Vaccines show promise for both preventing and treating leprosy by enhancing host immunity. Several candidate vaccines have been tested including BCG, killed M. leprae with BCG (Convit), and vaccines using other mycobacteria like M. w or ICRC bacilli. While some studies show protective efficacy of 30-65% against leprosy, well-designed randomized controlled trials are still needed. Future vaccines may combine antigens to provide multi-disease protection against tuberculosis and leprosy. Development of vaccines faces challenges due to leprosy's long incubation period and lack of good animal models.

1. Vaccines for leprosy
A short talk - Anand

3. • ‘Vaccine' ≈ 'la vacche' ≈ cow
• Vaccines- enhances host immunity
• Are perhaps the most effective means of
controlling infectious diseases by inducing
active immunity

4. Vaccines are of 3 types-
• Live vaccines
• Killed vaccine
• Toxoids

5. Attenuated Live Vaccines
• Attenuated live organisms.
• Initiate an infection without causing any injury
or death
• Immunity little lesser than natural infection
• Lasts for several years.
• Booster doses generally not required
(exception - polio).

6. Killed vaccine
• Killed organisms
• Less immunogenic
• Protection for short periods.
• Repeated booster doses.
Toxoids
• Toxins of bacteria are detoxified and used as
vaccines.
• Antibodies neutralize the toxin, but have no
effect on organism.

7. Need for leprosy vaccine
• New case detection rate - Not decreased.
• Large number of hidden cases continues to increase
• Even after MDT, highly bacilliferous cases (BL/LL)
continue to be smear positive leading to relapses
and reactions
• Therefore, combination of MDT & immunisation for
active cases & in endemic areas –
Long term measure for eradication of leprosy.

8. Parameters for determining vaccine
efficacy
• For other vaccines, usually determined by its
ability to lower incidence of the disease.
• But, this parameter cannot be used for leprosy
because it has long IP & will require long term
trials
• Mitsuda test ---Lepromin (+)

9. • Aims of vaccine
– Immunoprophylaxis
– Immunotherapy

10. Effects of immunotherapy
Promotion of CD 4 Th 1 cells effective
antibacterial process.
Overproduction of CD 4 Th 2 cells is switched
off.
Regulatory activity of CD 8 cells is relaxed to
allow Th 1 activity
More efficient killing of viable bacilli including
persisters

11. OUTCOME
– Faster clearance of dead & viable bacilli including
persistors leads to
– Duration of treatment
-- Morbidity and mortality.
– Transmission and relapse
– Case holding and better compliance
– Clinical improvement in skin lesions
– Improved Host immunity

12. Problems with development of vaccine for
leprosy
• Long incubation period of disease.
• Paucity of animal model (Armadillo)
• Inability to culture bacteria in lab
Dasypus novemcinctus

13. CLASSIFICATION OF “CANDIDATE
VACCINES
• 1st Generation
Non Cultivable (M.leprae) Cultivable M.bacteria
• 1. Killed M leprae 1. BCG
• 2. Killed M leprae + BCG 2. BCG + M.vaccae
• 3. Acetoacetylated M leprae 3. Killed M.welchii
4. Killed ICRC
5. M.vaccae
6. M.habana
7. M gordonnae
8. M.phlei
• Second generation (In vitro/ Animal studies only)
• Subunit vaccines
• Shuttle plasmid vaccines

14. • These are vaccines under trial
• Yet to achieve the status of a vaccine

16. BCG
• Bacille Calmette Guerin in 1921
• Living bacteria derived from an attenuated
bovine strain of tubercle bacilli
• WHO recommendation - Danish 1331 strain
• The most widely used vaccine

17. Studies with BCG vaccine
• BCG was found effective against the growth of
M.leprae in foot-pads of mice
• Katoch et al (1989)– BL/LL patients treated
with MDT for 2 years and who were still
smear positive were given BCG which led to
increased bacterial killing and clearance
• But BCG vaccination is no more considered to
be a modality for immunoprophylaxis of
leprosy

18. BCG
• Indian studies -Protective efficacy ranging from
20-70%
• Almost equal to its efficacy in preventing TB
• Better protection against MBL (93%)
• Faster clearance of both live and dead bacilli as
well as faster histological and clinical clearance
• Repeat vaccination affords further protection
especially in children less than 15 years of age
• There is increased risk of type I reaction
• Indicated increased risk of tuberculoid and
indeterminate leprosy after BCG vaccination

19. Other studies
Efficacy
• Brazil - 90%
• Kenya - 81%
• Uganda - 80%
• Myanmar- 65%

20. CONVIT GARCIA

21. Convit García’s vaccine
(BCG+ Killed M.leprae)
• A Venezuelan scientist- developed a vaccine in
an attempt to fight leprosy
• In 1987, Convit added heat killed M.leprae to
the BCG vaccine
• The combined vaccine was tested worldwide,
but was not more effective than regular BCG
• A vaccine for leishmaniasis was later
developed using Convit's method

22. Convit vaccine
• Produced favourable clinical and histological
responses in both indeterminate & LL
• Few recent trials from India -shown better
lepromin conversion and faster clinical and
histological cure with the use of Convit
vaccine along with MDT compared to BCG
with MDT.

