M M Gicheru

Kenyatta University, Nairoba, Nairobi Area, Kenya

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Publications (43)73.05 Total impact

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    ABSTRACT: Our current understanding of the host immune response during leishmaniases largely derives from studies performed in mice due to the intrusive techniques required to study infected human patients. Swiss mice are highly resistance to Leishmania infections in concordance with observed response in humans while BALB/c mice indicate a high susceptibility phenotype. Developing a cross-breed between BALB/c and Swiss mice may have important consequences on disease development, immune responses and parasite killing, as yet, response of the cross-breed to Leishmania infection is superficial. The aim of the present study was to determine disease course and immune responses in F1 cross-breed between BALB/c and Swiss albino mice infected with L. major. Three mice groups were infected intradermaly with stationary phase L. major parasites with parental strains (BALB/c and Swiss albino) as controls. Lesion development was monitored weekly for 8 weeks and Monocyte chemotactic protein (MCP-1), Macrophage inflammatory protein (MIP-1α), Interferon gamma (IFN-γ) and IgG antibody quantified by enzyme-linked Immunosorbent assay. The data was analyzed using one-way analysis of variance and Tukey's-Kramer test. Results indicated F1 mice having intermediate lesion sizes, type 1 cytokine levels and footpad parasite loads as compared to the parental strains. However the F1 mice had low levels of IgG antibodies and parasite burden in the spleen. (P < 0.05). This study concludes that the F1 cross-breed between resistant and susceptible mice may be used as a requisite model to study the role of genetics in Leishmaniases and perhaps other intracellular parasites. This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 02/2014; · 2.20 Impact Factor
  • International Journal of Morphology. 12/2013; 31(4):1322-1327.
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    ABSTRACT: The enumeration of absolute CD4 counts is of primary importance for many medical conditions especially HIV infection where therapeutic initiation depends on the count. These ranges tend to vary across populations. However, these ranges have not been comprehensively established in the Kenyan population. Therefore, this study aimed at establishing the reference ranges for the CD4 and CD8 T-lymphocytes in normal healthy individuals in Kenya. A total of 315 individuals of the ages between 16 and 60 years old, in 5 different regions of the country, were recruited into the study. They were screened for diseases that potentially cause lymphocyte homeostasis perturbation. CD4/CD8 Counts were performed by use of a FACSCalibur flow cytometer (Becton-Dickinson, NJ) equipped with automated acquisition and analysis software. Results were analysed according to age, sex and region. Results were presented as means and ranges (in parenthesis) generated non parametrically as 2.5 and 97.5 percentiles as follows; In general population; CD3 1655 (614-2685 cells/muL ), CD4 920 (343-1493cells/muL), and CD8 646 (187-1139cells/muL), while according to sex, females; CD3 1787 (697-2841 cells/muL), CD4 1010 (422-1572 cells/muL), CD8 659 (187-1180 cells/muL); males; CD3 1610 (581-2641 cells/muL), CD4 889(320-1459 cells/muL) and CD8 644 (185-1140 cells/muL). The general reference ranges for CD4/CD8 ratios were as follows; general population 1.57(0.50-2.74), males 1.51(0.49-2.64) and females 1.69(0.55-2.95). The lymphocyte reference ranges for the Kenyan population are fairly comparable to those established in other African populations. The ranges also differ appreciably from those established in Germany, Italy and Switzerland. Furthermore, the study reported significant differences in the ranges of different population clusters within Kenya, as well us between males and females.
    AIDS Research and Therapy 11/2013; 10(1):24. · 2.54 Impact Factor
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    ABSTRACT: Hepatitis B virus (HBV) and Hepatitis C virus (HCV) co-infections among HIV-1 infected individuals are growing worldwide health problems characterized by lack of effective vaccines, need for expensive treatment, chronicity of morbidity and associated mortality. Their prevalence and distribution patterns continue to vary across geographical locations with high prevalence being detected among high risk populations. To determine the prevalence of HBV and HCV among HIV-1 infected individuals, blood samples were collected from consenting study subjects visiting comprehensive HIV clinics in Nairobi during the period between October and December 2009. Blood samples from volunteers were screened with ELISA tests for detecting HIV, HBV surface antigen (HBsAg) and anti-HCV antibodies. In a total of three (300) hundred infected individuals consisting of 129 (43%) males and 171 (57%) females 15.3% (46/300) were HIV-1 co-infected with either HBV or HCV or both, 10.3% (31/300) with HIV-1 and HCV and 6% (18/300) with HIV-1 and HBV infections. However, only three individuals (1%) were coinfected with the three viruses (HIV/HBV/HCV). Though, low levels of co-infection with all three viruses were reported, there could be higher prevalence rates than reported here especially among high risk populations.
