Funding support lacking in search for HIV vaccine
NIAID hopes new incentives will crank up the flow
After more than a decade of vaccine research, AIDSVAX is the only candidate in a phase III efficacy trial. And while it may show promise as an HIV-antibody neutralizer, most experts agree that AIDSVAX is not the final word in an HIV vaccine.
The next phase III trial could be another three years or more down the road. Beyond that, it’s a big question mark, says William Heyward, MD, MPH, of the National Center for HIV, STD, and TB Prevention at the Centers for Disease Control and Prevention. "Out of all the billions of dollars of research, we should have three or four candidate vaccines in phase III today, and three or four more lined up, ready to go," he says.
Some of the difficulties in the HIV vaccine development "pipeline" (Heyward prefers the term "pipette") are the lack of incentives for the pharmaceutical industry combined with many uncertainties about HIV itself.1 Companies are waiting for research from the National Institutes of Health (NIH) or elsewhere to lead them to a concept, says Heyward. "The industry is reluctant to invest the tens or hundreds of millions of dollars in research and development necessary to bring a product to human testing."
The only way to overcome scientific uncertainties is to double your efforts to learn about it, says Heyward. "You can’t do that when you’re committing minuscule amounts of your research budget toward that end."
From the government side, funding had been an issue, with less than 10% of NIH’s total AIDS dollars going toward vaccine development, says Peggy Johnston, PhD, of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD, the NIH division that oversees vaccine research and development. "No matter how good the ideas are, if the money isn’t there to do the work, it doesn’t matter," adds Johnston. Not that the agency has remained static; some changes are under way to boost research and get more ideas flowing.
Currently, only a handful of vaccine candidates are in early clinical trials, with many more in basic research development. Of all the vaccine candidates, HIV-1 Delta 4 — made of live-attenuated human immunodeficiency virus — has received the lion’s share of attention in the lay press. Proponents say it is the only hope for a truly effective vaccine.
Generally speaking, the most effective vaccines are live-attenuated virus vaccines. Rubella, yellow fever, measles, mumps—all have been curbed using live viruses. However, HIV is a different type of virus. "Those [other] vaccines were serially passed through cell cultures or through animals, and over many passages the virus has been weakened so that it causes an immunizing effect but doesn’t cause disease. We have been able to show through animal models that it doesn’t cause disease," explains Heyward.
HIV-1 Delta 4, not yet in trials, is "a healthy, vigorous, deadly virus that had a couple of its wings clipped," says Heyward. "Otherwise, it’s very healthy and could cause disease. It also could mutate." A live-attenuated virus vaccine is a concept that should be pursued, he adds, but right now HIV-1 Delta 4 is not ready for humans. "We don’t put a vaccine into people when it’s killing your animals in experiments. You don’t do that, ever. It’s just far too premature to be thinking about that. It has not only consequences for the individual, but public health considerations as well."
Heyward is concerned about the public health risk of introducing a potentially deadly mutated new form of HIV into the population. "There are too many things we don’t know. We don’t know that it can or cannot be transmitted. We don’t know that it can or cannot mutate into another deadly virus. It is not scientifically or public-health responsible to conduct such a trial."
Says Johnston, "It is in the realm of possibility, but is it likely? So far, very few cancers appear to have resulted from an HIV integration event, and they have much higher levels of viral replication than we would see with an attenuated virus." There are only two documented cancers from an HIV integration event. The rest are opportunistic, probably caused by immune system breakdown. If that is what happens in a vigorously infected individual, Johnston says there could be a favorable risk-benefit ratio for high-risk individuals.
Whether there could be passage in the germ line to future generations is an issue that can be addressed in animal studies. Johnston says animal studies with macaque monkeys using the SIV analog are fairly reliable. "We have to minimize the leaps of faith we make, but it’s the best model we have available now."
With any vaccine there is a leap of faith, says Johnston. But some populations may want to take the risk. "It really boils down to a risk-benefit ratio," she says. A live-attenuated vaccine would never be acceptable in populations with low incidence. Polio is a good example. When the epidemic was raging, a live-attenuated virus wasn’t a problem because it caused polio only in a small number of children. "That was a risk that people were willing to take. Now that there’s no polio, people aren’t willing to take that risk."
Looking at the other candidates
Vaccine development is "kind of like the stock market: You play on several different fronts and hope that one of them is going to come in big," says Heyward. "We’re doing the best we can to overcome our ignorance and move forward at the same time, judiciously, cautiously. But we do have a global epidemic."
After AIDSVAX, the next best candidate is the canary pox-vector vaccine. Canary pox is a live-attenuated virus that causes disease in birds but not humans and can safely be used as a vehicle for an HIV antigen, says Heyward. "There’s no continued viral replication, yet you’ve mounted an immunologic response against HIV using a Trojan horse. The canary pox also induces CTL [cytotoxic t-lymphocyte] response in some people, which is considered necessary for long-lasting immunity," he says.
Tweaking both arms of the immune system’
A vaccine that combines the gp120-envelope version (like AIDSVAX) and the canary pox vaccine could be the answer, Heyward adds. "It’s a very reasonable approach. The gp120-envelope version, as far as we know, just induces neutralizing antibodies; it does not induce CTLs. With the canary pox as the prime and the gp120 as the boost, the combination is tweaking both arms of the immune system," he says.
Five different canary pox vectors are being investigated in early clinical trials, along with a trial to determine the most effective administration route to induce mucosal immune response. NIAID hopes to launch a large-scale trial of the canary pox/gp120 vaccine by late 2000 or early 2001.
In addition, two DNA vaccines, a peptide vaccine (with an improved vector) and a recombinant bacterial vector vaccine (with Salmonella as the vector) are in phase I trials. The latter has been found to induce mucosal immunity in animals. Canary pox induces some mucosal immune responses when given intramuscularly to human volunteers, says Johnston. However, researchers continue trying to determine whether it produces sufficient immunity.
Johnston admits that AIDS vaccine research isn’t where she would like it to be — and that NIAID is taking action to stimulate it.
In recent months, the agency has established new incentive programs aimed at supporting vaccine research at all stages, including preclinical laboratory work. These "innovation grant programs," as they are called, are intended to encourage high-risk, high-impact research. Applicants don’t need to provide extensive preliminary data in their applications.
With another new program, NIAID officials hope to spawn new research and development teams, says Johnston. "We hope they will be attractive to academics as well as companies without enough resources to pursue an aggressive development plan," she explains. "We want to support them at whatever point they are in the pipeline." NIAID also is redesigning its clinical trials networks. HIV vaccine clinical research and development programs will be consolidated in the HIV Vaccine Trials Network.
"Our hope is that it will rejuvenate this program, set up an atmosphere of collaboration and cooperation, [and] that investigators will gain more ownership of their research programs and feel more proactive about them," says Johnston.
"We have a very urgent epidemic and we need to move forward on several fronts simultaneously. We also need to improve communications between researchers," says Heyward. "AIDS is a very multidisciplinary field. People look at it very insularly from their own perspective. We’ve got to get out of this mindset. All these different agendas have pulled resources in different ways. If HIV vaccine development is approached by a passionate and uncompromising defense from either the theorist or empiricist positions, it is unlikely there will be much progress."
Reference
1. Heyward W, MacQueen K, Jaffe H. Obstacles and progress toward development of a preventive HIV vaccine. Journal of the International Association of Physicians in AIDS Care 1997; 8:28-34.
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