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A review of adjuvants forLeishmania vaccine candidates

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The Journal of Biomedical Research 2010年第1期24卷 16-25页

作者： Joshua M.Mutiso john C.macharia Michael M.Gicheru Department of Tropical and Infectious Diseases Institute of Primate ResearchNational Museums of Kenya Department of Zoological Sciences School of Pure and Applied SciencesKenyatta University

Over the last decade, there has been a flurry of research on adjuvants for vaccines, and several novel adjuvants are now licensed products or in late stage clinical development. The success of adjuvants in enhancing the immune response to antigens has led many researchers to re-focus their vaccine development programs. Although several vaccine candidates have been tested against leishmaniasis, there is yet no effective vaccine against this parasitic disease. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to lack of an appropriate adjuvant. In view of this, this review paper outlines some of the adjuvants that have been used in Leishmania vaccine candidates and cites a few of the responses obtained from these studies. The aim of the present review is to consolidate these findings to facilitate the application of these adjuvants in general and experimental vaccinology.

关键词： adjuvants Leishmania vaccines immune responses leishmaniasis.

Leishmania donovani whole cell antigen delivered with adjuvants protects against visceral leishmaniasis in vervet monkeys (Chlorocebus aethiops)

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The Journal of Biomedical Research 2012年第1期26卷 8-16页

作者： Joshua Muli Mutiso john Chege macharia Evans Taracha Michael Muita Gicheru Department of Tropical and Infectious Diseases Institute of Primate Research Department of Zoological Sciences Kenyatta University

In a previous immunogenicity and efficacy study in mice, montanide ISA 720 （MISA） was indicated to be a better adjuvant than bacillus calmette guerin vaccine （BCG） for a Leishmania vaccine. In the present study, we report the safety, immunogenicity and efficacy of Leishmania donovani （L. donovani） sonicated antigen delivered with alum-BCG （A1BCG）, MISA or monophosphoryl lipid A （MPLA） in vervet monkeys following intradermal inoculums. Vaccinated and control animals were challenged with virulent L. donovani parasites and the parasitic burden was determined. Only animals vaccinated with alum-BCG adversely reacted to the inoculum by produc- ing ulcerative erythematous skin indurations. Non-parametric ANOVA followed by a post test showed signifi- cantly higher IgG antibodies, and revealed the presence of lymphoproliferative and interferon gamma responses in both AIBCG＋Ag and MISA＋Ag as compared to the MPLA＋Ag or other groups （P 〈 0.001）. We conclude that L. donovani sonicated antigen containing MISA is safe and is associated with protective immune response against Leishmania donovani infection in the vervet monkey model.

关键词： visceral leishmaniasis Leishmania donovani vervet monkey sonicated antigen adjuvants

Development ofLeishmania vaccines:predicting the future from past and present experience

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The Journal of Biomedical Research 2013年第2期27卷 85-102页

作者： Joshua Muli Mutiso john Chege macharia Maria Ndunge Kiio James Maina Ichagichu Hitler Rikoi Michael Muita Gicheru Department of Tropical and Infectious Diseases Institute of Primate Research Department of Zoological Sciences Kenyatta University

Leishmaniasis is a disease that ranges in severity infection. Resistance to infection is associated with from skin lesions to serious disfigurement and fatal systemic a T-helper-1 immune response that activates macrophages to kill the intracellular parasite in a nitric oxide-dependent manner. Conversely, disease progression is generally associated with a T-helper-2 response that activates humoral immunity. Current control is based on chemothera- peutic treatments which are expensive, toxic and associated with high relapse and resistance rates. Vaccination remains the best hope for control of all forms of the disease, and the development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunization with defined subunit vaccines or live-at- tenuated strains of Leishmania. However, to date, no vaccine is available despite substantial efforts by many laboratories. Major impediments in Leishmania vaccine development include： lack of adequate funding from national and international agencies, problems related to the translation of data from animal models to human disease, and the transition from the laboratory to the field. Furthermore, a thorough understanding of protective immune responses and generation and maintenance of the immunological memory, an important but least-studied aspect of antiparasitic vaccine development, during Leishmania infection is needed. This review focuses on the progress of the search for an effective vaccine against human and canine leishmaniasis.