    BMC Research Notes 09/2013; 6(1):363.
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    ABSTRACT: Although there is currently no vaccine against leishmaniasis in routine use anywhere in the world, cases of self cure in cutaneous leishmaniasis, accompanied by solid immunity to reinfection, make vaccine development a feasible control method. Immunity against visceral leishmaniasis is mediated by IFN-γ-inducing parasite specific CD4+ and CD8+ T cells. We assessed the capacity of Leishmania donovani sonicate antigen delivered with alum-BCG (AlBCG), monophosphoryl lipid A (MPL) or montanide ISA 720 (MISA) to induce parasite specific CD4+ and CD8+ T cells involved in IFN-γ production following immunization of groups of the vervet monkey model of visceral leishmaniasis. Groups of vervet monkeys were immunized intradermally at three time points on days 0, 28 and 42 and T cell populations involved in the production of IFN-γ measured 21 days after final immunization. Significantly higher CD4+ T cells were induced in the group immunized with MISA+Ag compared to the AlBCG+Ag immunized animals (P<0.01) with both groups inducing significantly more CD4+ T cells than other groups (P<0.0001). Levels of CD8+ T cells were comparable between AlBCG+Ag and MISA+Ag groups, being significantly higher compared to the MPL+Ag group (P<0.001). The CD4+ T cells significantly correlated positively with CD8+ T cells in the studied groups (r=1.00; P=0.0167). We conclude that, immunization with MISA+Ag induces robust CD4+ as well as CD8+ T cells involved in the production of IFN-γ indicating stronger ability of this adjuvant over AlBCG in directing cellular immune response in the vervet monkey model. Keywords: Immunization; Adjuvants; CD4+ Th1 and CD8+ T cells; Th1 immune response; Visceral leishmaniasis; Vervet monkey model.
    scientia parasitologica. 03/2013; 14(1):7-9.
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    ABSTRACT: Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. Resistance to infection is associated with 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 chemotherapeutic 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-attenuated 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.
    Journal of biomedical research. 03/2013; 27(2):85-102.
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    Retrovirology 09/2012; 9(2). · 5.66 Impact Factor
  • J M Mutiso, J C Macharia, M M Gicheru
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    ABSTRACT: The availability of hundreds of adjuvants has prompted a need for identifying rational standards for the selection of adjuvant formulation based on sound immunological principles for human vaccines. As cytokines elaborated by activated T cells are required for the regulation of isotype switch during B-cell development, a study of Th2 cytokines and subclass distribution of the antibodies may shed new light on the processes involved in the polarization of the immune responses during vaccination studies. The aim of this study was to identify an appropriate Leishmania vaccine adjuvant based on low Th2 cytokine and high value IgG2 antibody responses. Groups of vervet monkeys were immunized with Leishmania donovani sonicate antigen (Ag) alone or in conjunction with alum-BCG (AlBCG), monophosphoryl lipid A (MPL) or montanide ISA 720 (MISA) as adjuvants. Following three time point intradermal injections on days 0, 28 and 42, IL-4, IL-10 and IgG antibody subclasses were quantified by enzyme-linked immunosorbent assay (ELISA) and data analysed by one-way analysis of variance, Tukey-Kramer test and Spearman's rank correlation analysis. Results indicated relatively higher IL-4 and IL-10 cytokine responses following MPL + Ag as compared to AlBCG + Ag or MISA + Ag immunization. There was a positive significant correlation between IL-4 and IL-10 levels (r = 1.000; P = 0.0167). Significantly higher IgG2 antibody responses were associated with either AlBCG + Ag or MISA + Ag as compared to MPL + Ag immunization (P < 0.05). The study concludes that both AlBCG and MISA may be used in Leishmania vaccine studies that favour low Th2 cytokine and strong IgG2 antibody responses.
