Last month, a team of scientists announced what could prove to be an enormous step forward in the fight against H.I.V.
Scientists at Scripps Research Institute said they had developed an artificial antibody that, once in the blood, grabbed hold of the virus and inactivated it. The molecule can eliminate H.I.V. from infected monkeys and protect them from future infections.
But this treatment is not a vaccine, not in any ordinary sense. By delivering synthetic genes into the muscles of the monkeys, the scientists are essentially re-engineering the animals to resist disease. Researchers are testing this novel approach not just against H.I.V., but also Ebola, malaria, influenza and hepatitis.
“The sky’s the limit,” said Michael Farzan, an immunologist at Scripps and lead author of the new study.
Dr. Farzan and other scientists are increasingly hopeful that this technique may be able to provide long-term protection against diseases for which vaccines have failed. The first human trial based on this strategy — called immunoprophylaxis by gene transfer, or I.G.T. — is underway, and several new ones are planned.
“It could revolutionize the way we immunize against public health threats in the future,” said Dr. Gary J. Nabel, the chief scientific officer of Sanofi, a pharmaceutical company that produces a wide range of vaccines.
Whether I.G.T. will succeed is still an open question. Researchers still need to gauge its safety and effectiveness in humans. And the prospect of genetically engineering people to resist infectious diseases may raise concerns among patients.
“The reality is we are touching third rails, and so it’s going to take some explanation,” said Dr. David Baltimore, a Nobel Prize recipient and virologist at Caltech who is testing I.G.T. against a number of diseases.
Conventional vaccines prompt the immune system to learn how to make antibodies by introducing it to weakened or dead pathogens, or even just their molecular fragments. Our immune cells produce a range of antibodies, some of which can fight these infections.
In some cases, these antibodies provide strong defenses. Vaccinations against diseases such as smallpox and measles can lead to almost complete protection.
But against other diseases, conventional vaccines often fail to produce effective antibodies. H.I.V., for example, comes in so many different strains that a vaccine that can protect against one will not work against others.
I.G.T. is altogether different from traditional vaccination. It is instead a form of gene therapy. Scientists isolate the genes that produce powerful antibodies against certain diseases and then synthesize artificial versions. The genes are placed into viruses and injected into human tissue, usually muscle.
Photo Dr. Michael Farzan, an immunologist at Scripps Research Institute, helped develop an artificial antibody that inactivated H.I.V. in monkeys. Credit Benjamin Rusnak for The New York Times
The viruses invade human cells with their DNA payloads, and the synthetic gene is incorporated into the recipient’s own DNA. If all goes well, the new genes instruct the cells to begin manufacturing powerful antibodies.
The idea for I.G.T. emerged during the fight against H.I.V. In a few people, it turned out, some antibodies against H.I.V. turn out to be extremely potent. So-called broadly neutralizing antibodies can latch onto many different strains of the virus and keep them from infecting new cells.
Dr. Philip R. Johnson, a virologist at the University of Pennsylvania, had an idea: Why not try to give broadly neutralizing antibodies to everybody?
At the time, Dr. Johnson and other researchers were experimenting with gene therapy for disorders like hemophilia. Researchers had figured out how to load genes into viruses and persuade them to invade cells, and it occurred to Dr. Johnson that he might be able to use this strategy to introduce the gene for a powerful antibody into a patient’s cells.
After the cells began producing antibodies, the patient in effect would be “vaccinated” against a disease.
The idea represented a radical new direction for gene therapy. Until then, researchers had focused on curing genetic disorders by providing working versions of defective genes. I.G.T., on the other hand, would protect healthy people from infectious diseases.
And there was no guarantee that it would succeed. For one thing, the best virus Dr. Johnson had for delivering genes worked only to invade muscle cells — which normally would never make antibodies.
In 2009, Dr. Johnson and his colleagues announced that the approach worked after all. In their experiment, they sought to protect monkeys from S.I.V., a primate version of H.I.V. To do so, they used viruses to deliver powerful genes to the monkeys’ muscles.
The muscle cells produced S.I.V. antibodies, as Dr. Johnson and his colleagues had hoped. Then they infected the monkeys with S.I.V. The monkeys produced enough antibodies in their muscles to protect them from S.I.V. infections, the scientists found. Without the I.G.T. procedure, monkeys dosed with the virus died.
Dr. Johnson’s study persuaded Dr. Farzan that I.G.T. has great promise. “I started drinking the Kool-Aid,” he said. Dr. Farzan and his colleagues have been modifying H.I.V. antibodies to develop more potent defenses against the virus.
