Caracterização imunológica da formulação vacinal baseada em VLP (Virus Like Particle) da Proteína Circumsporozoíta de Plasmodium vivax / Immunological characterization of the VLP (Virus Like Particle) vaccine formulation fused to Circumsporozoite Protein of Plasmodium vivax

O Plasmodium vivax é a espécie mais comum de parasita causador da malária humana encontrada fora da África, com maior endemicidade na Ásia, América Central e do Sul e Oceania. Embora o Plasmodium falciparum cause a maioria do número de mortes, o P. vivax pode levar à malária grave e resultar em morbimortalidade significativa. O desenvolvimento de uma vacina protetora será um passo importante para a eliminação da malária. Recentemente, uma formulação contendo as três variantes alélicas da proteína circumsporozoíta de P. vivax (PvCSP - All epitopes) induziu proteção parcial em camundongos após desafio com esporozoíto híbrido Plasmodium berghei (Pb), no qual as repetições centrais do PbCSP foram substituídas por repetições PvCSP-VK210 (esporozoítos Pb/Pv). No presente estudo, a proteína quimérica PvCSP contendo as variantes alélicas (VK210, VK247 e P. vivax-like) fusionadas com a proteína de nucleocapsídeo do vírus da caxumba (formando partículas semelhantes a nucleocapsídeos ou do inglês, NLP - Núcleo Like Particles) na ausência (NLP-CSPR) ou na presença do domínio C-terminal (CT) conservado da PvCSP (NLP-CSPCT). Para a realização do estudo selecionamos os adjuvantes Poly (I:C), um RNA sintético de dupla fita, agonista do receptor Toll do tipo 3 (TLR3) ou o adjuvante Montanide ISA 720, uma emulação óleo em agua. Para obter uma forte resposta imune, a levedura Pichia pastoris foi usada para expressar as proteínas recombinantes na forma de NLPs. Camundongos foram imunizados com cada uma das proteínas recombinantes em combinação com os adjuvantes citados. Embora ambas as NLPs tenham sido capazes de gerar uma forte resposta imune, com altos níveis de títulos e longevidade, apenas a formulação contendo a proteína NLP-CSPCT na presença do adjuvante Poly (I:C) foi selecionada para ser explorada em experimentos futuros. Esta proteína em combinação com o adjuvante Poly (I:C) induziu alta frequência de células secretoras de anticorpos específicas para o antígeno homólogo nos dias 5 e 30, no baço e na medula óssea, respectivamente. Altos títulos de IgG contra as 3 variantes de PvCSP foram detectados nos soros. Posteriormente camundongos imunizados com NLP-CSPCT foram desafiados com esporozoítos Pb/Pv e a parasitemia no 5º dia demonstrou proteção estéril em 30% dos camundongos desafiados. Portanto, a formulação vacinal gerada neste estudo tem potencial para ser explorada no desenvolvimento de uma vacina universal contra a malária causada por P. vivax

Plasmodium vivax is the most common species of human malaria parasite found outside Africa, with high endemicity in Asia, Central and South America, and Oceania. Although Plasmodium falciparum causes the majority of deaths, P. vivax can lead to severe malaria and result in significant morbidity and mortality. The development of a protective vaccine will be a major step toward malaria elimination. Recently, a formulation containing the three allelic variants of the P. vivax circumsporozoite protein (PvCSP--All epitopes) showed partial protection in mice after a challenge with the hybrid Plasmodium berghei (Pb) sporozoite, in which the PbCSP central repeats were replaced by the VK210 PvCSP repeats (Pb/Pv sporozoite). In the present study, the chimeric PvCSP allelic variants (VK210, VK247, and P. vivax-like) were fused with the mumps virus nucleocapsid protein (assembling into nucleo like particles - NLP) in the absence (NLP-CSPR) or presence of the conserved C-terminal (CT) domain of PvCSP (NLP-CSPCT). To carry out the study, we selected the adjuvants Poly (I:C), a synthetic double-stranded RNA, Toll-like receptor 3 (TLR3) agonist or Montanide ISA 720 adjuvant, an oil-water emulation. To elicit stronger immune response, Pichia pastoris yeast was used to produce the NLPs. Mice were immunized with each recombinant protein in combination with above. Although both NLPs were able to generate stronger immune response, with high antibodies titer levels and longevity, formulation containing NLP-CSPCT in the presence of Poly (I:C) was selected to be explored in future experiments. NLP-CSPCT with Poly (I:C) adjuvant presented a high frequency of antigen-specific antibody-secreting cells (ASCs) on days 5 and 30, respectively, in the spleen and bone marrow. Moreover, high IgG titers against all PvCSP variants were detected in the sera. Later, immunized mice with NLP-CSPCT were challenged with Pb/Pv sporozoites. Sterile protection was observed in 30% of the challenged mice. Therefore, this vaccine formulation use has the potential to be a good candidate for the development of a universal vaccine against P. vivax malaria.

