The Gambia, a slender sliver of land on the West Coast of Africa, had a reputation under British rule as "the white man's graveyard."

Today, the Republic of The Gambia still suffers from endemic malaria. So does the rest of Central Africa, along with a broad belt of tropical regions that girdle the globe.

Now in The Gambia, the first field test of the latest experimental vaccine against malaria is in the planning stage.

Infectious diseases physician Jose Stoute, of the Walter Read Army Institute of Research (WRAIR), in Washington, was principal investigator for this open Phase I/IIA study, which WRAIR conducted on 46 human volunteers in the District of Columbia. It proved strikingly more successful clinically than trials of earlier malaria vaccines over the past decade.

Stoute is first author of a paper in the current New England Journal of Medicine (NEJM), dated Jan. 9, 1997, which describes this development. Its title: "A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodim falciparum malaria."

Of the 46 adult subjects -- 25 men and 21 women -- 22 were inoculated with one of three formulations of the vaccine, with six unimmunized subjects serving as controls. All 28 then allowed themselves to be bitten by mosquitoes infected with Plasmodium falciparum, the deadliest malarial parasite.

Less than two weeks after vaccination, all six controls had contracted malaria (from which they fully recovered under treatment). So did most of the volunteers immunized with versions one and two of the vaccine, but only one who received version three came down with the infection. This 86 percent efficacy was far superior to performance by past vaccines. (See BioWorld Today, Sept. 17, 1996, p. 1.)

Getting Both B And T Cells Into The Act

Stoute told BioWorld Today why this recombinant vaccine formulation has apparently succeeded where all others have, for practical purposes, failed: "The secret was having a combination of the right antigen and the right set of adjuvants.

"The majority of the circumsporozoite-based vaccines in the past targeted only the central repeat portion of the parasite's molecule, the reiterative Asparagine-Alanine-Asparagine-Alanine-Proline amino acid sequence

"The protein that codes this sporozoite," Stoute continued, "flanks these repeats with non-repeating regions of amino acids on the left and on the right. Our vaccine contains not only the repeats, which we know are important B-cell [antibody-generating] epitopes, but the C-terminal portion, which contains important T-cell epitopes."

Stoute also made the point that "the addition of a new adjuvant obviously elicited the right kind of immune responses. Why and how it works," he added, "is not really clear We suspect that it allows whatever antigens are present in the vaccine to be engulfed by antigen-presenting cells in the immune system."

WRAIR and SmithKline Beecham Biologicals, in Rixensart, Belgium, are the twin architects of the new vaccine, which embodies the proprietary QS-21 adjuvant, obtained from Aquila Biopharmaceuticals Inc., Worcester, Mass., formerly Cambridge Biotech. (See BioWorld Today, April 11, 1996, p. 1.)

The version-three vaccine (which far surpassed the other two in efficacy) consists of the circumsporozoite antigen fused to hepatitis B antigens, plus the QS-21 adjuvant.

To produce this prophylactic package, Stoute said, "The artificial elements were inserted into yeast cells. There they recombined with the yeast DNA, inserted into the yeast chromosomes, and expressed constitutively." Besides the sporozoite-hepatitis fusion protein, the same yeast host cell included a non-fused hepatitis antigen.

"The hepatitis antigens were there," Stoute said, "because the immunologists felt it could be used as a carrier molecule, and because it is highly immunogenic, eliciting both humoral and cellular responses toward this sporozoite antigen."

The comma-shaped, nine-micron-long sporozoite replicates in a single liver cell into thousands of merozoites, which exit the liver to target red blood cells. (See BioWorld Today, May 8, 1995, p. 1.)

"If one single sporozoite escapes our vaccine, it can quickly repopulate the infection cycle," he said.

Insights that contributed to the new vaccine go back a decade to an off-beat malarial vaccine that is still ongoing, and actually protects human subjects from pathogenic parasites. It is based on irradiating their mosquito hosts, which kills the sporozoites, but preserves their antigenicity, then allowing those neutered insects to bite volunteers.

It's highly efficacious, but impractical, Stoute said. Subjects have to be bitten repeatedly for a matter of months, and the mosquitoes are hard to come by in quantity.

The irradiation experiment's main pay-off so far, he added, "is in the lessons it has taught us for creating this new vaccine.

"The main lesson," he said, "is that it is in fact possible to protect volunteers persistently over a period of time against malaria. Two, these subjects had strong humoral and cellular immune responses to the sporozoite antigen. That made us believe that if we tried to replicate those responses in a vaccine, perhaps we could confer protection."

Molecular biologist Joe Cohen, of SmithKline Beecham's Belgian subsidiary, is the NEJM paper's senior author, and head of the vaccine project.

"The final success of this experimental vaccine," Cohen cautioned, "in terms of making one vaccine that is broadly applicable, is by no means yet assured. I think the results we've obtained in a clinical challenge," he told BioWorld Today, "are extremely promising. It's really a milestone in this field, totally unprecedented in the efficacy that we've seen."

Cohen cited the hurdles that still lie ahead: "How will this particular vaccine behave under natural challenge conditions in the field? How long will its protective efficacy persist? Will we, or will we not, need additional antigens to make it indeed broadly applicable?"

Answering these questions, he observed, "is going to take several more years before we can confidently say we have a product that will be applicable to the endemic malarial regions, and to travelers, in the broad sense, including the military."

The impending double-blind, placebo-controlled field trial in The Gambia, Cohen said, "will involve two cohorts. Between 50 and 75 exposed villagers will receive the vaccine, and an equal number of controls "an irrelevant, though useful, immunization -- most likely of rabies vaccine.

Stoute concluded: "Besides the human tragedy of endemic malaria, there is an economic tragedy. What would happen to the world economy if 300 million people were not debilitated, and 2 million children didn't die every year? Having a vaccine that prevents this disease and death would be a tremendous boost for Third World countries, because malaria is robbing them of their productive human resources." *

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