    Scandinavian Journal of Immunology 08/2012; 76(5):471-7. · 2.20 Impact Factor
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    ABSTRACT: Malaria parasites are known to mediate the induction of inflammatory immune responses at the maternal-foetal interface during placental malaria (PM) leading to adverse consequences like pre-term deliveries and abortions. Immunological events that take place within the malaria-infected placental micro-environment leading to retarded foetal growth and disruption of pregnancies are among the critical parameters that are still in need of further elucidation. The establishment of more animal models for studying placental malaria can provide novel ways of circumventing problems experienced during placental malaria research in humans such as inaccurate estimation of gestational ages. Using the newly established olive baboon (Papio anubis)-Plasmodium knowlesi (P. knowlesi) H strain model of placental malaria, experiments were carried out to determine placental cytokine profiles underlying the immunopathogenesis of placental malaria. Four pregnant olive baboons were infected with blood stage P. knowlesi H strain parasites on the one fiftieth day of gestation while four other uninfected pregnant olive baboons were maintained as uninfected controls. After nine days of infection, placentas were extracted from all the eight baboons through cesarean surgery and used for the processing of placental plasma and sera samples for cytokine sandwich enzyme linked immunosorbent assays (ELISA). Results indicated that the occurrence of placental malaria was associated with elevated concentrations of tumour necrosis factor alpha (TNF-{\alpha}) and interleukin 12 (IL-12). Increased levels of IL-4, IL-6 and IL-10 and interferon gamma (IFN-{\gamma}) levels were detected in uninfected placentas. These findings match previous reports regarding immunity during PM thereby demonstrating the reliability of the olive baboon-P. knowlesi model for use in further studies.
    06/2012;
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    ABSTRACT: In this study, we report on the safety and skin delayed-type hypersensitivity (DTH), responses of the Leishmania donovani whole cell sonicate antigen delivered in conjunction with alum-BCG (AlBCG), Montanide ISA 720 (MISA) or Monophosphoryl lipid A (MPLA) in groups of vervet monkeys. Following three intradermal injections of the inoculums on days 0, 28 and 42, safety and DTH responses were assessed. Preliminary tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were also measured and these were compared with DTH. Only those animals immunized with alum-BCG reacted adversely to the inoculum by producing ulcerative erythematous skin indurations. Non-parametric analysis of variance followed by a post-test showed significantly higher DTH responses in the MISA+Ag group compared with other immunized groups (p < 0.001). The MPLA+Ag group indicated significantly lower DTH responses to the sonicate antigen compared with the AlBCG+Ag group. There was a significant correlation between the DTH and cytokine responses (p < 0.0001). Based on this study we conclude that Leishmania donovani sonicate antigen containing MISA 720 is safe and is associated with a strong DTH reaction following immunization.
    Revista do Instituto de Medicina Tropical de São Paulo 02/2012; 54(1):37-41. · 0.96 Impact Factor
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    ABSTRACT: 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 (AlBCG), 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 producing ulcerative erythematous skin indurations. Non-parametric ANOVA followed by a post test showed significantly higher IgG antibodies, and revealed the presence of lymphoproliferative and interferon gamma responses in both AlBCG+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.
    Journal of biomedical research. 01/2012; 26(1):8-16.
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    ABSTRACT: A live, attenuated vaccine is currently the only viable option to control of CBPP in Africa. It has been suggested that simple modifications to current vaccines and protocols might improve efficacy in the field. In this report we compared the current vaccine formulation with a buffered preparation that maintains Mycoplasma viability at ambient temperature for a longer time. Groups of animals were vaccinated with the two formulations and compared with non vaccinated groups. Half of the animals in each group were challenged 3 months post vaccination, the other half after 16 months. Protection levels were measured using the pathology index, calculated from post mortem scores of lesions from animals killed during the course of clinical disease. In the challenge at 3 months post vaccination, the protection levels were 52% and 77% for the modified and current vaccine preparations, respectively. At 16 months post vaccination, the protection levels were 56% and 62% for the modified and current vaccine preparations, respectively. These findings indicate that there are no differences in protection levels between the two vaccines. Because of its longer half life after reconstitution, the modified vaccine might be preferred in field situations where the reconstituted vaccine is likely not to be administered immediately.
