Development of a potent invigorator of immune responses endowed with both preventive and therapeutic properties

Abstract

This article reviews briefly the making of an immunoprophylactic-cum-immunotherapeutic vaccine against leprosy. The vaccine is based on cultivable, heat-killed atypical mycobacteria, whose gene sequence is now known. It has been named Mycobacterium indicus pranii. It has received the approval of the Drug Controller General of India and the US Food and Drug Administration. Besides leprosy, M. indicus pranii has found utility in the treatment of category II ("difficult to treat") tuberculosis. It also heals ugly anogenital warts. It has preventive and therapeutic action against SP2/O myelomas. It is proving to be a potent adjuvant for enhancing antibody titers of a recombinant vaccine against human chorionic gonadotropin, with the potential of preventing pregnancy without derangement of ovulation and menstrual regularity in sexually active women.

Keywords: adjuvant; anogenital warts; leprosy; myeloma; tuberculosis.

Figure 1

Representative cases of LL/BL multibacillary patients treated with MDT plus Mycobacterium w (M. indicus pranii). Note: Reproduced from Talwar GP. Leprosy is in principle eradicable: a possible approach. Curr Sci. 2014;106:1344–1345. Abbreviations: MDT, multidrug therapy; LL, lepromatous leprosy; BL, borderline leprosy.

Figure 2

Synergistic effect of Mycobacterium w vaccine in slow responders to drugs in two patients. Note: In both, the bacterial index started declining on immunization with vaccine. Reproduced from Zaheer SA, Mukherjee A, Ramesh V, et al. Immunotherapy benefits multibacillary patients with persistently high bacteriological index despite long term multidrug therapy. Immunol Infect Dis. 1995;5:115–122.

Figure 3

Bacterial index in two patients who continued to receive drugs with no vaccine given. Note: Reproduced from Zaheer SA, Mukherjee A, Ramesh V, et al. Immunotherapy benefits multibacillary patients with persistently high bacteriological index despite long term multidrug therapy. Immunol Infect Dis. 1995;5:115–122.

Figure 4

Conversion of lepromin status of BL/LL patients treated with MDT ± Mycobacterium w (M. indicus pranii). Abbreviations: BL, borderline leprosy; LL, lepromatous leprosy; MDT, multidrug therapy.

Figure 5

Protection test of Mycobacterium w (Mw) against tuberculosis in guinea pigs. Notes: (A, B) Guinea pigs challenged with M. tuberculosis H₃₇Rv. (C, D) Guinea pigs immunized with Mw before challenge with M. tuberculosis H₃₇R_V.

Figure 6

Effect of immunization with killed Mw or live BCG. Notes: Effects on development of pulmonary lesions in C3H and CBA (A) and in BALB/c and C57BL/6 (B) strains of mice. Animals were immunized with either 10⁷ heat-killed Mw subcutaneously or 10⁴ live BCG intravenously. Four weeks later, the animals were challenged with 10⁷ Mycobacterium tuberculosis H₃₇Rv intravenously. Four weeks postchallenge, the animals were killed and visible lesions in the lungs recorded. Data plotted are the means of results obtained from three sets of experiments with Mw and two sets of experiments with BCG, with n=7–10 animals per group. Data for the nonimmunized group of animals are also presented (blank bars). Reprinted from Vaccine, 9, Singh IG, Mukherjee R, Talwar GP, Resistance to intravenous inoculation of Mycobacterium tuberculosis H₃₇R_v in mice of different inbred strains following immunization with a leprosy vaccine based on Mycobacterium w, 10–14, Copyright 1991, with permission from Elsevier. Abbreviations: Mw, Mycobacterium w; BCG, bacillus Calmette–Guérin.

Figure 7

Relapse rate of category II tuberculosis patients after treatment with MDT alone (control) or MDT + Mycobacterium w (M. indicus pranii) (Mw). Abbreviation: MDT, multidrug therapy.

Figure 8

Effect of MIP on ugly anogenital warts. Notes: (A) A patient with giant condylomata. (B) The lesions completely subsided with intralesional immunotherapy with MIP. Reproduced from Gupta S, Malhotra AK, Verma KK, Sharma VK. Intralesional immunotherapy with killed Mycobacterium w vaccine for the treatment of anogenital warts: an open-label pilot study. J Eur Acad Dermatol Venereol. 2008;22:1089–1093 with permission from John Wiley and Sons. Abbreviation: MIP, Mycobacterium indicus pranii.

Figure 9

Action of MIP on ugly anogenital warts (A) before treatment and (B) after treatment with MIP. Abbreviation: MIP, Mycobacterium indicus pranii.

Figure 10

Cure of warts on feet: (A) before treatment and (B) after 5 months of treatment with MIP. Copyright ©2014. Reproduced from IJDVL. Singh S, Chouhan K, Gupta S. Intralesional immunotherapy with killed Mycobacterium indicus pranii vaccine for the treatment of extensive cutaneous warts. Indian J Dermatol Venereol Leprol. 2014;80:509–514. Abbreviation: MIP, Mycobacterium indicus pranii.

Figure 11

MIP treatment suppressed tumor growth and induced a T_h1 cytokine response. Notes: (A) General outline of in vivo experimental protocol. (B) Comparison of antitumor effects of MIP administered at different time points. Cohorts of ten mice were inoculated subcutaneously with ~10⁷ SP2/0 cells. Mice were injected intradermally with a single dose of MIP (~5×10⁸) either 1 day before (–1 D) or 3 (+3 D) or 6 (+6 D) days after tumor inoculation. Mice injected intradermally with PBS on day 3 were included as controls. Growth of tumors (mean ± SD [mm³]) at indicated days postimplantation. (C) Representative photographs of solid tumors from different treatment groups dissected on day 14. Significance between MIP and PBS treated groups are indicated as follows: *P<0.05; **P<0.01. Reproduced from Rakshit S, Ponnusamy M, Papanna S, Saha B, Ahmed A, Nandi D. Immunotherapeutic efficacy of Mycobacterium indicus pranii in eliciting anti-tumor T cell responses: critical roles of IFNγ. Int J Cancer. 2012;130:865–875, with permission from John Wiley and Sons. Abbreviations: MIP, Mycobacterium indicus pranii; T_h, T-helper; PBS, phosphate-buffered saline.

Figure 12

Enhancement of antibody response to hCGβ-LTB vaccine in BALB/c mice by MIP. Notes: Mice were immunized intramuscularly with 2 µg of the vaccine adsorbed on alum with or without MIP. Primary immunization consisted of three injections given at fortnightly intervals, followed by a booster on day 60 or 120. The symbols represent the titers in a given mouse. Bars give the geometrical means. (A) Observations in mice immunized with the hCGβ-LTB vaccine adsorbed on alum; (B) titers of antibodies in mice immunized with the vaccine plus MIP as adjuvant. Reprinted from Vaccine, 29, Purswani S, Talwar GP, Development of a highly immunogenic recombinant candidate vaccine against human chorionic gonadotropin,2341–2348, Copyright 2011, with permission from Elsevier. Abbreviations: hCGβ, human chorionic gonadotropin beta; MIP, Mycobacterium indicus pranii.