Unable to defeat a devastating tropical disease,schistosomiasis, parasitologists are testing a live-and-let-live vaccine to protect against its deadliest symptom.
Next to malaria, schistosomiasis is the most widespreadand destructive infection that afflicts the human race.Wherever humans make contact with shallow waterthroughout tropical Africa and South America, plus partsof South Asia, they risk its ravages.
The disease, a.k.a. bilharzia, occurs in some 70 tropicaland subtropical countries, where it infects more than 200million men, women and children. In the U.S., more than400,000 people _ mostly immigrants and returningtravelers _ are infected with the deadly liver flukes.
Worldwide, bilharzia-inflicted fibrosis of the liver killsmore than 800,000 people a year.
These horrendous statistics trace back to a thumb-sizedsnail (Biomphalaria sp.) that lurks in still, shallow waters_ often man-made irrigation paddies and ditches. Thesmall, spiral-shaped mollusks are thought to coat theirshells with a chemical attractant that seduces the inch-long, thread-thin schistosoma, the liver flukes. Onceinside the snails, these slender worms multiply mightilyfor a couple of months, then emerge as free-swimminglarvae.
Finding a warm human body, the larvae burrow into itsskin, and enter the bloodstream by wriggling through thecapillaries. Blood flow transports them to the lungs andheart, whence the larvae move into the hepatic portalvein, which nourishes the liver.
At this honeymoon venue, the larvae differentiate intomale and female, then mate. From their union come forthanywhere from 300 to 3,500 eggs a day, which the bloodsweeps into the liver. There, the double-pointed eggs,150 microns long by 60 thick, provoke deposition ofcollagen, to produce hepatic fibrosis _ a scar tissuebetter known to chronic alcoholics as cirrhosis of theliver.
"Fibrosis is the major hallmark of schistosomiasis," saysimmuno-parasitologist Alan Scher, who headsimmunobiology at the National Institute of Allergy andInfectious Diseases (NIAID).
Vaccine Strategy: Live And Let Live
Scher is senior author of a paper in the currentProceedings of the National Academy of Sciences(PNAS), dated August 14, which reports "An IL-12-basedvaccination method for preventing fibrosis induced byschistosome infection."
"Our vaccine strategy," Scher told BioWorld Today, "isbased, first, on the concept that the pathology of thisdisease is due almost entirely to the eggs. To create avaccine that would prevent the disease, you don'tnecessarily have to prevent the infection itself _ that is,keep the parasites from entering the host _ in order toblock the inflammatory and fibrotic responses to theeggs."
Those immune-system responses are perpetrated, in thefirst instance, by cytokines that helper T cells dispatch tothe scene of the egg invasion of the liver, in an over-killeffort to wall off the eggs entrapped in the hepatic tissue.Research in his laboratory, Scher said, found that onetype of T helper in particular, TH2, sends in thosespecific cytokines that propagate the granulomas andfibrosis.
"Therefore," he observed, "if you had a way to preventthe generation of those TH2 cells, you might block thedisease, or the pathology. And we found that interleukin-12, as one of its activities, does just that."
Immuno-parasitologist Thomas Wynn, first author of thePNAS paper, explained: "IL-12 appears to steer theimmune system away from the TH2-type responses thatlead to granuloma formation and fibrosis, and toward theTH1 cells. We call our strategy an `anti-pathologyvaccine,'" he continued. "It prevents the symptoms ofdisease rather than the infection."
To test this concept in vivo, Wynn and his co-authorsinoculated mice with schistosome eggs, with or withoutadjuvant doses of IL-12, then exposed them to through-the-skin infection by predatory larvae.
Mice Survive Infected But Fibrosis-Free
The lucky rodents who received IL-12 along with theirimmunogenic eggs produced fewer and mildergranulomas than mice vaccinated with eggs alone. But"the most striking effect of egg/IL-12 sensitization," thePNAS article reported, "was the inhibition of egg-inducedhepatic fibrosis. [It] caused a nearly 10-fold reduction inthe levels of induced expression of liver messenger RNAsrelative to that seen in unsensitized mice."
This anti-pathology vaccine approach, the paper stated,"is demonstrated successfully for the first time here."
"For the moment," Scher said, "we're using just crudeschistosoma eggs or egg extracts in our inocula. We don'tyet know what the relevant antigens are, and that's thenext step. Meanwhile," he continued, "we're going onwith our mouse experiments, which are holding up verynicely."
Human trials are something else again, in more ways thanone. They involve policy considerations as well asclinical.
"For starters," Scher observed, "We're going to need tohave the egg antigen purified. I don't think they'll let usstick eggs into people."
Then Scher turned to the non-clinical aspect of eventualhuman trials: "We're trying to get people to emphasize,"he said, "that work on this kind of disease has very littlesupport from industry, because it's a Third Worldproblem."
So far, his work is being supported entirely by theNational Institutes of Health, with some assistance fromthe World Health Organization.
Seeking First World Relevance
One way around this dead-end, Scher observed, "is thatthis general vaccine strategy has some very broadimplications, with more relevance in the developedworld. This kind of vaccination approach might be usefulfor a number of other kinds of diseases that are TH2-mediated, such as allergy ."
Immuno-parasitologist Edward Pearce is aschistosomiasis specialist on the faculty of CornellVeterinary College in Ithaca, N.Y. "I think the whole ideaof anti-pathology vaccines has been neglected," he toldBioWorld Today. "It's a great idea, and I think we'll seeseveral other reports in the near future of similar anti-pathology vaccines in infectious-disease situations."
Pearce added, "The big problem in parasitic diseases isthat most of these experimental vaccines are not fullyefficacious in preventing infection. Besides being usefulin themselves, one can envisage coupling these anti-pathology vaccines with a vaccine that is partiallyeffective in preventing infection. And the principle can beapplied to other diseases, obviously." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.