    Research in Veterinary Science 09/2011; 93(2):568-73. · 1.77 Impact Factor
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    ABSTRACT: HIV genetic recombination and high mutation rate increase diversity allowing it to escape from host immune response or antiretroviral drugs. This diversity has enabled specific viral subtypes to be predominant in specific regions. To determine HIV-1 subtypes among seropositive antenatal clinic attendees in Kenya's North Rift Valley, a cross-sectional study was carried out on 116 HIV-1-positive blood samples. Proviral DNA was extracted from peripheral blood mononuclear cells by DNAzol lysis and ethanol precipitation. Polymerase chain reactions using specific primers for HIV-1 gag and population sequencing on resulting amplicons were carried out. Phylogenetic analysis revealed that 81 (70%) were subtype A1, 13 (11%) subtype D, 8 (7%) subtype C, 3 (3%) subtype A2, 1 (1%) subtype G, and 10 showed possible recombinants: 5 (4%) subtype A1D, 4 (3%) subtype A1C, and 1 (1%) subtype A2C. These data support the need to establish circulating subtypes for better evaluation of effective HIV diagnostic and treatment options in Kenya.
    AIDS research and human retroviruses 08/2011; 28(5):523-6. · 2.18 Impact Factor
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    ABSTRACT: Unhygienic practices have been associated with the spread of parasitic and bacterial infections in rural areas. This study was designed to verify the link between the frequencies of malaria and typhoid fever with selected rural practices in Njoro District, Kenya. A cross-sectional study involving observations, questionnaires and interviews was conducted to determine the socio-economic variables and practices/lifestyles in 336 randomly selected homesteads. Frequencies of malaria and typhoid fever in two randomly selected health centers were determined through a retrospective study for the period from 2004 to 2009. The respondents had large families (68%), low education level (67%) and high responsibility burden (67%). Individuals who did not boil drinking water constituted 61%. Boiling drinking water was less common among the poor, Odds Ratio (OR) of 2.36, χ(2) = 9.88, 95% Confidence Interval (CI) of 1.38-4.03. Respondents who washed their hands in a basin after using the latrines comprised 79.8% while 4.8% did not. 18.5% of the respondents did not use a soap to wash their hands after using the latrine. One third (33.6%) of the homesteads had dirty and inappropriate pit latrines while 2.7% of the homesteads lacked latrines. Failure to use mosquito bed nets was more likely to occur among the poor respondents, OR of 1.44, χ(2) = 1.74, 95% CI of 0.84-2.48. The frequencies of malaria and typhoid fever were an average of 29 and 24% respectively. Malaria and typhoid fever cases were relatively frequent due to adoption of inappropriate lifestyles and practices that predisposed the residents to infectious agents. Poverty seemed to play a significant role in the spread of malaria and typhoid fever.
    Journal of Community Health 07/2011; 37(1):224-33. · 1.28 Impact Factor
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    ABSTRACT: The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be 2.28 ± 0.24 µg/mL while those of Dim and Art were 9.16 ± 0.3 µg/mL and 4.64 ± 0.48 µg/mL respectively. The IC50 for Amphot B was 0.16 ± 0.32 µg/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly (p < 0.001) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower (p < 0.05) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.
    Revista do Instituto de Medicina Tropical de São Paulo 06/2011; 53(3):129-32. · 0.96 Impact Factor
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    International Journal of Morphology 06/2011; 29(2):353-362. · 0.21 Impact Factor
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    ABSTRACT: African bovine trypanosomiasis caused by Trypanosoma sp., is a major constraint on cattle productivity in sub-Saharan Africa. Some African Bos taurus breeds are highly tolerant of infection, but the potentially more productive Bos indicus zebu breeds are much more susceptible. Zebu cattle are well adapted for plowing and haulage, and increasing their tolerance of trypanosomiasis could have a major impact on crop cultivation as well as dairy and beef production. We used three strategies to obtain short lists of candidate genes within QTL that were previously shown to regulate response to infection. We analyzed the transcriptomes of trypanotolerant N'Dama and susceptible Boran cattle after infection with Trypanosoma congolense. We sequenced EST libraries from these two breeds to identify polymorphisms that might underlie previously identified quantitative trait loci (QTL), and we assessed QTL regions and candidate loci for evidence of selective sweeps. The scan of the EST sequences identified a previously undescribed polymorphism in ARHGAP15 in the Bta2 trypanotolerance QTL. The polymorphism affects gene function in vitro and could contribute to the observed differences in expression of the MAPK pathway in vivo. The expression data showed that TLR and MAPK pathways responded to infection, and the former contained TICAM1, which is within a QTL on Bta7. Genetic analyses showed that selective sweeps had occurred at TICAM1 and ARHGAP15 loci in African taurine cattle, making them strong candidates for the genes underlying the QTL. Candidate QTL genes were identified in other QTL by their expression profile and the pathways in which they participate.