The Duffy binding protein as a key target for a Plasmodium vivax vaccine: lessons from the Brazilian Amazon

Plasmodium vivax infects human erythrocytes through a major pathway that requires interaction between an apical parasite protein, the Duffy binding protein (PvDBP) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). The importance of the interaction between PvDBP (region II, DBPII) and DARC to P. vivax infection has motivated our malaria research group at Oswaldo Cruz Foundation (state of Minas Gerais, Brazil) to conduct a number of immunoepidemiological studies to characterise the naturally acquired immunity to PvDBP in populations living in the Amazon rainforest. In this review, we provide an update on the immunology and molecular epidemiology of PvDBP in the Brazilian Amazon - an area of markedly unstable malaria transmission - and compare it with data from other parts of Latin America, as well as Asia and Oceania.

Esquema de inmunizaciones para niños, niñas y adolescentes en Venezuela: recomendaciones para 2013-2014 sociedad venezolana de puericultura y pediatría / Immunization schedule for children and adolescents in Venezuela: Venezuelan society 2013-2014 recommendations of child care and paediatrics

Las pandemias de influenza son eventos impredecibles pero recurrentes que pueden tener consecuencias graves para la salud humana y el bienestar económico mundial. La planificación y los preparativos anticipados son fundamentales a fin de atenuar el impacto de una pandemia.” Así cita el documento de orientación de la OMS de Preparación y respuesta frentea una pandemia de influenza. El sector de la salud (incluida la salud pública y los servicios de atención de salud)suministra la información esencial de carácter epidemiológico, clínico y virológico, que a su vez fundamenta las medidas de limitación de la propagación del virus pandémico y de la morbilidad y la mortalidad que este provoca. Desde abril de 2009 se inicio la pandemia por el virus AH1N1/2009. La primera vez que apareció este subtipo viral H1N1 fue en 1918 y se conoce como la influenza “española”, y se calcula que causó de 25 a 50 millones de muertes. Luego surgió, en 1956, el subtipo H2N2 y ocasionó un millón y medio de muertes. El subtipo H3N2, nuevo para el ser humano, en 1968 fue el responsable de la influenza de Hong Kong que mató cerca de un millón de personas. Cuando las pandemias desaparecen, estos subtipos virales permanecen en la población humana como virus estacionales. Es por ello que virus de los subtipos H1N1, H2N2 y H3N2 persisten ahora como virus estacionales. Esto hace reflexionar en la importancia de las vacunas contra la Influenza, muchas veces tomadas a menos para su administración rutinaria. La vacuna se debe administrar a todo el grupo familiar y en todos losgrupos de edades. Para 2013-2014 la Comisión de Inmunizaciones hace énfasis en la administración de la vacuna contra la influenza parala nueva temporada, así como de nuevas pautas para el uso de vacunas conjugadas tetravalentes contra el meningococo, vacuna dTpa y resoluciones recientes para la administración de la vacuna Antiamarilica.

