EDITORIAL ESPANOL:

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Hola Amigos de la red, DERMAGIC de nuevo con ustedes. La lepra, enfermedad bien conocida desde la antigüedad, se ha convertido en un verdadero reto para nuestros investigadores en la búsqueda de una VACUNA, que proteja CONTRA la infección del mycobacterium Leprae. 

Muchos intentos se han hecho, y hay varios grupos trabajando en ello, en VENEZUELA el Grupo del Dr. Convit trabaja con Cepas de Mycobacterium Leprae, también con BCG, quizás uno de los pioneros en esta búsqueda ansiosa, los resultados, alentadores. En ARGENTINA se está trabajando con Cepas de Mycobacterium Bovis y vaccae. 

En otros países (Brasil) también con EL BCG SOLO o con Mycobacterium Leprae, Pero encuentro que en la India NUEVA DELHI, se ha estado trabajando con 4 cepas, entre las que destacan Mycobacterium Habana y Mycobacterium w, este último del cual según ellos se pondra al mercado LA PRIMERA VACUNA contra la Lepra producida por Cadila Pharmaceuticals, (referencia 50), porque NO ES PATÓGENO. 

Pero si revisamos bien TODAS las referencias, NO SON VACUNAS PROPIAMENTE DICHAS, en el sentido estricto de la PREVENCIÓN de la infección, puesto que se usan en combinación con poliquimioterapia. (MTD). Recordemos también que la clásica vacuna BCG (bacillus Calmette-Guerin) , que protege contra la tuberculosis, también protege contra la lepra.. 

Por mi parte felicito a todos estos investigadores, pero seguiremos esperando por UNA REAL VACUNA contra la LEPRA... Espero que les guste este DERMAGIC, 

Saludos,,,

Dr. José Lapenta R.,,,

 EDITORIAL ENGLISH:

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Hello Friends of the net, DERMAGIC again with you. The leprosy, very well-known illness from the antiquity, has become a true challenge for our investigators in the search of a VACCINE that protects AGAINST the infection of the mycobacterium Leprae. 

Many intents have been made, and there are several groups working in it, in VENEZUELA the Group of the Dr. Convit begins with Strains of Mycobacterium Leprae, also the BCG, maybe one of the pioneers in this anxious search, the results, encouraging. In ARGENTINEAN are working with Strains o f Mycobacterium Bovis and vaccae. 

In other countries (Brazil) with THE BCG ALONE or plus Mycobacterium Leprae, But I find that in the India NEW DELHI, has been working with 4 strains, among those are the Mycobacterium Habana and Mycobacterium w, this last of which will put on to the market THE FIRST VACCINE against the Leprosy produced by Cadila Pharmaceuticals, according to them, (reference 50), because it IS NONPATHOGENIC. 

But if we revise ALL the references well, they ARE NOT VACCINE PROPERLY, this in the strict sense of the PREVENTION of the infection, since they are used in combination with multidrug therapy (MDT). Let us also remember that the classic VACCINE BCG (bacillus Calmette-Guerin) that protects against the tuberculosis, it also protects against the leprosy.. 

Greetings,,,

Dr. José Lapenta R. 

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REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 

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A.- World's  first vaccine developed in the india, to go on trial, 2016

B.- Mycobacterium Indicus Pranii (MIP) Vaccine: Pharmacology, Indication, Dosing Schedules, Administration, and Side Effects in Clinical Practice

C.- Reduction of a subpopulation of T lymphocytes in lepromatous leprosy

D.- Micobacteria indicus pranii

E.- Cost-effectiveness of incorporating Mycobacterium indicus pranii vaccine to multidrug therapy in newly diagnosed leprosy cases for better treatment outcomes & immunoprophylaxis in contacts as leprosy control measures for National Leprosy Eradication Programme in India

F.-A comprehensive research agenda for zero leprosy

G.-Mycobacterium Lepromatosis as a Second Agent of Hansen's Disease.

H.-Autophagy Induction by Mycobacterium Indicus Pranii Promotes Mycobacterium Tuberculosis Clearance From RAW 264.7 Macrophages.

I.- Lepra: tratamiento, prevención, respuesta inmune y función genética

J.- LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection

K.- A Phase 1 Antigen Dose Escalation Trial to Evaluate Safety, Tolerability and Immunogenicity of the Leprosy Vaccine Candidate LepVax (LEP-F1 + GLA-SE) in Healthy Adults.

L.- The Role of BCG in Prevention of Leprosy: A Meta-Analysis.

M.- Efficacy of BCG Vaccine Against Leprosy and Tuberculosis in Northern Malawi

1.) Causative organism and host response. 

2.) The GroES antigens of Mycobacterium avium and Mycobacterium paratuberculosis. 

3.) Human T cell recognition of the Mycobacterium leprae LSR antigen: epitopes 

and HLA restriction. 

4.) Quality control tests for vaccines in leprosy vaccine trial, Avadi. 

5.) Comparative leprosy vaccine trial in south India. 

6.) Effectiveness of bacillus Calmette-Guerin (BCG) vaccination in the 

prevention of leprosy; a case-finding control study in Nagpur, India. 

7.) Effectiveness of Bacillus Calmette Guerin (BCG) vaccination in the 

prevention of childhood pulmonary tuberculosis: a case control study in 

Nagpur, India. 

8.) Tuberculin sensitivity and skin lesions in children after vaccination with 

two batches of BCG vaccine. 

9.) Leprosy vaccine: influence of dissolved oxygen levels on growth of a 

candidate strain (Mycobacterium w), and storage stability of the vaccine. 

10.) Studies of vaccination of persons in close contact with leprosy patients in 

Argentina. 

11.) Why relapse occurs in PB leprosy patients after adequate MDT despite they 

are Mitsuda reactive: lessons form Convit's experiment on bacteria-clearing 

capacity of lepromin-induced granuloma. 

12.) BCG vaccination protects against leprosy in Venezuela: a case-control study. 

13.) Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine 

against leprosy: preliminary results. 

14.) IgM antibodies to native phenolic glycolipid-I in contacts of leprosy 

patients in Venezuela: epidemiological observations and a prospective study 

of the risk of leprosy. 

15.) Immunological changes observed in indeterminate and lepromatous leprosy 

patients and Mitsuda-negative contacts after the inoculation of a mixture 

of Mycobacterium leprae and BCG. 

16.) Comparative study of the 48-hour response to soluble antigens obtained from 

human and armadillo leprosy material in lepromatous leprosy patients and 

normal persons, contacts of leprosy patients. 

17.) Association of HLA specificity LB-E12 (MB1, DC1, MT1) with lepromatous 

leprosy in a Venezuelan population. 

18.) Immunotherapy with a mixture of Mycobacterium leprae and BCG in different 

forms of leprosy and in Mitsuda-negative contacts. 

19.) A 35-kilodalton protein is a major target of the human immune response to 

Mycobacterium leprae. 

20.) Immunogenicity and protection studies with recombinant mycobacteria and 

vaccinia vectors coexpressing the 18-kilodalton protein of Mycobacterium 

leprae. 

21.) Mycobacterial infections: are the observed enigmas and paradoxes explained 

by immunosuppression and immunodeficiency? 

22.) Leprosy patients with lepromatous disease recognize cross-reactive T cell 

epitopes in the Mycobacterium leprae 10-kD antigen. 

23.) [BCG vaccination to Mycobacterium leprae infection in mice] 

24.) Human leukocyte antigens in tuberculosis and leprosy. 

25.) Modulation of protective and pathological immunity in mycobacterial 

infections. 

26.) IL-2 and IL-12 act in synergy to overcome antigen-specific T cell 

unresponsiveness in mycobacterial disease. 

27.) Dharmendra antigen but not integral M. leprae is an efficient inducer of 

immunostimulant cytokine production by human monocytes, and M. leprae 

lipids inhibit the cytokine production. 

28.) Inhibition of multiplication of Mycobacterium leprae in mouse foot pads by 

immunization with ribosomal fraction and culture filtrate from 

Mycobacterium bovis BCG. 

29.) Techniques for genetic engineering in mycobacteria. Alternative host 

strains, DNA-transfer systems and vectors. 

30.) Leprosy vaccine: influence of dissolved oxygen levels on growth of a 

candidate strain (Mycobacterium w), and storage stability of the vaccine. 

31.) Lymphostimulatory and delayed-type hypersensitivity responses to a 

candidate leprosy vaccine strain: Mycobacterium habana. 

32.) Randomised controlled trial of single BCG, repeated BCG, or combined BCG 

and killed Mycobacterium leprae vaccine for prevention of leprosy and 

tuberculosis in Malawi. Karonga Prevention Trial Group [see comments] 

33.) Immunotherapy of lepromin-negative borderline leprosy patients with 

low-dose Convit vaccine as an adjunct to multidrug therapy; a six-year 

follow-up study in Calcutta. 

34.) A case-control study of the effectiveness of BCG vaccine for preventing 

leprosy in Yangon, Myanmar. 

35.) Immunotherapy of far-advanced lepromatous leprosy patients with low-dose 

convit vaccine along with multidrug therapy (Calcutta trial). 

36.) Protective immunization of monkeys with BCG or BCG plus heat-killed 

Mycobacterium leprae: clinical results. 

37.) Studies of vaccination of persons in close contact with leprosy patients in 

Argentina. 

38.) Restoration of proliferative response to M. leprae antigens in lepromatous 

T cells against candidate antileprosy vaccines. 

39.) Does bacille Calmette-Gu´erin scar size have implications for protection 

against tuberculosis or leprosy? 

40.) Protective efficacy of BCG against leprosy in S~ao Paulo. 

41.) Post-vaccination sensitization with ICRC vaccine. 

Author 

42.) Sensitization and reactogenicity of two doses of candidate antileprosy 

vaccine Mycobacterium w. 

43.) Tuberculin sensitivity and skin lesions in children after vaccination with 

two batches of BCG vaccine. 

44.) Association between leprosy and HIV infection in Tanzania. 

45.) A follow-up study of multibacillary Hansen's disease patients treated with 

multidrug therapy (MDT) or MDT + immunotherapy (IMT). 

46.) Novel O-methylated terminal glucuronic acid characterizes the polar 

glycopeptidolipids of Mycobacterium habana strain TMC 5135. 

47.) Regional lymphadenitis following antileprosy vaccine BCG with killed 

Mycobacterium leprae. 

48.) A major T-cell-inducing cytosolic 23 kDa protein antigen of the vaccine 

candidate Mycobacterium habana is superoxide dismutase. 

49.) Supervised Multiple Drug Therapy Program, Venezuela 

50.) NII DEVELOPES WORLD'S FIRST ANTI-LEPROSY VACCINE 

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1.) Causative organism and host response. 

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Lepr Rev 1999 Mar;70(1):95-102 

Krahenbuhl JL 

Whether or not the leprosy elimination target is met in all endemic 

countries by the year 2000, the MDT programme will have greatly reduced 

worldwide prevalence. However, our workshop chairmen were asked to ignore 

the prevalence-based leprosy 'elimination' programme and focus on 

recommendations for a long term, incidence-based eradication target where 

transmission is blocked. They were asked to be concerned with basic leprosy 

research goals in the post 2000 era. The members of our workshops are 

actively productive workers, committed to their special interests. They are 

fully cognizant of the obstacles faced daily in working with leprosy and M. 

leprae, the requirement for clever experimental design even with the 

availability of the powerful tools of molecular biology which can now be 

brought to bear on some of the research obstacles. They are also aware of 

our lack of understanding about leprosy and M. leprae. How do you block 

transmission if you don't know how infection is transmitted? Can infection 

be detected, diagnosis made earlier? Is there a non-human reservoir host, a 

carrier state, an environmental source? What is the basis of M. leprae's 

predilection for nerves, the mechanisms underlying reactions? What needs to 

be targeted to treat reactions? Can a vaccine play a role? There is nothing 

startling in the workshops' recommendations. Other individuals and groups 

of experts have made the same suggestions, with slightly varying 

priorities. What one can read between the lines of these reports, is a 

sense of urgency to get as much done as soon as possible. Worldwide 

interest in leprosy will soon be diminished, not by design but as a 

consequence of the laudable success of the MDT programme. The experiment is 

still underway, but chemotherapy alone, killing bacilli in the detectable 

human host, does not appear to be the answer to blocking transmission. A 

number of goals must be addressed while there are still intact national and 

international leprosy programmes, while there are still leprosy treatment 

and research centres that can co-ordinate and facilitate the necessary 

trials for early diagnosis, early detection of reactions, evaluation of 

immunosuppressive regimens for reactions. A key recommendation is concerned 

with the means of measuring progress. A clear and explicit means of 

reporting incidence, prevalence and 'case detection' should be implemented 

to avoid a distorted picture of worldwide leprosy. These recommendations 

are non-controversial. What should be done is clear. The uncertainty is in 

determining who will do the work. Who will fund the laboratories engaged in 

this work? Look around you. There are fewer scientists attending this 

Congress but browsing the abstracts and attending our sessions and posters 

clearly revealed to me that fewer of us are doing far better work than in 

the past. Alternative sources of funding will help. Tuberculosis research 

is enticing researchers away from leprosy in the developed countries but is 

visibly sustaining leprosy research in many centres in developing 

countries. Formation of alliances was a key goal of this Congress. I asked 

my colleagues from Carville to identify in their own discipline, dedicated 

people, committed laboratories that will sustain their leprosy research 

efforts over the next 5, 10 or more years. These are the people with whom 

we wish to collaborate, form alliances, share resources and expertise, 

address the future of worldwide leprosy. 

