Wednesday, March 15, 2023

Is There A Vaccine For Leprosy

Antigen Stimulation And Cytokine Responses

Leprosy drug could help in fight against COVID-19, UF Health researcher finds

Single-cell suspensions were prepared by disrupting spleens between frosted slides. Red blood cells were removed by lysis in 1.66% NH4Cl solution, then mononuclear cells enumerated by ViaCount assay with a PCA system . Single-cell suspensions were cultured at 2×105 cells per well in duplicate in a 96-well plate in RPMI-1640 supplemented with 5% heat-inactivated fetal calf serum and 50,000 Units penicillin/streptomycin . Cells were cultured in the presence of 10g/ml antigen for 7296h, after which culture supernatants were harvested and cytokine content assessed. IFN concentrations within culture supernatants were determined by ELISA performed according to manufacturers instructions and optical density was determined using an ELx808 plate reader.

International Textbook Of Leprosy

  • Infectious Disease Research Institute
  • 1616 Eastlake Ave E, Suite 400
  • Seattle, WA 98102 USA
  • Infectious Disease Research Institute
  • 1616 Eastlake Ave E, Suite 400
  • Seattle, WA 98102 USA
  • Reed SG, Duthie MS. 18 September 2016, posting date. Vaccines for prevention of leprosy, Chapter 6.3. In Scollard DM, Gillis TP , International textbook of leprosy.

    Morphometry And Histomorphometry Of Schwann Cells

    Intra epidermal nerve fiber densities in skin biopsies were determined using established counting rules,, and IENFD was expressed as fibers/mm. Schwann cell bands within the dermis were identified in the skin sections by the presence of brown colored cytoplasmic staining by p75 in the setting of elongated blue-staining nuclei . The Schwann cell nuclei were identified and quantified using a design-based stereology methodology. The area of interest was defined as the dermal region extending from the epidermal/dermal junction to a dermal depth of 2000µm. A contour was made at the area of interest under an ×2.5/0.075 PlanNeofluor objective of a Zeiss light microscope and the cells were counted using ×63/1.40, oil PlanNeofluor objective. A sampling grid 200mm×150mm, with a dissector height of 15mm and guard zones of 2mm was used and the absolute numbers of Schwann cells were obtained using the .DAT files of optical fractionator probe of Stereo Investigator ., The Schwann cell density was determined as number of cells/mm3. The sampling design achieved a Gundersen coefficient of error 0.1. All morphometric measurements were conducted in a double-blinded, coded manner with no knowledge of the identifying data.

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    What Is The Vaccine

    The indigenous vaccine is a heat-killed species of the bacteria called Mycobacterium indicus pranii or Mycobacterium w, which can be grown in the laboratory.

    The vaccine was developed by a team led by Dr G.P. Talwar at the All India Institute of Medical Sciences in New Delhi in the 1970s.

    MIP was found to be a close cousin of M.leprae and so was examined for its utility as a vaccine against leprosy. It is now being rolled out in phases in high-prevalence areas.

    Largest Trial In Kanpur

    Vaccine brings new hope to India

    The largest clinical trial so far, conducted in Kanpur Dehat, Uttar Pradesh, spanned 272 villages with a population of 420,832. A total of 1,226 multibacillary and 3,757 paucibacillary cases of leprosy were detected. Around 24,060 people who had been in close contact with leprosy patients were vaccinated with MIP and with placebo. The dosage efficacy was 68 per cent in the first year, 59 per cent in the second year and 39.3 per cent in the third year.

    The effect of the vaccine was sustained for 7-8 years and booster dose was administered to maintain immunity. This study showed that the vaccine is well-tolerated in large populations without the risk of serious side effects.

    Following this, the MIP vaccine was approved by the Drug Controller General of India as well as the US Food and Drug Administration .

