Malaria vaccines currently in development are recombinant, antigen-based products. Yet Stephen Hoffman, founder, CEO and chief scientific officer of Sanaria Inc., likes to point out that "most vaccines in the world are live attenuated."

That's one of the reasons why Rockville, Md.-based Sanaria is pursuing a live attenuated sporozoite vaccine for malaria.

Despite the availability of antimalarial treatments and insecticides, the Centers for Disease Control and Prevention estimates that between 350 million and 500 million cases of malaria occur worldwide each year, killing more than a million people. The parasite Plasmodium falciparum is responsible for more than 95 percent of malaria-associated severe illnesses and deaths. A prophylactic vaccine could decrease malaria incidence dramatically, but the fact that the disease is caused by a parasite rather than a virus has stumped vaccine researchers for decades.

Hoffman, who served as director of the malaria program at the Naval Medical Research Center from 1987 to 2001, said his team tried a "whole litany of different approaches" to creating a vaccine. Biotech efforts have focused mainly on antigens. GenVec Inc. is in Phase I/II trials with an adenoviral vector-delivered antigen vaccine; Pevion Biotech Ltd. is in Phase II with a virosome-delivered antigen vaccine; and GlaxoSmithKline plc is in Phase II with the recombinant protein vaccine Mosquirix (RTS,S/AS02).

Phase II data reported last fall showed that Mosquirix reduced the rate of malaria in infants by 65 percent during the first three months after immunization. Efficacy dropped to 35 percent after six months. While the vaccine could help control malaria in severely infected regions like Africa, Hoffman noted that the data are far from optimal and not good enough for broader use in travelers from the developed world.

But Hoffman, who contributed to the sequencing of the mosquito and malaria genomes while at the Navy and later at Celera Genomics Group, realized his Navy experiments had identified a different approach that potentially could produce a malaria vaccine with strong efficacy.

In 2002, he published data in the Journal of Infectious Diseases from an experiment in which 11 volunteers were immunized against malaria through the bites of irradiated mosquitoes. Ten people challenged with malaria within nine weeks were protected, although one person challenged at 10 weeks was not. Additional challenges over a 10 month period resulted in protection 24 out of 26 times, or 92 percent of the time.

As good as the data looked, Hoffman realized a vaccine couldn't realistically be administered through mosquito bites. So he founded Sanaria about five years ago to develop a practical delivery method and manufacturing procedure.

The company raised about $45 million in grants from the National Institutes of Health, CDC, U.S. Army, Program for Appropriate Technology in Health (PATH) malaria vaccine initiative, Institute for OneWorld Health and other organizations, as well as some angel and seed investors.

That money has been used to develop a method of delivering the attenuated malaria sporozoites through injection, an approach that Hoffman said has worked in mice.

Last fall, Sanaria opened a new manufacturing facility in which it raises mosquitoes, infects them with P. falciparum, irradiates them, harvests the sporozoites from their salivary glands and stores the biologic material in vials - all in a large-scale process that complies with the FDA's good manufacturing practice standards.

Sanaria, which employs about 40 people, has completed preclinical toxicology work with its vaccine and plans to file an investigational new drug application later this year. By the fall, the company hopes to begin a Phase I/IIa clinical trial that would assess safety and then evaluate protective efficacy through a malaria challenge. Hoffman said data would be available six to nine months after the trial begins, potentially allowing Sanaria to move on to larger trials in Africa in 2009.

While Sanaria's initial approach uses radiation to weaken the malaria parasite, the company also is studying genetic attenuation. Earlier this month, Sanaria entered into a four-year, $23.6 million project with Leiden, the Netherlands-based Top Institute Pharma; Radboud University Nijmegen Medical Centre; and Leiden University Medical Center to develop genetically modified malaria sporozoites. The approach previously has shown protective immunity in mice, and the project aims to conduct clinical trials in the Netherlands.