Abstract
Malaria, caused by Plasmodium parasite infection, continues to be one of the leading causes of worldwide morbidity and mortality. Development of an effective vaccine has been encumbered by the complex life cycle of the parasite that has distinct pre-erythrocytic and erythrocytic stages of infection in the mammalian host. Historically, malaria vaccine development efforts have targeted each stage in isolation. An ideal vaccine, however, would target multiple life cycle stages with multiple arms of the immune system and be capable of eliminating initial infection in the liver, the subsequent blood stage infection, and would prevent further parasite transmission. We have previously shown that immunization of mice with Plasmodium yoelii genetically attenuated parasites (GAP) that arrest late in liver stage development elicits stage-transcending protection against both a sporozoite challenge and a direct blood stage challenge. Here, we show that this immunization strategy engenders both T- and B-cell responses that are essential for stage-transcending protection, but the relative importance of each is determined by the host genetic background. Furthermore, potent anti-blood stage antibodies elicited after GAP immunization rely heavily on FC-mediated functions including complement fixation and FC receptor binding. These protective antibodies recognize the merozoite surface but do not appear to recognize the immunodominant merozoite surface protein-1. The antigen(s) targeted by stage-transcending immunity are present in both the late liver stages and blood stage parasites. The data clearly show that GAP-engendered protective immune responses can target shared antigens of pre-erythrocytic and erythrocytic parasite life cycle stages. As such, this model constitutes a powerful tool to identify novel, protective and stage-transcending T and B cell targets for incorporation into a multi-stage subunit vaccine.
Highlights
Unlike other infectious diseases, malaria parasites continue to defy the development of a protective vaccine
P. yoelii (Py) fabb/f—parasites that are deficient in endogenous fatty acid biosynthesis undergo substantial liver stage growth, develop into late stage exoerythrocytic schizonts but fail to complete differentiation into exoerythrocytic merozoites[29] As a consequence, mice immunized with Pyfabb/f—parasites only experience PE infection and are not exposed to blood stage (BS) parasites
Mice immunized with liver stage-arresting GAP (LAGAP) are protected against sporozoite challenge but are protected against direct intravenous challenge with Py-infected red blood cells (RBCs)[28]
Summary
Malaria parasites continue to defy the development of a protective vaccine. The sporozoites are carried into the sinusoids of the liver where they again traverse multiple cell types to reach and infect hepatocytes This begins the clinically silent liver stage development of infection, during which each parasite undergoes many rounds of replication in a single hepatocyte and eventually forms tens of thousands of red blood cell-infectious exoerythrocytic merozoites. They are released in to the circulation and begin the asexual blood stage (BS) cycle whereby cyclic infection, replication within and lytic release from red blood cells (RBCs) occurs. Success has been limited with these stage-specific approaches, raising the question as to whether there should be a greater emphasis on multi-stage vaccination approaches
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