    Proceedings of the National Academy of Sciences 05/2011; 108(22):9304-9. · 9.74 Impact Factor
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    ABSTRACT: This work reports the anti-plasmodial activities of Warburgia ugandensis and Zanthoxylum usambarense commonly used as phytomedicines against malaria by some Kenyan communities. To determine the anti-plasmodial activities of extracts from Warburgia ugandensis and Zanthoxylum usambarense against Plasmodium knowlesi and Plasmodium berghei. Eight plant extracts were screened for in vitro anti-plasmodial activity against Plasmodium knowlesi, in a 96-well plate incubated at 37 degrees C on a RPMI culture medium supplemented with baboon serum. Of the eight, three were investigated for prophylactic and curative activities in BALB/c mice against drug-sensitive Plasmodium berghei in a 4-day test at a dose rate of 200mg/kg/day. Inhibitory concentrations (IC(50)) values of between 3.14 and 75 microg/ml, up to 69% chemosuppression of parasites growth and over 80% survivorship of treated mice were observed. The two medicinal plants, Warburgia ugandensis and Zanthoxylum usambarense possess bioactive compounds against malaria parasites and could be exploited for further development into malaria therapy.
    Journal of ethnopharmacology 04/2010; 130(1):158-62. · 2.32 Impact Factor
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    ABSTRACT: Pregnant women have increased susceptibility to malaria infection. In these women, malaria parasites are frequently found sequestered in the placental intervillous spaces, a condition referred to as placental malaria (PM). Placental malaria threatens the health of the mother and the child's life by causing still births and reduction in gestational age. An estimated 24 million pregnant women in Sub-Saharan Africa are at risk. Mechanisms responsible for increased susceptibility in pregnant women are not fully understood. Pregnancy malaria studies have been limited by the lack of a suitable animal model. This research aimed to develop a baboon (Papio anubis) model for studying PM. The pregnancies of three adult female baboons were synchronized and their gestational levels confirmed by ultrasonography. On the 150th day of gestation the pregnant baboons were infected with Plasmodium knowlesi H strain parasites together with four nulligravid control baboons. Parasitaemia was monitored from two days post inoculation until the 159th day of gestation when caesarean section was done on one baboon in order to obtain the placenta. Two baboons aborted their conceptus. Smears prepared from placental blood demonstrated the presence of Plasmodium knowlesi parasites in all the three sampled placentas. These new finding shows that P. knowlesi sequesters in the baboon placenta. In addition, this study has characterized haemoglobin, eosinophil, Immunoglobulin G and Immunoglobulin M changes in this model. Thus a non human primate (baboon) model for studying PM has been established. The established baboon - P. knowlesi model for studying human placental/pregnancy malaria now offers an opportunity for circumventing the obstacles experienced during human studies like inaccurate estimation of gestational, moral, ethical and financial limitations.
    International Journal of Integrative Biology. 01/2010;
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    Joshua M Mutiso, John C Macharia, Michael M Gicheru
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    ABSTRACT: 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.
    Journal of biomedical research. 01/2010; 24(1):16-25.

Publication Stats

252 Citations
73.05 Total Impact Points

Institutions

  • 2009–2014
    • Kenyatta University
      • Department of Zoological Sciences
      Nairoba, Nairobi Area, Kenya
  • 2012
    • Kenya Medical Research Institute
      Nairoba, Nairobi Area, Kenya
  • 2001–2012
    • Institute of Primate Research
      Nairoba, Nairobi Area, Kenya
  • 1995–2008
    • National Museums of Kenya
      Nairoba, Nairobi Area, Kenya