Vervet Monkeys Vaccinated with Killed Leishmania major Parasites and Interleukin-12 Develop a Type 1 Immune Response but Are Not Protected against Challenge Infection (original) (raw)
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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 anima...
Vaccine-induced protection against Leishmania amazonensis is obtained in the absence of IL-12/23p40
Immunology letters, 2006
Protozoa of the genus Leishmania are intracellular parasites of macrophages and may cause diverse clinical forms of leishmaniasis, including cutaneous, diffuse cutaneous, mucocutaneous and visceral leishmaniasis. Infection with L. major in mice indicates that a protective immune response is achieved when Th1 cells are developed. Thus, adoptive or vaccine-induced protection against leishmaniasis is largely dependent on cell-mediated immunity and IFN-␥ production. Induction of a Th1 response is dependent on the presence of IL-12 whilst lymphocytes are activated. This study was aimed at evaluating the role of IL-12 during infection with L. amazonensis and after vaccination with Leishvacin ® (killed Leishmania amazonensis promastigotes), since the role of this cytokine in vaccine-induced immunity with this preparation in experimental models or in humans is not yet elucidated. Hence, C57BL/6 interleukin-12-deficient mice (IL-12p40 −/−) and wild-type controls (wt) were infected with L. amazonensis and the course of infection, parasite burden and cytokine production were compared. IL-12p40 −/− mice were more susceptible to L. amazonensis than wt: lesions and parasite burden were larger in IL-12p40 −/− when compared to wt. Interestingly, IL-4 was not produced in the absence of IL-12 in response to infection with L. amazonensis. To evaluate the role of IL-12 in the vaccine-induced immunity against L. amazonensis infection, IL-12p40 −/− wt mice were vaccinated in the base of the tail and subsequently challenged with L. amazonensis in the footpads. Surprisingly, vaccinated IL-12p40 −/− mice developed smaller lesions and had fewer parasites in footpads than non-vaccinated controls. Lymph node and spleen cells from vaccinated IL-12p40 −/− mice did not produce high levels of IFN-␥ in response do in vitro stimulus with antigen. Hence, partial protection against infection with L. amazonensis could be obtained in the absence of functional IL-12 and a typical Th1 response.
Journal of immunology (Baltimore, Md. : 1950), 1999
Protection from cutaneous leishmaniasis, a chronic ulcerating skin lesion affecting millions, has been achieved historically using live virulent preparations of the parasite. Killed or recombinant Ags that could be safer as vaccines generally require an adjuvant for induction of a strong Th1 response in murine models. Murine rIL-12 as an adjuvant with soluble Leishmania Ag has been shown to protect susceptible mice. We used 48 rhesus macaques to assess the safety, immunogenicity, and efficacy of a vaccine combining heat-killed Leishmania amazonensis with human rIL-12 (rhIL-12) and alum (aluminum hydroxide gel) as adjuvants. The single s.c. vaccination was found to be safe and immunogenic, although a small transient s.c. nodule developed at the site. Groups receiving rhIL-12 had an augmented in vitro Ag-specific IFN-gamma response after vaccination, as well as increased production of IgG. No increase in IL-4 or IL-10 was found in cell culture supernatants from either control or exper...
Interleukin-12 is indispensable for protective immunity against Leishmania major
Infection and immunity, 1997
Interleukin-12 (IL-12)-deficient mice derived from a strain genetically resistant to infection with Leishmania major were recently shown to be susceptible toward this parasite, developing a strong Th2 response after injection of a large number of parasites. We further investigated the role of IL-12 in L. major infection by studying the responses of mutant mice against smaller numbers of parasites. IL-12-deficient mice infected with only small numbers of parasites showed the progressive lesion development and high parasite burden associated with a polarized Th2 response. Our data show that IL-12 is indispensable for protective immunity against L. major. Even at low inocula, no salvage pathway appears to compensate for the lack of IL-12. However, genetically susceptible BALB/c mice infected with small numbers of parasites were able to resolve lesions and restrict the parasite burden to levels which were 10(5)-fold lower than those in IL-12-deficient mice. In contrast to mutant mice, B...
Memórias do Instituto Oswaldo Cruz, 2002
We have compared the efficacy of two Leishmania (Leishmania) major vaccines, one genetically attenuated (DHFR-TS deficient organisms), the other inactivated [autoclaved promastigotes (ALM) with bacillus Calmete-Guérin (BCG)], in protecting rhesus macaques (Macaca mulatta) against infection with virulent L. (L.) major. Positive antigen-specific recall proliferative response was observed in vaccinees (79% in attenuated parasite-vaccinated monkeys, versus 75% in ALM-plus-BCG-vaccinated animals), although none of these animals exhibited either augmented in vitro gamma interferon (IFN-γ) production or positive delayed-type hypersensitivity (DTH) response to the leishmanin skin test prior to the challenge. Following challenge, there were significant differences in blastogenic responses (p < 0.05) between attenuated-vaccinated monkeys and naïve controls. In both vaccinated groups very low levels of antibody were found before challenge, which increased after infective challenge. Protective immunity did not follow vaccination, in that monkeys exhibited skin lesion at the site of challenge in all the groups. The most positive result was in fact the lack of pathogenicity of the attenuated parasite, which persisted in infected animals for up to three months, but they were incapable of causing disease under the conditions employed. We concluded that both vaccine protocols used in this study are safe in primates, but require further improvement for vaccine application.
Scandinavian Journal of Immunology, 2012
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.
Journal of Biomedical Research, 2012
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.