23. Acetoacetylated M leprae
• Carrier modified form of M leprae.
• Talwar et al gave acetoacetylated M.leprae to
13 LL patients. They observed lepromin
conversion in 7/13 patients
• Acetoacetylation improves interaction of
bacteria with leucocytes- in vitro studies show
improved macrophage migration.
• Immunization of contacts- it made them
lepromin positive.

24. Pathology
• Cell mediated immunity (CMI) is the dominant
host defence against M.leprae and circulating
anti-M.leprae antibodies have little role
• Lipid component of cell wall of M.leprae prevents
the recognition of bacilli by macrophages
• Tuberculoid leprosy exhibit CMI response due to
high levels of serum lipase, which removes the
lipids of the cell wall
• Delipidified cell component (DCC)
of M.leprae have been shown to activate
macrophages and kill M.leprae in vitro.

25. De-lipified cel components of
M leprae
• Defective macrophages of leprosy patients
were able to recognize the delipified cell
components as antigens.
• It led to proliferation of lymphocytes in
cultures following production of the desired
lymphokines.
• Mice vaccinated with delipified cell
components were found to control the growth
of M leprae

26. ICRC
• ICRC bacilli ( to MAC complex)
• 1979 - Cancer Research Institute Mumbai
• ICRC bacilli exhibit antigenic cross-reactivity
with M.leprae with reference to both B & T
cell antigens
• Antigens of the ICRC bacilli are also more
accessible, making the organism a stronger
immunogen

27. ICRC
• From a cultivable organism & hence cheap
• No contamination with animal products
• Induces stable immunity
• Vaccine may also act against infections caused
by these opportunistic microbes
• Rapid and significant fall in BI

28. • Advantages:-
– Enhances T cell reactivity
– Induces lepromin conversion in LL patients
– Faster clearing of M.leprae
• More data is available on its role in
immunoprophylaxis than in immunotherapy.
• Each dose contains 1 X 108 bacilli

29. Mw(M.welchii)
• A rapid growing mycobacterium is said to be a
cultivable saphrophytic soil bacillus
• Dr. G. P. Talwar, founder- director of NII,New Delhi
• Since 1998 under the trade name of ‘Leprovac’ &
is currently -‘Immuvac’
• Induce lepromin conversion in BL/LL patients
• The vaccine has been used in patients with MBL
• ICRC and Mw are similar cell antigens
Hence having similar results

30. Mw
• Antigenically similar to M.leprae and M
tuberculosis.
• Effective and tolerable
• Role in both immunotherapy and
immunoprophylaxis.
• More rapid bacterial clearance
• Earlier achievement BI negativity in patients
given M.w+ MDT compared to only MDT.

31. • Advantages:-
– Earlier release of patients from treatment
– Slow responders to MDT are benefited
– Decreased incidence of type II reactions and neuritis
• ADR:-
• Fever
• Mild injection site erythema induration(7d)
ulceration(3wks) healing (4wks) scar
• Loco-regional LAP

32. M.Vaccae
• Used in trials for immunotherapy of- TB, AD,
Psoriasis, Leishmaniasis, & Adeno Ca Lung
• To induce immunoreactivity to M leprae in the
form of lepromin conversion, in both in vivo
and in vitro studies
• Stanford et al demonstrated lepromin
conversion in humans using
BCG and killed M. vaccae

33. M.habana
• A photochromogen
• CDRI Lucknow have shown CMI response in
mice, langur & rhesus monkeys to its vaccine
• A potential candidate vaccine for both TB &
leprosy
• Protect mice against MTB, M ulcerans &
M leprae

34. 2nd generation subunit vaccine
• Advances in cloning -- identified many protein
antigens of M. leprae-- 70Kd, 65 Kd, 35 Kd, 31
Kd, 18 kd, 10 Kd
• Natural or recombinant form of these proteins
are available.
• Peptide base vaccine can elicit humoral and
CMI response.
• They are used for immunoprophylaxis,
immunotherapy, immunodiagnosis.
• Chemically synthesized by recombinant DNA
technology– free of biological contamination .
• Still in experimental stage- Not in humans

35. • Using recombinant technology, the entire
genome of M.leprae has been cloned.
• Recombinant DNA clones containing gene
coding for 5 immunogenic proteins have been
isolated using monoclonals.
• If scientists succeed in identifying the
'protective' antigen(s) from amongst these
proteins
• Clones making 'protective' antigen(s) could be
a constant source of supply for the
preparation of a vaccine.