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2.) The GroES antigens of Mycobacterium avium and Mycobacterium paratuberculosis. 

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Vet Microbiol 1999 Jun 1;67(1):31-5 

Cobb AJ, Frothingham R 

Veterans Affairs Medical Center, Durham, NC 27705, USA. 

The GroES antigen provokes a strong immune response in human beings with 

tuberculosis or leprosy. We cloned and sequenced the Mycobacterium avium 

and Mycobacterium paratuberculosis GroES genes. M. avium and M. 

paratuberculosis have identical GroES sequences which differ from other 

mycobacterial species. This supports the current formal designation of M. 

paratuberculosis as M. avium subsp. paratuberculosis. Immunodominant 

epitopes from Mycobacterium tuberculosis GroES are conserved in M. avium, 

but some Mycobacterium leprae epitopes are distinct. GroES is unlikely to 

be specific as a serologic or skin test reagent, but may be an appropriate 

component of a broad mycobacterial vaccine. 

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3.) Human T cell recognition of the Mycobacterium leprae LSR antigen: epitopes 

and HLA restriction. 

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FEMS Immunol Med Microbiol 1999 Jun;24(2):151-9 

Oftung F, Lundin KE, Meloen R, Mustafa AS 

Department of Vaccinology, National Institute of Public Health, Oslo, 

Norway. frederik.oftung@folkehelsa.no 

We have in this work mapped epitopes and HLA molecules used in human T cell 

recognition of the Mycobacterium leprae LSR protein antigen. HLA typed 

healthy subjects immunized with heat killed M. leprae were used as donors 

to establish antigen reactive CD4+ T cell lines which were screened for 

proliferative responses against overlapping synthetic peptides covering the 

C-terminal part of the antigen sequence. By using this approach we were 

able to identify two epitope regions represented by peptide 2 (aa 29-40) 

and peptide 6 (aa 49-60), of which the former was mapped in detail by 

defining the N- and C-terminal amino acid positions necessary for T cell 

recognition of the core epitope. MHC restriction analysis showed that 

peptide 2 was presented to T cells by allogeneic cells coexpressing HLA-DR4 

and DRw53 or DR7 and DRw53. In contrast, peptide 6 was presented to T cells 

only in the context of HLA-DR5 molecules. In conclusion, the M. leprae LSR 

protein antigen can be recognized by human T cells in the context of 

multiple HLA-DR molecules, of which none are reported to be associated with 

the susceptibility to develop leprosy. The results obtained are in support 

of using the LSR antigen in subunit vaccine design. 

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4.) Quality control tests for vaccines in leprosy vaccine trial, Avadi. 

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Indian J Lepr 1998 Oct-Dec;70(4):389-95 

Sreevatsa, Hari M, Gupte MD 

BCG Vaccine Laboratory, Guindy, Chennai. 

All the vaccines supplied for the large scale comparative leprosy vaccine 

trial of ICRC bacilli, M.w, BCG plus killed M. leprae (candidate vaccines), 

BCG and normal saline (control arms) at CJIL Field Unit, Chennai were 

tested for quality control by the suppliers following the procedures laid 

down in the WHO protocol for killed M. leprae. Quality control for BCG was 

carried out at BCG vaccine laboratory as per protocol. Toxicity and 

sterility tests were done on all the vaccine batches/lots received. As part 

of the quality control, bacterial count, and protein estimation were also 

done. Studies showed that the bacterial content and protein concentration 

were comparable with the original preparations. Vaccines were free from 

micro-organisms, toxic materials and safe for human use. Thus the quality 

of all vaccine preparations was satisfactory. 

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5.) Comparative leprosy vaccine trial in south India. 

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Indian J Lepr 1998 Oct-Dec;70(4):369-88 

Gupte MD, Vallishayee RS, Anantharaman DS, Nagaraju B, Sreevatsa, 

Balasubramanyam S, de Britto RL, Elango N, Uthayakumaran N, Mahalingam VN, 

Lourdusamy G, Ramalingam A, Kannan S, Arokiasamy J 

This report provides results from a controlled, double blind, randomized, 

prophylactic leprosy vaccine trial conducted in South India. Four vaccines, 

viz BCG, BCG+ killed M. leprae, M.w and ICRC were studied in this trial in 

comparison with normal saline placebo. From about 3,00,000 people, 2,16,000 

were found eligible for vaccination and among them, 1,71,400 volunteered to 

participate in the study. Intake for the study was completed in two and a 

half years from January 1991. There was no instance of serious toxicity or 

side effects subsequent to vaccination for which premature decoding was 

required. All the vaccine candidates were safe for human use. Decoding was 

done after the completion of the second resurvey in December 1998. Results 

for vaccine efficacy are based on examination of more than 70% of the 

original "vaccinated" cohort population, in both the first and the second 

resurveys. It was possible to assess the overall protective efficacy of the 

candidate vaccines against leprosy as such. Observed incidence rates were 

not sufficiently high to ascertain the protective efficacy of the candidate 

vaccines against progressive and serious forms of leprosy. BCG+ killed M. 

leprae provided 64% protection (CI 50.4-73.9), ICRC provided 65.5% 

protection (CI 48.0-77.0), M.w gave 25.7% protection (CI 1.9-43.8) and BCG 

gave 34.1% protection (CI 13.5-49.8). Protection observed with the ICRC 

vaccine and the combination vaccine (BCG+ killed M. leprae) meets the 

requirement of public health utility and these vaccines deserve further 

consideration for their ultimate applicability in leprosy prevention. 

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6.) Effectiveness of bacillus Calmette-Guerin (BCG) vaccination in the 

prevention of leprosy; a case-finding control study in Nagpur, India. 

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Int J Lepr Other Mycobact Dis 1998 Sep;66(3):309-15 

Zodpey SP, Shrikhande SN, Salodkar AD, Maldhure BR, Kulkarni SW 

Clinical Epidemiology Unit, Government Medical College, Nagpur, India. 

A hospital-based, pair-matched, casecontrol study was carried out at 

Government Medical College Hospital in Nagpur in central India to estimate 

the effectiveness of BCG vaccination in the prevention of leprosy. The 

study included 314 incidence cases of leprosy [diagnosed by World Health 

Organization (WHO) criteria] below the age of 32 years. Each case was pair 

matched with one control for age, sex and socioeconomic status. Controls 

were selected from subjects attending this hospital for conditions other 

than tuberculosis and leprosy. A significant protective association between 

BCG and leprosy was observed (OR 0.29, 95% CI 0.21-0.41). The vaccine 

effectiveness (VE) was estimated to be 71% (95% CI 59-79). The BCG 

effectiveness against multibacillary and paucibacillary leprosy was 79% 

(95% CI 60-89) and 67% (95% CI 45-78), respectively. It was more effective 

during the first decade of life (VE 74%; 95% CI 38-90), among females (VE 

82%; 95% CI 64-90), and in the lower socioeconomic strata (VE 75%; 95% CI 

32-92). The prevented fraction was calculated to be 51% (95% CI 38-62). In 

conclusion, this study has identified a beneficial role of BCG vaccination 

in the prevention of leprosy in central India. 

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7.) Effectiveness of Bacillus Calmette Guerin (BCG) vaccination in the 

prevention of childhood pulmonary tuberculosis: a case control study in 

Nagpur, India. 

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Southeast Asian J Trop Med Public Health 1998 Jun;29(2):285-8 

Zodpey SP, Shrikhande SN, Maldhure BR, Vasudeo ND, Kulkarni SW 

Department of Preventive and Social Medicine, Government Medical College, 

Nagpur, India. 

A hospital-based, pair matched, case control study was carried out to 

estimate the effectiveness of BCG vaccination in the prevention of 

childhood pulmonary tuberculosis. The study included 126 incident cases of 

pulmonary tuberculosis (diagnosed by WHO criteria) below/equal the age of 

12 years. Each case was pair matched with one control for age, sex, 

socio-economic status. Controls were selected from subjects attending study 

hospital for conditions other than tuberculosis and leprosy. The 

significant protective association between BCG and childhood pulmonary 

tuberculosis was observed (OR = 0.39, 95% CI = 0.22, 0.68). The overall 

vaccine effectiveness was 61% (95% CI = 32%, 78%). BCG was nonsignificantly 

more effective in underfives, among males and in upper-middle socioeconomic 

strata. The overall prevented fraction was estimated to be 47.53% (95% CI = 

21.41%, 67.25%). Results of this study thus demonstrated a moderate 

effectiveness of BCG vaccination in prevention of childhood pulmonary 

tuberculosis in a Central India population. 

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8.) Tuberculin sensitivity and skin lesions in children after vaccination with 

two batches of BCG vaccine. 

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Indian J Lepr 1998 Jul-Sep;70(3):277-86 

Vallishayee RS, Anantharaman DS, Gupte MD 

CJIL Field Unit (ICMR), Avadi, Chennai. 

BCG is one of the vaccines used, as control arm, in an ongoing large scale 

comparative leprosy vaccine trial in South India. The objective of the 

present study was to examine, in the local population, the sensitizing 

ability, as measured by skin test reactions to tuberculin, and 

reactogenecity, in terms of skin lesions at the site of vaccination, for 

the two batches of BCG vaccine used in the above trial. The study was 

undertaken in 816 tuberculin-negative, previously not vaccinated school 

children, aged five to 14 years. Each child received one of the two batches 

of BCG vaccine or normal saline (control), by random allocation. At 12 

weeks from vaccination, character and size of local response, at the 

vaccination site, were recorded. At the same time, the children were 

retested with tuberculin and post-vaccination reactions to the test were 

measured after 72 hours. At three years after vaccination all available 

children were re-examined for the presence and size of BCG scar at the site 

of vaccination. It was found that healing of vaccination lesions was 

uneventful, with both batches of BCG. The mean size of the lesion was 

similar for the two batches, the overall mean being 6.3 mm. The mean size 

of post-vaccination tuberculin sensitivity increased with age, and it was 

14.5 mm and 15.6 mm. The sensitizing effect attributable to the vaccine was 

11 mm and 12 mm, for the two batches of BCG respectively. This study showed 

that the two batches of BCG, in a dose of 0.1 mg, used in the ongoing 

leprosy vaccine trial were acceptable in terms of vaccination lesion and 

were highly satisfactory in terms of development of hypersensitivity. 

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9.) Leprosy vaccine: influence of dissolved oxygen levels on growth of a 

candidate strain (Mycobacterium w), and storage stability of the vaccine. 

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Vaccine 1998 Aug;16(13):1344-8 

Mukhopadhyay A, Panda AK, Pandey AK 

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India. 

ashok@nii.ernet.in 

The growth of Mycobacterium w, a candidate strain for leprosy vaccine in 

submerged culture, was inhibited by the presence of over 40% oxygen 

saturation in the medium. Intracellular levels of superoxide dismutase and 

catalase were very low in the beginning. However, under controlled 

oxygenation, these levels increased with time. The augmentations of these 

antioxidant enzymes were associated with the elevated oxygen consumption by 

the culture. By maintaining the oxygen level below 20% during 6-day 

culture, it was possible to grow Mycobacterium w in five production batches 

up to a cell density of 3.7 +/- 0.70 x 10(9) bacilli ml-1. The shelf life 

of the vaccine produced in different batches was more than 2 years, both at 

4 degrees C and at 26 degrees C. This provides a cost-effective, unit 

culture technology for the production of this candidate leprosy vaccine 

from a nonpathogenic organism, which will facilitate the widespread use of 

the vaccine. 

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10.) Studies of vaccination of persons in close contact with leprosy patients in 

Argentina. 

