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SKMC Alumni Bulletin

It Takes a Village

In some places, you see children gingerly leading the elderly—their eyes milky blind—to work the fields, dependent on the young to find their way. In other places, whole villages are emptied of people, human sounds replaced by buzzing flies and the rush of a nearby river.

This is onchocerciasis—river blindness—a so-called “neglected tropical disease” that affects 15.5 million people, mostly in sub-Saharan Africa with incidences in South and Central America. The disease is spread by black flies, which breed in fast-moving water, but is caused by Onchocerca volvulus, a tiny parasitic worm.

The worm is David Abraham, PhD’s white whale. A professor of microbiology and immunology as well as the associate dean of undergraduate medical education and academic affairs, he has spent much of his career studying O. volvulus, part of a group of parasites known as filarial worms, which include well-known pests like heartworms.

Our antagonist begins its byzantine life cycle as a microfilaria, its larval stage, living in human skin tissue until a black fly comes along in search of a blood meal. The larva is ingested by the black fly, moving to the gut, where it matures to its second stage before moving back to the fly’s proboscis (mouth parts). After a few weeks, it is ready to depart its host the next time the fly feeds on a human.

Entering the second human host through the fly’s saliva, the larva takes up residency deep in the skin, forming a nodule, where it remains for the next six to 12 months until it is a fully mature adult worm. If a male and female are present in the same host, the male will make its way through the skin to the nodule that houses the female, where they will mate. After gestation, the female will lay between 700–1,500 microfilariae each day, which will spread throughout the skin until another black fly comes along.

Unsurprisingly, blindness tops the symptoms list, though it typically comes as a kind of parting shot from the adult worms that make their way to a patient’s head and face. When the microfilariae die, bacteria are released from their corpses and the body’s inflammatory response to these bacterial invaders can cause damage to the retinas. Over time, enough damage can lead to full blindness.

Severe as that side effect is, some say the accompanying dermatitis produced by the larvae is even worse. “It’s so bad that people will take hot metal to their skin to find some relief,” Abraham says. The larvae can cause much of a patient’s body to become rough or “lichenized” and depigmented. In more extreme cases, the skin become so inelastic that organ hernias form.

Abraham’s work on a river blindness vaccine—none currently exists—began in 1988 when the Edna McConnell Clark Foundation offered to support his research. They asked, “Does the immune system respond to Onchocerca volvulus larvae?”

As it turns out, there is an immune response to the worm. The body can “see” it and mount a defense.

Current medical treatments involve delivering doses of ivermectin, a general-use antiparasitic, to at-risk populations every year for up to 30 years. This multidecade horizon—aimed at interrupting the spread of microfilariae—is made difficult by the rural life of affected populations and the need to track them for extended timespans. Vaccination, on the other hand, is a one-and-done preventive intervention that would inoculate children against the infection.

Before developing a vaccine, investigators had to get O. volvulus to “hold still,” as the parasite tends to move about once introduced into a host (lab mice in this case), making extraction and monitoring a challenge. To resolve this issue, Abraham and his team utilized tiny diffusion chambers that keep the worms from straying. Covered with microns-wide holes that allow immune molecules and cells to interact with the worm, the minuscule holding chambers allow the team to observe “the scene of the crime” and understand in a fine-grained way what molecules are involved in a protective immune response. (Read “Know Thy Self” in the Fall 2019 issue of The Bulletin to learn more about the uses for Abraham’s chambers).

“We were sent antigens from different labs around the world,” recalls Abraham. “It was our job to see what response they elicited, as well as whether the response could be increased in combination with other known enhancers.” The collaborators developed an antiparasite cottage industry, vetting targets and brainstorming possible solutions together.

The Clark Foundation eventually moved on to support other new ventures, having fulfilled its mission of jump-starting research programs for this particular neglected tropical disease. “They’d assembled this whole group of people,” Abraham says. “We now have larvae producers and health screeners in Africa and at universities throughout the world, antigen producers, human immunologists, and my parasite group—all arranged around this one goal.”

The National Institutes of Health took up the challenge next, providing support to continue the basic science research required for the O.  volvulus vaccine’s development. A Small Business Innovation Research (SBIR) grant enabled the O. volvulus collaborators to finalize their list of antigen targets and to optimize the “recipe.” Now partnered with PAI Life Sciences, a Seattle-based health sciences firm with expertise in vaccine development, the team is on its way to market.

But before they could finish, they wanted to ensure that their treatment would work against the hardiest possible specimen. This is essential to developing a working vaccine that can kill not just sickly, weak worms out of place but healthy parasites in their native habitat. A species like O.  volvulus, with its just-so life cycle, makes this of the utmost importance, as the conditions under which they flourish are nothing if not particular.

Funded by the Bill & Melinda Gates Foundation, the Abraham lab engineered immunodeficient mice with a human immune system by injecting them with human umbilical cord stem cells, populating their bodies with the usual cast of T and B cells. The team went further by grafting human skin and muscle cells into their humanized mice to better replicate where O. volvulus spends much of its life, lengthening the worms’ life spans to over three months and increasing their size fourfold.

They are currently testing the vaccines in collaborative cross-mice models to determine the most effective combination of antigens and adjuvants (immune enhancers). “These mice are bred to be as genetically diverse as possible with the aim of getting reproducible results,” Abraham explains. “The idea is to replicate as closely as possible the kind of diversity you’d find in a population of people.”

The aim is to understand which molecular target works best and how that “best vaccine” functions. This last piece, aside from satisfying curiosity, will let them know their vaccine is working once it’s finally administered to the public. This will save valuable time, as they can determine through a simple blood test whether immunity has taken hold rather than waiting a year for the worms to complete their life cycle.

There is still some distance to go, more tests to be done, and regulators to satisfy, but Abraham and the international team he is a part of are closing in on the vaccine that’s been decades in the making.

Onchocerca volvulus has left countless individuals sightless and homeless, and entire villages empty and silent. But on the horizon the researchers can see a vision of what is to come: A world where the young look at their elders and have their gaze met in return, and villages where rivers do not mean foreboding, where the air is once again filled with voices.