36. HMW PP-I glycoprotein
• Fraction of sonicate of ICRC bacilli  gel
permeation HPLC  yields HMW glycoprotein
known as PP-I with molecular weight of 106 D.
• It is a strong immunogen, carrying epitopes
for B & T cells.
• Brings about lepromin conversion

37. M lepra 35 kD protein
• M lepra 35 kD protein
• Protective immunity in Guinea pigs was found
to be similar to BCG.

38. Other candidate Subunit vaccines
• M lepra 65 kD heat shock protein (hsp)
• M lepra: lsr antigen, 12 kD antigen
• M lepra groES, groEL, 70kD hsp
• M lepra 35kD + M tuberculosis 85B antigen
• M habana 65kD and 23 kd proteins

39. PLASMID EXPRESSING CYTOKINES
• Vector that expresses p35 and p40 chain of
murine IL-12 when combined with M.leprae
35Kd antigen
• Increases antigen specific production of
interferon γ
• Increased clearance of mycobacteria
compared to M.lepra 35kD vaccine alone.

40. SHUTTLE PLASMID VACCINES
• Approach has been to introduce genes coding
for protective antigens in BCG.
• Attempt to introduce several protective genes
from diverse organisms into BCG
• Simultaneouly with aim of developing
vaccines which will protect against many
disease including TB, leprosy, typhoid.

41. Advances
• October 2003 – Identification of M. leprae
antigens
• May 2005 – Completed screening of M.Leprae
for proteins strongly recognized by the human
immune system
• March 2006 – Identified 02 specific antigens
(MLO405 and ML2331) gave a significantly
greater sensitivity to PGL-1 antibody test

42. A vaccine for leprosy is being developed by American researchers
and is set for toxicology tests towards the end of 2014 and for
phase I clinical trials in human volunteers by 2015
The Guardian June 06,2014

43. PROBLEMS WITH THE CURRENT
VACCINES
1. Very few well-performed double-blind RCTs
with proper follow-up.
2. Vaccines such as Mw – 24m while MDT- 12 m
3. Bacteriological cure already 100% with MDT.
Hence No additional benefits
4. Unsatisfactory results in MBL with high BI at
onset.
5. Risk of type I reactions.
6. Observational studies overestimate the
efficacy of vaccines

44. CHALLENGES FOR NEW ANTI LEPROSY VACCINES
Complex host immunological response to
mycobacteria Eg:-quantity of mycobacterial
protein and the timing of exposure.
Testings limited mainly to animal models
For testing individual vaccines takes 9 -12 m
Limitations of the models for testing:-
 The sensitivity of mouse footpad infection
model is low
Complexity of the armadillo model
Limiting factors:-Not many new cases &
extensive infrastructure

45. Comparative Leprosy Vaccine Trial in
South India
– Double-blind, RCT prophylactic leprosy vaccine
– Compared BCG, BCG with Killed M.leprae, Mw,
ICRC with normal saline placebo.
– Study population- 2,90,000.
– Overall protective efficacy
• BCG-34.1%
• BCG with Killed M.leprae –64%
• ICRC— 65%
• Mw- 25.7%
– BCG with Killed M.leprae and ICRC vaccine were
found to be potentially more useful as
immunoprophylactic agent.

46. BCG BCG + killed M leprae ICRC Mw
Prophylactic efficacy 18-90% 50-64% 65.5% 25.7%
Therapeutic efficacy
(combined with MDT)
BI fall @ 2.4/ yr
BI-ve at end of 3.5 yrs
BI fall @
3/ yr
BI fall @
1.7/yr
BI fall @
1.7-2.72/ yr
2. BI-ve at end of 3 yrs
Type I reaction ↑ by 10% - - ↑ by 15%
Type II reaction ↓ by 30% - - ↓ by 25%

47. THE FUTURE
• BCG and ICRC Vaccine- future polyvalent
mycobacterial vaccine that might offer
protection against a wide spectrum of
mycobacterial diseases.
• Such a polyvalent mycobacterial vaccine
would reduce the number of vaccinations

49. References:
• Lepr Rev. 2004 Dec;75(4):357-66
• Bull World Health Organ1989; 67 : 389– 99.
• Indian J Lepr 1998; 70 : 369–388.
• Lancet 1996; 348: 17–24.
• Ind J Lper 2000; 72: 21–34.
• Int J Lepr Other Mycobact Dis 2001, 69: 10–13.
• Int J Lepr Other Mycobact Dis 2002; 70: 174–181.