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Vaccine 1998 Jul;16(11-12):1166-71 

Bottasso O, Merlin V, Cannon L, Cannon H, Ingledew N, Keni M, Hartopp R, 

Stanford C, Stanford J 

Instituto de Inmunologia, Facultad de Ciencias Medicas, Universidad 

Nacional de Rosario, Argentina. 

A total of 670 adults living or working with leprosy patients, were 

examined for a BCG vaccination scar, and skin-tested with four new 

tuberculins. Based on the results 513 were vaccinated, 65 with Bacille de 

Calmette et Guerin (BCG) alone, 66 with BCG plus killed Mycobacterium 

vaccae and 382 with killed M. vaccae alone. Skin-testing was repeated 2-3 

years later on 344 subjects, when all three vaccines were found to have 

been highly successful in increasing responses to Tuberculin and Leprosin A 

(p < 0.0005) with increased immune recognition of common and 

species-specific antigens. Mean diameters of induration to each skin-test 

were greatest in recipients of BCG alone (p < 0.05), which suggests that 

better immuno-regulation occurs after receiving vaccines that incorporate 

M. vaccae. The results suggest 10(8) M. vaccae alone might prove a valuable 

future vaccine, which would not require selective pre-vaccination procedures. 

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11.) Why relapse occurs in PB leprosy patients after adequate MDT despite they 

are Mitsuda reactive: lessons form Convit's experiment on bacteria-clearing 

capacity of lepromin-induced granuloma. 

===================================================================== 

Int J Lepr Other Mycobact Dis 1998 Jun;66(2):182-9 

Chaudhuri S, Hajra SK, Mukherjee A, Saha B, Mazumder B, Chattapadhya D, Saha K 

Department of Leprosy, School of Tropical Medicine, Calcutta, India. 

It is amazing how after years of scientific research and therapeutic 

progress many simple and basic questions about protective immunity against 

Mycobacterium leprae remain unanswered. Although the World Health 

Organization (WHO) has recommended short-term multidrug therapy (WHO/MDT) 

for the treatment of paucibacillary (PB) leprosy patients, from time to 

time several workers from different parts of the globe have reported 

inadequate clinical responses in a few tuberculoid and indeterminate 

leprosy patients following adequate WHO/MDT despite the fact that they are 

Mitsuda responsive. A few borderline tuberculoid patients harbor acid-fast 

bacilli (AFB) in their nerves for many years even though they become 

clinically inactive following MDT, a fact which has been ignored by many 

leprosy field workers. Keeping these patients in mind, we have attempted to 

investigate the cause of the persistence of AFB in PB cases and have looked 

into the question of why Mitsuda positivity in tuberculoid and 

indeterminate leprosy patients, as well as in healthy contacts, is not 

invariably a guarantee for protectivity against the leprosy bacilli. We 

have: a) analyzed the histological features of lepromin-induced granulomas, 

b) studied the bacteria-clearing capacity of the macrophages within such 

granulomas, and c) studied the in vitro leukocyte migration inhibition 

factor released by the blood leukocytes of these subjects when M. leprae 

sonicates have been used as an elicitor. The results of these three tests 

in the three groups of subjects have been compared and led us to conclude 

that the bacteria-clearing capacity of the macrophages within 

lepromin-induced granuloma (positive CCB test) may be taken as an indicator 

of the capability of elimination of leprosy bacilli and protective immunity 

against the disease. This important macrophage function is not invariably 

present in all tuberculoid and indeterminate leprosy patients or in all 

contacts even though they are Mitsuda responsive and are able to show a 

positive leukocyte migration inhibition (LMI) test. It is likely but not 

certain that this deficit of the macrophage is genetically predetermined 

and persists after completion of short-term WHO/MDT. Thus, after 

discontinuation of treatment slow-growing, persisting M. leprae multiply 

within macrophages leading to relapse. 

===================================================================== 

12.) BCG vaccination protects against leprosy in Venezuela: a case-control study. 

===================================================================== 

Int J Lepr Other Mycobact Dis 1993 Jun;61(2):185-91 

Convit J, Smith PG, Zuniga M, Sampson C, Ulrich M, Plata JA, Silva J, 

Molina J, Salgado A 

Instituto de Biomedicina, Caracas, Venezuela. 

A total of 64,570 household and other close contacts of about 2000 leprosy 

cases were screened for eligibility for entry into a trial of a new leprosy 

vaccine. The screening procedure included a clinical examination for 

leprosy and for the presence of BCG and lepromin scars. Ninety-five new 

cases of leprosy were identified, and the prevalence of BCG and lepromin 

scars among them was compared with similar data from matched controls 

selected from among those with no evidence of leprosy. The difference in 

the prevalence of BCG scars in the two groups was used to estimate the 

protection against leprosy conferred by BCG vaccination. One or more BCG 

scars was associated with a protective efficacy of 56% (95% confidence 

limits 27% to 74%). There was a trend of increasing protection with four or 

more BCG scars, but this was not statistically significant. There was no 

evidence that the efficacy of BCG varied with age or according to whether 

or not the contact lived in the same household as a case. The protective 

effect was significantly higher among males, and was significantly greater 

for multibacillary than for paucibacillary leprosy. 

===================================================================== 

13.) Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine 

against leprosy: preliminary results. 

===================================================================== 

Lancet 1992 Feb 22;339(8791):446-50 

Convit J, Sampson C, Zuniga M, Smith PG, Plata J, Silva J, Molina J, 

Pinardi ME, Bloom BR, Salgado A 

Instituto de Biomedicina, Caracas, Venezuela. 

In an attempt to find a vaccine that gives greater and more consistent 

protection against leprosy than BCG vaccine, we compared BCG with and 

without killed Mycobacterium leprae in Venezuela. Close contacts of 

prevalent leprosy cases were selected as the trial population since they 

are at greatest risk of leprosy. Since 1983, 29,113 contacts have been 

randomly allocated vaccination with BCG alone or BCG plus 6 x 10(8) 

irradiated, autoclaved M leprae purified from the tissues of infected 

armadillos. We excluded contacts with signs of leprosy at screening and a 

proportion of those whose skin-test responses to M leprae soluble antigen 

(MLSA) were 10 mm or more (positive reactions). By July, 1991, 59 

postvaccination cases of leprosy had been confirmed in 150,026 person-years 

of follow-up through annual clinical examinations of the trial population 

(31 BCG, 28 BCG/M leprae). In the subgroup for which we thought an effect 

of vaccination was most likely (onset more than a year after vaccination, 

negative MLSA skin-test response before vaccination), leprosy developed in 

11 BCG recipients and 9 BCG/M leprae recipients; there were 18% fewer cases 

(upper 95% confidence limit [CL] 70%) in the BCG/M leprae than in the BCG 

alone group. For all cases with onset more than a year after vaccination 

irrespective of MLSA reaction the relative efficacy was 0% (upper 95% CL 

54%; 15 cases in each vaccine group). Retrospective analysis of data on the 

number of BCG scars found on each contact screened suggested that BCG alone 

confers substantial protection against leprosy (vaccine efficacy 56%, 95% 

CL 27-74%) and there was a suggestion that several doses of BCG offered 

additional protection. There is no evidence in the first 5 years of 

follow-up of this trial that BCG plus M leprae offers substantially better 

protection against leprosy than does BCG alone, but the confidence interval 

on the relative efficacy estimate is wide. 

===================================================================== 

14.) IgM antibodies to native phenolic glycolipid-I in contacts of leprosy 

patients in Venezuela: epidemiological observations and a prospective study 

of the risk of leprosy. 

===================================================================== 

Int J Lepr Other Mycobact Dis 1991 Sep;59(3):405-15 

Ulrich M, Smith PG, Sampson C, Zuniga M, Centeno M, Garcia V, Manrique X, 

Salgado A, Convit J 

Instituto de Biomedicina, Caracas, Venezuela. 

In a randomized, double-blind vaccine trial in Venezuela, about 29,000 

contacts of leprosy patients have been vaccinated with either a mixture of 

heat-killed Mycobacterium leprae and BCG or BCG alone, and are being 

re-surveyed annually to detect new cases of leprosy. All contacts had a 

serum sample collected at the time of entry into the trial, and 13,020 of 

these sera have been analyzed for antibodies to phenolic glycolipid-I 

(PGL-I). Antibody levels have been related to various characteristics of 

the contacts and to their risk of developing leprosy in the following 4 

years. A strong association was found between PGL-I antibody level and the 

risk of developing leprosy, in spite of possible modification of the 

incidence rate induced by vaccination. Antibody levels were higher in 

females than in males, and declined progressively with age. Household 

contacts had higher levels than did non-household contacts, and levels were 

higher in individuals from the state in Venezuela which has the highest 

incidence of the disease. No substantial differences were found in antibody 

levels between contacts of multibacillary and paucibacillary patients, 

which may in part reflect the influence of treatment, and there was no 

clear association with the presence of BCG or lepromin scars or with 

skin-test responses to PPD and leprosy soluble antigen. The assay of 

antibodies to PGL-I seems unlikely to provide a sensitive or specific test 

for infection with M. leprae, and measuring PGL-I antibody levels as a 

screening procedure to identify those at high risk of developing leprosy is 

unlikely to be particularly useful in most leprosy control programs. Such 

assays may be useful for the epidemiological monitoring of changes in the 

intensity of infection with M. leprae in a community and for the study of 

carefully defined groups of contacts during some phases of control programs. 

===================================================================== 

15.) Immunological changes observed in indeterminate and lepromatous leprosy 

patients and Mitsuda-negative contacts after the inoculation of a mixture 

of Mycobacterium leprae and BCG. 

===================================================================== 

Clin Exp Immunol 1979 May;36(2):214-20 

Convit J, Aranzazu N, Pinardi M, Ulrich M 

This investigation was carried out to study the possibility of eliciting 

favourable immunological changes in small groups of Mitsuda-negative 

patients with indeterminate leprosy, lepromatous patients who were 

bacteriologically negative after prolonged treatment with sulphones, and in 

Mitsuda-negative contacts by means of stimulation with a mixture of 

autoclaved tissues from Mycobacterium leprae-infected armadillos and living 

BCG. A radical change was observed in the specific immunological activity 

of the indeterminate group, all of whom initially had occasional bacilli in 

cutaneous nerves in biopsies taken from hypopigmented spots, and in the 

persistently Mitsuda-negative contacts. The 48 hr and 30 day reactions to 

lepromin, the 48 hr reaction to supernatant antigen from lepromin, the test 

for bacillary clearence and in vitro lymphocyte transformation (LTT) to M. 

leprae from human and armadillo lesions all became positive. Of the 

lepromatous patients studied, only one became positive to all the criteria 

mentioned above. In the others, the 48 hr reaction to supernatant antigen, 

the LTT to antigen from a humn source, and the clearance test remained 

negative, while the Fernandez and Mitsuda reactions became positive. These 

results are discussed in terms of the possible use of this stimulation 

procedure in the prevention and immunotherapy of leprosy. 

===================================================================== 

16.) Comparative study of the 48-hour response to soluble antigens obtained from 

human and armadillo leprosy material in lepromatous leprosy patients and 

normal persons, contacts of leprosy patients. 

===================================================================== 

Int J Lepr Other Mycobact Dis 1976 Jan-Jun;44(1-2):284-6 

Convit J, Pinardi ME, Aranzazu N 

We prepared antigens by precipitating with 80% ammonium sulfate 

supernatants of human and armadillo antigen at a concentration of 160 X 

10(6) bacteria per ml. The precipitate was resuspended, dialyzed and 

filtered. The antigen obtained was inactivated with trypsin during 30 

minutes. The tests made with these antigens were negative for the 48-hour 

test in lepromatous patients and highly positive in normal persons who were 

contacts of leprosy patients. 

===================================================================== 

17.) Association of HLA specificity LB-E12 (MB1, DC1, MT1) with lepromatous 

leprosy in a Venezuelan population. 

===================================================================== 

Tissue Antigens 1984 Jul;24(1):25-9 

Ottenhoff TH, Gonzalez NM, de Vries RR, Convit J, van Rood JJ 

To investigate whether an association could be found between HLA and 

lepromatous leprosy a population study was performed in Tachira, Venezuela. 

This was done in the same endemic area in which recently both non-random 

parental HLA-haplotype and preferential segregation of the HLA specificity 

LB-E12 (MB1, DC1, MT1) was demonstrated in lepromatous leprosy patients 

from multicase families. In this study 32 lepromatous patients and 32 

healthy controls were typed for HLA-A, -B, -C, -DR and the specificities MB 

and MT. The frequency of LB-E12 (MB1, DC1, MT1) showed a significant 

increase in lepromatous leprosy patients (p = 0.04). This is the first 

report concerning HLA and leprosy which confirms in the same endemic area 

an association observed in families on the population level. 

