Plasmodium vivax: who cares?

More attention is being focused on malaria today than any time since the world's last efforts to achieve eradication over 40 years ago. The global community is now discussing strategies aimed at dramatically reducing malarial disease burden and the eventual eradication of all types of malaria, everywhere. As a consequence, Plasmodium vivax, which has long been neglected and mistakenly considered inconsequential, is now entering into the strategic debates taking place on malaria epidemiology and control, drug resistance, pathogenesis and vaccines. Thus, contrary to the past, the malaria research community is becoming more aware and concerned about the widespread spectrum of illness and death caused by up to a couple of hundred million cases of vivax malaria each year. This review brings these issues to light and provides an overview of P. vivax vaccine development, then and now. Progress had been slow, given inherent research challenges and minimal support in the past, but prospects are looking better for making headway in the next few years. P. vivax, known to invade the youngest red blood cells, the reticulocytes, presents a strong challenge towards developing a reliable long-term culture system to facilitate needed research. The P. vivax genome was published recently, and vivax researchers now need to coordinate efforts to discover new vaccine candidates, establish new vaccine approaches, capitalize on non-human primate models for testing, and investigate the unique biological features of P. vivax, including the elusive P. vivax hypnozoites. Comparative studies on both P. falciparum and P. vivax in many areas of research will be essential to eradicate malaria. And to this end, the education and training of future generations of dedicated "malariologists" to advance our knowledge, understanding and the development of new interventions against each of the malaria species infecting humans also will be essential

Measurement of two-halo neutron transfer reaction p(11^{11}Li,9^{9}Li)t at 3AA MeV

The p(\nuc{11}{Li},\nuc{9}{Li})t reaction has been studied for the first time at an incident energy of 3$A$ MeV delivered by the new ISAC-2 facility at TRIUMF. An active target detector MAYA, build at GANIL, was used for the measurement. The differential cross sectionshave been determined for transitions to the \nuc{9}{Li} ground andthe first excited states in a wide range of scattering angles. Multistep transfer calculations using different \nuc{11}{Li} model wave functions, shows that wave functions with strong correlations between the halo neutrons are the most successful in reproducing the observation.Comment: 6 pages, 3 figures, submitted to Physical Review Letter

Comparison of the human immune responses to recombinant proteins representing three distinct surface proteins of Plasmodium vivax merozoites

Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM) Departamento de Microbiologia, Imunologia e ParasitologiaUniversidade Federal do Pará Departamento de PatologiaCenters for Disease Control and Prevention Division of Parasitic DiseasesInstituto Evandro ChagasUniversidade Federal de Minas Gerais Departamento de ParasitologiaUNIFESP, EPM, Depto. de Microbiologia, Imunologia e ParasitologiaSciEL

