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Better than vaccines

Last Updated 16 March 2015, 18:03 IST

Recently, a team of scientists announced what could prove to be an enormous step forward in the fight against HIV.

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 HIV 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 HIV, 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. Michael 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 IGT – is underway, and several new ones are planned.

Revolutionary initiative

“It could revolutionise the way we immunise 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 IGT 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 IGT 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. HIV, for example, comes in so many different strains that a vaccine that can protect against one will not work against others.

Intelligent therapy

IGT 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 synthesise artificial versions. The genes are placed into viruses and injected into human tissue, usually muscle. 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 IGT emerged during the fight against HIV. In a few people, it turned out, some antibodies against HIV turn out to be extremely potent. So-called broadly neutralising 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 neutralising antibodies to everybody? At the time, Philip 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 Philip 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. IGT, 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 Philip had for delivering genes worked only to invade muscle cells – which normally would never make antibodies. In 2009, Philip and his colleagues announced that the approach worked after all. In their experiment, they sought to protect monkeys from SIV, a primate version of HIV. To do so, they used viruses to deliver powerful genes to the monkeys’ muscles.
The muscle cells produced SIV antibodies, as Philip and his colleagues had hoped. Then they infected the monkeys with SIV. The monkeys produced enough antibodies in their muscles to protect them from SIV infections, the scientists found. Without the IGT procedure, monkeys dosed with the virus died.

Shows great promise

Philip’s study persuaded Michael that IGT has great promise. “I started drinking the Kool-Aid,” he said. Michael and his colleagues have been modifying HIV antibodies to develop more potent defenses against the virus. Meanwhile, in 2011, David and his colleagues showed that antibodies delivered into cells with viruses could protect mice against injections of HIV, suggesting that IGT could protect people against HIV in contaminated needles. But most HIV infections occur through sex. So, David and his colleagues also infected female mice with HIV 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,” David 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 David’s results and wondered if IGT could be marshalled against another major disease that has eluded vaccines: malaria. Gary, David and their colleagues found a potent antibody against malaria and used a virus to deliver the gene for making it into mice. Last year, they reported that when malaria-laden mosquitoes bit the mice, up to 80 per cent of the treated animals were protected. “It is encouraging,” Gary said. “It’s good for a first shot of an unproven method, but it should be better.”

Now Gary is searching for better antibodies that provide more protection in a smaller dose. These experiments suggest that antibodies created by IGT could help against diseases that have esisted vaccines for decades. Other studies suggest that IGT might also help against sudden outbreaks in the future. For Philip, the growing interesting in IGT is gratifying. “It’s catching on, but it’s certainly not mainstream,” he said.

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(Published 16 March 2015, 18:03 IST)

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