Efficience of human Plasmodium falciparum malaria vaccine candidates in Aotus lemurinus monkeys

The protective efficacy of several recombinat and a synthetic Plasmodium falciparum protein was assessed in Aoutus monkeys. The rp41 aldolase, the 190L fragment of the MSA-1 protein and fusion 190L-CS. T3 protein containg the CS. T3 helper "universal epitope were emulsified in Freund's adjuvants and injected 3 times in groups of 4-5 monkeys each one. The synthetic polymer Spf (66)30 also emulsified in Freund's adjuvants was injected 6 times. Control groups for both experiments were immunized with saline solution in the same adjuvant following the same schedules. Serology for malaria specific antibodies showed seroconversion in monkeys immunized with the recombinant proteins but not in those immunized with the polymer nor in the controls. Challenge was performed with the 10 (elevado a quinta potência) parasites from the P. falciparum FVO isolate. Neither rp41 nor SPf (66)30 induced protection, whereas 190L induced significant delay of parasitemia. The fusion of the CS. T3 epitope to 190L significantly increased is protective capacity.

Vaccine strategies against schistosomiasis

In this review the authors analyze the effector and regulatory mechanisms in the immune response to schistosomiasis. To study these mechanisms two animal models were used, mouse and rat. The mouse totaly permissive host like human, show prominent-T cell control in the acquisition of resistance. But other mechanisms like antibody mediated cytotoxity (ADCC) involving eosinophils and IgG antibodies described in humans, are observed in rats. Also in this animal, it is observed specific IgE antibody high production and blood and tisssue eosinophilia. Using the rat model and schistosomula as target, some ADCC features have emerged: the cellular population involved are bone marrow derived inflammatory cell (mononuclear phagocytes, eosinophils and platelets), interacting with IgE through IgE Fc receptors. Immunization has been attempted using the recombinant protein Sm28/GST. Protection has been observed in rodents with significant decrease of parasite fecundity and egg viability affecting the number, size and volume of liver egg granulomas. The association of praziquantel and immunization with with Sm28/GST increases the resistance to infection and decreases egg viability. The authors suggest the possibility of the stablishment of a future vaccine against Schistosoma mansoni.

Vaccine strategies against schistosomiasis

Schistosomiasis, the second major parasitic disease in the world after malaria affects at least 200 million people, 500 million being exposed to the risk of infection. It is widely agreed that a vaccine strategy wich could lead to the induction of effector mechanisms reducing the level of reinfection and ideally parasite fecundity would deeply affect the incidence of pathological manifestations as well as the parasite transmission potentialities. Extensive studies performed in the rat model have allowed the identification of novel effector mechanisms involving IgE antibodies and various inflammatory cell populations (eosinophils, macrophages and platelets) whereas regulation of immune response by blocking antibodies has been evidencial. Recent epidemiological studies have now entirely confirmed in human populations the the role of IgE antibodies in the acquisition of resistance and the association of IgG4 blocking antibodies with increased susceptibility. On the basis of these concepts, several schistosome glutathion S-transferase (Sm 28 GST) appears as a pronising vaccine candidate. Immunization experiments have shown that two complementary goals can be achieved: (a) a partial but significant reduction of the worm population (up to 60//in rats); (b) a significant reduction of parasite fecundity (up in the mice and 85//in cattle) and egg viability (up to 80//). At least two distinct immunological mechanisms account for these two effects. IgE antibodies appear as a major humoral component of acquired resistance whereas IgA antibodies appear as a major humoral factor affecting parasite fecundity. These studies seem to represent a parasite diseases through the identification of potentially protective antigens and of the components of the immune response which vaccination should aim at inducing.

