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RELEVANCE OF MALARIA IN THE AMERICAS |
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THE IMPORTANCE OF A MULTISPECIES MALARIA VACCINE |
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As part of this endeavor during the past 5 years, the Malaria Vaccine and Drug Development Center (MVDC) together with the Immunology Institute at Universidad del Valle in Cali, Colombia, have initiated a translational research program on P. vivax. The group has benefited from the availability of Aotus monkeys, access to parasites under natural conditions, and the susceptibility of Anopheles albimanus mosquitoes to experimental infection to establish a non-human primate model for sporozoite challenge infection. This model is being used to assess the protective efficacy of pre-erythrocytic subunit vaccine candidates and to develop a P. vivax irradiated-sporozoite vaccine model as a means to characterize protective immune responses. Detailed analyses of immune responses to natural infection, as well as responses to current malaria vaccine candidates, in individuals from malaria-endemic areas and from Aotus monkeys are being studied in the development of P. vivax vaccine.
As a product of the Tropical Medicine Research Center (TMRC) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), and the International Malaria Research Training Program sponsored by the Fogarty International Center, the Cali group conducted a series of research studies, reported here, addressing multiple aspects of P. vivax vaccine development. Considerable effort in the immunologic characterization of the P. vivax CS protein, using cells and sera from semi-immune donors from malaria-endemic regions8 and preclinical studies conducted in non-human primates,9 indicated the significant potential of long synthetic peptides as vaccine candidates. These studies led to a Phase I clinical trial where synthetic peptides encompassing the respective amino (N), repeat (R), and carboxyl regions of the CS protein were tested in malaria-naïve volunteers in a dose-escalating study. The resulting safety, high immunogenicity, and good tolerability of these peptides initiated the design of new trials to optimize the formulation, to analyze protective efficacy, and to develop homologue protein fragments as recombinant products. Preclinical studies of recombinant fragments derived from the P. vivax MSP-1 and the DBP in Aotus monkeys were conducted. Both proteins induced partial protection and are now being optimized for further testing in both non-human primates and human volunteers. The immunogenicity of a recombinant Pvs25 product, an antigen expressed only at the sporogonic cycle, was tested in Aotus monkeys and found to induce antibodies capable of efficiently blocking parasite transmission to Anopheles albimanus mosquitoes. Antibody titers and functional blocking activity were maintained for a period of 10 months, which in most P. vivax–endemic areas would provide adequate transmission-blocking protection to the population for up to two transmission cycles. A complementary field study was conducted to determine the prevalence of transmission-blocking responses in individuals acutely infected with P. vivax. A majority of individuals produced antibodies with significant transmission-blocking activity, which may contribute to the relatively moderate and unstable malaria transmission in the region.
The potential immunopathogenic effect of vaccination in the development of anemia was studied in vaccine trials in non-human primates. There was no evidence of anemia associated with the antigens tested despite concerns that immunization with DBP may risk production of antibodies that cross-react with chemokines specifically interacting with the Duffy antigen receptor for chemokines (DARC) or the Duffy antigen receptor. The proportion of P. vivax clinical cases in different regions of Colombia is variable due to its significant geographical and ethnic specificity. In the Colombian Pacific coastal region, the most endemic area of the country, the vast majority of the population is of African origin, thus there is a high prevalence of Duffy-negative individuals that are naturally protected from P. vivax. However, some villages in the region report an approximately equal number of P. falciparum and P. vivax infections. Sixty-one of the individuals were of African origin and the remainder from Indian or mestizo groups. Mild anemia was found in half of the individuals studied, but no severe anemia was found in the study.
The relatively equal prevalence of P. falciparum and P. vivax malaria in the Pacific coastal region of Colombia allows studies on the human immune response to both parasite species, homologous and heterologous transmission-blocking activity, as well as the study of parasite gene polymorphism. Data was collected on the gene polymorphism of P. falciparum MSP-1 within the scope of a larger study on the polymorphism of vaccine candidate antigens of both parasite species.
The immune responses to P. vivax, particularly the antibodies induced by pre-erythrocytic parasite antigens in both Fy-positive and Fy-negative individuals, were compared with blood stage responses that only develop in Fy-positive persons to a select group of novel antigens obtained from available P. vivax genome sequence data.10
The success achieved thus far with some P. vivax vaccine candidates has created considerable optimism toward the possibility of a malaria vaccine in the coming years. With support from the NIAID, the Fogarty International Center, the World Health Organization, the Colombian Research Council (Colciencias), the Ministry of Social Protection, and the collaboration of numerous scientists from around the world, the research group in Colombia has established a center of excellence for malaria research. Through a convergence of excellent science, collaboration, training, and determination, the MVDC has brought together a unique vaccine research center that is a resource for the research community. This supplement itself is the product of targeted workshops in science writing and proves the merit of such an undertaking. The papers testify to scientific creativity and to focused hard work while offering both progress in the field of P. vivax vaccinology and a model for building independent research capacity in a limited resource setting.
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This article has been cited by other articles:
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  C. Guinovart and P. L. Alonso Methods for Determining Vaccine Efficacy and Effectiveness and the Main Barriers to Developing a Fully Deployable Malaria Vaccine Am J Trop Med Hyg, December 1, 2007; 77(6_Suppl): 276 - 281. [Abstract] [Full Text] [PDF]
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