===================================================================== 

18.) Immunotherapy with a mixture of Mycobacterium leprae and BCG in different 

forms of leprosy and in Mitsuda-negative contacts. 

===================================================================== 

Int J Lepr Other Mycobact Dis 1982 Dec;50(4):415-24 

Convit J, Aranzazu N, Ulrich M, Pinardi ME, Reyes O, Alvarado J 

A total of 529 weak or non-reactors to M. leprae, including 

Mitsuda-negative contacts and patients with leprosy, were vaccinated once 

or repeatedly, as necessary, with a mixture of 6 x 10(8) purified, 

heat-killed M. leprae and 0.01 mg to 0.2 mg of viable BCG. Clinical, 

histopathological and immunological criteria were used to evaluate the 

response of these individuals. Clinical changes, including sharper 

definition of borders and progressive flattening and regression of lesions, 

were observed in 57% of the active LL cases and 76% of the active BL cases. 

Histopathological study revealed infiltration of the lesions by mononuclear 

cells, appearance of epithelioid differentiation, and fragmentation of the 

microorganisms. Delayed-type skin tests with soluble antigen from purified 

M. leprae became positive in significant numbers of each group studied. 

These results demonstrate the efficacy of combined immunotherapy in 

low-resistance forms of leprosy and potential utility in the 

immunoprophylaxis of the disease. 

===================================================================== 

19.) A 35-kilodalton protein is a major target of the human immune response to 

Mycobacterium leprae. 

===================================================================== 

Author 

Triccas JA; Roche PW; Winter N; Feng CG; Butlin CR; Britton WJ 

Address 

Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South 

Wales, Australia. 

Source 

Infect Immun, 64(12):5171-7 1996 Dec 

Abstract 

The control of leprosy will be facilitated by the identification of major 

Mycobacterium leprae-specific antigens which mirror the immune response to 

the organism across the leprosy spectrum. We have investigated the host 

response to a 35-kDa protein of M. leprae. Recombinant 35-kDa protein 

purified from Mycobacterium smegmatis resembled the native antigen in the 

formation of multimeric complexes and binding by monoclonal antibodies and 

sera from leprosy patients. These properties were not shared by two forms 

of 35-kDa protein purified from Escherichia coli. The M. smegmatis-derived 

35-kDa protein stimulated a gamma interferon-secreting T-cell proliferative 

response in the majority of paucibacillary leprosy patients and healthy 

contacts of leprosy patients tested. Cellular responses to the protein in 

patients with multibacillary leprosy were weak or absent, consistent with 

hyporesponsiveness to M. leprae characteristic of this form of the disease. 

Almost all leprosy patients and contacts recognized the 35-kDa protein by 

either a T-cell proliferative or an immunoglobulin G antibody response, 

whereas few tuberculosis patients recognized the antigen. This specificity 

was confirmed in guinea pigs, with the 35-kDa protein eliciting strong 

delayed-type hypersensitivity in M. leprae-sensitized animals but not in 

those sensitized with Mycobacterium tuberculosis or Mycobacterium bovis 

BCG. Therefore, the M. leprae 35-kDa protein appears to be a major and 

relatively specific target of the human immune response to M. leprae and is 

a potential component of a diagnostic test to detect exposure to leprosy or 

a vaccine to combat the disease. 

===================================================================== 

20.) Immunogenicity and protection studies with recombinant mycobacteria and 

vaccinia vectors coexpressing the 18-kilodalton protein of Mycobacterium 

leprae. 

===================================================================== 

Author 

Baumgart KW; McKenzie KR; Radford AJ; Ramshaw I; Britton WJ 

Address 

Centenary Institute of Cancer Medicine and Cell Biology, University of 

Sydney, Newtown, New South Wales, Australia. 

Source 

Infect Immun, 64(6):2274-81 1996 Jun 

Abstract 

The activation of antigen-specific T lymphocytes is essential for the 

control of leprosy infection in humans and experimental animals. T cells 

recognize a variety of protein antigens from Mycobacterium leprae, 

including the 18-kDa protein, which is limited in distribution among 

mycobacteria and which is absent from Mycobacterium tuberculosis and the 

vaccine strain, Mycobacterium bovis BCG. Adjuvant preparations of 

mycobacterial protein antigens have had limited protective efficacy for 

experimental infections in animals. Since recombinant vectors may elicit 

more effective T-cell responses than adjuvant preparations, recombinant 

vaccinia virus (VV18) and M. bovis BCG (BCG18) vectors expressing the 

18-kDa protein of M. leprae were prepared. Both VV18 and BCG18 stimulated 

anti-18-kDa protein antibody and lymphocyte proliferative responses. 

Sequential immunization with VV18 followed by BCG18 induced higher levels 

of specific immunoglobulin G2a antibodies than immunoglobulin G1 

antibodies, in contrast to immunization with VV18 or BCG18 alone. The 

protective efficacy of immunization with VV18 from a challenge with BCG18 

was examined in two murine models of mycobacterial infection. After 

intravenous challenge, mice immunized with recombinant vaccinia virus 

exhibited lower initial levels of replication and earlier clearance of 

BCG18 from their spleens than mice immunized with vaccinia virus expressing 

an unrelated protein. After footpad infection in a dissemination model, 

there was earlier clearance of BCG18 from specifically immunized mice. 

However, immunization of mice with VV18 did not prevent a productive 

mycobacterial infection. 

===================================================================== 

21.) Mycobacterial infections: are the observed enigmas and paradoxes explained 

by immunosuppression and immunodeficiency? 

===================================================================== 

Author 

Maes HH; Causse JE; Maes RF 

Address 

Microbiology and Genetics Unit, University of Louvain Medical School, 

Brussels, Belgium. 

Source 

Med Hypotheses, 46(2):163-71 1996 Feb 

Abstract 

The enigmas and paradoxes observed in tuberculous patients, in Bacille 

Calmette-Gu&acute;erin-vaccinated people and in Bacille Calmette-Gu&acute;erin-treated 

cancer patients have been examined, in an attempt to explain them through 

the mechanisms of immunodeficiency and immunosuppression. A dual effect is 

postulated: an immunosuppression induced by the infecting mycobacteria that 

adds to a pre-existing or emerging state of immunodeficiency of the 

infected individual. The immunological cellular and humoral anergies 

observed at the beginning of a tuberculous therapy are usually lifted after 

the first two weeks of treatment. This restoration of immune responsiveness 

may be attributed to the destruction or to the growth inhibition of 

immunosuppressive mycobacteria. The observation that drugs cytocidal in 

vitro do not always sterilize the patients under treatment whereas 

bacteriostatic drugs do, may find an explanation in the dual 

immunosuppression induced by cytocidal drugs and mycobacteria. The fact 

that Bacille Calmette-Gu&acute;erin applied as an immunotherapy to residual 

cancer has either a favorable or an unfavorable action may be due to the 

immunosuppressive activity attached to some Bacille Calmette-Gu&acute;erin 

strains and to some cancers. The variable protective activity of Bacille 

Calmette-Gu&acute;erin vaccines may be due to the immunological status of the 

vaccinated people and the compositional differences between strains. The 

protective activity of subunit vaccines in experimental models can be 

attributed to the elimination of immunosuppressive factors present in whole 

killed mycobacteria. 

===================================================================== 

22.) Leprosy patients with lepromatous disease recognize cross-reactive T cell 

epitopes in the Mycobacterium leprae 10-kD antigen. 

===================================================================== 

Author 

Hussain R; Dockrell HM; Shahid F; Zafar S; Chiang TJ 

Address 

Department of Microbiology, The Aga Khan University, Karachi, Pakistan. 

Source 

Clin Exp Immunol, 114(2):204-9 1998 Nov 

Abstract 

T cell responses play a critical role in determining protective responses 

to leprosy. Patients with self-limiting tuberculoid leprosy show high T 

cell reactivity, while patients with disseminated lepromatous form of the 

disease show absent to low levels of T cell reactivity. Since the T cell 

reactivity of lepromatous patients to purified protein derivative (PPD), a 

highly cross-reactive antigen, is similar to that of tuberculoid patients, 

we queried if lepromatous patients could recognize cross-reactive epitopes 

in Mycobacterium leprae antigens as well. T cell responses were analysed to 

a recombinant antigen 10-kD (a heat shock cognate protein) which is 

available from both M. tuberculosis (MT) and M. leprae (ML) and displays 

90% identity in its amino acid sequence. Lymphoproliferative responses were 

assessed to ML and MT 10 kD in newly diagnosed leprosy patients 

(lepromatous, n = 23; tuberculoid, n = 65). Lepromatous patients showed 

similar, but low, lymphoproliferative responses to ML and MT 10 kD, while 

tuberculoid patients showed much higher responses to ML 10 kD. This 

suggests that the tuberculoid patients may be recognizing both 

species-specific and cross-reactive epitopes in ML 10 kD, while lepromatous 

patients may be recognizing only cross-reactive epitopes. This was further 

supported by linear regression analysis. Lepromatous patients showed a high 

concordance in T cell responses between ML and MT 10 kD (r=0.658; P<0.0006) 

not observed in tuberculoid patients (r=0.203; P>0.1). Identification of 

cross-reactive T cell epitopes in M. leprae which could induce protective 

responses should prove valuable in designing second generation 

peptide-based vaccines. 

===================================================================== 

23.) [BCG vaccination to Mycobacterium leprae infection in mice] 

===================================================================== 

Author 

Nomaguchi H; Yogi Y; Matsuoka M; Fukotomi Y; Okamura H; Nagata K; Nagai S; 

Ohara N; Yamada T 

Address 

National Institute for Leprosy Research. 

Source 

Nippon Rai Gakkai Zasshi, 65(2):106-12 1996 Jul 

Abstract 

BCG vaccine (Tokyo strain) was given in BALB/cA mice intradermally 1 or 3 

months before Mycobacterium leprae (M. leprae) challenge as modified 

Shepard's method. The vaccine dosage was 10(7-8) or 10(6). The BCG gave 

good protection in both dosages and both challenges against M. leprae 

infection. Lymphocytes proliferations of BCG-vaccinated splenocyte cultures 

in response to M. leprae lysate or BCG components (hsp65, 38 kD, 30 kD or 

12 kD protein) were tested, and potent proliferative responses were seen in 

the cultures with M. leprae lysate and hsp65. Furthermore, gamma-IFN 

productions were positive in the cultures with M. leprae lysate or hsp65, 

but negative with other antigens. The production of gamma-IFN with hsp65 

was never inhibited with polymyxin B, but inhibited with IL-10. These 

results show that BCG (Tokyo strain) is a useful vaccine for M. leprae 

infection in mice, and one of the components of BCG, hsp65, may be a 

effective antigen component for protection of M. leprae infection inducing 

Th1 type cytokine. 

===================================================================== 

24.) Human leukocyte antigens in tuberculosis and leprosy. 

===================================================================== 

Author 

Meyer CG; May J; Stark K 

Address 

Institute for Tropical Medicine, Berlin, Germany. cgmeyer@ukrv.de 

Source 

Trends Microbiol, 6(4):148-54 1998 Apr 

Abstract 

Human mycobacterial infections are characterized by a spectrum of clinical 

and immunological manifestations. Specific human leukocyte antigen (HLA) 

factors are associated with the subtypes of leprosy that develop and the 

course of tuberculosis after infection. The identification of protective 

mycobacterial antigens presented by a broad variety of HLA molecules will 

have important implications for the design of vaccines. 

===================================================================== 

25.) Modulation of protective and pathological immunity in mycobacterial 

infections. 

===================================================================== 

Author 

Ottenhoff TH; Spierings E; Nibbering PH; de Jong R 

Address 

Department of Immunohematology and Blood Bank, University Hospital, Leiden, 

The Netherlands. ihbsecr@euronet.nl 

Source 

Int Arch Allergy Immunol, 113(4):400-8 1997 Aug 

Abstract 

Mycobacterial infections represent major problems to global health care. 

Tuberculosis is feared particularly because of its high mortality rates 

whereas in leprosy the occurrence of immunopathology, particularly nerve 

damage, is a major problem since the bacillus itself is relatively 

harmless. Thus, both effective vaccination strategies as well as novel 

immunomodulating regimens are warranted for the control of morbidity and 

mortality in mycobacterial diseases. Since CD4+ Th1 cells and type-1 

cytokines play a key role both in protective immunity and immunopathology 

in mycobacterial infections, we here describe new pharmacological and 

cytokine-based strategies to regulate Th1 immunity. 

===================================================================== 

26.) IL-2 and IL-12 act in synergy to overcome antigen-specific T cell 

unresponsiveness in mycobacterial disease. 

