Malaria Prevention by a New Technology: Vectored Delivery of Antibody Genes
Abstract
Malaria is among the world s deadliest infectious diseases, responsible for roughly one million deaths annually and hundreds of millions of symptomatic cases among residents of malaria endemic areas. Malaria additionally threatens U.S. Armed Forces personnel deployed in malaria endemic areas that include Afghanistan, Korea, and Central and West Africa, and has been designated a Topic Area for the Peer Reviewed Medical Research Program for 2014. Malaria is a parasitic disease transmitted to each new victim by the bite of a mosquito that has been infected by feeding previously on an individual that has malaria. As the mosquito bites the new host, she (malaria is transmitted only by female mosquitoes) injects a form of the parasite called a sporozoite. The sporozoite invades the liver, beginning a complex life cycle that results in very high levels of parasites in the blood, which can cause severe anemia, serious central nervous system damage, and other life-threatening symptoms. Traditional approaches to malaria control such as antimalarial drug treatment, mosquito control by habitat modification and insecticide use, and use of treated bednets that reduce exposure to infected mosquitoes can be effective both in military and civilian settings. These approaches, however, can be difficult to sustain in the face of growing drug resistance among parasites, insecticide resistance in mosquito populations and, particularly for the military, under the difficult conditions associated with many of their missions. These issues would in principle be resolved by an effective method of providing immunity to malaria infection. Malaria infection can be prevented in animals and humans by antibodies against a single protein, circumsporozoite protein (CSP), which is found on the surface of the sporozoite. Antibodies to CSP block the first stage of malaria growth (invasion of the liver) and thus prevent disease and transmission of malaria to new mosquitoes and new human victims. Despite identification of CSP as a promising target for vaccination, work on conventional approaches to malaria immunization has not yet produced an effective vaccine. Novel approaches to inducing malaria immunity are urgently needed. This proposal will explore, with experiments in mice and monkeys, the application to malaria of a new technology that can prevent pathogen infection by providing genes encoding protective antibodies directly to individuals, bypassing the uncertain process of induction of immunity by conventional methods. Our approach to the induction of malaria immunity, termed vectored immunoprophylaxis (VIP), employs a modified adeno-associated virus (AAV). AAV is a ubiquitous human virus that causes no disease, and in the form used here is incapable of growth in humans or animals. Thus, it presents no infectious danger. To arm the virus against malaria, most of the DNA of the AAV is replaced with a gene that will direct the production of a human antimalarial antibody when the AAV vector is injected into muscle cells in an animal or person. VIP has proved effective in mouse models in preventing HIV (human immunodeficiency virus), influenza A, and in our previous work, malaria infection. The work proposed here will expand on the success in mice of VIP, taking the next step of evaluation of VIP against malaria in a non-human primate model of human malaria infection. The proposed work comprises two specific aims. First, a study of newly constructed AAV vectors producing antibodies directed against CSP and other promising immune targets will be conducted in order to identify vectors producing antibodies with the greatest potency. Efficacy will be determined in the mouse system. AAV vectors producing the most promising antibodies then will be tested for efficacy in Aotus monkeys, a new world monkey genus that is sensitive to human malaria sporozoite infection and thus provides a system for measuring the protective ability of antimalar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510401
Entities
People
- Gary Ketner
Organizations
- Johns Hopkins University
- United States Army