Development of a vaccine candidate against Schistosoma mansoni: production, immunogenicity assessment and vaccine protection trial in rhesus macaques

• Grant number: 23/13588-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2024
• Status: Discontinued
• Field of knowledge: Biological Sciences - Parasitology - Helminthology of Parasites
• Principal Investigator: Murilo Sena Amaral
• Grantee: Filipe Vilaça Guimaraes de Oliveira
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Flatworms of the genus Schistosoma are responsible for causing schistosomiasis, a neglected disease that affects more than 200 million people worldwide. These worms have a heteroxenous life cycle, dependent on two hosts to fully develop: snails of the genus Biomphalaria as intermediate hosts, and a mammal as the definitive host. The disease affects populations without adequate basic sanitation, where individuals come into contact with water contaminated by the parasite. Infected humans may develop symptoms such as fever, abdominal pain and swelling, fatigue, paraplegia and may die. This disease has a considerable mortality rate, especially when untreated, however, the greatest impact is the high morbidity, which affects millions of individuals due to reinfection and chronic form of the disease. Recurrent treatment is based on the administration of praziquantel, the only anthelmintic indicated. However, this medication is not effective in preventing reinfections and there is already evidence of the development of parasite resistance. Therefore, one way to overcome this problem is to develop a vaccine that protects against this infection. As it is a complex multicellular helminth, the construction of an immunizer is a challenge and dozens of vaccine candidates have already been tested, however none of them have been successful so far. Therefore, the purpose of this project is to test, in rhesus macaques, whether a new formulation vaccine composed of multiple peptides is capable of providing protection against S. mansoni. These peptides were selected as vaccine candidates because they were identified in previous studies by our group as recognized by antibodies from rhesus macaques that self-cured from S. mansoni infection. The gene sequences that code for these peptides will be concatenated into a chimeric construct, interspersed by spacers, fused to the adjuvants rhizavidin or cathelicidin, and cloned into vectors of replication and expression. Vectors containing the gene sequences that code for the chimeric protein construct, in addition to the chimeric protein itself, will be purchased from Genescript company. The chimeric protein, adsorbed to outer membrane vesicles, will be used to immunize rhesus macaques, in which three doses will be applied, spacedfor four weeks. Six rhesus macaques will be immunized with the chimeric proteinfused to rhizavidin and six other rhesus macaques with the chimeric protein fused tocathelicidin. 12 weeks after the first dose of immunizer, the animals will be challenged with700 Cercariae of S. mansoni and, 20 weeks later, they will be perfused for recoverpossible surviving worms. The course of the infection will be monitored by quantifying thecirculating anodic antigen of the parasite in the systemic circulation of macaques, byquantification of eggs in feces and the number of worms obtained in the perfusion. Thoseparameters, to be obtained here in immunized and challenged macaques, will be comparedto those previously obtained in non-immunized and challenged macaques, in recent workpublished by our research group. The immune response induced in macaques will be measured by evaluating the production of antibodies against candidate peptides through peptide arrays. It is expected to obtain total protection of rhesus macaques, induced by the formulation vaccine tested against S. mansoni infection.