===================================================================== 

Author 

de Jong R; Janson AA; Faber WR; Naafs B; Ottenhoff TH 

Address 

Department of Immunohematology & Bloodbank, University Hospital Leiden, The 

Netherlands. 

Source 

J Immunol, 159(2):786-93 1997 Jul 15 

Abstract 

IL-12 secretion by APC is critical for the development of protective 

Th1-type responses in mycobacterial (Mycobacterium avium and Mycobacterium 

tuberculosis) infections in mice. We have studied the role of IL-12 and 

IL-2 in the generation of Mycobacterium leprae-specific T cell responses in 

humans. Leprosy patients were defined as low/nonresponders or high 

responders based on the level of T cell proliferation in M. 

leprae-stimulated PBMC. In high responders, M. leprae-induced proliferation 

was markedly suppressed by neutralizing anti-IL-12 mAb (inhibition 55 +/- 

6%). Neutralization of IL-2 activity resulted in an inhibition of 77 +/- 

4%. Given the importance of endogenous IL-2 and IL-12 in M. leprae-induced 

responses, we investigated the ability of rIL-2 and rIL-12 to reverse T 

cell unresponsiveness in low/nonresponder patients. Interestingly, rIL-12 

and rIL-2 strongly synergized in restoring both M. leprae-specific T cell 

proliferation and IFN-gamma secretion almost completely to the level of 

responder patients. A similar synergy between rIL-2 and rIL-12 was also 

observed in high responders when suboptimal M. leprae concentrations were 

used for T cell stimulation. Our data demonstrate a crucial role for 

endogenous IL-12 and IL-2 in M. leprae-induced T cell activation. Most 

importantly, we show that rIL-2 and rIL-12 act in synergy to overcome 

Ag-specific Th1 cell unresponsiveness. These findings may be applicable to 

the design of antimicrobial and antitumor vaccines. 

===================================================================== 

27.) Dharmendra antigen but not integral M. leprae is an efficient inducer of 

immunostimulant cytokine production by human monocytes, and M. leprae 

lipids inhibit the cytokine production. 

===================================================================== 

Author 

Nakamura C; Fukutomi Y; Kashiwabara Y; Oomoto Y; Kojima M; Hayashi H; 

Onozaki K 

Address 

Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, 

Nagoya City University, Japan. 

Source 

Int J Lepr Other Mycobact Dis, 65(1):63-72 1997 Mar 

Abstract 

Killed integral Mycobacterium leprae, Mitsuda antigen, and 

chloroform-treated M. leprae, Dharmendra antigen (Dh-Ag), have been used 

for the classification of leprosy patients based on cell-mediated immunity. 

Heat-killed M. leprae also were used as a component of the Convit vaccine. 

Human blood monocytes were stimulated with M. leprae or Dh-Ag and their 

cytokine-inducing ability was compared. Monocytes were cultured in the 

presence of fresh human serum because of the efficiency of cytokine 

induction and the phagocytosis of M. leprae have been shown to be optimal 

in the presence of fresh serum. M. leprae and Dh-Ag were equally 

phagocytosed by monocytes. Dh-Ag was more potent than M. leprae in the 

induction of immunostimulatory/proinflammatory cytokines, interleukin-1 

(IL-1), IL-6 and tumor necrosis factor (TNF). In contrast, a comparable 

level of IL-1ra, an immunosuppressive cytokine, was induced by M. leprae 

and Dh-Ag. The lipids extracted from M. leprae induced none of these 

cytokines by monocytes. Nevertheless, when monocytes were pretreated with 

the lipids followed by stimulation with Dh-Ag, productions of IL-1, IL-6 

and TNF were all inhibited in a dose-dependent manner. However, the lipids 

did not inhibit the cytokine production induced by other stimuli including 

BCG and lipopolysaccharide. Moreover the lipids did not affect the 

production of IL-1ra. These results suggest that the lipids from M. leprae 

are responsible for the poor cytokine-inducing ability of M. leprae, thus 

favoring their infection. These results also suggest that Dh-Ag rather than 

integral M. leprae may be useful as a vaccine candidate because Dh-Ag is 

able to induce a large amount of cytokines from monocytes. 

===================================================================== 

28.) Inhibition of multiplication of Mycobacterium leprae in mouse foot pads by 

immunization with ribosomal fraction and culture filtrate from 

Mycobacterium bovis BCG. 

===================================================================== 

Author 

Matsuoka M; Nomaguchi H; Yukitake H; Ohara N; Matsumoto S; Mise K; Yamada T 

Address 

National Institute for Leprosy Research, Tokyo, Japan. 

Source 

Vaccine, 15(11):1214-7 1997 Aug 

Abstract 

Immunization of mice with the ribosomal fraction from ruptured 

Mycobacterium bovis Bacillus Calmette-Gu&acute;erin (BCG) and the culture 

filtrate reduced remarkably the multiplication of Mycobacterium leprae in 

the foot pads of mice. This is the first reported case of the protective 

activity against M. leprae multiplication in mice of the BCG ribosomal 

fraction and culture filtrate. The inhibition was more evident with the 

culture filtrate than with the ribosomal fraction. When the ribosomal 

proteins separated from ribosomal RNA were injected into mice, only slight 

inhibition was observed. Ribosomal RNA alone did not inhibit at all, in 

contrast to the conclusion reported by Youmans and Youmans. 

===================================================================== 

29.) Techniques for genetic engineering in mycobacteria. Alternative host 

strains, DNA-transfer systems and vectors. 

===================================================================== 

Author 

Hermans J; de Bont JA 

Address 

Department of Food Science, Agricultural University, Wageningen, The 

Netherlands. 

Source 

Antonie Van Leeuwenhoek, 69(3):243-56 1996 Apr 

Abstract 

The study of mycobacterial genetics has experienced quick technical 

developments in the past ten years, despite a relatively slow start, caused 

by difficulties in accessing these recalcitrant species. The study of 

mycobacterial pathogenesis is important in the development of new ways of 

treating tuberculosis and leprosy, now that the emergence of 

antibiotic-resistant strains has reduced the effectiveness of current 

therapies. The tuberculosis vaccine strain M. bovis BCG might be used as a 

vector for multivalent vaccination. Also, non-pathogenic mycobacterial 

strains have many possible biotechnological applications. After giving a 

historical overview of methods and techniques, we will discuss recent 

developments in the search for alternative host strains and DNA transfer 

systems. Special attention will be given to the development of vectors and 

techniques for stabilizing foreign DNA in mycobacteria. 

===================================================================== 

30.) Leprosy vaccine: influence of dissolved oxygen levels on growth of a 

candidate strain (Mycobacterium w), and storage stability of the vaccine. 

===================================================================== 

Author 

Mukhopadhyay A; Panda AK; Pandey AK 

Address 

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India. 

ashok@nii.ernet.in 

Source 

Vaccine, 16(13):1344-8 1998 Aug 

Abstract 

The growth of Mycobacterium w, a candidate strain for leprosy vaccine in 

submerged culture, was inhibited by the presence of over 40% oxygen 

saturation in the medium. Intracellular levels of superoxide dismutase and 

catalase were very low in the beginning. However, under controlled 

oxygenation, these levels increased with time. The augmentations of these 

antioxidant enzymes were associated with the elevated oxygen consumption by 

the culture. By maintaining the oxygen level below 20% during 6-day 

culture, it was possible to grow Mycobacterium w in five production batches 

up to a cell density of 3.7 +/- 0.70 x 10(9) bacilli ml-1. The shelf life 

of the vaccine produced in different batches was more than 2 years, both at 

4 degrees C and at 26 degrees C. This provides a cost-effective, unit 

culture technology for the production of this candidate leprosy vaccine 

from a nonpathogenic organism, which will facilitate the widespread use of 

the vaccine. 

===================================================================== 

31.) Lymphostimulatory and delayed-type hypersensitivity responses to a 

candidate leprosy vaccine strain: Mycobacterium habana. 

===================================================================== 

Author 

Singh NB; Gupta HP; Srivastava A; Kandpal H; Srivastava UM 

Address 

Division of Microbiology, Central Drug Research Institute, Lucknow, India. 

Source 

Lepr Rev, 68(2):125-30 1997 Jun 

Abstract 

Lymphostimulatory and delayed-type hypersensitivity (DTH) immune responses 

to a candidate antileprosy vaccine Mycobacterium habana have been 

quantified in inbred AKR mice. M. habana vaccine in three physical states, 

live, heat-killed and gamma-irradiated, was given intradermally to separate 

groups of mice and after 28 days these mice were given subcutaneous 

challenge with heat-killed M. leprae and heat-killed M. habana in the left 

hind footpad. Live BCG vaccine alone and in combination with 

gamma-irradiated M. habana were also compared similarly. A sufficient 

degree of DTH response was generated in mice by M. habana vaccine in all 

physical forms against two challenge antigens (lepromin and habanin). The 

BCG combination with M. habana did not increase the DTH response indicating 

internal adjuvanticity endowed in M. habana. The active hypersensitivity of 

immunized mice was transferable to syngeneic mice by the transfer of 

sensitized cells from the donor to the recipient mice intravenously. M. 

leprae-infected Rhesus monkey PBMC have shown comparable stimulatory 

response with M. habana (sonicate), and M. leprae (sonicate) antigens. The 

possibility of developing M. habana as a candidate antileprosy vaccine is 

discussed. 

===================================================================== 

32.) Randomised controlled trial of single BCG, repeated BCG, or combined BCG 

and killed Mycobacterium leprae vaccine for prevention of leprosy and 

tuberculosis in Malawi. Karonga Prevention Trial Group [see comments] 

===================================================================== 

Source Lancet, 348(9019):17-24 1996 Jul 6 

Abstract 

BACKGROUND: Repeat BCG vaccination is standard practice in many countries 

for prevention of tuberculosis and leprosy, but its effectiveness has not 

been evaluated. The addition of Mycobacterium leprae antigens to BCG might 

improve its effectiveness against leprosy. A double-blind, randomised, 

controlled trial to evaluate both these procedures was carried out in 

Karonga District, northern Malawi, where a single BCG vaccine administered 

by routine health services had previously been found to afford greater than 

50% protection against leprosy, but no protection against tuberculosis. 

METHODS: Between 1986 and 1989, individuals lacking a BCG scar were 

randomly assigned BCG alone (27,904) or BCG plus killed M leprae (38,251). 

Individuals with a BCG scar were randomly allocated placebo (23,307), a 

second BCG (23,456), or BCG plus killed M leprae (8102). Incident cases of 

leprosy and tuberculosis were ascertained over the subsequent 5-9 years. 

FINDINGS: 139 cases of leprosy were identified by May, 1995; 93 of these 

were diagnostically certain, definitely postvaccination cases. Among 

scar-positive individuals, a second BCG vaccination gave further protection 

against leprosy (about 50%) over a first BCG vaccination. The rate ratio 

for all diagnostically certain, definitely postvaccination cases, all ages, 

was 0.51 (95% CI 0.25-1.03, p = 0.05) for BCG versus placebo. This benefit 

was apparent in all subgroups, although the greatest effect was among 

individuals vaccinated below 15 years of age (RR = 0.40 [95% CI 0.15-1.01], 

p = 0.05). The addition of killed M leprae did not improve the protection 

afforded by a primary BCG vaccination. The rate ratio for BCG plus killed M 

leprae versus BCG alone among scar-negative individuals was 1.06 

(0.62-1.82, p = 0.82) for all ages, though 0.37 (0.11-1.24, p = 0.09) for 

individuals vaccinated below 15 years of age. 376 cases of postvaccination 

pulmonary tuberculosis and 31 of glandular tuberculosis were ascertained by 

May, 1995. The rate of diagnostically certain tuberculosis was higher among 

scar-positive individuals who had received a second BCG (1.43 [0.88-2.35], 

p = 0.15) than among those who had received placebo and there was no 

evidence that any of the trial vaccines contributed to protection against 

pulmonary tuberculosis. INTERPRETATION: In a population in which a single 

BCG vaccination affords 50% or more protection against leprosy, but none 

against tuberculosis, a second vaccination can add appreciably to the 

protection against leprosy, without providing any protection against 

tuberculosis. 

===================================================================== 

33.) Immunotherapy of lepromin-negative borderline leprosy patients with 

low-dose Convit vaccine as an adjunct to multidrug therapy; a six-year 

follow-up study in Calcutta. 

===================================================================== 

Author 

Chaudhury S; Hajra SK; Mukerjee A; Saha B; Majumdar V; Chattapadhya D; Saha K 

Address 

School of Tropical Medicine, Calcutta, India. 

