|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.
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.
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
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.
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
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
technical approaches that allow the biological characterization
of rodent and primate Plasmodium sp.
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
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
renal insufficiency, the pathogenesis of anemia, placental
malaria and pulmonary edema is controversial and in need of
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.