It takes a little courage to step off some of the third-floor elevators at the University of Rochester Medical Center. Signs reading "Infectious Disease Unit" can be intimidating. One hallway has bio-hazard signs. Green arrows point to large showerheads and pull chains, which hang from the ceiling every few feet, for emergency rinses. Then there are the signs that say "human specimens."
Even in a hospital environment, even after 25 years, HIV/AIDS can still evoke fear and misunderstanding.
But if the work on this floor is as successful as Dr. Michael Keefer hopes, someday the trauma of HIV will be eliminated. Keefer, an associate professor of medicine at the University of Rochester, has been a leading architect of the Center's HIV vaccine trials. Thirty research centers in a global network are developing and testing HIV vaccines, and the UR site has been in operation longer than most of them. The UR started its first studies, or trials, in 1988, just seven years after the disease was discovered. Keefer leads a group of 10 researchers at the MedCenter (some of whom also work on other projects).
The UR site doesn't develop vaccines. Instead, its role is to test how well the vaccines work through a series of studies using volunteers who agree to be vaccinated.
"We will get a whole bunch of vaccines that are coming through the pipeline --- big pharma like Wyeth may be developing a vaccine, Merck, Glaxo Smith Kline, and some smaller companies," says Keefer.
Keefer has worked at the UR site almost from the beginning. A slim, middle-aged man with graying hair, Keefer doesn't oversell. He's been there too long to underestimate the formidable challenge that HIV presents. Still, he speaks optimistically. And he likes to make a few things clear at the beginning of an interview. It's his way of taking time now to save time later, something he has learned from years of dealing with media.
1) The trials are part of a search for an HIV vaccine, not a search for a cure for AIDS. Prevention and cure are two different worlds.
2) The vaccine trials are completely safe. "There is no chance of getting HIV from the vaccine," he says. "There is a chance of being infected with HIV through your behavior. So we counsel everyone to continue low-risk behavior."
3) There is a constant need for new volunteers because many vaccines are being tested at once, and each volunteer can participate in only one study. And while many people like to volunteer in medical studies, some are turned off by a trial involving HIV.
Certainly the most frequent question Keefer is asked is "when": When will you have a vaccine? He doesn't avoid the answer, but he says he can't predict a date. He prefers to say it will happen within a decade. But even that seems too vague for some people.
"The media tend to say things like 'Call me back when you've got an AIDS vaccine,'" he says. "They don't want to know anything about the process."
There's reason to believe the first effective HIV vaccine --- one good enough to be licensed and used on humans --- could be available within the next 10 years, Keefer says.
"We're probably talking about a vaccine that will be available for your children or your grandchildren, depending on your age," he says. "But the first vaccine probably won't be exactly right. It could be luck and we get it to perform exactly as we need it to from the start, but we are not planning for that. There will be improvement and variations made on that vaccine."
The struggle to find the vaccine, Keefer says, is buried in the trial process. And if more people understood the process, more would volunteer.
"Every drug your doctor prescribes must go through a process like this to be sure that it is safe," Keefer says. "And that's what we're doing."
In the HIV trials, volunteers are injected with one of the vaccines being studied. The vaccines are harmless: they don't contain HIV, and they can't cause AIDS. They're designed to trigger a response in the body that will fight the virus.Volunteers then go to the MedicalCenter periodically to have samples of their blood taken. That blood is exposed to the virus in the laboratory to see if the blood will kill it.
"The battle between the vaccine and the virus is only in the laboratory," Keefer stresses. It's not happening in the volunteers enrolled in the trial, a misunderstanding that causes some people not to volunteer.
Each vaccine in a trial must pass through three phases if it is to qualify for FDA approval.
Phase I trials use small numbers of volunteers who are considered at low risk of coming in contact with HIV. They are healthy and HIV-negative. If they are sexually active, they are in a monogamous relationship and practice safe sex. If the vaccine performs well enough in that group, it graduates to Phase II trials.
Phase II uses larger numbers of volunteers, and the vaccines are often "tweaked" at this stage, testing variations that could lead to improvements, says Keefer.
