|
|
|
|
|
|
|
|
|
| |
|
| |
| |  Advances in immunology, biochemistry, and biology have enabled scientists to rapidly identify the sequences and structures of antigens, the substances in vaccines that stimulate immune responses against disease. For an antigen to be valuable as a vaccine, however, scientists must identify ways of giving it to individuals that predictably results in the desired immune response. Attenuated vaccines, composed of weakened organisms incapable of causing disease, provide prolonged exposure to antigens and have proven effective against several viral or bacterial diseases.
Dr. Kappe’s team is attempting to extend this concept to a malaria vaccine. In the case of malaria, disease develops when the malaria sporozoite – the form of the parasite that is transmitted from mosquitoes to humans – enters the bloodstream and moves to the liver. There, it grows and divides into thousands of parasites that invade and destroy red blood cells, causing disease.
Dr. Kappe's team is working toward development of a malaria vaccine using a malaria sporozoite that has been weakened by gene deletion to stimulate immune response . The project builds upon the team's previous studies in rodent malaria parasites, which showed that deleting specific genes from the sporozoite completely blocked its development in the liver, thereby preventing subsequent blood-stage infection. Investigators found that rodents vaccinated with these genetically attenuated parasites, or GAPs, are fully protected against infection when challenged again with the malaria sporozoite.
The project aims to identify genes critical for liver stage development. Using these findings, they will develop genetically attenuated P. falciparum vaccine candidates for testing in clinical trials.
Investigators are now testing their gene deletion strains of P. falciparum, for in vitro growth in hepatocyte culture and in a chimeric mouse model that harbors human hepatocytes. The team anticipates entering Phase 1 testing with one of the P. falciparum GAP vaccine strains in the near future. |
| | |
| | | Identify a comprehensive set of sporozoite and liver-stage specific genes that are conserved between rodent and human malaria (Plasmodium falciparum) | | | | Create genetically attenuated rodent malaria parasites with deficiencies in liver-stage development | | | | | Test in rodent models of malaria for safety and immunogenicity against subsequent infection following sporozoite challenge.Use these findings to create genetically attenuated P. falciparum parasites, and test promising candidate lines for liver-stage development defects in vitro | | | | | Test lead candidate lines for immunogenicity and protective efficacy in clinical trials | | |
| |
| | BACK TO THE TOP |
| | |
| | | Using microarrays, investigators have made progress in analyzing genome-wide gene expression in liver stages, a challenging task due to scarcity of this stage. They have isolated rodent malaria liver stages at different points of development and have obtained high-quality gene expression data. | | | | | Working toward their goals of obtaining all genes expressed in liver-stage development and prioritizing these genes for deletion, investigators have deleted nearly 100 candidate genes in the rodent malaria parasites and have found a variety of phenotypic defects among the mutants. | | | | | Investigators have created the first murine malaria genetically attenuated parasites that carry double gene deletions and demonstrated that these GAPs induce sterile protection for at least twelve months. Testing for longer-lasting protection is ongoing. | | | | | The team has identified genes in the parasite P. falciparum, the major cause of malaria in humans, that are equivalent to those in the rodent malaria models, and have created the first gene deletion strains. | | |
| |
| | BACK TO THE TOP |
| | | |
| | | University of Heidelberg, Heidelberg, Germany - DE | | | | | The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia - AU | | | | | Walter Reed Army Institute of Research, Maryland, United States - US | | |
| |
| | BACK TO THE TOP |
|
|
|
|
|
|
|
|
|
|
|