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Avalia????o em modelos animais de uma vacina para mal??ria utilizando como vetor de express??o o v??rus de febre amarela vacinal 17D

By Ana Carolina dos Reis Albuquerque Cajaraville

Abstract

O desenvolvimento de uma vacina para mal??ria ?? considerado atualmente uma prioridade em sa??de p??blica pelo impacto socioecon??mico e morbidade da doen??a com 250 milh??es de novos casos por ano. A vacina de febre amarela ?? considerada uma das vacinas mais bem sucedidas por sua imunogenicidade duradora obtida ap??s uma ??nica dose. Frente a elucida????o das respostas polivalentes dirigidas ao v??rus vacinal 17D, a utiliza????o do mesmo como vetor de express??o para ant??genos heter??logos t??m sido encorajada. Tendo em vista que febre amarela e mal??ria compartilham grandes zonas end??micas nos continentes americano e africano, a constru????o de uma vacina para mal??ria baseada no vetor de febre amarela 17D se tornou uma abordagem interessante. Foram constru??dos dois v??rus recombinantes contendo a prote??na heter??loga MSP-119de P. falciparum (FA17D/MSP-119fal) e P. vivax (FA17D/MSP-119vivax) entre os genes E/NS1 de FA. Esta prote??na ?? constitu??da de um fragmento de 19 kDa obtido ap??s o processamento proteol??tico da prote??na de superf??cie do merozo??ta 1 (MSP-1) durante a invas??o do eritr??cito e ?? descrita como alvo de anticorpos protetores em animais e pessoas imunes. Os v??rus recombinantes foram caracterizados in vitro quanto ?? capacidade proliferativa em c??lulas Vero, estabilidade gen??tica e express??o da prote??na heter??loga por microscopia confocal de imunofluoresc??ncia e western blotting. A imuniza????o de camundongos BALB/c e primatas n??o-humanos da esp??cie Saimiri sciureus foi usada para avaliar as constru????es quanto ?? imunogenicidade. Ambos os v??rus foram capazes de induzir a produ????o de anticorpos neutralizantes contra a FA, por??m em menores t??tulos do que os induzidos pelo v??rus vacinal 17DD. A indu????o de anticorpos espec??ficos para a prote??na heter??loga ap??s a imuniza????o com os diferentes v??rus recombinantes, tamb??m foi demonstrada e resultou em baixos t??tulos de IgG.em ambos os modelos. Os anticorpos induzidos no modelo com macacos Saimiri reconheceram a prote??na nativa do parasita em hem??cias infectadas por P. falciparum. No entanto, o desafio realizado neste modelo de primata n??o-esplenectomizado ap??s a imuniza????o com FA17D/MSP-119fal n??o gerou resultados conclusivos. Estes resultados sugerem a necessidade de aprimoramento da plataforma de express??o em busca de maior imunogenicidade.The development of a vaccine for malaria is currently considered a priority in public health due to the socioeconomic impact and morbidity of the disease with 250 million new cases registered every year. The yellow fever vaccine is considered one of the most successful vaccines for its longlasting immunogenicity obtained after a single dose. As a result of the elucidation of the polyvalent responses directed to YF17D vaccine virus, the use of this virus as an expression vector of heterologous antigens has been encouraged. Considering that yellow fever and malaria share the major endemic areas in American and African continents, the construction of a vaccine for malaria based on the yellow fever 17D vector became an interesting approach. Two recombinant viruses containing the heterologous protein MSP-119 from P. falciparum (YF17D/MSP-119fal) and P. vivax (YF17D/MSP-119vivax) inserted between the E/NS1 genes have been constructed. This protein consists of a 19 kDa fragment obtained after proteolytic processing of the merozoite surface protein 1 (MSP-1) during invasion of erythrocytes and is described as a target for protective antibodies in animals and immune people. Recombinant viruses were characterized in vitro for their proliferative capacity in Vero cells and genetic stability and expression of heterologous protein were assessed by confocal immunofluorescence and Western blotting. Immunization of BALB/c mice and non-human primate species Saimiri sciureus allowed the evaluation of the constructions in terms of immunogenicity. Both viruses were capable of inducing neutralizing antibodies to YF, but in lower titers than those induced by the vaccine virus 17DD.The induction of specific antibodies for the heterologous protein by the different recombinant viruses was also demonstrated by low levels of IgG in both models. The antibodies induced in this monkey model bound to the native protein in parasite-infected red blood cells by immunofluorescence. The challenge carried out in after immunization of Saimiri monkeys with FA17D/MSP-119fal did not generate conclusive results. These data suggest the need to improve the platform of expression towards higher viral immunogenicity

Topics: Flavivirus, V??rus FA 17D, Mal??ria, Express??o de MSP-119 de P. falciparum e P. vivax, Flavivirus, Virus FA 17D, Malaria, Expression of MSP-119 of P. falciparum and P. vivax, Yellow fever virus, Flavivirus, Mal??ria, V??rus da Febre Amarela
Publisher: Instituto Oswaldo Cruz.
Year: 2012
OAI identifier: oai:agregador.ibict.br.RI_FIOCRUZ:oai:localhost:icict/6391
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