Perhaps the only aspects of tropical diseases that might be considered entertaining are the names they collect. Mal morado, volvulosis, Robles' disease and river blindness, for instance, all describe a single parasitic infection formally known as onchocerciasis.
The cause of this nonfatal, chronic infection is the round worm Onchocerca volvulus. Spread by blood-sucking female blackflies, river blindness can produce symptoms that range from rashes to skin atrophy to blindness.
Eighteen million people, most in Africa and Latin America, may have river blindness. Merck & Co. Inc., of Whitehouse Station, N.J., provides its treatment for the disease, Mectizan (or Ivermectin), on a nonprofit basis.
While Merck's contribution and local insect control programs have greatly relieved the threat to human health posed by the disease, there is still a significant need for a vaccine. Unfortunately, developing a vaccine for river blindness may be more challenging than developing one for AIDS, if the lack of candidates and clinical trials is any indication. The complexity of the infectious worm and its life cycle contributes to the problem.
The blackfly deposits infective larvae when it bites. They penetrate the skin and underlying tissue and grow to adulthood in one year. An adult female worm, which may live 15 years, releases many young called microfilariae that travel throughout the host. These microfilariae can live 2.5 years. Uninfected flies that bite the host pick up the larvae and continue the infective cycle.
Adult worms form nodules under the skin. When microfilariae die, they may elicit rashes and skin atrophy. Itching may be local or general, moderate or severe. Scratching often results in lesions and abrasions. If many motile larvae are in the region of the head and eyes, blindness can result.
Fever, headache and tiredness occur. The infection presents a significant challenge to the immune system.
A report in the June 23, 1998, issue of the Proceedings of the National Academy of Sciences in the U.S. points to an important clue about the way the immune system responds to the presence of the invading worm.
Immune Response Can Hurt And Help
The article, “Tropomyosin implicated in host protective responses to microfilariae in onchocerciasis,“ indicates some individuals might limit the density of microfilariae in their bodies by producing antibodies to a worm version of a protein called tropomyosin.
The same report underscores the importance for vaccine developers to remember that the immune system can produce both positive and negative results.
Albert Bianco, professor of parasitology at the Liverpool School of Tropical Medicine, in the U.K., and his co-authors knew the serum of mice vaccinated with worm extracts can confer protection to the disease.
New data show this serum contains large amounts of anti-tropomyosin antibody. Furthermore, they demonstrate humans with high levels of serum anti-tropomyosin have low densities of microfilariae in their skin and vice versa. The more endemic the infection is in a population, the more prevalent the antibody.
These same antibodies that appear to provide some defense against the infection, however, may also be responsible for hypersensitivity reactions to dead microfilariae, according to the authors.
“Microfilariae are assumed to die in very large numbers simply because they are present in such high density. That can drive some of the pathological states. And the bodies' reactions to dying parasites can drive immunopathological states,“ Bianco told BioWorld International.
Antibodies don't respond to whole antigens. They respond to epitopes, localized regions on the surface of antigens. Bianco and his colleagues identified an epitope in worm tropomycin that, interestingly, matches an epitope in shrimp tropomyosin that is believed to cause allergic responses to shellfish in susceptible individuals.
It is possible, therefore, that anti-tropomyosin antibodies may be linked to both beneficial and pathological responses of the immune system in river blindness.
“The concept that you have antigens which are basically 'good guys' or 'bad guys' - things that drive protective responses or things that drive disease-generating responses - is probably overly naive. We do know that the kind of immune response you get to an antigen governs the outcome for the host,“ Bianco said.
Tropomyosin is a well-characterized component of muscle in mammals. It is found in muscle and other parts of the parasitic worm. Why should it elicit an immune response? The authors suggested that because muscle tropomyosin is unlikely to be exposed in living microfilariae, it might be released by dead or dying larvae. Antibodies generated in response might cross-react with a nonmuscle form of the protein that is accessible to immune cells.
Electron microscopy supports this suggestion by showing that anti-tropomyosin antibodies bind to an exposed portion of microfilariae called the cuticle.
Bianco suggested other possible explanations of why tropomyosin is antigenic. The worms may secrete tropomyosins in some fashion. Or they may secrete something that looks to the immune system like tropomyosin.
“We haven't yet nailed down the nature of that secreted molecule,“ Bianco said.
Vaccine Will Include Antigen Cocktail
A few other molecules besides tropomyosin have been found to confer some protection against the parasite, but none comes close to wiping it out.
“The levels of protection we recorded, about 50 percent reduction, are fairly typical of the levels people are producing with defined cloned antigens,“ Bianco said.
While study of tropomyosin is providing important insights into the immune responses elicited in river blindness, the protein will not be the source of a vaccine.
Instead, any successful vaccine likely will consist of a cocktail of antigens or epitopes. That is probably a common feature of vaccine development for any multicellular parasite, according to Bianco, who feels that protection and pathology in this disease are closely related. The new results strongly suggest the same antigens can be involved in both processes.
“If you are trying to direct the outcome, for example, by vaccination, you really have to be in control of that outcome. Otherwise, there is potential danger in not being fully in control of the responses induced by vaccination,“ Bianco said. *