Phase III trials involve the largest number of volunteers. Since the vaccines have shown significant promise by this point, they are tested using volunteers who have historically been at higher risk of acquiring HIV.
That's when researchers give some volunteers a vaccine and others a placebo, and then test to see which blood gets infected in the laboratory.
"We don't want to do these huge studies with vaccines that don't even create immune responses in people," says Keefer. "So you sort this out in the smaller studies."
The goal is to have many trials of different vaccines undergoing different phases of testing, all happening at once within the global network. Keefer advises the network on which sites are best suited for the trials of vaccines coming through the pipeline.
"The studies themselves are all kind of similar," says Keefer. "It's the vaccine that's different."
The UR has long been the major site for the small Phase I studies. The reason: most of the area's population is low risk.
"Don't get me wrong," says Keefer. "We do have AIDS in Rochester. There are a lot of cases being treated here, and there are definitely some high-risk groups here, but they are nowhere as big as in San Francisco, New York City, or South Africa."
It's labor intensive to get vaccines throughthe trials and ready to withstand the rigor of FDA approval. Then there's the cost: hundreds of millions of dollars is a conservative estimate of what has already been spent worldwide. The Rochester site, says Keefer, helps stimulate the field by conducting numerous small studies, something the large companies would never invest in on their own.
"A lot of the money comes from [government] grants from the National Institutes of Health," he says, "because the companies themselves aren't highly attracted to AIDS vaccine work."
Vaccines provide an enormous public service, but they aren't huge moneymakers. Three doses of a vaccine that prevents HIV/AIDS won't be as profitable as long-term treatment of the sick.
"That's three doses for one person instead of three doses for one person every single day for the rest of their lives," notes Keefer.
Adding to the time and expense: breakthroughs in HIV/AIDS research are hard won. The concept of a vaccination is to use harmless pieces of the virus to create a synthetic replica that mimics the real thing. A vaccination triggers the immune system to produce antibodies in your body. If you become exposed to the real virus, the antibodies your body has developed launch a massive attack and destroy the virus.
The early HIV vaccine trials concentrated on stimulating the immune system's antibody response, particularly targeting HIV's outer coating.
"And that was really the approach for seven to eight years," says Keefer. That strategy was used successfully in Hepatitis B research, and a Hep B vaccine is now on the market.
But with HIV, that approach turned out to be a dead end. HIV is crafty, and one of the ways it defends itself is to constantly mutate. So the antibodies alone are not effective.
The more recent direction HIV vaccine research has taken is through the body's white blood cells --- the cells that fight infection. The newer HIV vaccines stimulate a particular set of white blood cells, T-lymphocytes --- or as Keefer calls them, killer-T's --- to identify the virus and destroy its inner proteins.
This approach has been so promising that Keefer says a Phase III trial of one vaccine is underway in Rochester, using volunteers from higher risk groups. Trials of the same vaccine will be launched in South Africa in early 2007.
Keefer acknowledges that it is unusual for the UR to be involved in a Phase III study, but for this trial the site made sense. It's a Merck vaccine, and Rochester has a long history with the company. "We enrolled the volunteers for the very first Merck vaccine back in 1999," says Keefer.
You can't miss the posters seeking volunteers for HIV trials. They hang in entranceways of grocery stores, bars, restaurants, coffee shops, and retailers throughout Rochester. One of the volunteers who responded when she saw them is Anne Michalenka, who has been participating in a trial for over a year.
"I wanted to be involved in this because it [AIDS] is definitely not going away," she says. "I didn't really know anyone with AIDS, except my boyfriend's uncle, who died of it a while ago. So I wasn't motivated by that. It wasn't as personal for me. But I know it has been harder for them to find people for these studies."
Like all volunteers in the UR's small studies, Michalenka is in good health, and her HIV status is tested regularly to be sure that she is negative. When Michalenka began, she was given three initial doses of the vaccine being tested in her trial. Since then, she has returned to the clinic every few months to have blood drawn.
"The biggest difficulty for me really has been the scheduling of the follow-up visits," says Michalenka. "I'm used to giving blood, because I have donated to the Red Cross for years. But this is actually easier. For one thing, they don't draw that much blood."