Antigenicity and Immunogenicity of Plasmodium vivax Merozoite Surface Protein-3

A recent clinical trial in African children demonstrated the potential utility of merozoite surface protein (MSP)-3 as a vaccine against Plasmodium falciparum malaria. the present study evaluated the use of Plasmodium vivax MSP-3 (PvMSP-3) as a target antigen in vaccine formulations against malaria caused by P. vivax. Recombinant proteins representing MSP-3 alpha and MSP-3 beta of P. vivax were expressed as soluble histidine-tagged bacterial fusions. Antigenicity during natural infection was evaluated by detecting specific antibodies using sera from individuals living in endemic areas of Brazil. A large proportion of infected individuals presented IgG antibodies to PvMSP-3 alpha (68.2%) and at least 1 recombinant protein representing PvMSP-3 beta (79.1%). in spite of the large responder frequency, reactivity to both antigens was significantly lower than was observed for the immunodominant epitope present on the 19-kDa C-terminal region of PvMSP-1. Immunogenicity of the recombinant proteins was studied in mice in the absence or presence of different adjuvant formulations. PvMSP-3 beta, but not PvMSP-3 alpha, induced a TLR4-independent humoral immune response in the absence of any adjuvant formulation. the immunogenicity of the recombinant antigens were also tested in formulations containing different adjuvants (Alum, Salmonella enterica flagellin, CpG, Quil A, TiterMax (R) and incomplete Freunds adjuvant) and combinations of two adjuvants (Alum plus flagellin, and CpG plus flagellin). Recombinant PvMSP-3 alpha and PvMSP-3 beta elicited higher antibody titers capable of recognizing P. vivax-infected erythrocytes harvested from malaria patients. Our results confirm that P. vivax MSP-3 antigens are immunogenic during natural infection, and the corresponding recombinant proteins may be useful in elucidating their vaccine potential.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)US National Institutes of Health, National Institute for Allergy and Infectious DiseasesSIgNHorizontal Programme on Infectious Diseases under the Agency for Science, Technology and Research (A*STAR, Singapore)Wellcome Trust of Great Britain, as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust-Mahidol UniversityUniv São Paulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, São Paulo, BrazilUniv Estadual Campinas, Dept Genet Evolucao & Bioagentes, Inst Biol, Campinas, SP, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Microbiol, BR-05508 São Paulo, BrazilNatl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol, Singapore 117595, SingaporeAgcy Sci Technol & Res, Singapore Immunol Network, Biopolis, Singapore, SingaporeChurchill Hosp, Ctr Vaccinol & Trop Med, Oxford OX3 7LJ, EnglandMahidol Oxford Univ Trop Med Res Programme, Shoklo Malaria Res Unit, Mae Sot, ThailandEmory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USAEmory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USAEmory Univ, Dept Med, Div Infect Dis, Atlanta, GA 30322 USACtr Dis Control & Prevent, Malaria Branch, Div Parasit Dis, Chamblee, GA USAUniversidade Federal de São Paulo, CTCMOL, Dept Microbiol Imunol & Parasitol, Escola Paulista Med, São Paulo, BrazilUniversidade Federal de São Paulo, CTCMOL, Dept Microbiol Imunol & Parasitol, Escola Paulista Med, São Paulo, BrazilFAPESP: 2010/09893-0US National Institutes of Health, National Institute for Allergy and Infectious Diseases: 1R01AI24710Web of Scienc

Influence of HLA-DRB1 and HLA-DQB1 Alleles on IgG Antibody Response to the P. vivax MSP-1, MSP-3α and MSP-9 in Individuals from Brazilian Endemic Area

Background: the antibody response generated during malaria infections is of particular interest, since the production of specific IgG antibodies is required for acquisition of clinical immunity. However, variations in antibody responses could result from genetic polymorphism of the HLA class II genes. Given the increasing focus on the development of subunit vaccines, studies of the influence of class II alleles on the immune response in ethnically diverse populations is important, prior to the implementation of vaccine trials.Methods and Findings: in this study, we evaluated the influence of HLA-DRB1* and -DQB1* allelic groups on the naturally acquired humoral response from Brazilian Amazon individuals (n = 276) against P. vivax Merozoite Surface Protein-1 (MSP-1), MSP-3 alpha and MSP-9 recombinant proteins. Our results provide information concerning these three P. vivax antigens, relevant for their role as immunogenic surface proteins and vaccine candidates. Firstly, the studied population was heterogeneous presenting 13 HLA-DRB1* and 5 DQB1* allelic groups with a higher frequency of HLA-DRB1*04 and HLA-DQB1*03. the proteins studied were broadly immunogenic in a naturally exposed population with high frequency of IgG antibodies against PvMSP1-19 (86.7%), PvMSP-3 (77%) and PvMSP-9 (76%). Moreover, HLA-DRB1*04 and HLA-DQB1*03 alleles were associated with a higher frequency of IgG immune responses against five out of nine antigens tested, while HLA-DRB1* 01 was associated with a high frequency of non-responders to repetitive regions of PvMSP-9, and the DRB1*16 allelic group with the low frequency of responders to PvMSP3 full length recombinant protein.Conclusions: HLA-DRB1*04 alleles were associated with high frequency of antibody responses to five out of nine recombinant proteins tested in Rondonia State, Brazil. These features could increase the success rate of future clinical trials based on these vaccine candidates.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Yerkes National Primate Research Center BaseNational Center for Research Resources of the National Institutes of HealthNIHCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Inst Oswaldo Cruz, Lab Immunoparasitol, BR-20001 Rio de Janeiro, BrazilOswaldo Cruz Fdn Fiocruz, Ctr Technol Dev Hlth CDTS, Rio de Janeiro, BrazilInst Oswaldo Cruz, Lab Simulideos & Oncocercose, BR-20001 Rio de Janeiro, BrazilEmory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USAUniv Estado Rio de Janeiro, Histocompatibil & Cryopreservat Lab, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Ctr Terapia Celular & Mol CTCMol, Escola Paulista Med, São Paulo, BrazilEmory Univ, Sch Med, Div Infect Dis, Atlanta, GA USACDC Natl Ctr Infect Dis, Div Parasit Dis, Atlanta, GA USAUniversidade Federal de São Paulo, Ctr Terapia Celular & Mol CTCMol, Escola Paulista Med, São Paulo, BrazilFAPESP: 2009/15132-4Yerkes National Primate Research Center Base: RR00165NIH: RO1 AI0555994Web of Scienc