Source 

Int J Lepr Other Mycobact Dis, 65(1):56-62 1997 Mar 

Abstract 

The present report, which describes management of lepromin-negative 

borderline leprosy patients with low-dose Convit vaccine, is an extension 

of our earlier study on the treatment of lepromatous leprosy patients with 

low-dose Convit vaccine as an adjunct to multidrug therapy (MDT). The test 

Group I, consisting of 50 lepromin-negative, borderline leprosy patients, 

were given low-dose Convit vaccine plus MDT. The control group II consisted 

of 25 lepromin-negative, borderline leprosy patients given BCG vaccination 

plus MDT and 25 lepromin-negative, borderline leprosy patients given killed 

Mycobacterium leprae (human) vaccine plus MDT. The control group III 

consisted of 50 lepromin-positive, borderline leprosy patients not given 

any immunostimulation but given only MDT. Depending upon the lepromin 

unresponsiveness, the patients were given one to four inoculations of the 

various antileprosy vaccines and were followed up every 3 months for 2 

years for clinical, bacteriological and immunological outcome. All patients 

belonging to the test and control groups showed clinical cure and 

bacteriological negativity within 2 years. However, immunologic 

potentiation, assessed by lepromin testing and the leukocyte migration 

inhibition test (LMIT), was better in the test patients receiving low-dose 

Convit vaccine plus MDT than in the control patients receiving BCG vaccine 

plus MDT or killed M. leprae vaccine plus MDT or MDT alone. But the 

capacity of clearance bacteria (CCB) test from the lepromin granuloma 

showed poor bacterial clearance in the test patients. However, there was no 

relapse during 6 years of follow up. Two mid-borderline (BB) patients had 

severe reversal reactions with lagophthalmos and wrist drop during 

immunotherapy despite being given low-dose Convit vaccine. 

===================================================================== 

34.) A case-control study of the effectiveness of BCG vaccine for preventing 

leprosy in Yangon, Myanmar. 

===================================================================== 

Author 

Bertolli J; Pangi C; Frerichs R; Halloran ME 

Address 

Epidemiology Program Office, US Centers for Disease Control and Prevention, 

Atlanta, GA, USA. 

Source 

Int J Epidemiol, 26(4):888-96 1997 Aug 

Abstract 

BACKGROUND: Five randomized trials, a follow-up study, and six case-control 

investigations of BCG vaccine's effectiveness (VE) for preventing leprosy 

have been conducted internationally, with widely varying estimates of VE. 

Because of the difficulty of generalizing from disparate results, local 

estimates of VE are needed for health planning purposes and are currently 

particularly relevant, given the World Health Organization's (WHO) goal to 

eliminate leprosy by the year 2000. METHODS: We conducted a case-control 

study in Yangon, Myanmar. Residents of Yangon between the ages of 6 years 

and 24 years who were listed in the National Leprosy Registry as being on 

active treatment for leprosy between December 1992 and April 1993 were 

eligible to participate in the study as cases. Control subjects were 

matched to the cases on age, sex, and neighbourhood. RESULTS: One or more 

doses of BCG were associated with a VE of 66%. The results show a 

significant trend of increasing VE with increasing number of BCG doses (one 

dose, VE = 55%; two doses, VE = 68%; three doses, VE = 87%). One dose of 

BCG vaccine appeared to provide protection substantially higher than that 

found in an earlier vaccine trial in Myanmar, but consistent with results 

from case-control studies in other countries. CONCLUSIONS: These data 

suggest that BCG reduces the risk of leprosy in Myanmar, and that BCG 

vaccination of infants, along with early case-finding and treatment, should 

be considered an important part of the leprosy intervention strategy. 

===================================================================== 

35.) Immunotherapy of far-advanced lepromatous leprosy patients with low-dose 

convit vaccine along with multidrug therapy (Calcutta trial). 

===================================================================== 

Author 

Majumder V; Mukerjee A; Hajra SK; Saha B; Saha K 

Address 

School of Tropical Medicine, Calcutta, India. 

Source 

Int J Lepr Other Mycobact Dis, 64(1):26-36 1996 Mar 

Abstract 

This report describes a promising mode of treatment of 

lepromin-unresponsive, far-advanced, lepromatous (LL) leprosy patients with 

antileprosy vaccines as an adjunct to multidrug therapy (MDT). The Trial 

Groups included 50 highly bacilliferous, lepromin-negative, untreated LL 

patients. They were given MDT for 2 years. Of them, 30 patients were 

administered a mixed antileprosy vaccine containing killed Mycobacterium 

leprae of human origin plus M. bovis BCG. The remaining 20 patients were 

given M. bovis BCG. Depending on the severity of lepromin unresponsiveness, 

they were given one to six inoculations at 3-month intervals. Another 20 

similar LL patients were taken in the Control Group. They were given only 

MDT for 2 years. From the start of the study, all patients belonging to the 

Trial and Control Groups were followed every 3 months for clinical, 

bacteriological and immunological outcomes. Within 2 years all 50 patients 

of the Trial Groups and 19 of the 20 patients of the Control Group became 

clinically inactive and bacteriologically negative. However, the clinical 

cure and the falls of the bacterial and morphological indexes were much 

faster in those patients receiving the mixed vaccine therapy than in those 

patients who were given BCG plus MDT or only MDT. The immunological 

improvements in the patients of the Trial and Control Groups were assessed 

by: a) lepromin testing at the beginning of the study and at 3-month 

intervals and also by b) the in vitro leukocyte migration inhibition (LMI) 

test at both the beginning and end of the study. As the patients were given 

more and more vaccinations, the incidence of lepromin conversion increased, 

more so in the patients receiving the mixed vaccine. Thus, 63%, 15% and 5% 

of the patients became lepromin positive in those patients receiving the 

mixed vaccine, BCG, and MDT only, respectively. Lamentably, the 

vaccine-induced lepromin positivity was temporary and faded away within 

several months. At the beginning of the study, the LMI test against 

specific M. leprae antigen was negative in all patients of both the Trial 

and Control Groups. After the end of the chemo-immunotherapy schedule, the 

LMI test became positive in 50% and 20% of LL patients receiving the mixed 

vaccine and BCG, respectively. None of the Control Group could show LMI 

positivity after completion of the MDT schedule. These results show that 

treatment of LL patients with the mixed vaccine and MDT could quickly 

reverse the clinical course of the disease, remove immunologic anergy in 

some patients, and induce a rapid decrease in the bacterial load in them. 

===================================================================== 

36.) Protective immunization of monkeys with BCG or BCG plus heat-killed 

Mycobacterium leprae: clinical results. 

===================================================================== 

Author 

Gormus BJ; Baskin GB; Xu K; Bohm RP; Mack PA; Ratterree MS; Cho SN; Meyers 

WM; Walsh GP 

Address 

Department of Microbiology, Tulane Regional Primate Research Center, 

Covington, LA 70433, USA. 

Source 

Lepr Rev, 69(1):6-23 1998 Mar 

Abstract 

Rhesus and sooty mangabey monkeys (RM and SMM) were vaccinated and boosted 

with BCG or BCG + low dose (LD) or high dose (HD) heat-killed Mycobacterium 

leprae (HKML). One group was not vaccinated. Except for a group of 

controls, all monkeys were challenged with live M. leprae. All animals were 

studied longitudinally to determine antileprosy protective efficacy. BCG 

reduced the numbers of RM with histopathologically-diagnosed leprosy by 70% 

and slowed and ameliorated the appearance of symptoms. BCG + LDHKML reduced 

the number of RM with leprosy by 89% and BCG + HDHKML by 78%. BCG did not 

protect SMM from developing leprosy, but disease progress was slowed; 

disease in SMM was exacerbated by the addition of HKML to the vaccine. RM, 

as a species, are prone to paucibacillary (PB) forms of leprosy, whereas 

SMM are prone to multibacillary (MB) forms. Thus, BCG vaccination offers 

significant protection from clinical disease and slows/ameliorates the rate 

of progression/degree of disease at the PB end and appears to at least 

ameliorate symptoms at the MB end of the leprosy spectrum. BCG + HKML 

protects at the PB end and exacerbates disease progress at the MB end of 

the leprosy spectrum. 

===================================================================== 

37.) Studies of vaccination of persons in close contact with leprosy patients in 

Argentina. 

===================================================================== 

Author 

Bottasso O; Merlin V; Cannon L; Cannon H; Ingledew N; Keni M; Hartopp R; 

Stanford C; Stanford J 

Address 

Instituto de Inmunologia, Facultad de Ciencias Medicas, Universidad 

Nacional de Rosario, Argentina. 

Source 

Vaccine, 16(11-12):1166-71 1998 Jul 

Abstract 

A total of 670 adults living or working with leprosy patients, were 

examined for a BCG vaccination scar, and skin-tested with four new 

tuberculins. Based on the results 513 were vaccinated, 65 with Bacille de 

Calmette et Gu&acute;erin (BCG) alone, 66 with BCG plus killed Mycobacterium 

vaccae and 382 with killed M. vaccae alone. Skin-testing was repeated 2-3 

years later on 344 subjects, when all three vaccines were found to have 

been highly successful in increasing responses to Tuberculin and Leprosin A 

(p < 0.0005) with increased immune recognition of common and 

species-specific antigens. Mean diameters of induration to each skin-test 

were greatest in recipients of BCG alone (p < 0.05), which suggests that 

better immuno-regulation occurs after receiving vaccines that incorporate 

M. vaccae. The results suggest 10(8) M. vaccae alone might prove a valuable 

future vaccine, which would not require selective pre-vaccination procedures. 

===================================================================== 

38.) Restoration of proliferative response to M. leprae antigens in lepromatous 

T cells against candidate antileprosy vaccines. 

===================================================================== 

Author 

Mustafa AS 

Address 

Department of Microbiology, Faculty of Medicine, Kuwait University, Safat, 

Kuwait. 

Source 

Int J Lepr Other Mycobact Dis, 64(3):257-67 1996 Sep 

Abstract 

Several studies conducted in the last decade suggest that Mycobacterium 

lepraereactive T cells exist in lepromatous patients, but their number may 

be too few to yield a detectable response in cell-mediated immunity (CMI) 

assays. Immunizations with candidate antileprosy vaccines and stimulation 

of T cells with M. leprae + interleukin-2 restore the M. leprae-induced CMI 

response in lepromatous leprosy patients. These immunizations and 

stimulation may enrich the pre-existing M. leprae-responsive T cells in 

lepromatous patients and, thereby, induce a detectable CMI response to M. 

leprae antigens upon repeat testing. To verify this proposition, we carried 

out a study in a group of 10 lepromatous leprosy patients. Peripheral blood 

mononuclear cells (PBMC) obtained from these patients were anergic to M. 

leprae antigens in proliferative assays, but they responded to the antigens 

of candidate antileprosy vaccines, i.e., M. bovis BCG, M. bovis BCG + M. 

leprae, and Mycobacterium w. The enrichment of M. leprae-responsive T cells 

was performed by establishing T-cell lines from the PBMC after in vitro 

stimulation with M. leprae, M. bovis BCG, M. bovis BCG + M. leprae, and 

Mycobacterium w. When tested for their proliferative responses, 1/10, 3/10, 

6/10 and 2/10 T-cell lines established against M. leprae, M. bovis BCG, M. 

bovis BCG + M. leprae, and Mycobacterium w, respectively, responded to M. 

leprae. These results suggest that enrichment of pre-existing M. 

leprae-responsive T cells may contribute to the restoration of the T-cell 

response to M. leprae in some lepromatous patients. Four of the 10 M. 

leprae-induced T-cell lines proliferated in response to the 65 kDa, 36 kDa, 

28 kDa, and 12 kDa recombinant antigens of M. leprae, suggesting that the 

nonresponsiveness of T cells in some lepromatous patients may be overcome 

by using recombinant antigens of M. leprae. 

===================================================================== 

39.) Does bacille Calmette-Gu&acute;erin scar size have implications for protection 

against tuberculosis or leprosy? 

===================================================================== 

Author 

Sterne JA; Fine PE; P&uml;onnighaus JM; Sibanda F; Munthali M; Glynn JR 

Address 

Communicable Disease Epidemiology Unit, London School of Hygiene and 

Tropical Medicine, UK. 

Source 

Tuber Lung Dis, 77(2):117-23 1996 Apr 

Abstract 

SETTING: Total population study in Karonga District, northern Malawi, in 

which the overall vaccine efficacy of bacille Calmette-Gu&acute;erin (BCG) has 

been found to be -7% against tuberculosis and 54% against leprosy. 