Experimental models in vaccine research: malaria and leishmaniasis

Animal models have a long history of being useful tools, not only to test and select vaccines, but also to help understand the elaborate details of the immune response that follows infection. Different models have been extensively used to investigate putative immunological correlates of protection against parasitic diseases that are important to reach a successful vaccine. The greatest challenge has been the improvement and adaptation of these models to reflect the reality of human disease and the screening of vaccine candidates capable of overcoming the challenge of natural transmission. This review will discuss the advantages and challenges of using experimental animal models for vaccine development and how the knowledge achieved can be extrapolated to human disease by looking into two important parasitic diseases: malaria and leishmaniasis.

Pregnancy malaria: cryptic disease, apparent solution

Malaria during pregnancy can be severe in non-immune women, but in areas of stable transmission, where women are semi-immune and often asymptomatic during infection, malaria is an insidious cause of disease and death for mothers and their offspring. Sequelae, such as severe anaemia and hypertension in the mother and low birth weight and infant mortality in the offspring, are often not recognised as consequences of infection. Pregnancy malaria, caused by Plasmodium falciparum, is mediated by infected erythrocytes (IEs) that bind to chondroitin sulphate A and are sequestered in the placenta. These parasites have a unique adhesion phenotype and distinct antigenicity, which indicates that novel targets may be required for development of an effective vaccine. Women become resistant to malaria as they acquire antibodies against placental IE, which leads to higher haemoglobin levels and heavier babies. Proteins exported from the placental parasites have been identified, including both variant and conserved antigens, and some of these are in preclinical development for vaccines. A vaccine that prevents P. falciparum malaria in pregnant mothers is feasible and would potentially save hundreds of thousands of lives each year.

TLR5-dependent immunogenicity of a recombinant fusion protein containing an immunodominant epitope of malarial circumsporozoite protein and the FliC flagellin of Salmonella Typhimurium

Recently, we described the improved immunogenicity of new malaria vaccine candidates based on the expression of fusion proteins containing immunodominant epitopes of merozoites and Salmonella enterica serovar Typhimurium flagellin (FliC) protein as an innate immune agonist. Here, we tested whether a similar strategy, based on an immunodominant B-cell epitope from malaria sporozoites, could also generate immunogenic fusion polypeptides. A recombinant His6-tagged FliC protein containing the C-terminal repeat regions of the VK210 variant of Plasmodium vivax circumsporozoite (CS) protein was constructed. This recombinant protein was successfully expressed in Escherichia coli as soluble protein and was purified by affinity to Ni-agarose beads followed by ion exchange chromatography. A monoclonal antibody specific for the CS protein of P. vivax sporozoites (VK210) was able to recognise the purified protein. C57BL/6 mice subcutaneously immunised with the recombinant fusion protein in the absence of any conventional adjuvant developed protein-specific systemic antibody responses. However, in mice genetically deficient in expression of TLR5, this immune response was extremely low. These results extend our previous observations concerning the immunogenicity of these recombinant fusion proteins and provide evidence that the main mechanism responsible for this immune activation involves interactions with TLR5, which has not previously been demonstrated for any recombinant FliC fusion protein.

Induction and maintenance of protective CD8+ T cells against malaria liver stages: implications for vaccine development

CD8+ T cells against malaria liver stages represent a major protective immune mechanism against infection. Following induction in the peripheral lymph nodes by dendritic cells (DCs), these CD8+ T cells migrate to the liver and eliminate parasite infected hepatocytes. The processing and presentation of sporozoite antigen requires TAP mediated transport of major histocompatibility complex class I epitopes to the endoplasmic reticulum. Importantly, in DCs this process is also dependent on endosome-mediated cross presentation while this mechanism is not required for epitope presentation on hepatocytes. Protective CD8+ T cell responses are strongly dependent on the presence of CD4+ T cells and the capacity of sporozoite antigen to persist for a prolonged period of time. While human trials with subunit vaccines capable of inducing antibodies and CD4+ T cell responses have yielded encouraging results, an effective anti-malaria vaccine will likely require vaccine constructs designed to induce protective CD8+ T cells against malaria liver stages.

Platform for Plasmodium vivax vaccine discovery and development

Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80-100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development.

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject.

