In biotechnology's endless efforts to overpower malaria, this weekbrings bad news and good news.
First, the down-beat report:
A massive, three-year field trial of a promising malarial vaccine hasended with the verdict _ rendered by its investigators _ that "thereappears to be little justification for further trials with this vaccine."
For some 15 months, from October 1993 to April 1995, 1,221children at a remote refugee camp in northwestern Thailand receivedthree shots of the malaria vaccine, or of a vaccine for hepatitis Bvirus, as a placebo. The former consisted of four antigenic peptidesfrom the deadliest malarial parasite, Plasmodium falciparum.
This formulation, code-named SPf66, registered 34 percent efficacyin Colombia, where vaccinologist Manuel Patarroyo had developedit. That 34 percent success rate _ 396 symptomatic cases among1,548 volunteers _ may not seem like much, but in fighting aworldwide infection that afflicts 300 million people and kills upwardsof two million children a year, it's a whole lot better than today'snothing.
In the high-malaria, sub-Saharan regions of Africa, Patarroyo'svaccine did less well, attaining borderline results in Tanzania,negative ones in the Gambia.
So hopes shifted to a far more pivotal study in Southeast Asia, wheremalaria transmission intensity lies midway between that of Africa andSouth America. The Phase II trial had the approval of Thailand'sMahidol University's Faculty of Tropical Medicine, and the SurgeonGeneral of the U.S. Army. The FDA issued an investigational newdrug permit for the use of SPf66 vaccine.
The trial vaccinated 1,221 boys and girls, ages two to 12, in theKaren refugee camp, population 8,000.
The study's results appear in the current issue of The Lancet, datedSept. 14, 1996, titled: "Randomized double-blind placebo-controlledtrial of SPf66 malaria vaccine in children in northwestern Thailand."
During the 15-month follow-up period, there were 379 first cases offalciparum symptomatic cases, 195 among the SPf66 recipients, 184in the placebo group. This came to an efficacy rating of minus 9percent for the malaria vaccine.
Now For The Good News
Malaria, described in the Lancet paper as "the most importantparasitic disease of mankind," is theoretically susceptible to threekinds of control: environmental (dry up stagnant water, killmosquitoes, sleep under netting), prophylactic (perfect a vaccine),and therapeutic (antimalarial drugs).
All three have turned out to be non-starters, but not for lack of trying.
When DDT was riding high in the 1950s, national and internationalpublic health authorities foresaw wiping the anopheles mosquito andits parasites off the face of the earth. When atabrine and othercompounds _ most recently and potently chloroquine _ provedefficacious at eradicating P. falciparum from the liver and blood ofmalaria victims, medicinal chemists were riding high. Not any longer.
As fast as medicinal chemists come up with new forms ofantimalarial chemicals, the parasites come up with new resistance tothose new drugs.
Goaded by this death-dealing Catch 22, molecular microbiologists atWashington University in St. Louis, and structural biochemists at theNational Cancer Institute (NCI) in Frederick, Md., are on to a newstrategy for terminating P. falciparum during its sojourn in humanblood.
Their interim report in today's Proceedings of the National Academyof Sciences (PNAS) bears the title: "Structure and inhibition ofplasmepsin II, a hemoglobin-degrading enzyme from Plasmodiumfalciparum."
That parasite, explained the paper's first author, X-raycrystallographer Abelardo Silva at the NCI, "invades its human host'sred blood cells, and consumes their hemoglobin contents as a sourceof amino acids for their own reproduction." Evidence for thisbehavior pattern, Silva told BioWorld Today, "is that the time of theparasite's reproduction coincides with high fever and acute anemia inthe patient. This is consistent with a high rate of hemoglobinconsumption."
Chloroquine, he and his co-authors point out, appears to disrupt thefunctioning of the parasite's digestive vacuole, by mincing thehemoglobin up into bite-size pieces. Whereupon, P. falciparum hasdeveloped resistance to disrupt the functioning of chloroquine.
To degrade its meal of hemoglobin, the parasite deploys a kit ofenzymes, and here is where the PNAS co-authors are seeking towiden this chink in P. falciparum's armor. One of them, DanielGoldberg, of Washington University, discovered a pair of theseenzymes, which he named plasmepsin I and plasmepsin II.
"Goldberg actually discovered the aspartic proteases," Silva said, "aspart of the proteolytic pathway for the degradation of hemoglobin. Incollaboration with him," he continued, "our main work here at NCIwas to solve the 3-D structure of one of these plasmepsins. It is thefirst structure ever determined out of a P. falciparum parasite."
Aspartic proteases "are much more promiscuous enzymes," Silvasaid, "than for example serine or cysteine enzymes. Their range ofspecificity is wider." As human counterparts, he cites pepsin, "a veryabundant digestive enzyme," and "the very famous proteases of theHIV virus are also aspartic proteases."
But this human connection goes even farther.
"Cathepsin D," he pointed out, "is a lysosomal enzyme, present inalmost all tissues. We know that one of its functions, workingtogether with other lysosomal enzymes, is as a degradation machineryof useless proteins."
He continued: "What led us into the malarial field is that years agowe determined the structure of human cathepsin D, for which we nowhave several inhibitors."
So the team's plan is to construct similar inhibitors for destroying theparasite's enzymatic meal tickets, plasmepsin I and II.
"The problem," Silva said, "is the specificity. Given the 35 percenthomology with human cathepsin D, the question arises how todevelop inhibitors, able to target the parasite's enzymes, and notinhibit the human one. We were very lucky in solving this problemfor plasmepsin II with an inhibitor called pepstatin A _ but notplasmepsin I."
The recombinant protein the team developed to inhibit plasmepsin IIinitially resisted structural folding. Silva and his group at NCI grewcrystals of the protein, collected diffraction data, solved its structure,and produced inhibitors that do fold, as precursors to rationalantimalarial drug design.
In culture, he observed, "they inhibited the growth of the parasites,and were slightly more specific with respect to plasmepsin than tocathepsin D." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.