Malaria Vaccine, via 'Mosquito Bioreactors,' May be in View

BioWorld Today Science Editor

In work that has moved from the lab to the clinic and back, and is now poised to enter the clinic yet again, researchers have figured out how to manufacture and administer what they believe is the first highly effective malaria vaccine – one that can provide protection lasting at least six to 24 months to 80 percent of those vaccinated.

For now, the vaccine – which consists of purified, irradiated malaria parasites – has to be administered intravenously. But its makers are hoping to change that.

And even if the vaccine ends up needing to be administered intravenously in the field, Stephen Hoffman told BioWorld Today that given the improvements in global health such a vaccine could bring about, "it's inconceivable to me that we, meaning the biomedical community, won't be able to figure out how to get it to people" if it does become available. Malaria infects 250 million individuals and kills close to a million people annually.

"That doesn't mean it's the easiest thing," Hoffman added. But "there is an entire field being developed" that is focused on how to best deliver vaccines. Hoffman, who is the CEO and CSO of Rockville, Md.-based biopharmaceutical company Sanaria Inc., and his colleagues are collaborating with several partners to work out how to best deliver the vaccine.

The fact that weakened sporozoites can protect against malaria itself has been known for decades, when researchers showed that by injecting rodents intravenously with malaria spores, it was possible to protect them from malaria. It was soon shown that it was possible to protect people by exposing them to the bites of mosquitoes that had been irradiated to weaken the malaria parasites.

But, Hoffmann said, "there wasn't much anybody could do with that." More than 1,000 mosquito bites were necessary to achieve the sort of lasting protection that would be useful. That delivery route was impractical even if it had been compatible with manufacturing practices likely to be smiled upon by the FDA – which, of course, it was not.

Scientists next turned their attention to duplicating such immunity through a subunit recombinant vaccination, which would use immunogenic proteins of the parasite to mimic the effects of the whole weakened parasite itself. However, Hoffmann said despite decades of trying, "thus far, no one has come close to duplicating" the immunity provided by mosquito bites.

So Hoffman, who was working at the Naval Medical Research Center at the time, and his colleagues turned back to the mosquito-bite method of immunity – not to make a vaccine, but rather to learn more about the mechanisms of immunity.

That approach was partially successful. "We did that for 10 years and learned a lot, but didn't get any closer to making a modern vaccine," he said.

And so, Hoffmann ultimately decided that the best way to a vaccine was to use the only thing that was known to induce immunity: weakened sporozoites.

The first order was figuring out how to make such sporozoites in a way that would pass muster with the FDA.

"We had to invent a method of turning mosquitoes into bioreactors for making sporozoites," Hoffman said.

Once the manufacturing hurdle had been overcome, the team started a Phase I trial. As usual, that trial was "first and foremost a safety trial," he said.

But the team did look at whether the vaccination – which, in this trial, was delivered either intradermally or subcutaneously – conferred immune protection. And they found that "we did protect a few people, but definitely not to the level we were after." The vaccine was safe, but of 80 volunteers, only two developed what Hoffman described as the goal of the vaccination: high levels of interferon-gamma secreting CD8 "killer" T cells in their liver.

Such lack of protection could be due to two possibilities: either a vaccine that did not stimulate the immune system enough to confer protection, or a route of administration that did not allow the vaccine to reach its full potential. To differentiate between those possibilities, Hoffman and his colleagues tested the vaccine by administering it intravenously to both primates and mice.

And such intravenous injection led to success. Both primates and mice developed "huge numbers of the CD8 T cells," and mice were also protected against contracting malaria.

The authors reported their findings in the Sept. 8, 2011, issue of Sciencexpress, the advance online edition of Science.

The work is now scheduled to return to the clinic. In a trial scheduled to start next month, the team will test human volunteers both in a second clinical trial, and, in parallel, in the field in Tanzania.

Published: September 9, 2011