Lectures
Ninth Dr Yellapragada SubbaRow memorial Lecture of Indra Prastha University, New Delhi January 12, 2012
MISSION-ORIENTED RESEARCH ON RELEVANT PROBLEMS
An Immuno-Therapeutic Vaccine for Multi-bacillary Leprosy
By Professor G P Talwar DSc, Director-Research, Talwar Research Foundation
Founder-Director of the National Institute of Immunology, Dr Talwar headed the Department of Biochemistry at the All-India Institute of Medical Sciences earlier for 27 years
I shifted from basic studies on the mechanism of action of hormones to a project relevant to problems facing India when in 1970 a team of distinguished immunologists accompanied by Dr Howard Goodman of the World Health Organisation asked me to head WHO Research and Training Centre in Immunology for India and the South East Asia Region. I was initially reluctant but agreed when posed the question if I expected Americans to solve the problem facing India as the country with the largest number of lepers in the world.
It was a challenge. Lepers evoked my sympathy but I knew nothing about leprosy. I began to learn about leprosy, spending the next two summers in the Danish Save the Children Leprosaria in Orissa and Andhra Pradesh along with two of my students and established a field laboratory.
As discovered by Norwegians over 200 years back, leprosy is caused by Mycobacterium leprae but there is no medium in which a microbe can grow. M. leprae obligatorily requires a host cell to grow. Most (99%) of those who are exposed to it do not develop leprosy. Those who do contract the disease fall in a spectrum between polar tuberculoid TT and polar lepromatous leprosy LL depending on the degree of immune deficit. To understand the nature of immune deficit, it was necessary to develop in vitro experimental systems.
My student, A D Krishnan, and I obtained macrophages from monocytes of human blood which could be maintained in culture. This could be employed as host cells to determine the growth of M. leprae or lack of it in various situations. The only source of M. leprae was lepromas obtainable from LL patients. These contained variable number of live and dead bacilli. M. leprae is a slow grower with a division time of 13 days.
To employ this inoculum to determine growth demanded a novel approach. Counting was an impracticable possibility.
I thought of employing H3-thymidine as a discriminatory tracer. It would be incorporated by M. leprae if it would make DNA without interference from the host cell which does not have the machinery to incorporate H3-thymidine. By this approach, quantitative data was obtained on the growth of M. leprae in a human cell.
Employing this system, we learnt that the T-cells of patients played a critical role in generating a signal for macrophages to either kill the resident M. leprae or let it grow. We found that the nature of defect in Lepromatous Leprosy was the inability of T-cells to react with key antigens of M. leprae.
Our task next was to find a way to overcome this immune deficit. We devised a heterogenous approach for searching a Mycobacterium that could generate the signal from T-cells of LL patients. We took all the known mycobacteria including atypicals and investigated their reaction to T cells. We found a non-pathogenic, fast-growing mycobacterium that shared antigens with M. leprae and M. tuberculosis. We code named it M.w.
After pre-clinical toxicology in the 1980s, we did Phase I study for human safety and Phase II and Phase III studies for efficacy and then, with approvals from DGCI and Ethics Committees, conducted the field trials in 1990 at Kanpur, where leprosy is endemic, and proved that Mw could be used as an immunotherapeutic vaccine for multi-bacillary leprosy.
Along with the standard multi-drug regime, this shortened the recovery period and enhanced bacillary clearance.
We gave the technology to Cadila Pharmaceuticals of Ahmedabad in return for `50,000 to the National Institute of Immunology.
Treated with this vaccine, patients recover to an extent that nobody believes that they had at one time ugly lesions of LL. There is no relapse even after a year whereas there is a 24.4% relapse with MDT alone. Therefore the vaccine is being used along with MDT.
Mw vaccine has also been found to be of utility in category 2 (‘difficult to treat’) cases of tuberculosis. It completely heals ugly ano-genital warts.
The gene sequence of Mw has been done by a consortium of three national laboratories. Previously unlisted in the World Data Bank, the marvellous bacillus has been named after me as Mycobacterium indicus pranii. (With inputs from Abhishek Gupta)
(Professor G P Talwar, Talwar Research Foundation, E-8 Neb Valley, Neb Sarai, New Delhi 110068. P: 91-11-29531028/29536769. © 8800322055. email: gptalwar@gmail.com)