While her friends have been supportive, says Michalenka, none have volunteered. "I understand, though, because it is a real commitment," she says. "Once you start, you have to commit to staying with it. You have to make time for the appointments and realize this will go on for months. Plus you have to commit to staying out of the risk zone, which you should do anyway."
Because the early vaccines produced antibodies, and HIV tests look for the presence of antibodies rather than the virus, subsequent blood tests on some volunteers showed a false positive.
"That's why we like to tell our volunteers to come to us for their testing, because we know the history," Keefer says. "If there is a problem, we can usually go through the files and figure out what is happening. But those were the early days. Now, more and more of the area's physicians know about us, and a lot of them will ask if you have been enrolled in a vaccine trial."
Keefer is convinced that the network is close to finding an effective vaccine. But he says the solution may turn out to be a multi-pronged approach
"It may be one vaccine works for some people and another vaccine works better for others," says Keefer. "Maybe it will be one dose. Maybe it will be three doses. Maybe we will have a vaccine that gets combined with a drug. But I do think it is possible to talk in terms of a vaccine that offers at least some significant protection against HIV infection."
But we can't talk in terms of a cure for AIDS at this time, says Keefer. Some researchers are speculating that once effective vaccines become available, they might boost the body's natural immunity to the point that the need for drug therapy could be reduced. Currently, the treatment for AIDS includes combinations of powerful antiretrovirals, "AIDS cocktails," that are hard for some patients to tolerate, and over time can become less effective.
"A cure for AIDS is entirely different, because we are talking about someone who is already dealing with a compromised immune system," Keefer says. "The disease has progressed, and you're talking about stopping the progression of the disease."
It will be hard to eliminate the presence of the virus from every cell in the body, says Keefer, since HIV has a remarkable ability to hide and the detection technology isn't yet available.
"I would say we're talking about several generations from now when AIDS is like smallpox and the virus only exists in laboratories and controlled settings," says Keefer. "I don't know: that might be 40 to 50 years from now."
Like a coach, Keefer comes right back with a note of reassurance, however.
"But look how far we've come," he says, referring to early AIDS drugs like Retrovir. The drug commonly known as AZT is used to slow the progression of the disease, but was initially hailed as a cure. "It didn't turn out to be the end of the virus like we hoped, but it is still a breakthrough drug. Because of AZT, we can stop transmission of the virus from mother to fetus. We don't usually see babies born in Rochester with HIV anymore."
The HIV trials
To learn more about the HIV Vaccine Trial Network: www.hvtn.org.
To enroll in an HIV vaccine trial at the UR, call 756-2329 or go to www.vaccineunit.org.
• Number of AIDS deaths worldwide since the first cases were identified in 1981: more than 20 million.
• Number of people living with AIDS worldwide: about 40 million.
• Number of new cases reported each day: 14,000.
• Number of people living with HIV/AIDS in the Greater Rochester area in 2004: more than 3,000.
• HIV/AIDS demographics in Greater Rochester: More than half of new cases reported in 2004 were among blacks and Hispanics.
• “HIV” stands for human immunodeficiency virus. The virus causes the medical condition AIDS: acquired immune deficiency syndrome.
• AIDS-related deaths have declined in the US because of new antiretroviral drugs, but there is no cure.
• After declining for several years, the rate of HIV infection in the US has begun to increase, particularly among teens, gay men, blacks, and Hispanics.
• After sweeping through sub-Saharan Africa, HIV/AIDS is now hitting Southeast Asia, India, China, and Russia the hardest.
• AIDS is preventable. Having multiple sex partners, practicing unsafe sex, and sharing needles are the most common ways HIV is spread.
• Studies show that using drugs and alcohol lowers the guard against unsafe sex.
• Know your status. Anyone who is sexually active should be tested for HIV. People who delay testing delay treatment and risk spreading the disease.
• Practice safe sex only. It takes just one exposure to contract HIV.
*Sources: New York State Department of Health and The AIDS Vaccine Handbook, Global Perspectives by the AIDS Vaccine Advisory Coalition.