Evaluación preclínica de antígenos candidatos a vacuna frente a la leishmaniasis visceral humana
Author
Fernández Fernández, LauraEntity
UAM. Departamento de Biología Molecular; Instituto de Salud Carlos III (ISCIII)Date
2017-09-12Subjects
Leishmaniasis; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 12-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 12-09-2023
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Leishmaniasis is a vector borne neglected tropical disease transmitted by females of
genus Phlebotomus and Lutzomya. With an annual incidence of 1.5 million cases, the
most severe clinical form, visceral leishmaniasis (VL) is producing between 20,000 and
40,000 deaths per year. There is no vaccine against human visceral leishmaniasis,
although it is considered that it would be the best cost-effectiveness measure for
disease control. In order to find an effective vaccine against human VL, in this thesis
work, we have studied the suitability of 4 Leishmania antigens as vaccine candidates:
LACK, KMP-11, and the two chimeric proteins Leish-F3 and Leish-F3+). We have
evaluated the presence of T-cell epitopes in these proteins and the type of immune
response that they were able to induce in PBMCs of individuals with immunological
memory against L. infantum. In addition, the efficacy of 11 different vaccine
formulations against L. infantum infection has been evaluated in the hamster model.
Two of them were DNA vaccines with the LACK antigen as an immunogen. The
remaining nine formulations, were multiprotein vaccines, in which the Leishmania
antigens KMP-11 and Leish-F3 or KMP-11 and Leish-F3+ were combined with the
vector salivary protein LJL-143. The antigens were combined or not with the adjuvant
GLA-SE, and included or not in virosomes as antigen delivery system. We found that
the Leishmania antigens had T-cell epitopes, and that they induced the specific
secretion of cytokines characteristic of the Th1 type response involved in disease
control as shown by numerous works. Regarding to efficacy trials carry out in hamster
model, the two DNA vaccines were found to be protective against L. infantum infection.
In the case of multiprotein vaccines, the inclusion of the virosomes and the adjuvant in
the final formulation made the combination of the KMP-11 (5μg), Leish-F3+ (5μg) and
LJL-143 (1μg) antigens was significantly effective against infection. In summary, the
two DNA-LACK vaccines evaluated generated protection in the hamster model,
suggesting that they are exceptional vaccine candidates to study in clinical trials; as
well as the multiprotein vaccine composed of KMP-11 (5 μg), Leish-F3 + (5 μg) and LJL-
143 (1 μg) formulated in virosomes in combination with GLA-SE. These results about
efficacy of multiprotein vaccines have been taken into account to begin clinical phase
studies in humans in the framework of the FP7European project “Mulevaclin”.
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