Malaria transmission blocking immunity and sexual stage vaccines for interrupting malaria transmission in Latin America

Malaria is a vector-borne disease that is considered to be one of the most serious public health problems due to its high global mortality and morbidity rates. Although multiple strategies for controlling malaria have been used, many have had limited impact due to the appearance and rapid dissemination of mosquito resistance to insecticides, parasite resistance to multiple antimalarial drug, and the lack of sustainability. Individuals in endemic areas that have been permanently exposed to the parasite develop specific immune responses capable of diminishing parasite burden and the clinical manifestations of the disease, including blocking of parasite transmission to the mosquito vector. This is referred to as transmission blocking (TB) immunity (TBI) and is mediated by specific antibodies and other factors ingested during the blood meal that inhibit parasite development in the mosquito. These antibodies recognize proteins expressed on either gametocytes or parasite stages that develop in the mosquito midgut and are considered to be potential malaria vaccine candidates. Although these candidates, collectively called TB vaccines (TBV), would not directly stop malaria from infecting individuals, but would stop transmission from infected person to non-infected person. Here, we review the progress that has been achieved in TBI studies and the development of TBV and we highlight their potential usefulness in areas of low endemicity such as Latin America.

Actividad funcional de anticuerpos inducidos por péptido-miméticos derivados del antígeno MSP-2 del Plasmodium, como potenciales agentes inmunoterapéuticos en malaria causada por Plasmodium yoelii y Plasmodium berghei en ratones BALB/c / Functional activity of antibodies induced by peptido-mimetics derived from the Plasmodium MSP-2 antigen, as potential immuno-therapeutic agents in rodent malaria induced by P. berghei and P. yoelii strains

Teniendo en cuenta el alto grado de conservación genética de los residuos críticos de la estructura primaria del péptido 4044 (21KNESKYSNTFINNAYNMSIR40) identificado como crucial en el antígeno MSP-2 para que el Plasmodium falciparum pueda unirse con alta capacidad específica a glóbulos rojos y causar malaria, se diseñaron y sintetizaron dos secuencias en formas monomérica y polimérica de péptido-miméticos denominados pseudopéptidos amida reducida en las cuales se sustituyó un enlace peptídico normal por su isóstero ψ[CH2-NH] entre los residuos fenilalanina-isoleucina y entre los residuos isoleucina-asparagina, para dar lugar a los pseudopéptidos codificados ψ-128 forma monomérica (ψ-129 forma polimérica) y ψ-130 forma monomérica (ψ-131 forma polimérica). Con estos péptido-miméticos se generaron anticuerpos monoclonales de isotipo IgM. Mediante experimentos controlados de inmunización in vitro se indujo el cambio isotipo de los clones reactivos a las subclases IgG1, IgG2a, IgG2b e IgG3. Estas inmunoglobulinas se ensayaron por su actividad funcional antimalárica in vivo mostrando una alta eficacia en el control de la infección por malaria al ser administradas por transferencia pasiva. El efecto neutralizador del desarrollo biológico del patógeno por parte de estos anticuerpos inducidos de manera sitio-dirigida los hacen potencialmente útiles, como una potencial herramienta para el control de la infección por malaria.

Bearing in mind the high degree of genetical conservation of critical binding residues from the primary structure of the peptide 4044 (21KNESKYSNTFINNAYNMSIR40), which was previously identified as being crucial for the MSP-2 antigen to lead Plasmodium falciparum to bind red blood cells with high specific capacity, and so causing malaria, two peptido-mimetics so-named reduced amide pseudopeptides, in which a nature-made amide bond was replaced with a ψ[CH2-NH] methylene amide isoster bond, one between the Phe-Ile aminoacid pair and the second between Ile-Asn, were designed and synthesized in a site-directed manner as monomer and polymer forms, and were coded as ψ-128 for the monomer (ψ-129 polymer) and ψ-130 for the monomer (ψ-131 for polymer) respectively. These peptido-mimetics were used to produce monoclonal antibodies which displayed in both cases IgM isotype. By controlled in vitro immunization experiments their parent reactive hybridomas were induced to a Ig isotype-switching to IgG1, IgG2a, IgG2b and Ig3 sub-classes. These immunoglobulins were tested for their in vivo functional activity against malaria, showing a high efficacy property for controlling the malaria infection when passively transferred into BALB/c mice. The neutralizing effect of these site-directed designed antibodies on the Plasmodium biological development, make them a potential tool for the control of malaria.