OBJECTIVE: To examine the relationship between BCG scar size and protection 

against tuberculosis and leprosy. DESIGN: Cohort study in which 85,134 

individuals were screened for tuberculosis and 82,265 for leprosy between 

1979 and 1984, and followed up between 1986 and 1989. RESULTS: Of the BCG 

scar positive individuals whose scars were measured, 31/3 2471 were later 

identified with tuberculosis and 81/31 879 with leprosy. In 19,114 

individuals, of whom 17 developed tuberculosis, tuberculin induration was 

measured at first examination. Mean scar sizes increased with increasing 

tuberculin induration in all except the oldest individuals. Mean scar sizes 

were lowest in individuals aged < 10 years, highest in individuals aged 

10-29 years and intermediate in older individuals. There was some evidence 

(P = 0.08) for an increase in tuberculosis risk with increasing scar size, 

which probably reflects the known correlation between scar size and 

tuberculin status at the time of vaccination. There was no clear 

association between BCG scar size and leprosy incidence. CONCLUSIONS: We 

find no evidence that increased BCG scar size is a correlate of 

vaccine-induced protective immunity against either tuberculosis or leprosy. 

===================================================================== 

40.) Protective efficacy of BCG against leprosy in S~ao Paulo. 

===================================================================== 

Author 

Lombardi C; Pedrazzani ES; Pedrazzani JC; Filho PF; Zicker F 

Address 

Pan American Health Organization, Bras&acute;ilia, Brazil. 

Source 

Bull Pan Am Health Organ, 30(1):24-30 1996 Mar 

Abstract 

The case-control study reported here evaluated the protective effect of BCG 

vaccine against leprosy in S~ao Paulo, Brazil. Seventy-eight patients under 

age 16 who had been diagnosed as having leprosy (cases) and 385 healthy 

individuals (controls) were selected and matched by sex, age, place of 

residence, and type of exposure to leprosy (intradomiciliary or 

extradomiciliary). The cases were drawn from an active patient registry and 

from a group of new leprosy cases treated at 50 health centers in the 

cities of Bauru and Ribeir~ao Preto in the state of S~ao Paulo. In order to 

estimate the protective effect of BCG, the prevalences of BCG scars in 

cases and controls were compared. The presence of one or more scars was 

associated with an estimated protective efficacy of 90% (95% confidence 

interval: 78% to 96%). Stratified analysis by age group, sex, socioeconomic 

level, and clinical form of the disease revealed no significant differences 

in the protection provided by the vaccine. However, it seems clear that 

more data will be needed in order to accurately assess the true relevance 

of BCG for leprosy control programs. 

===================================================================== 

41.) Post-vaccination sensitization with ICRC vaccine. 

Author 

===================================================================== 

Vallishayee RS; Gupte MD; Anantharaman DS; Nagaraju B 

Address 

CJIL Field Unit (ICMR), Madras. 

Source 

Indian J Lepr, 68(2):167-74 1996 Apr-Jun 

Abstract 

ICRC vaccine is one of the candidate anti-leprosy vaccines under test in a 

large scale comparative vaccine in trial. The objectives of the present 

study was to study the sensitization potential, as measured by Rees' MLSA 

and lepromin, and reactogenicity of this vaccine preparation in the local 

population. The study included 368 'healthy' individuals aged 1-70 years. 

Each individual received either ICRC vaccine or normal saline (control) by 

random allocation. They were also tested with Rees' MLSA and lepromin-A, 12 

weeks after vaccination. Reactions to Rees' MLSA were measured after 48 

hours and those to lepromin-A after 48 hours and three weeks. Character and 

size of local response, at the vaccination site, were recorded at 3rd, 8th 

and 15th week after vaccination. The results of the study showed that 

healing of vaccination lesion was uneventful, the mean size of the lesion 

being 10.3 mm. The mean sizes of post-vaccination reactions, to Rees' MLSA 

and lepromin (both early and late reactions), were significantly higher in 

the vaccine group compared to that in the normal saline group; the 

sensitizing effect attributable to the vaccine was of the order of 3.5 mm, 

1.7 mm and 2.2 mm respectively. In conclusion, the study has demonstrated 

that ICRC vaccine was 'safe' and produced significant sensitizing effect as 

measured by post-vaccination sensitization to Rees' MLSA and lepromin, in 

the local population. 

===================================================================== 

42.) Sensitization and reactogenicity of two doses of candidate antileprosy 

vaccine Mycobacterium w. 

===================================================================== 

Author 

Gupte MD; Vallishayee RS; Anantharaman DS; Britto RL; Nagaraju B 

Address 

CJIL Field Unit (ICMR), Avadi, Madras. 

Source 

Indian J Lepr, 68(4):315-24 1996 Oct-Dec 

Abstract 

M.w vaccine is one of the antileprosy vaccines under test in an ongoing 

comparative vaccine trial in South India. The objective of the present 

study was to examine the sensitizing ability, as measured by skin test 

reactions to Rees' MLSA and lepromin, and reactogenicity of M.w vaccine in 

the local population. Two doses of M.w, 1 x 10(9) bacilli and 5 x 10(9) 

bacilli, were used, in two separate studies of 395 and 400 "healthy" 

individuals aged 1-65 years. In each study, the study subjects received 

either M.w vaccine or normal saline (control), by random allocation. The 

results showed that healing of vaccination lesions was uneventful although 

the healing process was somewhat prolonged with the higher dose. The mean 

size of lesions was 7.0 mm and 9.5 mm with the low and high doses of the 

vaccine, respectively. The results also showed that M.w vaccine in a dose 

of 1 x 10(9) bacilli, failed to induce post-vaccination sensitization as 

measured by reactions to Rees' MLSA and by Fernandez and Mitsuda reactions 

to lepromin-A. However, when the dose of the vaccine was increased to 5 x 

10(9) bacilli the mean sizes of post-vaccination reactions to Rees' MLSA 

and lepromin-A (both early and late) were significantly larger in the 

vaccine group compared to that in the control group. The sensitizing effect 

attributable to the vaccine was of the order of 1.5 mm to 1.8 mm. 

===================================================================== 

43.) Tuberculin sensitivity and skin lesions in children after vaccination with 

two batches of BCG vaccine. 

===================================================================== 

Author 

Vallishayee RS; Anantharaman DS; Gupte MD 

Address 

CJIL Field Unit (ICMR), Avadi, Chennai. 

Source 

Indian J Lepr, 70(3):277-86 1998 Jul-Sep 

Abstract 

BCG is one of the vaccines used, as control arm, in an ongoing large scale 

comparative leprosy vaccine trial in South India. The objective of the 

present study was to examine, in the local population, the sensitizing 

ability, as measured by skin test reactions to tuberculin, and 

reactogenecity, in terms of skin lesions at the site of vaccination, for 

the two batches of BCG vaccine used in the above trial. The study was 

undertaken in 816 tuberculin-negative, previously not vaccinated school 

children, aged five to 14 years. Each child received one of the two batches 

of BCG vaccine or normal saline (control), by random allocation. At 12 

weeks from vaccination, character and size of local response, at the 

vaccination site, were recorded. At the same time, the children were 

retested with tuberculin and post-vaccination reactions to the test were 

measured after 72 hours. At three years after vaccination all available 

children were re-examined for the presence and size of BCG scar at the site 

of vaccination. It was found that healing of vaccination lesions was 

uneventful, with both batches of BCG. The mean size of the lesion was 

similar for the two batches, the overall mean being 6.3 mm. The mean size 

of post-vaccination tuberculin sensitivity increased with age, and it was 

14.5 mm and 15.6 mm. The sensitizing effect attributable to the vaccine was 

11 mm and 12 mm, for the two batches of BCG respectively. This study showed 

that the two batches of BCG, in a dose of 0.1 mg, used in the ongoing 

leprosy vaccine trial were acceptable in terms of vaccination lesion and 

were highly satisfactory in terms of development of hypersensitivity. 

===================================================================== 

44.) Association between leprosy and HIV infection in Tanzania. 

===================================================================== 

Author 

van den Broek J; Chum HJ; Swai R; O'Brien RJ 

Address 

Ministry of Health, Tuberculosis and Leprosy Central Unit, Dar es Salaam, 

Tanzania. 

Source 

Int J Lepr Other Mycobact Dis, 65(2):203-10 1997 Jun 

Abstract 

SETTING: An epidemiological study of the interaction of leprosy and HIV 

infection in Tanzania. OBJECTIVE: To establish the prevalence of HIV 

infection among leprosy patients, and to measure the association of HIV and 

leprosy by comparing the HIV prevalence in leprosy patients and blood 

donors. DESIGN: Testing for HIV infection in consecutively diagnosed 

leprosy patients (new and relapsed after MDT) in all regions in Tanzania 

successively for a period of 3 to 6 months during 1991, 1992 and 1993. 

RESULTS: Out of the total estimated eligible leprosy patients, 697 patients 

(69%) entered the final analysis. The HIV prevalence among these leprosy 

patients was 12% (83/697) as compared to 6% (8960/ 158,971) in blood donors 

examined in Tanzania during the same period. There were no significant 

differences in HIV seroprevalence by age, sex, residence or type of 

disease. However, the adjusted odds ratio (OR) of the presence of a BCG 

scar was 1.9 [95% confidence interval (CI) 1.1-3.3] among HIV-positive 

leprosy cases compared to HIV-negative leprosy cases. Comparing leprosy 

cases with blood donors as controls, the logistic regression model, 

controlling for sex, age group and residence, showed the OR for HIV 

seropositivity among leprosy patients to be 2.5 (95% CI 2.0-3.2). This 

association existed in all strata, but was strongest in the 15-34-year age 

group. No difference of HIV status between multibacillary and 

paucibacillary leprosy could be shown to exist. The point estimate of the 

population attributable risk of HIV infection for leprosy was 7%. 

CONCLUSION: HIV infection is associated with leprosy and might reverse the 

epidemiological trend of the slow decline in case notification in Tanzania 

if HIV infection is increasing greatly. Previous BCG vaccination loses its 

protection against leprosy in the presence of HIV infection. A repeated 

study is recommended in order to validate these findings, whereby recording 

of the disability grading of the cases is necessary to adjust for delay in 

diagnosis. 

===================================================================== 

45.) A follow-up study of multibacillary Hansen's disease patients treated with 

multidrug therapy (MDT) or MDT + immunotherapy (IMT). 

===================================================================== 

Author 

Rada E; Ulrich M; Aranzazu N; Rodriguez V; Centeno M; Gonzalez I; Santaella 

C; Rodriguez M; Convit J 

Address 

Instituto de Biomedicina, Caracas, Venezuela. 

Source 

Int J Lepr Other Mycobact Dis, 65(3):320-7 1997 Sep 

Abstract 

Multibacillary (MB) leprosy patients treated with multidrug therapy (MDT) 

or MDT + immunotherapy (IMT) with BCG + heat-killed Mycobacterium leprae 

were tested annually for their ability to proliferate in vitro to the 

mycobacterial antigens BCG, M. leprae soluble extract, and intact M. 

leprae. IgM antibody responses to phenolic glycolipid I (PGL-I) were 

measured, as well as serum nitrite levels in patients' sera, before, during 

and after treatment. Patients who received only MDT did not present 

cellular reactivity to intact M. leprae antigens, in contrast to the 

results obtained with BCG, which elicited reactivity at time zero, that 

increased after treatment. Regarding PGL-I antibody variations in relation 

to the initial value, we observed a statistically significant marked 

decrease at the end of 2 years which continued to fall in successive 

evaluations. MB patients showed high initial serum nitrite concentrations 

which dropped drastically with treatment. This decay was apparently 

associated with the bacillary load present in these patients. The group 

submitted to IMT + MDT showed high and long-lasting T-cell responses to 

mycobacterial antigens in a significant number of initially unresponsive MB 

patients. There was a marked increase to M. leprae soluble extract and BCG, 

as well as a more variable response to whole bacilli. The antibody levels 

in this group of patients are sustained for a somewhat longer period and 

decreased more slowly during the 5-year follow up. 

Language 

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46.) Novel O-methylated terminal glucuronic acid characterizes the polar 

glycopeptidolipids of Mycobacterium habana strain TMC 5135. 

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Author 

Khoo KH; Chatterjee D; Dell A; Morris HR; Brennan PJ; Draper P 

Address 

Department of Microbiology, Colorado State University, Fort Collins 80523, 

USA. 

