Leishmaniose visceral humana: reflexões éticas e jurídicas acerca do controle do reservatório canino no Brasil / Human visceral leishmaniasis: ethical and legal reflections on the canine reservoir control in Brazil

O Brasil enfrenta atualmente dificuldades no combatea leishmaniose visceral humana.De acordo a Organização Mundial da Saúde, a eutanásia dos cães sintomáticos e soropositivos é uma das medidas de controle do agravo, conforme decreto vigente 51.838, de 14 de março de 1963, o que se torna importantediscutir o diálogo entre Saúde e Direito como estratégia para se evitar a expansão da doença, devido à resistência dos proprietários em entregar seus cães, com alto valor afetivo, a zoonoses. Conclui-se que para uma política pública efetiva vários elementos devem levados em consideração, sobretudo a interdisciplinaridade, enfatizando reflexões jurídicas e saúde, envolvendo questões que permeiam as relações humanas no contexto da ética e da legislação (AU)

Brazil currently faces difficulties in combating human visceral leishmaniasis. According to the World Health Organization, euthanasia of symptomatic and seropositive dogs is one of injury control measures, according to current Decree 51838 of March 14, 1963, which becomes important to discuss the dialogue between health and law as a strategy to prevent the spread of the disease, due to the owners ' resistance to deliver their dogs with high emotional value, zoonoses. It is concluded that for effective public policy more elements are taken into consideration, especially interdisciplinary, emphasizing legal and health considerations involving issues that permeate the human relationships in the context of ethics and law (AU)

Adaptive immunity against Leishmania nucleoside hydrolase maps its c-terminal domain as the target of the CD4+ T cell-driven protective response.

Nucleoside hydrolases (NHs) show homology among parasite protozoa, fungi and bacteria. They are vital protagonists in the establishment of early infection and, therefore, are excellent candidates for the pathogen recognition by adaptive immune responses. Immune protection against NHs would prevent disease at the early infection of several pathogens. We have identified the domain of the NH of L. donovani (NH36) responsible for its immunogenicity and protective efficacy against murine visceral leishmaniasis (VL). Using recombinant generated peptides covering the whole NH36 sequence and saponin we demonstrate that protection against L. chagasi is related to its C-terminal domain (amino-acids 199-314) and is mediated mainly by a CD4+ T cell driven response with a lower contribution of CD8+ T cells. Immunization with this peptide exceeds in 36.73±12.33% the protective response induced by the cognate NH36 protein. Increases in IgM, IgG2a, IgG1 and IgG2b antibodies, CD4+ T cell proportions, IFN-γ secretion, ratios of IFN-γ/IL-10 producing CD4+ and CD8+ T cells and percents of antibody binding inhibition by synthetic predicted epitopes were detected in F3 vaccinated mice. The increases in DTH and in ratios of TNFα/IL-10 CD4+ producing cells were however the strong correlates of protection which was confirmed by in vivo depletion with monoclonal antibodies, algorithm predicted CD4 and CD8 epitopes and a pronounced decrease in parasite load (90.5-88.23%; p = 0.011) that was long-lasting. No decrease in parasite load was detected after vaccination with the N-domain of NH36, in spite of the induction of IFN-γ/IL-10 expression by CD4+ T cells after challenge. Both peptides reduced the size of footpad lesions, but only the C-domain reduced the parasite load of mice challenged with L. amazonensis. The identification of the target of the immune response to NH36 represents a basis for the rationale development of a bivalent vaccine against leishmaniasis and for multivalent vaccines against NHs-dependent pathogens.

FML vaccine against canine visceral leishmaniasis: from second-generation to synthetic vaccine.

The Leishmania donovani glycoprotein fraction, known as FML, successfully underwent preclinical and clinical (Phase I-III) vaccine trials against canine visceral leishmaniasis (92-95% of protection and 76-80% of vaccine efficacy) when formulated with a QS21 saponin-containing adjuvant. It became the licensed Leishmune vaccine for canine prophylaxis in Brazil. The immune response raised by the vaccine is long lasting, immunotherapeutic and reduces dog infectivity blocking the transmission of the disease, as revealed by an in vivo assay. The preliminary epidemiological control data of vaccinated areas in Brazil indicate that, in spite of the still low vaccine coverage, there was a significant decrease in the incidence of the human and canine disease. A 36-kDa glycoprotein, in the FML complex, is the human marker of the disease, which was protective in mice as native recombinant protein or DNA vaccine. The DNA vaccine is now being tested against the canine disease. This review resumes the development of the second-generation FML-saponin-Leishmune vaccine, its adjuvant and of the NH36 DNA vaccine, toward the identification of its major epitopes that might be included in a possible future synthetic vaccine.

Improving methods for epidemiological control of canine visceral leishmaniasis based on a mathematical model: impact on the incidence of the canine and human disease

O modelo matemático descrito por Dye (1996) condenava a campanha de controle do calazar canino por considerá-la ineficaz. Usando esse modelo, demonstramos matematicamente que a ineficácia somente ocorre com valores baixos de k (índice de remoção de cães infecciosos pela campanha de controle), que coincide com os valores de soropositividade detectados no campo, pelo método de imunofluorescência (IF) em eluatos. Aplicando valores maiores de k, o controle se tornaria eficaz: valores de k correspondentes a IF (k = 0.07) ou ELISA em soros (k = 0.25) diminuiriam o numero de cães infecciosos, levando o valor de Ro a 1 ou 0 respectivamente, impedindo com isso a transmissão e o avanço da epidemia. Demonstramos experimentalmente que a remoção de cães conforme os resultados de IF nos soros em lugar de eluatos diminuiu 57% dos casos caninos (p < 0.005) e de 87.5% dos casos humanos (p < 0.005). Os nossos resultados, demonstram que a campanha de controle se torna eficaz aumentando a sensibilidade do método diagnóstico.

Improving methods for epidemiological control of canine visceral leishmaniasis based on a mathematical model. Impact on the incidence of the canine and human disease.

The mathematical model described by Dye (1996) condemned the epidemiological canine visceral leishmaniasis control campaign, considering it non-efficient. Using this model, we mathematically demonstrate that the control is not efficient, only at low kappa values (rate at which latent and infectious dogs are lost by the destruction program) which match the canine seropositivity observed in the field by the immunofluorescency (IF) blood eluates analysis. With higher k values, corresponding to IF (kappa = 0.07) or ELISA (kappa = 0.25) results in sera samples, the number of infectious dogs declines to a Ro =1 or Ro =0, respectively, interrupting the transmission and the advancement of epidemics. We also experimentally demonstrate that the dog removal, following the results of IF of sera, instead of eluates lead to a 57% (p < 0.005) decrease in canine cases and 87.5% (p < 0.005) in human cases. Our mathematical and experimental results indicate that the control campaign become more efficient by enhancing the sensitivity of the diagnostic assay.