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    The Influence Of Leprosy

    • Selma Regina Penha Silva Cerqueira,

      Roles Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Resources, Software, Visualization, Writing original draft

      Affiliations Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil, Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil

    • Roles Data curation, Formal analysis, Software, Writing review & editing

      Affiliation Post-Graduation Programme of Infectious Diseases, Federal University of Espírito Santo, Vitória, Brazil

    • Roles Data curation, Formal analysis, Investigation

      Affiliation Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil

    Immunization With Lepvax Delays Motor Nerve Function Impairment

    Fig. 2

    Experimental set-up to examine post-exposure immunoprophylaxis in M. leprae-infected armadillos. Armadillos underwent intravenous inoculation with M. leprae, then 1 month later were: left untreated immunized with BCG one time immunized with ID93+GLA-SE, for a total of three times at monthly intervals or immunized with LepVax , for a total of three times at monthly intervals. The animals were monitored for compound muscle action potential and motor nerve conduction velocity at monthly intervals, underwent three mm skin punches 16 months, and had their posterior tibial nerves biopsied at 28 months, after M. leprae inoculation. The photograph is the authors own

    Fig. 3

    Immunization with LepVax delays M. leprae-induced motor nerve damage. Armadillos were monitored for compound muscle action potential and motor nerve conduction velocity at monthly intervals following infection and immunization. In a, the first month at which each animal first showed an abnormal nerve conduction was recorded and in b the time at which three consecutive abnormal readings were obtained for each particular animal is noted. The cumulative percent for each group is shown, and data shown are from one of two similar experiments. In c, CMAP measurements from 24 months after infection are shown. Each point depicts the data from a single armadillo, while the box and vertical bars show the mean and s.e.m, respectively. *p-value< 0.05 versus unimmunized, infected control animals

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    Leprosy Vaccines Obstacles And Hurdles

    Apart from various socioeconomic and political issues, there are many theoretical and practical obstacles in the way of developing an effective leprosy vaccine. The precise nature of immune responses responsible for the clinical spectrum of leprosy still remains incompletely understood. Just as the exact mechanism by which 35%70% of infections with M. leprae resolve naturally without causing the disease, remains unknown. The lack of reliable tests to detect infection and simple biomarkers to predict treatment response and vaccine efficacy is still daunting. These limitations also make it difficult to select the study population to be vaccinated. Vaccine efficacy trials are marred by the long incubation period of leprosy and vaccine production by the inability to culture M. leprae in artificial media. Exposure to environmental mycobacteria with cross-reacting antigens to M. leprae could modify the immune responses post-vaccination and thus alter the protective efficacy of the vaccines against leprosy. All these gaps in our understanding of leprosy need to be addressed, before our goal for an effective vaccine against leprosy can be met.

    Vaccines In Clinical Trials: At The Crossroad Between Leprosy And Tb

    Covid-19 vaccine update: India’s CSIR testing anti-leprosy Mw vaccine

    Although BCG vaccination trials in leprosy were executed decades ago, the current leprosy clinical vaccine pipeline is three times smaller than that of TB . This situation is relatively recent considering that in 2001 there were four candidate leprosy vaccines tested in clinical trials vs. none against TB.

    Figure 1. Leprosy and tuberculosis vaccine pipelines. Schematic representation of leprosy and TB candidate vaccines in clinical trials. Source: adapted from Ref. , TBVI/Aeras September 2017 and . The primary endpoints are indicated for each trial with the exception of TB/FLU-04L for which primary outcome is yet not registered. POI, prevention of infection POR, prevention of recurrence POD, prevention of disease.

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    The Effect Of Clofazimine

    In the study, the researchers administered clofazimine to hamsters with SARS-CoV-2 and prophylactically to other hamsters that did not yet have the virus.

    Both groups that the researchers treated with clofazimine had less SARS-CoV-2 in their lungs after taking the drug.

    Clofazimine also prevented the often deadly inflammatory overreaction that commonly occurs in humans. This is called the cytokine storm.

    Co-senior study author Dr. Ren Sun, of the University of Hong Kong, reports, The animals that received clofazimine had less lung damage and lower viral load, especially when receiving the drug before infection.

    Dr. Sun adds, Besides inhibiting the virus, there are indications that the drug also regulates the host response to the virus, which provides better control of the infection and inflammation.

    The study suggests that clofazimine fights SARS-CoV-2 by doing two things: blocking the viruss entry into cells and disrupting RNA replication of the virus.

