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Leprosy (Hansen
disease) and vaccines.
Lepra (Enfermedad de Hansen) y vacunas.
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****** DATA-MÉDICOS *********
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LEPRA (HANSEN) Y VACUNAS
LEPROSY (HASEN) AND VACCINES
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***** DERMAGIC-EXPRESS No 65 *******
**
11 AGOSTO1.999 / 11 AUGUST 1999**
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EDITORIAL ESPAÑOL:
=====================
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, quizá uno de los pioneros en esta búsqueda ansiosa, al
igual que la India
En ARGENTINA se esta trabajando con Cepas de
Mycobacterium Bovis y vaccae. 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 ultimo del cual
según ellos se pondrá 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 a todos !!!
Dr. José Lapenta R.,,,
EDITORIAL ENGLISH:
=====================
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,
In ARGENTINA are working with Strains o f Mycobacterium Bovis and vaccae. In other countries (Brazil) with THE BCG ALONE or plus Mycobaterium 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 NONPATHOGEN.
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 multidrugtherapy (MTD).
Let us also remember that the classic VACCINE BCG (bacillus Calmette-Guerin) that protects against the
Tuberculosis, it also protects against the Leprosy..
I congratulate all these investigators, but we will continue waiting for A REAL VACCINE against the LEPROSY... I hope you like this DERMAGIC,
Greetings to ALL, !!
Dr. José Lapenta R.,,,
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DERMAGIC/EXPRESS(65)
================================================================
REFERENCIAS BIBLIOGRÁFICAS /
BIBLIOGRAPHICAL REFERENCES
================================================================
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-Guerin 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
================================================================
=====================================================================
1.) Causative organism and host response.
=====================================================================
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.
=====================================================================
2.) The GroES antigens of Mycobacterium avium and Mycobacterium paratuberculosis.
=====================================================================
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.
=====================================================================
3.) Human T cell recognition of the Mycobacterium leprae LSR antigen: epitopes
and HLA restriction.
=====================================================================
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. [email protected]
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.
=====================================================================
4.) Quality control tests for vaccines in leprosy vaccine trial, Avadi.
=====================================================================
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.
=====================================================================
5.) Comparative leprosy vaccine trial in south India.
=====================================================================
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.
=====================================================================
6.) Effectiveness of bacillus Calmette-Guerin (BCG) vaccination in the
prevention of leprosy; a case-finding control study in Nagpur, India.
=====================================================================
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.
=====================================================================
7.) Effectiveness of Bacillus Calmette Guerin (BCG) vaccination in the
prevention of childhood pulmonary tuberculosis: a case control study in
Nagpur, India.
=====================================================================
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.
=====================================================================
8.) Tuberculin sensitivity and skin lesions in children after vaccination with
two batches of BCG vaccine.
=====================================================================
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.
=====================================================================
9.) Leprosy vaccine: influence of dissolved oxygen levels on growth of a
candidate strain (Mycobacterium w), and storage stability of the vaccine.
=====================================================================
Vaccine 1998 Aug;16(13):1344-8
Mukhopadhyay A, Panda AK, Pandey AK
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
[email protected]
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.
=====================================================================
10.) Studies of vaccination of persons in close contact with leprosy patients in
Argentina.
=====================================================================
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.
=====================================================================
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-Guerin-vaccinated people and in Bacille CalmetteGuerin-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-Guerin 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-Guerin
strains and to some cancers. The variable protective activity of Bacille
Calmette-Guerin 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. [email protected]
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. [email protected]
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-Guerin (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.
[email protected]
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 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.
=====================================================================
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-Guerin scar size have implications for protection
against tuberculosis or leprosy?
=====================================================================
Author
Sterne JA; Fine PE; P¨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-Guerin (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´ilia, Brazil.
Source
Bull Pan Am Health Organ, 30(1):24-30 1996 Mar
Abstract
TThe 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.
===================================================================== br>
441.) Post-vaccination sensitization with ICRC vaccine.
=====================================================================
Author br>
Vallishayee RS; Gupte MD; Anantharaman DS; Nagaraju B
Address
CJIL Field Unit (ICMR), Madras.
Source
IIndian 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.
===================================================================== br>
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
IIndian J Lepr, 68(4):315-24 1996 Oct-Dec
Abstract br>
MM.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.
===================================================================== br>
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
IIndian 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.
===================================================================== br>
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
IInt 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.
===================================================================== br>
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
InInt 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.
===================================================================== r>
4646.) Novel O-methylated terminal glucuronic acid characterizes the polar glycopeptidolipids of Mycobacterium habana strain TMC 5135.
===================================================================== r>
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 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. T
he
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.
===================================================================== r>
47.) Regional lymphadenitis following antileprosy vaccine BCG with killed
Mycobacterium leprae.
=====================================================================
Author
De Britto RL; Ramanathan VD; Gupte MD
Address
CJIL Field Unit (Indian Council of Medical Research, Avadi, Madras, India.
Source
InInt 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.
===================================================================== r>
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
MiMicrobiology, 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
=====================================================================
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 (65) 11/08/99 DR. JOSÉ LAPENTA R.
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Produced by Dr. José Lapenta R.
Dermatologist
Maracay Estado Aragua Venezuela 1999-2026
Telf.:
04142976087 - 04127766810
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