Morphological and virological studies in six autopsies of children with adenovirus pneumonia

Pulmonary lesions compatible with adenovirus infection were detected by gross and microscopic examination of autopsy tissues children aged from 5 to 34 months. Hepatic lesions indicative of systemic infection were also found in four of the chisldren. The viral etiology was confirmed in three cases by in-situ hibridization, electro-microscopy and immunofluorescence performed in parafin-embedded tissues, and in one case by cell culture isolation of adenovirus type 2 from nasopharyngeal exudate. Routine testing by methods additional to conventional light microscopy would probably have revealed a larger number of adenovirus infections among the 1.103 autopsy records analyzed in this study.

Toxoplasmosis and mental retardation: report of a case-control study

A case-control study evaluating the association between mental retardation and toxoplasmosis was conducted among 845 school children in Belo Horizonte, MG, Brazil. Cases (450) were mentally retarded children attending a public school for special education. Controls (395) were children from the regular public school system. Clinical and anthropometric examinations and interviews were carried out to determine risk factors for toxoplasmosis and mental retardation. Diagnosis of Toxoplasma gondii infection was based upon an indirect immunofluorescent test (IFA); 55% of cases and 29% of controls were positive. The Relative Odds of mental retardation in children with positive serology was 3.0 (95% CI 2.2-4.0). Maternal exposure to cats and contact with soil were associated with an increased risk of mental retardation. Retinochoroiditis was fourfold more prevalent among cases than controls and was only diagnosed in T. gondii IFA positive participants. Congenital toxoplasmosis, in its subclinical form, appears to be an important component in the etiology of mental retardation, especially in high risk (lower socio-economic) groups. The population attributable risk was estimated as 6.0 - 9.0%, suggesting the amount of mental retardation associated with this infection.

A simple and economic slide micro-immunoenzymatic (Micro-SIA) test for epidemiological studies of toxoplasmosis

A slide micro-immunoenzymatic assay (micro-SIA) to detectantibodies to non-particulate Toxoplasma gondii antigens is described. This assay allows the diagnosis of toxoplasmosis infection in about 1 hr. Twenty-four determinations can be performed per slide. Five hundred ng of antigen and 5 or 10 µl drop of each reactive are necessary per well. The clear contrast of colours obtained for negative and positive sera after the test is finished, allows direct discrimination of the results. However, it is possible to quantify the results of the reaction using a minireader. Sera dilution cutoff value, determined as themost frequent titre for the general population, is 1:100. The toxoplasma micro-SIA correlates well with indirect immunofluorescence (IIF), its sensitivity is atleast three times as much as IIF. The test has an intra and inter assay variation coefficient of 5.46 per cent and of 6.24 per cent respectively. Sera obtained at random from argentinian people were analyzed and a 56 per cent of infection was found. The main features of the Toxoplasma micro-SIA are its simplicity, sensitivity, reproducibility, and the virtual absence of background making it very suitable for screening tests.

Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines

Rapport de synthèse: Enjeux de la recherche : La pneumonie communautaire chez l'enfant est un problème de santé publique considérable. Elle est responsable de 2 millions de mort par année, 70% survenant dans les pays en voie de développement. Sous nos latitudes son incidence est de 40/1000 enfants par année, ce qui représente une morbidité importante. Deux difficultés surviennent lorsqu'on cherche à diagnostiquer une pneumonie. La première est de distinguer une pneumonie bactérienne d'une virale, particulièrement chez les petits enfants où les infections virales des voies respiratoires inférieures sont fréquentes. L'OMS a définit la pneumonie selon des critères exclusivement cliniques et une étude effectuée à Lausanne en 2000 a montré que ces critères peuvent être utilisés dans nos contrées. La seconde difficulté est de définir l'agent causal de la pneumonie, ceci pour plusieurs raisons : L'aspiration endotrachéale, seul examen fiable, ne peut être obtenue de routine chez l'enfant vu son caractère invasif, la culture des secrétions nasopharyngées reflète la flore physiologique de la sphère ORL et une bactériémie n'est présente que dans moins de 10% des pneumonies. L'étiologie de la pneumonie reste souvent inconnue, et de ce fait plusieurs enfants reçoivent des antibiotiques pour une infection non bactérienne ce qui contribue au développement de résistances. L'objectif de cette étude était d'effectuer une recherche extensive de l'agent causal de la pneumonie et de déterminer quels facteurs pourraient aider le clinicien à différencier une pneumonie virale de bactérienne, en corrélant l'étiologie avec la sévérité clinique et les marqueurs de l'inflammation. Contexte de la recherche : II s'agissait d'une étude prospective, multicentrique, incluant les enfants âgés de 2 mois à 5 ans hospitalisés pour une pneumonie, selon les critères de l'OMS, dans le service de pédiatrie de Lausanne et Genève entre mars 2003 et Décembre 2005, avant l'implantation de la vaccination antipneumococcique de routine. Chaque enfant, en plus des examens usuels, bénéficiait d'une recherche étiologique extensive : Culture virale et bactérienne, PCR (Mycoplasma Pneumoniae, Chlamydia Pneumoniae, Virus Influenza A et B, RSV A et B, Rhinovirus, Parainfluenza 1-3, enterovirus, human metapneumovirus, coronavirus OC43, E229 ; et NL 63) et détection d'AG viraux dans les sécrétions nasopharyngées ; sérologies virales et bactériennes à l'entrée et 3 semaines après la sortie (AG Influenza A et B, Parainfluenza 1,2 et 3, RSV, Adenovirus, M.Pneumoniae et S.Pneumoniae). Conclusions : Un agent pathogène a été découvert chez 86% des 99 patients retenus confirmant le fait que plus la recherche étiologique est étendue plus le pourcentage d'agent causal trouvé est élevé. Une infection bactérienne a été découverte chez 53% des patients dont 45% avaient une infection à S. Pneumoniae confirmant l'importance d'une vaccination antipneumococcique de routine. La déshydratation et les marqueurs de l'inflammation tels que la C-Reactive Protein et la Procalcitonine étaient significativement plus élevés dans les pneumonies bactériennes. Aucune corrélation n'a été trouvée entre le degré de sévérité de la pneumonie et l'étiologie. L'étude a confirmé la haute prévalence d'infections virales (67%) et de co-infection (33%) dans la pneumonie de l'enfant sans que l'on connaisse le rôle réel du virus dans la pathogenèse de la pneumonie. Perspectives : d'autres études à la suite de celle-ci devraient être effectuées en incluant les patients ambulatoires afin de déterminer, avec un collectif plus large de patient, une éventuelle corrélation entre sévérité clinique et étiologie. Abstract : Community-acquired pneumonia (CAP) is a major cause of death in developing countries and of morbidity in developed countries. The objective of the study was to define the causative agents among children hospitalized for CAP defined by WHO guidelines and to correlate etiology with clinical severity and surrogate markers. Investigations included an extensive etiological workup. A potential causative agent was detected in 86% of the 99 enrolled patients, with evidence of bacterial (53%), viral (67%), and mixed (33%) infections. Streptococcus pneumoniae was accounted for in 46% of CAP. Dehydration was the only clinical sign associated with bacterial pneumonia. CRP and PCT were significantly higher in bacterial infections. Increasing the number of diagnostic tests identifies potential causes of CAP in up to 86% of children, indicating a high prevalence of viruses and frequent co-infections. The high proportion of pneumococcal infections re-emphasizes the importance of pneumococcal immunization.

Opportunities and constraints in schistosomiasis vaccine development: infection characteristics and industry realities

The notes provided in this article relate to two components of the development of vaccines against schistosomiasis: (1) The characteristics of schistosome infections (eg. features of the schistosome life cycle), and the parasite itself, that have implications for vaccination strategies; (2) The characteristics of the biopharmaceutical industry that have implications for product development. As will be seen, these two topic areas are not vastly disparate.