Avaliação da atividade antimalárica de substância obtidas de espécies vegetais nativas ou endêmicas do semi-árido brasileiro e derivados sintéticos / Evaluation of antimalarial activity of a substance obtained from native or endemic plant species of arid and semi-synthetic derivatives

A malária é uma das mais importantes infecções parasitárias de seres humanos devido à alta morbidade e mortalidade atribuídas a esta doença, que constitui uma ameaça para mais de dois bilhões de pessoas vivendo nas áreas de alta incidência. O Plasmodium falciparum, um dos agentes causadores da malária, apresenta alta capacidade de adaptação por mutação e pode ser resistente a vários tipos de drogas antimaláricas já disponíveis, como a cloroquina, o que torna importante a busca de novos antimaláricos. A região do semi-árido brasileiro abrange cerca de 11,5% do território nacional, e possui o bioma menos estudado em relação à flora e fauna, e um dos que tem sofrido maior degradação pelo uso desordenado e predatório nos últimos 400 anos. Tendo em vista o potencial farmacológico dos produtos naturais, o objetivo desse trabalho foi avaliar a atividade antimalárica de substâncias puras extraídas de espécies vegetais nativas ou endêmicas do semi-árido brasileiro e derivados sintéticos. A partir de uma biblioteca de 160 substâncias triadas para atividade antimalárica, foram selecionadas duas classes de compostos para avaliações in vitro e in vivo: o ácido betulínico e derivados, bem como o lapachol e derivados. Foi selecionada ainda uma terceira classe de moléculas, as fisalinas, utilizando o método do Similarity Ensemble Approach (SEA), que previu a ação antimalárica dessas substâncias. Dentre os derivados do ácido betulínico testados, o acetato do ácido betulínico apresentou a maior potência farmacológica in vitro quando comparado com os outros derivados, e foi ativo in vivo. A atividade antimalárica das fisalinas foi confirmada em ensaios in vitro. Ao serem analisadas in vivo, as fisalinas F e D apresentaram resultados opostos (exacerbação e proteção contra a infecção, respectivamente), possivelmente devido à atividade imunossupressora da fisalina F e ausente na fisalina D. A análise do lapachol e seus derivados iniciou-se através de estudos in silico por Quantitative Structure-Activity Relationship (QSAR), que indicaram ser o isolacet o derivado com maior atividade, o que foi confirmado por ensaios in vitro. A atividade antimalárica do isolacet foi confirmada in vivo, sendo ainda realizados estudos de Docking desta molécula com a falcipaína 2 de P. falciparum, que indicaram ser esta cisteíno-protease um possível alvo do isolacet. Nossos resultados indicam o potencial antimalárico de compostos isolados a partir de plantas do semi-árido e demonstram a importância da associação de várias abordagens para entendimento dos mecanismos de ação de moléculas com atividade farmacológica.

Transmission blocking vaccines to control insect-borne diseases: a review

Insect-borne diseases are responsible for severe mortality and morbidity worldwide. As control of insect vector populations relies primarily on the use of insecticides, the emergence of insecticide resistance as well to unintended consequences of insecticide use pose significant challenges to their continued application. Novel approaches to reduce pathogen transmission by disease vectors are been attempted, including transmission-blocking vaccines (TBVs) thought to be a feasible strategy to reduce pathogen burden in endemic areas. TBVs aim at preventing the transmission of pathogens from infected to uninfected vertebrate host by targeting molecule(s) expressed on the surface of pathogens during their developmental phase within the insect vector or by targeting molecules expressed by the vectors. For pathogen-based molecules, the majority of the TBV candidates selected as well as most of the data available regarding the effectiveness of this approach come from studies using malaria parasites. However, TBV candidates also have been identified from midgut tissues of mosquitoes and sand flies. In spite of the successes achieved in the potential application of TBVs against insect-borne diseases, many significant barriers remain. In this review, many of the TBV strategies against insect-borne pathogens and their respective ramification with regards to the immune response of the vertebrate host are discussed.

