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Longlasting insecticidal nets for prevention of Leishmania donovaniinfection in India and Nepal: Paired cluster randomised trial
(2011) Albert Picado; Shri Prakash Singh; Suman Rijal; Shyam Sundar; Bart Ostyn; François Chappuis; Surendra Uranw; Kamlesh Gidwani; Basudha Khanal; Madhukar Rai; Ishwari Sharma Paudel; Murari Lal Das; Rajiv Kumar; Pankaj Srivastava; Jean Claude Dujardin; Veerle Vanlerberghe; Elisabeth Wreford Andersen; Clive Richard Davies; Marleen Boelaert
Objective: To test the effectiveness of large scale distribution of longlasting nets treated with insecticide in reducing the incidence of visceral leishmaniasis in India and Nepal. Design: Paired cluster randomised controlled trial designed to detect a 50% reduction in incidence of Leishmania donovani infection. Setting: Villages in Muzaffarpur district in India and Saptari, Sunsari, and Morang districts in Nepal. Participants: 13 intervention and 13 control clusters. 12 691 people were included in the analysis of the main outcome (infection), and 19 810 were enrolled for the secondary (disease) end point. Intervention: Longlasting insecticidal nets (treated with deltamethrin) were distributed in the intervention clusters in December 2006. Main outcome measures: Infection was determined by direct agglutination test at 12 and 24 months after the intervention in those who had negative results (titre <1:1600) at baseline. The effect estimate was computed as the geometric mean of the risk ratios for seroconversion for each cluster pair (net/no net), with its 95% confidence interval. Formal tests of effect of no intervention were obtained with a paired t test. Results: There was no significant difference in the risk of seroconversion over 24 months in intervention (5.4%; 347/6372) compared with control (5.5%; 345/6319 people) clusters (risk ratio 0.90, 95% confidence interval 0.49 to 1.65) nor in the risk of clinical visceral leishmaniasis (0.99, 0.46 to 1.40). Adjustment for covariates did not alter these conclusions. Conclusions: There is no evidence that large scale distribution of longlasting insecticidal nets provides additional protection against visceral leishmaniasis compared with existing control practice in the Indian subcontinent. The observed effect was small and not significant, though the confidence intervals did not exclude a 50% change in either direction. Trial registration: Clinical Trials NCT 2005-015374.
Vaccine human clinical trial
(Elsevier, 2022) Bhawana Singh; Shyamali; Dharmendra Kumar Maurya; Rajiv Kumar; Shashi Bhushan Chauhan; Shyam Lal Mudavath; Ram Niwas Meena; Shyam Sundar; Om Prakash Singh
Globally incidence of infectious diseases has declined over the past decades, but still, they continue to have major public health and economic costs. Treatment of infectious diseases is complicated by patients’ late presentation at an advanced stage of their illness. Other challenges include high cost of treatment (drug and hospitalization) and increasing drug resistance. Because of this lack of effective, affordable, minimally toxic drug therapies, an effective vaccine to control infectious diseases is needed. The development of a prophylactic vaccine would prove to be the most effective strategy of disease control and one of the most cost-effective investments in the health sector. However, each newly developed vaccine needs to be evaluated for safety, immunogenicity, and prophylactic efficacy in humans before it is licensed for public use. In this book chapter, we discuss the key elements that should be considered to conduct the vaccine clinical trials against infectious diseases including COVID-19. © 2022 Elsevier Inc. All rights reserved.
Rapid accurate field diagnosis of Indian visceral leishmaniasis
(Elsevier B.V., 1998) Shyam Sundar; Steven G. Reed; Vijay P. Singh; Prasanna C. K. Kumar; Henry W. Murray
Background. A firm diagnosis of visceral leishmaniasis (kala-azar) requires demonstration of the parasite in organ aspirates or tissue biopsy samples. The aim of this prospective study was to assess the diagnostic usefulness of non-invasive testing for antibody to the leishmanial antigen K39 by means of antigen-impregnated nitrocellulose paper strips adapted for use under field conditions. Methods. One drop of peripheral blood is applied to the nitrocellulose strip. Three drops of test buffer (phosphate-buffered saline plus bovine serum albumin) are added to the dried blood. The development of two visible bands indicates presence of IgG anti-K39. 323 consecutive patients with suspected kala-azar referred to two specialist units in India, and 25 healthy controls, provided fingerstick blood samples for the test. Spleen aspirates were taken from 250 patients. Findings. Kala-azar was confirmed by microscopy of spleen-aspirate smears in 127 patients. The K39 strip test was positive in all 127; the estimated sensitivity was therefore 100% (95% CI 98-100). Four patients had positive strip tests but negative aspirate smears; all four responded to treatment for leishmaniasis. 217 individuals, including the 25 healthy controls, 73 patients with malaria or tuberculosis, and 119 spleen-aspirate-negative patients who had presumed malaria or cirrhosis (79) or no final diagnosis (40), had negative strip-test results. None of the 119 aspirate-negative patients developed evidence of kala-azar during 3-6 months of follow-up. The estimated specificity of the strip test was 98% (95-100; 217/221). Interpretation. Detection of anti-K39 by immunochromatographic strip testing is a rapid and non-invasive method of diagnosing kala-azar, which has good sensitivity and specificity and is well suited for use in field conditions.