Meanwhile, in 2011, Dr. Baltimore and his colleagues showed that antibodies delivered into cells with viruses could protect mice against injections of H.I.V., suggesting that I.G.T. could protect people against H.I.V. in contaminated needles.
But most H.I.V. infections occur through sex. So Dr. Baltimore and his colleagues also infected female mice with H.I.V. through their vaginal membranes. Last year, they reported that the technique also protected mice from infection in this way.
“We’re going around the immune system, rather than trying to stimulate the immune system,” Dr. Baltimore said. “So what we’re doing is pretty fundamentally different from vaccination, although the end result is pretty similar.”
Gary W. Ketner, a microbiologist at the Johns Hopkins Bloomberg School of Public Health, was intrigued by Dr. Baltimore’s results and wondered if I.G.T. could be marshaled against another major disease that has eluded vaccines: malaria.
Photo Dr. Philip R. Johnson, a virologist at the University of Pennsylvania, developed an approach of giving neutralizing antibodies to healthy people. Credit Jessica Kourkounis for The New York Times
Dr. Ketner, Dr. Baltimore and their colleagues found a potent antibody against malaria and used a virus to deliver the gene for making it into mice. Last August, they reported that when malaria-laden mosquitoes bit the mice, up to 80 percent of the treated animals were protected.
“It is encouraging,” Dr. Ketner said. “It’s good for a first shot of an unproven method, but it should be better.” Now Dr. Ketner is searching for better antibodies that provide more protection in a smaller dose.
These experiments suggest that antibodies created by I.G.T. could help against diseases that have resisted vaccines for decades. Other studies suggest that I.G.T. might also help against sudden outbreaks in the future.
Dr. James M. Wilson, a pathologist at the University of Pennsylvania, and his colleagues have investigated using gene therapy to treat cystic fibrosis by delivering genes into the cells lining patients’ airways. It occurred to him that many fast-spreading viruses, such as influenza and SARS, also attack the same cells.
In 2013, Dr. Wilson and his colleagues reported that viruses carrying antibody genes into airway cells can enable mice and ferrets to fight off a wide range of flu strains. Since then, he and his colleagues have tested I.G.T. against other viruses causing deadly outbreaks — including Ebola.
Dr. Wilson and his colleagues teamed with Mapp Biopharmaceutical, a company that has developed an antibody against Ebola called ZMapp. The scientists have synthesized a gene for the ZMapp antibody and have delivered the gene into mouse muscles. The experiments are only in their early stages, but “we have encouraging data,” Dr. Wilson said.
For Dr. Johnson, the growing interesting in I.G.T. is gratifying. “It’s catching on, but it’s certainly not mainstream,” he said. That seems likely to change, and soon.
Last February, Dr. Johnson began the first clinical trial of I.G.T. in humans. His team has placed H.I.V. antibody genes into the muscles of volunteers to see if the treatment is safe. The researchers expect to finish gathering the results this spring. “We’re optimistic. We’re hopeful,” Dr. Johnson said.
Dr. Baltimore is collaborating with the National Institutes of Health to start a similar trial of an I.G.T.-engineered virus against H.I.V. Dr. Wilson is preparing to test I.G.T. against the flu later this year.
There is no guarantee that the successes in the animal trials can be replicated in humans. “Humans are not just big mice,” said Dr. Ronald G. Crystal, chairman of genetic medicine at Weill Cornell Medical College.
Human immune systems may attack the artificial antibodies or the viruses delivering them, destroying their protection. Or muscle cells might make too many antibodies, because they do not have the built-in regulation that immune cells do.
Dr. Farzan and other researchers are investigating molecular switches that can turn off the production of antibodies, or just adjust their dose. “If we really want to see this blossom, we need regulatory ‘off’ switches,” he said.
Despite the lingering concerns about I.G.T., Dr. Nabel says he remains optimistic. “There are safety concerns that have to be addressed, but there are logical ways to approach them,” he said.
Bioethicists do not foresee major ethical hurdles to I.G.T., because it is based on gene therapy, which has been developed for more than 30 years. “It doesn’t strike me as a radical departure,” said Jonathan Kimmelman, an associate professor at McGill University.
Still, Dr. Baltimore says that he envisions that some people might be leery of a vaccination strategy that means altering their own DNA, even if it prevents a potentially fatal disease.
“But my feeling, as a basic scientist, is that it’s our responsibility to take things into the clinic that we feel will make a difference,” he said.
