June 1996
BETHESDA, Md. — Finding a vaccine to prevent HIV infection and disease progression requires new techniques, creative ways around scientific obstacles and, above all, patience and perseverance.
The first vaccines to successfully reach licensure may be pediatric products, said Jack Lambert, MD, clinical director of the AIDS Vaccine Evaluation Unit, Johns Hopkins Medical Institutions, Baltimore.
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Using hepatitis B virus as a model, researchers are exploring combining HIV immune globulin (HIVIG) with a vaccine given at birth to prevent maternal transmission of the virus. With hepatitis B virus, such a combined strategy is about 95% successful in blocking transmission from mother to baby.
A current study is examining the effects of HIVIG in preventing vertical transmission; if those results are promising, Lambert said, the next step will be to add a pediatric vaccine to the regimen.
"If it successfully works with hepatitis B, there is great hope that we can do the same thing with HIV," Lambert said. "We believe the majority of transmission of HIV from mother to infant occurs close to labor and delivery. If we give HIVIG to the baby, that [introduces] neutralizing antibody to inactivate any virus that may have gotten into the baby's circulation from the mother. Then you give the baby an HIV vaccine to stimulate [the immune system]."
That vaccine, however, is still years away. The National Institute of Allergy and Infectious Diseases (NIAID) is not sponsoring any large scale clinical studies, but it has a number of candidates in early trials.
Researchers are approaching HIV vaccines from two fronts: therapeutic vaccines, which are intended to boost the immune systems of people who are already infected with HIV; and traditional prophylactic vaccines, which are hoped to prevent infection, said Patricia Fast, MD, PhD, of NIAID's Division of AIDS.
Data so far have been disappointing for therapeutic vaccines, Fast said. For prevention, however, some animal model and human phase 1 studies are encouraging. Currently, the most promising approach is to combine a live vector for priming the system and boosting with envelope protein.
"It is very difficult to predict which approach will work," Fast said. "There is much disagreement: some think one type will work, some think another type will work. The NIH approach is to pursue different types of vaccine, especially preclinically. We know most vaccines will never get into clinical trials, and some that are in early development won't make it out of the lab."
The technology runs the gamut from traditional inactivated vaccines to genetically engineered proteins and snippets of DNA. The most promising strategy may be a combination of approaches, said vaccine researcher Samuel Katz, MD, former chairperson and professor of pediatrics, Duke University Medical Center, Durham, N.C.
"HIV is a different infection than we've ever dealt with before in man, so the idea that conventional approaches to immunization would necessarily succeed is, to me, not very realistic," Katz said.
One promising strategy, pioneered by the NIAID-supported AIDS Vaccine Evaluation Group and currently in phase 1 trials, not only combines separate vaccines — a vectored and a subunit vaccine — but it also marries two developers. The immune system is first primed with a canarypox-vectored vaccine produced by Pasteur Mérieux-Connaught, followed by a gp120 subunit booster developed by Chiron-Biocine.
Such a multi-pronged approach may be the key to an effective vaccine. HIV is one of a group of viruses that exists in the body not only as free virus but also within infected cells.
"If you are exposed to HIV, you want to neutralize that virus before it gets into the cell; that is what a neutralizing antibody does," Lambert said. "But there still may be virus that gets into the cells, and neutralizing antibody only gets cell-free virus; it won't attack cell-associated virus. The fact that we are able to generate with [combination] vaccines cytotoxic T-cell responses, gives us hope that we will come up with an efficacious vaccine that will prevent infection, both cell-free and cell-associated."
The ability of HIV to exist both within and outside cells is only one of several characteristics that make vaccine development particularly challenging. For starters, HIV mutates rapidly.
"In a way, it is somewhat similar to influenza virus," Katz said. "Every year we have to develop a different influenza virus vaccine because of the change in the circulating strains. [HIV] is not the same exactly, but it is similar in the sense that different HIV viruses may be prevalent in Uganda or Tanzania in contrast to Brazil, the United States, Thailand, or India. Given our current knowledge or ignorance, it would require a number of different vaccines. Ideally, you would hope to find so-called conserved regions of the virus — that is, regions of the virus that are the same in different strains — and they would be sufficiently immunogenic to use a single vaccine everywhere, but no one has been able to do that up to this point."
Rather than having multiple vaccines, Lambert suggested that the ultimate HIV vaccine may be more similar to the 23-valent pneumococcal vaccine.
"We are going to have to have multi-valent vaccines," he said. "The pneumococcal vaccine has proteins against 23 different types of pneumococci; it is not just one strain. We currently know that with standard licensed vaccines like influenza and pneumococcus, you have to have multi-valent vaccines that will protect against multiple strains."
Finally, correlates of immunity are conspicuously absent. That is, no specific immune response has been found that indicates whether an individual is protected from infection.
"Given our current knowledge, patients who have HIV infection or AIDS have antibodies to their virus, but those antibodies seem to be insufficient or impotent in preventing continuation of chronic infection and progression to AIDS," Katz said. "We measure antibodies in these people, but we don't know how to mimic them in a way that would be more effective than they are in the already-infected patient.
"With HIV, it is probably more important to understand the function of T cells rather than [measuring] antibodies as correlates of immunity," he said.
No matter what approach is taken, however, all HIV vaccine candidates must go through large-scale human trials. This raises perhaps the most difficult obstacle: where will the vaccines be tested, and who will pay for the trial?
"There are studies planned in Thailand and Uganda because those are two nations where, unfortunately, the rate of infection is becoming so high that you may have anywhere from 8% to 25% of pregnant women infected," Katz said. "You can very quickly numerically and statistically collect the data that would take years to collect in this country."
Once again, the problem of virus mutations arises. If a vaccine is to be tested in a developing country, should it include a strain common only in the United States? So far, all of the experimental vaccines contain clade B, the strain common in the United States, Lambert said.
"Ninety percent of the [HIV-infected] population is infected with non-clade B virus," he said. "We have promising vaccines, but they are not going to benefit the world's population."
Development and production of HIV vaccines may ultimately involve coalitions consisting of industry, government and international health organizations.
"Producing a vaccine costs tens of millions if not hundreds of millions of dollars," Katz said. "Could an American producer recover those costs in ... economically deprived populations? That is an economical question that becomes an ethical one. Can you test a vaccine in a country where later they couldn't even afford to use it? The World Health Organization doesn't have the funds to back something of that sort. Would the World Bank do it? Could UNICEF do it?"
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