Alberto Moreno, M.D.

Area of Research: Malaria

In his pursuit of a viable vaccine against malaria, Dr. Alberto Moreno is identifying and functionally characterizing universal T cell epitopes from Plasmodium proteins that have a promiscuous binding profile for binding to several MHC Class II molecules. Dr. Moreno has designed novel approaches to effectively deliver subunit vaccines that include malaria universal T cell epitopes. Dr. Moreno is also participating in and leading several projects focused on the characterization of animal models to understand the immunobiological mechanisms underlying the physiopathology of severe malaria cases.

In addition, Dr. Moreno is Co-director of the EVC’s Malaria Vaccine Core, which supports specific research needs that cut across the Malaria Research Program at the EVC. Key to this Core, Dr. Moreno established a facility to infect mosquitoes with malaria parasites and to dissect the mature sporozoite form of the malaria parasite from their salivary glands. The availability of the sporozoite forms is essential for studies of the liver stage of malaria infections and for conducting preclinical vaccine trials based on sporozoite challenges.

Dr. Moreno is an Assistant Professor at the Yerkes National Primate Research Center of Emory University. Prior to joining Emory in 2000, he headed the Immuno-parasitology Unit at Fundacion Instituto de Inmunologia in Bogota, Colombia, where he trained over forty students and postdoctoral fellows in malaria and other infectious disease research. He earned his M.D. from Pontificia Universidad Javeriana in Bogotá, Colombia. Dr. Moreno was also a Fogarty International Fellow in the Department of Medical and Molecular Parasitology at New York University Medical Center from 1990-1993.

Research

Development of novel delivery systems for subunit vaccines
The intricacies of the Plasmodium sp. life cycle and the complex mechanisms involved in protection against malaria substantiate the premise that an effective malaria vaccine must include several stage-specific antigens. The parasite that causes malaria has the inherent capability to down-modulate protective immune responses and impede the generation of an effective long-term memory response. In addition, malaria antigens show poor immunogenicity, as shown recently in vaccine trials using synthetic peptides, recombinant proteins or DNA constructs. The struggle to produce better vaccine formulations includes the use of biological adjuvants and exogenous T cell epitopes.

Our research indicates that an effective malaria vaccine requires the careful selection and inclusion of parasite T helper epitopes. The genetic restriction associated with the precise stoichiometry of the MHC-peptide-TCR interaction is the major impediment for selecting T cell epitopes. However, the use of universal T cell epitopes, which have the ability to interact with several MHC alleles, can overcome this structural constraint.

Several years ago, we reported the first universal T cell epitope in Plasmodium falciparum. This epitope is currently in clinical trials as a component of a recombinant construct. More recently, we have identified 27 putative universal T cell epitopes from two Plasmodium vivax merozoite proteins using peptide competition assays to isolate DRB1* molecules. We have used these T cell epitopes to design polymeric linear synthetic peptide chimeras that can overcome the genetic restriction characteristic of several B cell epitopes. The results of these experiments, along with data obtained from immuno-epidemiological surveys conducted in endemic areas, will help us develop new vaccine constructs. Our approach is appropriate for designing synthetic peptide vaccine constructs, and can also be applied to recombinant proteins and DNA-based vaccines.

Biology of the liver-stage malaria parasites
From the standpoint of malaria vaccine development, generating anti-liver stage immunity offers several advantages, including lower parasite loads, the putative expression of MHC class I and II molecules by hepatocytes, and the absence of erythrocyte stage factors involved in down-regulation of specific immunity. Immunization with irradiated sporozoites – the infective form of the parasite – induces an immune response that provides complete protection against malaria by stimulating the parasites to differentiate to their liver-stage forms, called the exo-erythrocytic stage (EEF). Effector mechanisms involved in this response include both CD4+ and CD8+ T cells.

Although this approach was described several years ago, little is known about the antigen specificity involved. Genomic and proteomic information provides new insights on the stage-specificity of P. yoelii and P. falciparum parasites, although liver-stage parasites were not included in the arrays used to elaborate the Plasmodium transcriptome. Our priority is to better define the biochemical and immunological features of the liver-stage proteins, and to generate molecular tools to characterize ex vivo the immune response elicited by EEF. To do this, we are using methodologies established to characterize primary hepatocytes in vitro to develop technical approaches that allow the biological characterization of rodent and primate Plasmodium sp.

Malaria pathogenesis
Severe malaria is a major complication of P. falciparum infections, resulting in high parasitemia, anemia, placental malaria, cerebral malaria, renal insufficiency, and respiratory distress syndrome. The molecular mechanisms involved in severe malaria pathogenesis involve both host and parasite factors. An obligatory intracellular parasite, Plasmodium sp. has evolved several strategies to modify the morphology and physiology of the parasitized cells and to modulate the immune response of the host. Among these strategies, the expression of polymorphic domains in proteins present on the surface of infected erythrocytes is associated with sequestration, the most characterized physiopathological event in malaria. Although this mechanism plays a significant role in cerebral malaria and renal insufficiency, the pathogenesis of anemia, placental malaria and pulmonary edema is controversial and in need of much better scientific understanding. Animal models have shown that complex host-parasite dynamics are involved in severe malaria pathogenesis. The availability of rhesus macaques and simian malaria parasites offer the unique opportunity to advance research in these areas.

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