The global distribution of the Duffy blood group

Blood group variants are characteristic of population groups, and can show conspicuous geographic patterns. Interest in the global prevalence of the Duffy blood group variants is multidisciplinary, but of particular importance to malariologists due to the resistance generally conferred by the Duffy-negative phenotype against Plasmodium vivax infection. Here we collate an extensive geo-database of surveys, forming the evidence-base for a multi-locus Bayesian geostatistical model to generate global frequency maps of the common Duffy alleles to refine the global cartography of the common Duffy variants. We show that the most prevalent allele globally was FY*A, while across sub-Saharan Africa the predominant allele was the silent FY*BES variant, commonly reaching fixation across stretches of the continent. The maps presented not only represent the first spatially and genetically comprehensive description of variation at this locus, but also constitute an advance towards understanding the transmission patterns of the neglected P. vivax malaria parasite

Identification of Plasmodium vivax Proteins with Potential Role in Invasion Using Sequence Redundancy Reduction and Profile Hidden Markov Models

BACKGROUND: This study describes a bioinformatics approach designed to identify Plasmodium vivax proteins potentially involved in reticulocyte invasion. Specifically, different protein training sets were built and tuned based on different biological parameters, such as experimental evidence of secretion and/or involvement in invasion-related processes. A profile-based sequence method supported by hidden Markov models (HMMs) was then used to build classifiers to search for biologically-related proteins. The transcriptional profile of the P. vivax intra-erythrocyte developmental cycle was then screened using these classifiers. RESULTS: A bioinformatics methodology for identifying potentially secreted P. vivax proteins was designed using sequence redundancy reduction and probabilistic profiles. This methodology led to identifying a set of 45 proteins that are potentially secreted during the P. vivax intra-erythrocyte development cycle and could be involved in cell invasion. Thirteen of the 45 proteins have already been described as vaccine candidates; there is experimental evidence of protein expression for 7 of the 32 remaining ones, while no previous studies of expression, function or immunology have been carried out for the additional 25. CONCLUSIONS: The results support the idea that probabilistic techniques like profile HMMs improve similarity searches. Also, different adjustments such as sequence redundancy reduction using Pisces or Cd-Hit allowed data clustering based on rational reproducible measurements. This kind of approach for selecting proteins with specific functions is highly important for supporting large-scale analyses that could aid in the identification of genes encoding potential new target antigens for vaccine development and drug design. The present study has led to targeting 32 proteins for further testing regarding their ability to induce protective immune responses against P. vivax malaria

PfRH5: A Novel Reticulocyte-Binding Family Homolog of Plasmodium falciparum that Binds to the Erythrocyte, and an Investigation of Its Receptor

Multiple interactions between parasite ligands and their receptors on the human erythrocyte are a condition of successful Plasmodium falciparum invasion. The identification and characterization of these receptors presents a major challenge in the effort to understand the mechanism of invasion and to develop the means to prevent it. We describe here a novel member of the reticulocyte-binding family homolog (RH) of P. falciparum, PfRH5, and show that it binds to a previously unrecognized receptor on the RBC. PfRH5 is expressed as a 63 kDa protein and localized at the apical end of the invasive merozoite. We have expressed a fragment of PfRH5 which contains the RBC-binding domain and exhibits the same pattern of interactions with the RBC as the parent protein. Attachment is inhibited if the target cells are exposed to high concentrations of trypsin, but not to lower concentrations or to chymotrypsin or neuraminidase. We have determined the affinity, copy number and apparent molecular mass of the receptor protein. Thus, we have shown that PfRH5 is a novel erythrocyte-binding ligand and the identification and partial characterization of the new RBC receptor may indicate the existence of an unrecognized P. falciparum invasion pathwa