关键词： Leishmania leishmaniasis vaccine immunization immune response

In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis

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The Journal of Biomedical Research 2015年第3期29卷 214-223页

作者： Samuel W.Mwololo Joshua M.Mutiso john C.macharia Alain J.Bourdichon Michael M.Gicheru Department of Zoological Sciences Kenyatta University Department of Tropical and Infectious Diseases Institute of Primate Research BPM Bulk Medicine and Pharmaceuticals Production TROPMED GMbH

The present study evaluated the in vitro activity and in vivo efficacy of diminazene combined with chloroquine as a potential drug against Leishmania donovani. Amphotericin B was used as a positive control drug. In vitro activity involved incubation of various drug concentrations with promastigotes or vero cells in culture before determination of parasite growth inhibition or cell death while in vivo evaluations involved infection of various mice groups with virulent L. donovani parasites and treatment with test drug compounds following disease establishment. Weight changes in experimental mice were also evaluated before infection and throughout the experiment. The results indicated that the diminazene-chloroquine combination was at least nine times more efficacious than individual drugs in killing promastigotes in culture. The diminazene-chloroquine combination was safer （Ld50=0.03±0.04） than Amphotericin B （Ld50=0.02±0.01）. Body weight in infected mice increased significantly （P=0.0007） from day 7 to day 37 following infection （P=0.026）. However, body weight remained comparable in all mice groups during treatment （P=0.16）. The diminazene-chloroquine combination significantly reduced splenic parasite numbers as compared to individual drug therapies （P=0.0001） although Amphotericin B was still more efficacious than any other treatment （P=0.0001）. Amongst the test compounds, the diminazene-chloroquine combination showed the lowest level of IgG antibody responses with results indicating significant negative correlation between antileishmanial antibody responses and protection against disease. These findings demonstrate the positive advantage and the potential use of a combined therapy of diminazene-chloroquine over the constituent drugs. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.

关键词： efficacy diminazene-chloroquine combination therapy Leishmania donovani visceral leishmaniasis BALB/c mice

Evaluation of the Therapeutic Potential of Warburgia ugandensis,Prunus africana,and Piliostigma thonningii against Leishmania donovani in vitro and in Balb/c Mice

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Journal of Zoological Research 2022年第4期4卷 1-6页

作者： Maria Divinah Mogaka Joshua M.Mutiso john C.macharia Rebecca M.Ayako Bernard Osero Michael M.Gicheru Department of Zoological Sciences of the School of Pure and Applied Sciences Kenyatta UniversityKenya Department of Tropical and Infectious Diseases Institute of Primate ResearchKenya Centre for Biotechnology Research and Development Kenya Medical Research InstituteKenya

Leishmaniasis is a zoonotic disease caused by protozoan parasites of the genus *** chemotherapy remains to be the most preferred measure against leishmaniasis despite being associated with high toxicity and relapse *** are also expensive and require hospitaliza***-based compounds provide a better treatment alternative because they are effective,cheap,and less associated with toxicity and *** study examined the therapeutic potential of Warburgia ugandensis,Prunus africana,and Piliostigma thonningii against Leishmania donovani infection in BALB/c ***-promastigote and toxicity studies were evaluated by incubating the test compound with promastigotes and Vero cells,*** was obtained from the mice for total immunoglobulin gamma(IgG)*** in vivo studies,the mice were infected with virulent Leishmania donovani then treated with methanolic extracts of Warburgia ugandensis,Prunus africana,and Piliostigma thonningii and control drug,pentostam(sodium stibogluconate).Treatment with the plant extracts and standard drug resulted to significant reduction in parasite *** in the mice treated with plant extracts were comparable to those treated with pentostam(P≥0.05).In the promastigote assay,all the test compounds killed more than half of the promastigotes at the highest concentration(500μg/mL).Warburgia ugandensis,***,and *** reduced the number of promastigotes from 2.0×10^(6) to 7.7×10^(3),72.0×10^(3),and 5.0×10^(3),*** had the lowest IC50(210μg/mL),followed by Warburgia ugandensis(IC50 of 270μg/mL).Piliostigma thonningii and *** were less toxic with IC50 of 720μg/mL and 500μg/mL,*** was low production of IgG antibodies following treatment with the plant extracts and high levels in the untreated control.

关键词： Promastigotes Amastigotes Toxicity Parasite burden IgG antibodies