An Insight Into Systemic Immune Response in Leishmania donovani Mediated Atypical Cutaneous Leishmaniasis in the New Endemic State of Himachal Pradesh, India
(Frontiers Media S.A., 2022) Lovlesh Thakur; Priyanka Madaan; Aklank Jain; Vinay Shankar; Ajeet Negi; Shashi Bhushan Chauhan; Shyam Sundar; Om Prakash Singh; Manju Jain
Leishmaniasis continues to afflict known and newer endemic sites despite global efforts towards its control and elimination. In this regard, the emergence of newer endemic sites with unusual disease formats is recognized wherein Leishmania donovani complex classically known to cause visceral disease is demonstrated to cause cutaneous manifestation. In this context, atypical cutaneous leishmaniasis (CL) cases caused by L. donovani genetic variants from the newer endemic state of Himachal Pradesh (HP) in India are beginning to be understood in terms of parasite determinants. The atypical CL manifestation further needs to be explored to define host immune correlates with a possible role in driving the unusual disease progression. In the given study, we performed comprehensive systemic-immune profiling of the atypical CL patients from the study area in HP, India, in comparison with the classical visceral leishmaniasis (VL) patients from the northeast region of India. The systemic immune response was studied using ELISA-based assessment of Th1, Th2, Th17, Treg, and Th22 specific plasma cytokine expression pattern and parasite-specific total serum IgG/IgG subclasses. The specified immune correlates are known to exhibit heterogeneous association with the different infecting parasite species, infection load, and co-lateral host immunopathology in classical CL and VL. In the atypical CL patient group, altered expression of IL-10 emerged as the key finding that could potentially fine-tune the Th1/Th17/Th22 effector cytokine axis towards a localized cutaneous manifestation. A reduced expression of IL-10 along with a high IFN-γ/IL-10 ratio as a readout of effective parasite killing defined atypical cutaneous outcome. In contrast, high circulatory IL-10 levels and a depressed IFN-γ/IL-10 ratio were seen in classical VL patients in line with an ineffective parasite-killing cytokine response. Overall, the study highlights new knowledge on host immune correlates in terms of cytokine expression pattern and IgG subclasses that underline atypical disease manifestation such that L. donovani, a generally visceralizing parasite species cause skin localized cutaneous lesions. Copyright © 2022 Thakur, Madaan, Jain, Shankar, Negi, Chauhan, Sundar, Singh and Jain.