    Combined Chemoprophylaxis And Immunotherapy

    Various chemoprophylaxis trials have demonstrated benefit in individuals at high risk of leprosy infection. A single dose of rifampicin given to contacts of new patients with leprosy was 57% effective in preventing the development of clinical leprosy after 2 years, but a further effect could not be shown between 2 and 4 years in the COLEP study from Bangladesh. However, if the contact had received BCG vaccination as part of a childhood vaccination program , the protective effect of SDR was 80%. The protective effect, thus, appears to be additive to the effect of BCG.

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    Advances Toward Defined Vaccines

    Experimental immunizations with crude antigens have been conducted, demonstrating that proteins within the M. leprae cell wall, cell membrane and cytosol all provide protection when administered with adjuvant before infection.74,75 As with the use of killed M. leprae, major constraints regarding the use of crude M. leprae antigens in a vaccine are the prohibitive nature of cultivating large enough numbers of M. leprae and the lack of consistency in production. A defined sub-unit vaccine produced by standard methods could circumvent the production and quality control issues surrounding live or purified whole cell or cell component vaccines, but such a vaccine for leprosy is still lacking.

    In an attempt to make BCG more immunogenic and to extend its protective lifespan, several investigators have genetically-refined the bacteria. This is a major area of interest in the TB field, with several recombinant BCG being produced and advancing toward clinical trial . The protection that these rBCG can afford against leprosy, and therefore the impact that these could have on leprosy control programs, is unclear.

    Bcg + Killed M Leprae

    India rolls out world

    Killed M. leprae was added to BCG to enhance its immunogenicity. However, Convit et al. conducted a trial in Venezuela between 1983 and 1991 and found no significant advantage for the combination of BCG plus M. leprae over BCG alone after 5 years of follow-up. A trial in Malawi, too, found no significant difference in efficacy between BCG plus killed M. leprae or BCG at 59 years.

    However, the South Indian trial by Gupte et al., a five-arm RCT comparing four vaccines vaccine: 24 years of follow-up and Mycobacterium w vaccine: 24 years of follow-up) versus normal saline indicated that a BCG/M. leprae vaccine, and the ICRC vaccine, offered significant protection against leprosy versus normal saline. However, irrespective of the results, a vaccine based on M. leprae that has production constraints in artificial media, is unlikely to bear fruit.

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    Immunohistochemistry Of Skin Sections

    Skin biopsies were fixed in 2% paraformaldehyde/lysine/periodate for 24h, sectioned with a sliding microtome into 50-µm thick, frozen, vertical, free-floating sections, which then were placed in 24-well tissue culture plates for immunostaining. Each skin section was incubated with the following primary antibodies diluted in blocking buffer: anti-PGP 9.5 , as a pan axonal marker, and mouse anti-p75 nerve growth factor receptor , as a phenotypic marker for Schwann cells. Nonspecific binding of secondary antibodies was prevented by incubating sections with 4% normal goat serum diluted in 1.0% Triton X-100, 0.5% nonfat powdered milk in Tris-buffered saline ]. Sections were rinsed in Tris-buffered saline and transferred to secondary antibodies. Secondary antibodies included goat anti-rabbit IgG and goat anti-mouse IgG . The sections were then incubated with AvidinBiotin Complex solution , and color was developed with chromogens. PGP 9.5-stained sections were developed with blue/gray chromophore and p75-stained sections with diaminobenzidine. One percent eosin and Mayers hematoxylin were used as counterstains.

    Determination Of Bacterial Burden In Mice

    To assess M. leprae growth, live M. leprae bacilli were purified from the footpads of nu/nu nude mice at NHDP or NIID. Mice were inoculated with 1×104 bacilli by s.c. injection into each foot pad. Foot pads were harvested 12 months later and the bacilli were enumerated by direct microscopic counting of acid-fast bacilli according to the method of Shepard and McRae.

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    Lepvax Activity In Prevention Of Leprosy Infection

    Vaccine immunogenicity studies show the vaccine’s ability to induce immunity is based on the vaccine’s ability to interact with CD4 T helper cells. This interaction can release Th1 cell-type cytokines that play an important role in controlling mycobacterial infections . Reaction with Th1 cells can limit the development of pathogens by localizing infection through the production of the cytokine IL-8 which in turn can induce TNF- release from Schwann cells which are the site of pathogen invasion . The presence of an immunological response from the presence of cytokines in Schwann cells means pathogenic infections can be localized and not spread to other target locations. Induction of cytokines can improve nerve function when infected by M. leprae and prevent damage to Schwann cells due to infection .