Schistosomiasis vaccine development: approaches and prospects

Mounting evidence for acquired immunity to schistosomiasis in humans supports the case for immunological intervention. On the other hand, rapid reinfection poses a threat to younger age groups due to the slow maturation of natural resistance. However, rational approaches, based on advances in immunology and molecular biology, have substantially increased the odds of producing an effective vaccine. Since the parasite cannot replicate in the human host and serious morbidity generally occurs only after a relatively long period of heavy worm burden, complete protection against infection is not essential. The chances of success would increase if more than one of the various host/parasite interphases were targeted, for example reducing morbidity through decreased worm loads as well as through suppression of egg production. Several promising schistosome antigens have now reached an advanced phase of development and are currently undergoing independent confirmatory testing according to a standardized protocol. A few molecules are being contemplated for scaled-up production but, so far, only one has reached the stage of industrial manufacture and safety testing. Since schistosomiasis cannot realistically be controlled by a single approach, vaccination is envisaged to be implemented in conjunction with other means of control, notably chemotherapy.

Development of a vaccine strategy against human and bovine schistosomiasis: background and update

Schistosomiasis is a chronic and debilitating parasitic disease that affects over 200 million people throughout the world and causes about 500,000 deaths annually. Two specific characteristics of schistosome infection are of primordial importance to the development of a vaccine: schistosomes do not multiply within the tissues of their definitive hosts (unlike protozoan parasites) and a partial non-sterilizing immunity can have a marked effect on the incidence of pathology and on disease transmission. Since viable eggs are the cause of disease pathology, a reduction in worm fecundity whether or not accompanied by a reduction in parasite burden is a sufficient goal for vaccine induced immunity. We originally showed that IgE antibodies played in experimental models a pivotal role for the development of protective immunity. These laboratory findings have been now confirmed in human populations. Following the molecular cloning and expression of a protein 28 kDa protein of Schistosoma mansoni and its identification as a glutathion S-transferase, immunization experiments have been undertaken in several animal species (rats, mice, baboons). Together with a significant reduction in parasite burden, vaccination with Sm28 GST was recently shown to reduce significantly parasite fecundity and egg viability leading to a decrease in liver pathology. Whereas IgE antibodies were shown to be correlated with protection against infection, IgA antibodies have been identified as one of the factors affecting egg laying and viability. In human populations, a close association was found between IgA antibody production to Sm28 GST and the decrease of egg output. The use of appropriate monoclonal antibody probes has allowed the demonstration that the inhibition of parasite fecundity following immunization was related to the inhibition of enzymatic activity of the molecule. Epitope mapping of Sm28 GST has indicated the prominent role of the N and C terminal domains. Immunization with the corresponding synthetic peptides was followed by a decrease of 70% of parasite fecundity and egg viability. As a preliminary step towards phase I human trials, vaccination experiments have been performed in cattle, a natural model for Schistosoma bovis. Vaccination of calves with the S. bovis GST has led to a reduction of ever 80% of egg output and tissue egg count. Significant levels of protection were also observed in goats after immunization with the recombinant S. bovis GST. Increasing evidence of the participation of IgA antibodies in protective immunity has prompted us toward the development of mucosal immunization. Preliminary results indicate that significant levels of protection can be achieved following oral immunization with live attenuated vectors or liposomes. These studies seem to represent a promising approach towards the future development of a vaccine strategy against one of major human parasitic diseases.

Vaccination against schistosomiasis and fascioliasis with the new recombinant antigen Sm14: potential basis of a multi-valent anti-helminth vaccine?

Molecular cloning of components of protective antigenic preparations have suggested that related parasite fatty acid binding proteins could form the basis of the well documented protective, immune cross reactivity between the parasitic trematode worms Fasciola hepatica and Schistosoma mansoni. We have now confirmed the cross protective potential of parasite fatty acid binding proteins and suggest that it may be possible to produce a single vaccine that would be effective against at least two parasites, F. hepatica and S. mansoni of veterinary and human importance respectively.