Rifampicin induced thrombocytopenia
(2003) M. Rai; Akhila Srinivasan; Shyam Sundar; V.P. Singh
[No abstract available]
A proteomics screen implicates HSP83 and a small kinetoplastid calpain-related protein in drug resistance in Leishmania donovani clinical field isolates by modulating drug-induced programmed cell death
(2007) Baptiste Vergnes; Benjamin Gourbal; Isabelle Girard; Shyam Sundar; Jolyne Drummelsmith; Marc Ouellette
The therapeutic mainstay against the protozoan parasite Leishmania is still based on the antiquated pentavalent antimonials (Sb(V)), but resistance is increasing in several parts of the world. Resistance is now partly understood in laboratory isolates, but our understanding of resistance in field isolates is lagging behind. We describe here a comparative analysis of a genetically related pair of Sb(V)-sensitive and -resistant Leishmania donovani strains isolated from kala-azar patients. The resistant isolate exhibited cross-resistance to other unrelated Leishmania drugs including miltefosine and amphotericin B. A comparative proteomics screen has highlighted a number of proteins differentially expressed suggesting that programmed cell death (PCD) is modified in the resistant parasite. Indeed drug-induced PCD progression was altered in the SbM-resistant strain as determined using early and late markers of apoptosis. Two proteins, the heat shock protein HSP83 and the small kinetoplastid calpain-related protein (SKCRP14.1) were shown to be intimately implicated in the drug-induced PCD phenotype. HSP83 increased drug resistance and reduced drug-mediated PCD activation by interfering with the mitochondrial membrane potential, whereas SKCRP14.1 promoted antimonial-induced PCD but protected against miltefosine-induced PCD. This study highlights the important role of PCD in drug susceptibility/resistance in the protozoan parasite Leishmania. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
Antimony Resistant Leishmania donovani but Not Sensitive Ones Drives Greater Frequency of Potent T-Regulatory Cells upon Interaction with Human PBMCs: Role of IL-10 and TGF-β in Early Immune Response
(Public Library of Science, 2014) Rajan Guha; Shantanabha Das; June Ghosh; Shyam Sundar; Jean Claude Dujardin; Syamal Roy
In India the sand fly, Phlebotomus argentipes, transmitted parasitic disease termed kala-azar is caused by Leishmania donovani (LD) in humans. These immune-evading parasites have increasingly developed resistance to the drug sodium antimony gluconate in endemic regions.Lack of early diagnosis methods for the disease limits the information available regarding the early interactions of this parasite with either human tissues or cell lineages. We reasoned that peripheral blood mononuclear cells (PBMCs) from healthy human beings could help compare some of their immune signatures once they were exposed for up to 8 days, to either pentavalent antimony sensitive (SbS-LD) or resistant (SbR-LD) Leishmania donovani isolates.At day 2, PBMC cultures exposed to SbS-LD and SbR-LD stationary phase promastigotes had four and seven fold higher frequency of IL-10 secreting monocyte-macrophage respectively, compared to cultures unexposed to parasites. Contrasting with the CD4+CD25-CD127- type-1 T-regulatory (Tr1) cell population that displayed similar features whatever the culture conditions, there was a pronounced increase in the IL-10 producing CD4+CD25+CD127low/- inducible T-regulatory cells (iTregs) in the PBMC cultures sampled at day 8 post addition of SbR-LD.Sorted iTregs from different cultures on day 8 were added to anti-CD3/CD28 induced naïve PBMCs to assess their suppressive ability. We observed that iTregs from SbR-LD exposed PBMCs had more pronounced suppressive ability compared to SbS-LD counterpart on a per cell basis and is dependent on both IL-10 and TGF-β, whereas IL-10 being the major factor contributing to the suppressive ability of iTregs sorted from PBMC cultures exposed to SbS-LD. Of note, iTreg population frequency value remained at the basal level after addition of genetically modified SbR-LD lacking unique terminal sugar in surface glycan.Even with limitations of this artificial in vitro model of L. donovani-human PBMC interactions, the present findings suggest that SbR-LD have higher immunomodulatory capacity which may favour aggressive pathology. © 2014 Guha et al.
Th1 stimulatory proteins of Leishmania donovani: Comparative cellular and protective responses of rTriose phosphate isomerase, rProtein disulfide isomerase and relongation factor-2 in combination with rHSP70 against visceral leishmaniasis
(Public Library of Science, 2014) Anil Kumar Jaiswal; Prashant Khare; Sumit Joshi; Pramod Kumar Kushawaha; Shyam Sundar; Anuradha Dube
In visceral leishmaniasis, the recovery from the disease is always associated with the generation of Th1-type of cellular responses. Based on this, we have previously identified several Th1-stimulatory proteins of Leishmania donovani -triose phosphate isomerase (TPI), protein disulfide isomerase (PDI) and elongation factor-2 (EL-2) etc. including heat shock protein 70 (HSP70) which induced Th1-type of cellular responses in both cured Leishmania patients/hamsters. Since, HSPs, being the logical targets for vaccines aimed at augmenting cellular immunity and can be early targets in the immune response against intracellular pathogens; they could be exploited as vaccine/adjuvant to induce long-term immunity more effectively. Therefore, in this study, we checked whether HSP70 can further enhance the immunogenicity and protective responses of the above said Th1-stimulatory proteins. Since, in most of the studies, immunogenicity of HSP70 of L donovani was assessed in native condition, herein we generated recombinant HSP70 and tested its potential to stimulate immune responses in lymphocytes of cured Leishmania infected hamsters as well as in the peripheral blood mononuclear cells (PBMCs) of cured patients of VL either individually or in combination with above mentioned recombinant proteins. rLdHSP70 alone elicited strong cellular responses along with remarkable up-regulation of IFN-γ and IL-12 cytokines and extremely lower level of IL-4 and IL-10. Among the various combinations, rLdFISP70 + rLdPDI emerged as superior one augmenting improved cellular responses followed by rLdHSP70 + rLdEL-2. These combinations were further evaluated for its protective potential wherein rLdHSP70 + rLdPDI again conferred utmost protection ( 80%) followed by rLdHSP70 + rLdEL-2 (∼75%) and generated a strong cellular immune response with significant increase in the levels of iNOS transcript as well as IFN-γ and IL-12 cytokines which was further supported by the high level of lgG2 antibody in vaccinated animals. These observations indicated that vaccine(s) based on combination of HSP70 with Th1-stimulatory protein(s) may be a viable proposition against intracellular pathogens. © 2014 Jaiswal et al.
