Study of the safety, immunogenicity and efficacy of attenuated and killed Leishmania (Leishmania) major vaccines in a rhesus monkey (Macaca mulatta) model of the human disease

Amaral, Verônica F.; Têva, Antônio; Oliveira-Neto, Manoel P.; Silva, A. J.; Pereira, M. S.; Cupolillo, Elisa; Porrozzi, Renato; Coutinho, S.; Pirmez, Claude; Beverley, Stephen M.; Grimaldi, Gabriel

doi:10.1590/s0074-02762002000700019

Cited by 62 publications

(43 citation statements)

References 28 publications

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“…long-term protection, the idea of using live-attenuated organisms as a vaccine against leishmaniasis has been pursued by several laboratories, but has been hampered by limited efficacy (11,22,23). We report here that lpg2 Ϫ parasites, which persist without causing overt cutaneous lesions (17), induce protection against virulent challenge in an experimental model, indicating that these parasites might be used as an attenuated vaccine for leishmaniasis.…”

Section: Discussionmentioning

confidence: 85%

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

The Journal of Immunology

119

115

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Long-term immunity to Leishmania may require the continued presence of parasites, but previous attempts to create attenuated parasites that persist without causing disease have had limited success. Since Leishmania major mutants that lack lipophosphoglycan and other secreted phosphoglycans, termed lpg2−, persist indefinitely in infected mice without inducing any disease, we tested their ability to provide protection to virulent L. major challenge. In response to leishmanial Ag stimulation, cells from lpg2−-infected mice produced minimal levels of IL-4 and IL-10, as well as very low levels of IFN-γ. Nevertheless, when BALB/c mice infected with lpg2− parasites were challenged with virulent L. major they were protected from disease. Thus, these findings report on attenuated parasites that may be used to induce long-term protection against leishmaniasis and indicate that the immunity induced can be maintained in the absence of a strong Th1 response.

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Section: Discussionmentioning

confidence: 85%

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

The Journal of Immunology

119

115

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“…Complete elimination of wild-type parasites from the livers of LdCen1 Ϫ/Ϫ immunized mice after virulent challenge, is superior to the protection induced by L. donovani BT1 Ϫ/Ϫ , the only other complete gene knockout strain reported to target VL, which reduced parasite level in liver by 75% of the level in naive challenged mice (12). The dhfr-ts Ϫ auxotropic L. major line was safe in both mice and rhesus monkeys but protected only the mice (4,5). Because the immune responses due to dhfr-ts Ϫ were not studied in those animals, it would be difficult to know if there were weakness in the mouse immune response that could have predicted failure in the monkey.…”

Section: Ldcen1mentioning

confidence: 99%

Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis

Selvapandiyan

Dey

Nylén

et al. 2009

The Journal of Immunology

152

203

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No vaccine is currently available for visceral leishmaniasis (VL) caused by Leishmania donovani. This study addresses whether a live attenuated centrin gene-deleted L. donovani (LdCen1−/−) parasite can persist and be both safe and protective in animals. LdCen1−/− has a defect in amastigote replication both in vitro and ex vivo in human macrophages. Safety was shown by the lack of parasites in spleen and liver in susceptible BALB/c mice, immune compromised SCID mice, and human VL model hamsters 10 wk after infection. Mice immunized with LdCen1−/− showed early clearance of virulent parasite challenge not seen in mice immunized with heat killed parasites. Upon virulent challenge, the immunized mice displayed in the CD4+ T cell population a significant increase of single and multiple cytokine (IFN-γ, IL-2, and TNF) producing cells and IFN-γ/IL10 ratio. Immunized mice also showed increased IgG2a immunoglobulins and NO production in macrophages. These features indicated a protective Th1-type immune response. The Th1 response correlated with a significantly reduced parasite burden in the spleen and no parasites in the liver compared with naive mice 10 wk post challenge. Protection was observed, when challenged even after 16 wk post immunization, signifying a sustained immunity. Protection by immunization with attenuated parasites was also seen in hamsters. Immunization with LdCen1−/− also cross-protected mice against infection with L. braziliensis that causes mucocutaneous leishmaniasis. Results indicate that LdCen1−/− can be a safe and effective vaccine candidate against VL as well as mucocutaneous leishmaniasis causing parasites.

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“…This justifies further investigation of first generation leishmaniasis candidate vaccines for therapeutic purposes. The accumulated evidence suggests that protective immunity followed by healing is attributed to the development of a strong Leishmania-specific CD4 + Th1 cell response, which produces and releases Th1 cytokines, mainly Interferon-γ, which has the ability of activating macrophages to inhibit and/or kill parasites (Amaral et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Comparative evaluation of phenol and thimerosal as preservatives for a candidate vaccine against American cutaneous leishmaniasis

Mayrink¹,

Tavares

Deus

et al. 2010

Mem. Inst. Oswaldo Cruz

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Study of the safety, immunogenicity and efficacy of attenuated and killed Leishmania (Leishmania) major vaccines in a rhesus monkey (Macaca mulatta) model of the human disease

Abstract: We have compared the efficacy of two Leishmania (Leishmania) major vaccines, one genetically attenuated (DHFR-TS deficient organisms)

Cited by 62 publications

References 28 publications

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis

Comparative evaluation of phenol and thimerosal as preservatives for a candidate vaccine against American cutaneous leishmaniasis

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