Every year, a quarter million people worldwide are diagnosed with one of the best known but least understood diseases of mankind—leprosy. Leprosy is a cruel disease. It rarely kills its victims, but can leave them maimed, crippled, disfigured, and blind, often with terrible quality of life. Some cases may be milder and present with only a few skin lesions, loss of sensation, and some nerve damage, but still can be disabling. Globally, seventy percent of new cases come from India and Brazil, with most of the balance spread around the tropical regions of the world.

Almost every aspect of leprosy is unusual, strange or weird. It has afflicted humanity for more than 4,000 years, yet no one knows for certain how it is transmitted. It cannot be cultured in a laboratory and infects only humans and armadillos. M. leprae, the mycobacteria that causes leprosy, is a close cousin of the bug that produces tuberculosis. TB is a considered slow growing because it takes 24 hours to double. By comparison, M. leprae takes two weeks to double. Leprosy may be slow, but it is relentless. The incubation period for leprosy typically ranges from one to seven years, but it can be as short as a few weeks to as long as 20 years. Curiously, it is believed that 85- to 90 percent of the world’s population may be inherently able to fend off the infection of leprosy, but no one knows why.

The Advent of Multi-Drug Treatment

In the mid-1980s, the number of new cases of leprosy reported each year was in the millions. Then a new multi-drug treatment (MDT) made an effective cure possible. Since 1995, the World Health Organization (WHO) has provided free MDT for all reported leprosy patients. Aided by aggressive country-specific efforts to identify and treat people with leprosy in high-risk areas, the combined WHO-MDT campaign has driven new case rates down to 250,000 new cases per year.

Lepromatous leprosy patient [From WHO pamphlet on leprosy; unknown origin or date]

But this apparent success is not without its problems. While MDT is effective in the majority of cases, relapse (or possibly reinfection) can occur. Patients often neglect their treatments, sometimes because one of the drugs causes skin discoloration during the span of the therapy, and sometimes because they become weary of the six to 12 months that it takes to complete treatment.

Dr. Malcolm Duthie, senior scientist with the Infectious Disease Research Institute (IDRI), says, “The WHO-MDT campaign drove the numbers down to 250,000 cases a year, but that number has not changed in nearly a decade. It’s clear that current detection methods and treatment are not going to eliminate this disease completely.”

Bill Simmons, CEO and president of American Leprosy Missions (ALM), adds, “Under-reporting of leprosy is a problem. Two examples will suffice: in India, where a sample survey was done, the actual new case detection rate was two to three-and-a-half times what was reported, and in Bangladesh in 2010, the reported number of cases went from 5,000 to 3,000. NGOs reported cases but the Bangladesh Ministry of Health didn’t report any!”

The Dream

Simmons says, “In 2001, one of our board members, John Dawson, felt strongly that a vaccine in leprosy is the only long-term solution to the disease. The other board members agreed. John, now passed on, was also a board member at IDRI, so we asked IDRI to help us in vaccine development.

He adds, “The idea was that IDRI would do the bench work, where they have lots of expertise in vaccine development and manufacturing processes, and we would provide guidance and leprosy expertise through a scientific advisory committee. The work began in earnest in 2003-2004 with ALM’s centennial campaign to drive awareness and funding from donors to support the vaccine.”

“For a vaccine to be effective,” Simmons says, “you have to know where the cases are, so strong case-finding is critical to the success of the vaccine.”

Erik Iverson, executive vice president for business development and external affairs at IDRI, agrees. “We decided that we would like to go out in two different directions at the same time. One would be to develop a fast, easy diagnostic test for leprosy, one that could be done by any doctor anywhere, hopefully with just a pinprick of blood. The other would be the development of a vaccine that could be used to immunize people against leprosy and also to provide treatment to people who the diagnostic test indicates have been exposed to leprosy but are not yet showing symptoms.”

The Diagnostic Test

The point of a fast, easy, low-tech diagnostic test for leprosy is to identify people with leprosy as early as possible. Leprosy presents with a wide range of symptoms that can be easily misinterpreted. It is common for patients to be treated for fungal infections or even cancer before a proper diagnosis is made. The longer a correct diagnosis is delayed, the greater the likelihood of irreversible nerve damage and loss of feeling.
Duthie says, “If you screen a population of people with a leprosy diagnostic tool, you’ll find three different things. Some people will have clear signs of exposure to leprosy in their blood, and they exhibit some symptoms. These you treat with MDT as soon as possible.”