Evaluation of leishmania donovani protein disulfide isomerase as a potential immunogenic protein/vaccine candidate against visceral leishmaniasis
(2012) Pramod Kumar Kushawaha; Reema Gupta; Chandrav Dev Pati Tripathi; Shyam Sundar; Anuradha Dube
In Leishmania species, Protein disulfide isomerase (PDI) - a redox chaperone, is reported to be involved in its virulence and survival. This protein has also been identified, through proteomics, as a Th1 stimulatory protein in the soluble lysate of a clinical isolate of Leishmania donovani (LdPDI). In the present study, the molecular characterization of LdPDI was carried out and the immunogenicity of recombinant LdPDI (rLdPDI) was assessed by lymphocyte proliferation assay (LTT), nitric oxide (NO) production, estimation of Th1 cytokines (IFN-γ and IL-12) as well as IL-10 in PBMCs of cured/endemic/infected Leishmania patients and cured L. donovani infected hamsters. A significantly higher proliferative response against rLdPDI as well as elevated levels of IFN-γ and IL-12 were observed. The level of IL-10 was found to be highly down regulated in response to rLdPDI. A significant increase in the level of NO production in stimulated hamster macrophages as well as IgG2 antibody and a low level of IgG1 in cured patient's serum was observed. Higher level of IgG2 antibody indicated its Th1 stimulatory potential. The efficacy of pcDNA-LdPDI construct was further evaluated for its prophylactic potential. Vaccination with this construct conferred remarkably good prophylactic efficacy (~90%) and generated a robust cellular immune response with significant increases in the levels of iNOS transcript as well as TNF-α, IFN-γ and IL-12 cytokines. This was further supported by the high level of IgG2 antibody in vaccinated animals. The in vitro as well as in vivo results thus indicate that LdPDI may be exploited as a potential vaccine candidate against visceral Leishmaniasis (VL). © 2012 Kushawaha et al.
Longitudinal seroepidemiologic study of visceral leishmaniasis in hyperendemic regions of Bihar, India
(American Society of Tropical Medicine and Hygiene, 2009) Kamlesh Gidwani; Rajiv Kumar; Madhukar Rai; Shyam Sundar
We conducted a seroepidemiologic study of visceral leishmaniasis (VL) in hyperendemic communities in Bihar, India, to determine its seroprevalence. A direct agglutination test (DAT) and rK39 antigen strip test were used as serologic tests. Capillary blood samples were collected on filter papers from 870 healthy persons (574 and 296 from households with or without VL, respectively). Of these persons, 230 (26.43%) were positive by DAT (titer ≥ 1:1,600) and 120 (13.79%) were positive by the rK39 antigen strip test. During a two-year follow-up, 25 persons developed VL; 1 and 8 persons were positive by the rK39 strip test and DAT, respectively, and 1 was positive by both tests. Fifteen (2.57%) persons who were seronegative at baseline also developed VL. Disease occurred more among persons living in the same household (24 of 25). However, there was no significant difference in disease conversion among children (5-15 years of age) and adults (> 15 years of age). Seropositivity among asymptomatic persons is not a predictor for development of VL. Copyright © 2009 by The American Society of Tropical Medicine and Hygiene.

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