failed to provoke strong immune responses. In the upcoming Merck trial, two naked DNA injections will be “boosted” with a third shot designed to maximize killer T-cell response. The third shot contains HIV genes ferried into the body inside a deactivated cold virus called an adenovirus. The CU Health Sciences Center is one of 13 U.S. institutions participating in the first trial. In the second Merck vaccine trial, the naked DNA approach is dropped, and all the HIV genes are delivered in adenoviruses. Six U.S. centers are part of that trial. Because only one or two HIV genes are used in the Merck vaccines, the whole virus can’t replicate inside the volunteers, Schooley said. Viruses, bundles of genes sealed inside a protein coat, can’t multiply by themselves and must commandeer a host cell’s metabolic machinery to reproduce. “I don’t see any runaway trains here,” Schooley said. “I see this as really being a safe intervention.” The possibility of accidental infection from vaccinations has been a concern since the 1950s, when 260 children contracted polio from the Salk vaccine. The protocol for CU’s upcoming trial was evaluated by the Colorado Multiple Institutional Review Board, which checks human clinical trials for safety and ethical concerns. Board members wanted to be sure there was no way uninfected volunteers could contract HIV from the vaccine, said board director Lisa Jensen. “There were several board members who examined that aspect at length and felt convinced that the scientists involved in the research had really done their homework to disable the virus,” Jensen said. “They’re only using portions of the virus, so theoretically it’s impossible for the virus to replicate,” she said. “But because the consequences of an experiment like this going wrong are so high, you want to be very, very careful.” Though board members were “fairly well-satisfied” that accidental HIV infection won’t happen, the trial is still considered high-risk, Jensen said. Once the new HIV vaccine is injected into the volunteers’ arms, their cells take in the foreign DNA and use it to make viral proteins. Some of those viral proteins will leak to the surface of the human cells, where patrolling immune-system watchdogs will spot them and sound the alarm that triggers production of killer T-cells. Killer T-cells release chemicals into infected cells to kill them before new viral particles mature. The new Merck vaccine is designed to boost killer T-cell numbers so the immune system will be primed to quickly attack and suppress a real HIV infection. “Laboratories worldwide have begun exploring approaches to using vaccines that will generate these killer T-cell responses. It’s a whole new generation of vaccines, the prototypes of which have never gone into humans before,” said Dr. Norman L. Letvin, an HIV vaccine expert at Harvard medical school. Worldwide, an estimated 36 million people are infected with HIV, including an estimated 11,000 to 15,000 Coloradans. The new vaccines, if they work in humans, will not help those already infected, and they won’t prevent future infections. But they could dramatically improve the lives of people who become infected after being vaccinated, Letvin said. “Let’s say you are in charge of public health in Zambia or Zimbabwe or an area of the world where this virus is endemic, where 25, 30, 35, 40 percent of the population is infected with this virus. “If you can perhaps not block infection from occurring but can turn an infection into a slightly less catastrophic situation for individuals and therefore for the population, that’s a substantial advance. “The hope is that the aggressiveness of the disease will be dramatically diminished.” For the upcoming Colorado trials, Schooley said he will recruit volunteers through advertisements at the Health Sciences Center, and he might also ask the Colorado AIDS Project for help. What kind of person volunteers for an HIV vaccine trial? David Williams, coordinator of volunteers at the Colorado AIDS Project, is currently enrolled in an HIV vaccine trial at Denver Health Medical Center. “I work with people who have AIDS on a daily basis,” Williams said. “I know it sounds cliche in this day and age, but I have seen a lot of people suffer and endure and die, and I would like to see some easement of that—if we can’t stop it altogether.”

Contact Jim Erickson at (303) 892-5129 or ericksonj@RockyMountainNews.com.

March 19, 2001

Questions? Comments?

<http://denver.rockymountainnews.com/aboutus/contactus.shtml>Talk to Us.

ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE. THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.