Análisis proteómico de Plasmodium, el agente causal de la malaria / Proteomic analysis of Plasmodium, the causal agent of Malaria

Los plasmodios son protozoarios cuyo complejo ciclo de vida se lleva a cabo en dos hospederos, el vertebrado y el mosquito. La infección de los seres humanos produce la enfermedad conocida como malaria. La secuenciación del genoma de Plasmodium falciparum y el desarrollo de la proteómica han permitido un gran avance en el conocimiento de la biología de este letal parásito. La presente revisión se centra en describir los logros recientes en el estudio del proteoma de Plasmodium falciparum y algunas de las implicaciones en la búsqueda de nuevos fármacos antimaláricos, así como en la generación de vacunas para el control de la enfermedad.

Plasmodia are protozoa whose complex life cycle takes place in two different hosts, the vertebrate and the mosquito. The human infection produces the malaria disease. The genome sequence of Plasmodium falciparum and the proteomic tools have enabled a huge advance in knowledge of the biology of this parasite. This review will focus on the recent advances in proteomic studies of Plasmodium falciparum and some implications for the search of new antimalarial drugs as well as vaccines for the control of the disease.

Plan estratégico institucional 2008-2012 / Institutional strategic plan 2008-2012

El plan estratégico del control y vigilancia de la malaria esta enmarcado en el plan sectorial de salud que tiene como objetivo la eliminacion de la exclusión social, que se conseguirá con la implementación del Sistema Único, Intercultural y Comunitario de Salud. Este sistema deberá ser inclusivo, equitativo, solidario, de calidad y calidez.

Nanotecnologia farmacêutica aplicada ao tratamento da malária: [revisão] / Application of pharmaceutical nanotechnology to the treatment of malaria: [review]

Apesar do desenvolvimento tecnológico e científico, a malária permanece como um dos maiores problemas de saúde a serem combatidos. As estratégias modernas para o controle da doença prevêem ações conjuntas, como o combate do inseto vetor, diagnóstico rápido e preciso, garantia de terapêutica adequada, redução dos casos de resistência, além do desenvolvimento de novos agentes terapêuticos e vacina e através da otimização da ação de fármacos utilizados na atualidade. Os sistemas de liberação controlada de fármacos vêm recebendo atenção especial nesta área de pesquisa, com o desenvolvimento de estratégias para a veiculação de agentes bioativos e vacinas na forma de nanodispositivos tais como lipossomas, nanopartículas e micropartículas. Diversos nanossistemas já demonstraram eficácia na otimização de vacinas e quimioterápicos destinados ao controle da malária. Este artigo de revisão tem por objetivo avaliar o estado da arte na terapêutica da malária e demonstrar o potencial da nanotecnologia farmacêutica como ferramenta destinada ao combate da doença.

In spite of living in a scientific and technological era, malaria continues to be one of the worldwide greatest health challenges. The state-of-the-art policy to keep malaria under control is expected to comprise joint-strategies, such as the vector control, fast diagnosis, therapeutic guarantee, resistance cutback, drug optimization and development of new therapeutic agents and vaccines. Nano and microcarrier systems have been receiving a special attention, including the development of strategies for carrying bioactive agents, vaccines through nanodevices, such as liposomes and nanoparticles, and microdevices, such as microparticles and microemulsions. Numerous nanosystems have already substantiated their effectiveness to optimize vaccines, insecticides, and chemotherapeutic agents applied to the control of malaria. This review is intended to explain the malaria scenario though the world, and to show the nanotechnology as a promising alternative for malaria control and treatment.