“Another group will have no sign of exposure to leprosy and no symptoms. These people do not require MDT treatment, but you might want to immunize them against leprosy if they live in close proximity to people who have the disease. Long-term exposure to people who have leprosy is the biggest known risk factor for contracting the disease.”

“Finally,” Duthie says, “some people will show clear signs of exposure to leprosy in their blood, but no symptoms. We would like to treat them with a vaccine to ‘intercept’ the disease and prevent its development before they become symptomatic.”

Currently, IDRI is going through validation trials of a rapid diagnostic tool in the laboratory. If the diagnostic tool can be replicated in large quantities with consistency, IDRI expects a usable diagnostic kit could be rolled out to the world within 18 months.

The Vaccine

The ideal vaccine against leprosy would induce strong, long-lasting immune responses directed against M. leprae that would both prevent disease and reduce bacterial transmission. The vaccine would include proteins from the pathogen as well as an immune stimulant, so that the vaccine would produce an immune response that can act during an actual infection.

Duthie says, “We are now conducting experiments that will define the final configuration of the vaccine. We’ve identified three or four proteins and zippered them together. We’re now looking at way to reproduce the fusion protein on a large scale.”

Iverson adds, “IDRI has mouse testing of a potential vaccine going on, and it is showing reduction of bacterial replication and growth. We expect full experiments by the middle of the year. After that, we anticipate process development and scale-up to show that the vaccine can be produced in quantity and then phase one clinical trials.

Dr. Indira Nath, MD, Raja Ramanna Fellow & Emeritus Professor, National Institute of Pathology, India, has collaborated with IDRI on validating targets for both the vaccine and diagnostic tool. She says, “The theory has already been proven that we can tickle the immune response in these patients to produce a good result.”

Bumps in the Road

The road to realizing ALM/IDRI’s vision for the elimination of leprosy through the use of a rapid diagnostic tool and a vaccine has not always been smooth. Sometimes there have been sharp philosophical differences in the approach to dealing with leprosy.

More than one clinician has told IDRI, “What do I need a diagnostic test for? I can recognize a person with leprosy when they walk in the door.”

Others within the leprosy treatment community have questioned whether a leprosy vaccine was wanted, needed, or even possible.

“One of the key things we needed to learn,” Iverson says, “is how to find common ground to work together even when you disagree about philosophy or tactics.”

Collaboration

Both Iverson and Duthie are adamant that in-depth collaboration has been the heart of the project and the key to moving forward, from funding to every step of the research. Despite extensive experience with diagnostics and vaccine development, leprosy was new to IDRI at the beginning of this program. The ALM Scientific Advisory Board and others provided needed education about the disease which, in turn, allowed IDRI to respond with fresh perspective and energy.

American Leprosy Missions has provided multi-year research funding for the effort. Renaissance Health Service Corporation is a founding sponsor of the implementation phase of the leprosy elimination project. Additional funding was received from The Leprosy Mission Canada, National Institutes of Health, and the Heiser Foundation for Research in Leprosy and Tuberculosis.

Tests of experimental vaccination in animals were performed with collaboration from the National Hansen’s Disease Program, based at Louisiana State University, and at the National Institute of Infectious Diseases, Tokyo. Leprosy patient samples and related data that were critical to both diagnostic and vaccine development were provided by a host of collaborators in Brazil, Venezuela, Philippines, India, Bangladesh and Nepal.

Prototype diagnostic kit development using licensed IDRI technology is ongoing at ChemBio Diagnostics (New York), EASE-MedTrend (San Francisco, Shanghai), CTK Diagnostics (San Diego, Beijing), and OrangeLife (Rio de Janeiro). Partners in India are key producers of reagents for the diagnostic test (SAI Advantium Pharma, Ltd., Hyderabad) and ultimately of the vaccine (Gennova Biopharmaceuticals Ltd. in Pune).

IDRI has also collaborated in endemic countries with government laboratories and institutions such as CREDESH (The National Reference Center for Hansen’s Disease in Brazil). In addition to facilitating the research so far, this network may lead to the possibility of government support for the implementation of the diagnostic tool and vaccine developed by IDRI and other collaborators.

John S. Spencer, PhD, assistant professor, Colorado State University Mycobacteria Research Laboratories, worked with IDRI on target discovery for the diagnostic tool and vaccine. He says, “We’re part of a consortium—IDEAL (Initiative for Diagnostic and Epidemiological Assays for Leprosy)—and so is IRDI, so we decided to dance together. Like us, they have a heart for people with leprosy and are willing to do whatever works to move forward.”

By Jock Elliott