    The activity of the pathogenic M. leprae that proliferates in Schwann cells is supported by the peripheral environment of the body which is located in environments of low oxygen tension so that it can colonize the area of infection and cause nerve ischemia resulting in axonal damage . The effect is the onset of neuropathy in the infected area as indicated by a decrease in CMAP and damage to sensory tissue. LepVax vaccine can maintain CMAP in motor nerves and prevent nerve damage due to M. leprae infection through preventing damage to Schwann cells which can disrupt the electrical conduction of nerves and restore the form of Schwann cells to normal conditions .

    Development Of New Defined Vaccines

    Vaccine against leprosy has been developed in

    The ideal vaccine against leprosy would appear to need to induce strong, long-lasting T-cell responses directed against M. leprae antigens, thereby limiting infection, preventing disease, and, furthermore, reducing bacterial transmission to others. Not until recently has it been practical to contemplate the development and delivery of a new generation of vaccines for leprosy. Key technological and conceptual advances that put this possibility within reach stem from enabling antigen discovery through molecular cloning techniques, most notably aided by the completion and publication of the M. leprae genome . Gene synthesis and antigen production, previously an insurmountable problem when dealing with an organism that had never been cultured in the laboratory, are now achievable at scales appropriate for vaccine development. Of even more critical importance is the recent availability of adjuvants to enable a new generation of T-cell vaccines. Evidence supporting the development of a defined leprosy vaccine came in part from studies showing that immunization with crude antigens preparations derived from the M. leprae cell wall, cell membrane, and cytosol can provide protection ,, building on data using whole M. leprae for prophylactic immunization. Although developing usable vaccine from whole cells or fractions thereof is not practical, these earlier studies demonstrated the potential, at least in experimental models, of developing a vaccine against leprosy.

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    Characterization Of Peripheral Nerves Of Armadillos By Electron Microscopy

    The nerves were fixed for 48h in 4% paraformaldehyde -3% glutaraldehyde and then transferred to 0.1M Sorensens phosphate buffer. Sections were post-fixed with osmium, embedded in plastic and one-micron thick sections were made and stained with 1% toluidine blue. Thin 6070-nm sections were mounted on Formvar-coated 50 mesh grids and stained with uranyl acetate and lead citrate . The nerve sections were examined with a digital Zeiss Libra 120 electron microscope and Remak bundles identified using previously specified criteria., Point lists were randomly made at 4000×to scan different sites in the sections and a minimum of 50 digital photographs were captured at a magnifications of 8000× to 16000×. Images were uploaded onto iTEM program , and Remak Schwann cells carrying unmyelinated axons were identified by specified criteria., An individual linear array was used to measure the mean axonal and Schwann cell diameter and the total number of unmyelinated axons per Remak Schwann cell quantified according to the established methodology.,

    A Vaccine For Leprosy

    The development of a vaccine to counter multibacillary leprosy is a significant event for India, which has the largest number of leprosy patients in the world.

    A VACCINE to “immunise” patients suffering from a severe type of leprosy, called the Multibacillary leprosy, has been developed by Dr. G.P. Talwar, founder-Director of the National Institute of Immunology. The vaccine, Mycobacterium w , was launched in the market on January 30. The institute has also received from the Drugs Controller of India authorisation for its commercial production. “While research on a leprosy vaccine goes on in many parts of the world, this is one which has signalled the end of the search,” Talwar told Frontline.

    The M.B. type is a severe type of leprosy. Patients afflicted with it serve as reservoirs of infection. They have failed to respond to lepromin, the antigen for ordinary cases of leprosy.

    Talwar said that while the prevalence of leprosy had gone down in some countries, the incidence of the disease continued to be alarming in many others, including India. He said that this was because of the continuing existence of a foyer of infection.

    “This vaccine will play a very important role in the eventual eradication of leprosy,” said Talwar, a recipient of the Padma Bhushan. He is currently Professor of Eminence and Senior Consultant at the International Centre for Genetic Engineering and Biotechnology.

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