Adjuvant requirement for successful immunization with recombinant derivatives of Plasmodium vivax merozoite surface protein-1 delivered via the intranasal route

Recently, we generated two bacterial recombinant proteins expressing 89 amino acids of the C-terminal domain of the Plasmodium vivax merozoite surface protein-1 and the hexa-histidine tag (His6MSP1(19)). One of these recombinant proteins contained also the amino acid sequence of the universal pan allelic T-cell epitope (His6MSP1(19)-PADRE). In the present study, we evaluated the immunogenic properties of these antigens when administered via the intra-nasal route in the presence of distinct adjuvant formulations. We found that C57BL/6 mice immunized with either recombinant proteins in the presence of the adjuvants cholera toxin (CT) or the Escherichia coli heat labile toxin (LT) developed high and long lasting titers of specific serum antibodies. The induced immune responses reached maximum levels after three immunizing doses with a prevailing IgG1 subclass response. In contrast, mice immunized by intranasal route with His6MSP1(19)-PADRE in the presence of the synthetic oligonucleotides adjuvant CpG ODN 1826 developed lower antibody titers but when combined to CT, CpG addition resulted in enhanced IgG responses characterized by lower IgG1 levels. Considering the limitations of antigens formulations that can be used in humans, mucosal adjuvants can be a reliable alternative for the development of new strategies of immunization using recombinant proteins of P. vivax.

Plasmodium vivax thrombospondin related adhesion protein: immunogenicity and protective efficacy in rodents and Aotus monkeys

The thrombospondin related adhesion protein (TRAP) is a malaria pre-erythrocytic antigen currently pursued as malaria vaccine candidate to Plasmodium falciparum. In this study, a long synthetic peptide (LSP) representing a P. vivax TRAP fragment involved in hepatocyte invasion was formulated in both Freund and Montanide ISA 720 adjutants and administered by IM and subcutaneous routes to BALB/c mice and Aotus monkeys. We measured specific humoral immune responses in both animal species and performed a sporozoite challenge in Aotus monkeys to assess the protective efficacy of the vaccine. After immunization both mice and Aotus seroconverted as shown by ELISA, and the specific anti-peptide antibodies cross reacted with the parasite in IFAT assays. Only two out of six immunized animals became infected after P. vivax sporozoite challenge as compared with four out of six animals from the control group. These results suggest that this TRAP fragment has protective potential against P. vivax malaria and deserves further studies as vaccine candidate.

Norma técnica de salud para la atención de la malaria y malaria grave en el Perú / Technical norm of health care for malaria and severe malaria in Peru

La publicación define y unifica criterios normativos que deben ser observados por los prestadores de salud en el diagnóstico y atención curativa de la malaria y malaria grave, sobre la base de los esquemas terapéuticos estandarizados de eficacia comprobada que garanticen la curación de los pacientes, la administración del tratamiento respectivo, siendo de aplicación obligatoria en todos los establecimientos de salud del ámbito nacional públicos y privados

Cytoadhesion of Plasmodium falciparum-infected erythrocytes and the infected placenta: a two-way pathway

Malaria is undoubtedly the world's most devastating parasitic disease, affecting 300 to 500 million people every year. Some cases of Plasmodium falciparum infection progress to the deadly forms of the disease responsible for 1 to 3 million deaths annually. P. falciparum-infected erythrocytes adhere to host receptors in the deep microvasculature of several organs. The cytoadhesion of infected erythrocytes to placental syncytiotrophoblast receptors leads to pregnancy-associated malaria (PAM). This specific maternal-fetal syndrome causes maternal anemia, low birth weight and the death of 62,000 to 363,000 infants per year in sub-Saharan Africa, and thus has a poor outcome for both mother and fetus. However, PAM and non-PAM parasites have been shown to differ antigenically and genetically. After multiple pregnancies, women from different geographical areas develop adhesion-blocking antibodies that protect against placental parasitemia and clinical symptoms of PAM. The recent description of a new parasite ligand encoded by the var2CSA gene as the only gene up-regulated in PAM parasites renders the development of an anti-PAM vaccine more feasible. The search for a vaccine to prevent P. falciparum sequestration in the placenta by eliciting adhesion-blocking antibodies and a cellular immune response, and the development of new methods for evaluating such antibodies should be key priorities in mother-child health programs in areas of endemic malaria. This review summarizes the main molecular, immunological and physiopathological aspects of PAM, including findings related to new targets in the P. falciparum var gene family. Finally, we focus on a new methodology for mimicking cytoadhesion under blood flow conditions in human placental tissue.