Bloodletting in Bosnia, Chechnya and other death-dealing troublespots around the world dwindle to statistical triviality, compared tothe loss of blood wreaked on humans by a tiny worm.

That thread-thick hookworm, half an inch or so long, sucks bloodfrom the small intestines of nearly 1 billion men, women and childrenin the Third World. China alone counts 190 million people infected.

A single Ancylostoma-genus hookworm can consume about 0.2milliliters of gut blood a day per person, said infectious diseasespecialist Michael Cappello, a senior investigator in YaleUniversity's medical helminthology laboratory. An average infectedadult, he told BioWorld Today, hosts 20 to 200 of the parasites, for adaily exsanguination of some 20 milliliters. That amounts to anannual blood loss of over 15 liters from each individual sufferer.

The true extent of this statistic is measured not in liters but in mentaland physical energy drained from the hookworm's victims by thewashout of iron in the red blood cells it loots from their bodies.

Cappello is first author of an article in Tuesday's Proceedings of theNational Academy of Sciences (PNAS), dated June 20, titled:"Ancylostoma caninum anticoagulant peptide: A hookworm-derivedinhibitor of human coagulation factor Xa." Its senior author, PeterHotez, directs the helminth lab, and co-authored an article,"Hookworm infection," in this month's (June) Scientific American.

"Human hookworm infection," his PNAS paper leads off, "is aleading cause of anemia in the tropics and subtropics." Childrensuffer most from the iron-deficiency anemia, Cappello pointed out inan interview, "because they get more worms [and] women ofreproductive age, who lose iron every month."

Hookworms lurk in soil contaminated with human or canine feces.When a bare foot or other skin surface contacts their larvae, thesebore their way into the bloodstream, which floats them to the lungs.Here, they leave the capillaries for the mucosa lining the airways.From these respiratory surfaces, they are coughed up, and swallowedinto the gastrointestinal tract.

Alternatively, the larvae can begin their life cycle by direct ingestioninto the mouth, a route often taken by small children.

"When the larvae enter the host," Hotez told BioWorld, "they releaseseveral molecules, which appear to be immunogenic. We have nowcloned the major immunogenic molecule from those infective larvae.It is a 40-kilodalton protein, which we call ASP for ancylostomasecreted polypeptide. That is the first protein that we are evaluatingas a vaccine candidate."

Hookworm's Clot-Buster Slated As Worm-Busting Vaccine

Once at home in the gut, the mature worm goes to work cutting intothe mucosal lining with its sharp mouth parts. It then injects a potent8.7-kilodalton molecule called "A. caninum anti-coagulant peptide"(AcAP). This prevents the victim's blood from clotting, thus makingit easier to suck.

Hotez and co-author George Vlasuk of San Diego-based CorvasInternational, Inc., cloned the AcAP gene, and expressed its 75-amino-acid recombinant product.

"We think AcAP is the more interesting molecule, because of itspharmacological properties," Hotez observed, "for drugs unrelated tohookworm infection. More interesting as a vaccine candidate," headded, "is the ASP larval protein."

Hotez and his co-authors are counting on ASP to create a vaccine thatthey hope will control the scourge in the Third World. We'veactually been able to produce enough recombinant material to beginvaccine animal trials here at Yale, Cappello said, so far, in hamsters."

"We've hypothesized," he explained, "that a vaccine that interferedwith the worm's ability to feed on blood, could, if not preventinfection, prevent blood loss.

Bloodthirsty leeches, ticks and mosquitoes also soften up their targetsby injecting species-specific anticoagulants. The hookworm's AcAP,Cappello said, "can dramatically prolong the time it takes for bloodto clot, probably 100 to 1,000 times more potent than tickanticoagulant peptide, and comparable to the leech's hirudin."

Patented Technology Licensed To Biomedsyn

Mosquitoes, he said, make an anticoagulant that, like AcAP andhirudin, acts by inhibiting factor Xa in the blood's clotting cascade.Xa activates thrombin, which sets up fibrin to form a clot'sunderpinning meshwork.

A couple of months ago, the U.S. Patent Office notified Yale that itwas allowing its patent application covering the hookwormtechnology. Four months ago, the university licensed it to a biotechstart-up firm, Biomedsyn Corp., in nearby Woodbridge, Conn.

This firm was founded last December by Franklin Volvovitz, formerchairman, president and CEO of MicroGeneSys Inc., of Meriden,Conn. He told BioWorld Today that besides the vast Third-Worldneed for such a hookworm vaccine as Yale is testing, the U.S.veterinary industry offers a "very substantial potential." Volvovitzexplained that "the worms are developing resistance to existing anti-helminthic drugs, so the pharmaceutical industry is beginning to takean interest in vaccines."

Chinese Connection To Cut Third-World Costs

"Veterinary applications in the First World," Volvovitz predicted,"will help support financing of any prospective vaccine campaign inthe Third World." He estimated the total market at $250 million, andadded that "the People's Republic of China will help drive downcosts."

On this theme, Hotez said: "We've started collaborating withscientists at the Chinese Academy of Sciences' Institute for ParasiticDiseases in Shanghai. They are carrying out large-scale trials in dogsof our recombinant ASP candidate vaccine."

"The flip-side," Volvovitz observed, "is that the AcAP anti-coagulantmolecule has potential First-World applications in treatingcardiovascular and oncological diseases." Factor Xa, which AcAPblocks, is implicated in a number of disease states, myocardialinfarction, thrombosis, restenosis, tumor metastasis.

Hotez is now in the process of soliciting support for large-scalehuman vaccine trials in the endemic areas of the Third World. But, ashe wrote in Scientific American, "Pharmaceutical manufacturers areloath to invest in vaccines for the Third World because lack of awealthy market means the companies will not recoup their costs."

However, Hotez told BioWorld, "China is such a huge market, that_ though it has some features of an underdeveloped country _ ithas a large potential, because of its market for attracting investorsupport for a human hookworm vaccine." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.