Source 

J Biol Chem, 271(21):12333-42 1996 May 24 

Abstract 

Mycobacterium "habana" strain TMC 5135, which has been proposed as a 

vaccine against both leprosy and tuberculosis, is considered to be a strain 

of serotype I of the recognized species Mycobacterium simiae. We have now 

shown that each of these strains possesses characteristic polar 

glycopeptidolipids (GPL) which are sufficiently different to allow 

unequivocal strain identification. Thin layer chromatographic analysis 

demonstrated that M. habana synthesizes a family of apolar GPLs and three 

distinct polar GPLs (pGPL-I to -III) which exhibited migration patterns 

different from those of M. simiae serotype I (pGPL-Sim). Using a 

combination of chemical, mass spectrometric, and proton-NMR analyses, the 

GPLs from M. habana were determined to be based on the same generic 

structure as those from the M. avium complex, namely N-fatty 

acyl-D-Phe-(O-saccharide)-D-allo-Thr-D-Ala-L-alaninyl-O-m onosaccharide. 

The de-O-acetylated apolar GPLs contain a 3-O-Me-6-deoxy-Tal attached to 

the allo-Thr and either a 3-O-Me-Rha or a 3,4-di-O-Me-Rha attached to the 

alaninol. In the pGPLs, oligosaccharides were found to be attached to the 

allo-Thr. The oligoglycosyl alditol reductively released from the least 

polar pGPL-I was fully characterized as L-Fucp alpha 1 in --7 with 

3-(6-O-Me)-D-Glcp beta 1 in --7 with 3-(4-O-Me)-L-Rhap alpha 1 in --7 with 

3-L-Rhap alpha 1 in --7 with 2-(3-O-Me)-6-deoxy-Tal. In pGPl-II and -III, 

the terminal Fuc residue is further 3-O-methylated and 4-O-substituted with 

an additional 2,4-di-O-Me-D-GlcA and 4-O-Me-D-GlcA, respectively. The 

corresponding oligosaccharide from pGPL-Sim was shown to be of identical 

molecular weight to pGPL-II but terminating with a 3,4-di-O-Me-GlcA. 

Enzyme-linked immunosorbent assay-based serological studies using anti-M. 

habana and anti-M. simiae sera against whole cells and purified pGPLs 

firmly established the polar GPLs as important antigens and indicated that 

the terminal epitopes L-Fuc-, 2,4-di-O-Me-D-GlcA, and 4-O-Me-D-GlcA 

uniquely present in pGPL-I, -II, and -III, respectively, confer sufficient 

specificity for the identification of M. habana as a distinct serotype of 

M. simiae. 

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47.) Regional lymphadenitis following antileprosy vaccine BCG with killed 

Mycobacterium leprae. 

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Author 

De Britto RL; Ramanathan VD; Gupte MD 

Address 

CJIL Field Unit (Indian Council of Medical Research, Avadi, Madras, India. 

Source 

Int J Lepr Other Mycobact Dis, 65(1):12-9 1997 Mar 

Abstract 

Phase-II and extended Phase-II studies were conducted in three different 

sets of the population in Thiruthani Taluk, Chengalpattu District, South 

India, involving BCG and killed Mycobacterium leprae (KML) combination 

vaccines to ascertain the acceptability of the vaccines. In the Phase-II 

study, 997 healthy volunteers were vaccinated on individual randomization 

with one of the vaccines arms: BCG 0.1 mg + 6 x 10(8) KML, BCG 0.1 mg + 5 x 

10(7) KML, BCG 0.1 mg + 5 x 10(6) KML, BCG, 0.1 mg or normal saline. Blood 

samples were taken and the serum was tested for antibody levels against 

phenolic glycolipid-I (PGL-I) and the 35-kDa protein of M. leprae. In this 

study, we observed regional suppurative adenitis in 6% (6 out of 100), 3% 

(3 out of 100), and 3% (3 out of 100) of the vaccinees in the BCG 0.1 mg + 

6 x 10(8) KML, BCG 0.1 mg + 5 x 10(7) KML, and BCG 0.1 mg + 5 x 10(6) KML 

vaccine arms, respectively, in the 13-70 year age group. Earlier BCG scar 

status, skin-test reactions to lepromin-A, Rees' MLSA, and serum antibody 

levels against PGL-I and the 35-kDa protein did not help to identify the 

group at risk of developing suppurative adenitis. Suppurative adenitis 

appears to have a different relationship between the age of the subject and 

the dose of the vaccine. In order to overcome the problem of regional 

suppurative adenitis and to know the mechanism involved, an extended 

Phase-II study was conducted in similar groups of the population by 

reducing the BCG and KML doses, i.e., with BCG 0.05 mg + 6 x 10(8) KML, BCG 

0.05 mg + 5 x 10(7) KML, and BCG 0.01 mg + 5 x 10(7) KML. Biopsy specimens 

were collected from lymph nodes of the suppurative adenitis cases and were 

subjected for culture and histopathological examination. The observations 

showed that regional suppurative adenitis could be reduced to 1% in the BCG 

0.05 + 6 x 10(8) KML group, 0.5% in the BCG 0.05 + 5 x 10(7) KML group, and 

0.5% in the BCG 0.01 + 5 x 10(7) KML group. This phenomenon of suppurative 

adenitis appears to be related to the total dose of mycobacterial antigens. 

Suppurative adenitis was seen by weeks 18 and 20 post-vaccination in the 

latter two lower doses; whereas it was seen by week 8 in the higher dose of 

the combination vaccines. No case of suppurative adenitis was observed in 

the BCG 0.1 mg group. Culture and histopathology ruled out the 

possibilities of progressive BCG infection and superadded infection. 

Considering the above results, BCG 0.05 mg + 6 x 10(8) KML was acceptable 

for a large-scale vaccine trial in South India. 

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48.) A major T-cell-inducing cytosolic 23 kDa protein antigen of the vaccine 

candidate Mycobacterium habana is superoxide dismutase. 

===================================================================== 

Author 

Bisht D; Mehrotra J; Dhindsa MS; Singh NB; Sinha S 

Address 

Division of Membrane Biology, Central Drug Research Institute, Lucknow, 

India. 

Source 

Microbiology, 142 ( Pt 6)():1375-83 1996 Jun 

Abstract 

This study describes the purification and immunochemical characterization 

of a major 23 kDa cytosolic protein antigen of the vaccine candidate 

Mycobacterium habana (TMC 5135). The 23 kDa protein alone was salted out 

from the cytosol at an ammonium sulfate saturation of 80-95%. It 

represented about 1.5% of the total cytosolic protein, appeared 

glycosylated by staining with periodic acid/Schiff's reagent, and showed a 

pl of approximately 5.3. Its native molecular mass was determined as 

approximately 48 kDa, suggesting a homodimeric configuration. 

Immunoblotting with the WHO-IMMLEP/IMMTUB mAbs mc5041 and IT61 and activity 

staining after native PAGE established its identity as a mycobacterial 

superoxide dismutase (SOD) of the Fe/Mn type. The sequence of the 18 

N-terminal amino acids, which also contained the binding site for mc5041, 

showed a close resemblance, not only with the reported deduced sequences of 

Mycobacterium leprae and Mycobacterium tuberculosis Fe/MnSODs, but also 

with human MnSOD. In order to study its immunopathological relevance, the 

protein was subjected to in vivo and in vitro assays for T cell activation. 

It induced, in a dose-related manner, skin delayed hypersensitivity in 

guinea-pigs and lymphocyte proliferation in BALB/c mice primed with M. 

habana. Most significantly, it also induced lymphocyte proliferative 

responses, in a manner analogous to M. Ieprae, in human subjects comprising 

tuberculoid leprosy patients and healthy contacts. 

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49.) Supervised Multiple Drug Therapy Program, Venezuela 

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Dr Jacinto Convit Director, Institute of Biomedicine, Caracas 

A supervised multiple drug therapy program (SMDT) for the treatment of 

leprosy has been in progress in our country since 1985. It has been 

supported by the Novartis Leprosy Fund since 1991. In contrast to the WHO 

MDT regime, the SMDT program provides a single treatment regime for both 

multibacillary (MB) and paucibacillary (PB) leprosy, differing only in the 

duration of treatment (two years for MB; six months for PB). Twice a month, 

health workers visit patients at home to supervise the taking of 

medication–600 milligrams of clofazimine each visit and 600 milligrams of 

rifampicine once a month. The daily 100 milligram dose of dapsone is 

checked indirectly with sulfone-in-urine tests done at random. 

The Venezuelan program also includes health education activities, 

examination of patients’ families, and a research program in connection 

with the quest for a leprosy vaccine. Once the treatment has been 

completed, former patients are kept under surveillance over a period of two 

(for PB) or five (for MB) years for a possible relapse of the disease. 

Our leprosy program in Venezuela has brought highly gratifying results. 

More than 4,200 patients have been cured and are now under post-treatment 

surveillance; a further 3,000 are still in treatment. Although the number 

of newly detected cases has scarcely changed, averaging around 450 a year, 

the number of patients undergoing treatment has gone down distinctly. The 

program’s activities have also brought about an improved public attitude to 

the disease. Most new patients seek treatment on their own initiative, and 

the manifest improvement in the condition of those who have been treated is 

the best publicity for the program. 

To secure the success of the leprosy program we have had to reorganize the 

Public Health Dermatology Services and reinforce their infrastructure and 

central data registration system. Carrying out the program of visits at 

patients’ homes necessitated providing the health workers with 

transportation and allowances to defray travel expenses. Finally, an 

extensive health education program had to be mounted so as to ensure that 

patients come regularly for follow-up examinations after they are cured. 

Not least thanks to the backing we have received from the Novartis Leprosy 

Fund, we have been able to solve all these problems or move them closer to 

a solution. 

Our future efforts will be directed toward integrating our leprosy work 

with the control of other endemic diseases such as tuberculosis, 

leishmaniasis, and Chagas’ disease. The training programs for this are now 

under way, and some are already completed. In future, MDT as recommended by 

the WHO will be used. We also plan to develop a vaccination program in 

conjunction with the current curative program and, through further research 

projects, to improve early diagnosis. 

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50.) NII DEVELOPES WORLD'S FIRST ANTI-LEPROSY VACCINE 

===================================================================== 

The National institute of Immunology, New Delhi has developed 

Anti-Leprosy vaccine and has conducted Phase I,II and III clinicaltrials to 

study its immunotherapeutic and immunoprophylactic effects in leprosy 

patients. The development of this vaccine was initiated during early 1980s. 

Phase II clinical trial of this vaccine was launched in December 1986 in 

two Urban Leprosy centres of Delhi namely safdarjung Hospital and Dr. Ram 

Manohar Lohia Hospital after obtaining due approval of Drugs controller 

Genral of India and the Institutional Ethics commuttee of Hospitals. 

Patients receving this vaccine as adjunct to multidrug therapy (MDT) 

have shown repid clinical improvement, bacteriological negativity and 

histopathological upgradation. This observation of hastening of healing 

induced by Mw vaccine has been consistent from 1987 till date. The vaccine 

is also free from any serious side effects and well accepted by rural as 

well as urban population. The encouraging results of clinical trials in 

Delhi Urban Leprosy Centres led the Institute to expand the trials in 

larger population in field situation in Kanpur Dehat. The vaccine was 

tested on Leprosy patients as well as their healthy households contacts. 

The data produced has been thoroughly examined by two separate Expert 

Committees constituted by the Department of Biotechnology. The statistical 

analysis of the immunotherapeutic data of Mw vaccine with MDT shows the 

improvement in clinical profiles of the leprosy patients as early as six 

months. 

The technology for manufacture of the product has been trasferred to 

M/s cadila Pharmaceuticals, Ahmedabad. Drugs controller General of India 

has provided the clearance for commercialisation of this vaccine to M/S. 

Cadila Pharmaceuticals. Cadila will soon launch the product in the market, 

witth a mechanism for post market surveillance. Looking at the problem 

globally, although leprosy is found in about 80 countries in Asia, Africa 

and Latin America, India alone contributes to about 60 per cent of the 

global pool of leprosy patients. Though the number of leprosy patients in 

the world have reduced from approximately 12 million to 6 million from 1985 

to 1995, there are difficulties in accurate estimation of disease burden 

due to ambiguity in early detection of the disease and self-healing nature 

in a large number of cases. 

This is the first anti-leprosy vaccine developed in the world. while 

its immunotherapeutic effects have been well established, its role for 

immunoprophylaxis is being examined by regulatory agencies. There are 

indicators showing that the vaccine has profound effects on healthy 

household contacts. 

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DATA-MÉDICOS/DERMAGIC-EXPRESS No (68) 11/08/99 DR. JOSE LAPENTA R. 

=================================================================== 

 

Produced by Dr. José Lapenta R. Dermatologist
Venezuela 1.998-2.024

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024

Tlf: 0414-2976087 - 04127766810