The Potential Economic Value of a Trypanosoma cruzi (Chagas Disease) Vaccine in Latin America

The substantial burden of Chagas disease, especially in Latin America, and the limitations of currently available treatment and control strategies have motivated the development of a Trypanosoma cruzi (T. cruzi) vaccine. Evaluating a vaccine's potential economic value early in its development can answer important questions while the vaccine's key characteristics (e.g., vaccine efficacy targets, price points, and target population) can still be altered. This can assist vaccine scientists, manufacturers, policy makers, and other decision makers in the development and implementation of the vaccine. We developed a computational economic model to determine the cost-effectiveness of introducing a T. cruzi vaccine in Latin America. Our results showed vaccination to be very cost-effective, in many cases providing both cost savings and health benefits, even at low infection risk and vaccine efficacy. Moreover, our study suggests that a vaccine may actually “pay for itself”, as even a relatively higher priced vaccine will generate net cost savings for a purchaser (e.g., a country's ministry of health). These findings support continued investments in and efforts toward the development of a human T. cruzi vaccine

Short-term follow-up of chagasic patients after benznidazole treatment using multiple serological markers

<p>Abstract</p> <p>Background</p> <p>Conventional serological tests, using total soluble proteins or a cocktail of recombinant proteins from <it>T. cruzi </it>as antigens, are highly sensitive for Chagas disease diagnosis. This type of tests, however, does not seem to be reliable tools for short- and medium-term monitoring of the evolution of patients after antiparasitic treatment. The aim of the present study was to search for immunological markers that could be altered in the sera from Chagas disease patients after benznidazole treatment, and therefore have a potential predictive diagnostic value.</p> <p>Methods</p> <p>We analyzed the reactivity of sera from chagasic patients during different clinical phases of the disease against a series of immunodominant antigens, known as KMP11, PFR2, HSP70 and Tgp63. The reactivity of the sera from 46 adult Chronic Chagas disease patients living in a non-endemic country without vector transmission of <it>T. cruzi </it>(15 patients in the indeterminate stage, 16 in the cardiomiopathy stage and 16 in the digestive stage) and 22 control sera from non-infected subjects was analyzed. We also analyzed the response dynamics of sera from those patients who had been treated with benznidazole.</p> <p>Results</p> <p>Regardless of the stage of the sickness, the sera from chagasic patients reacted against KMP11, HSP70, PFR2 and Tgp63 recombinant proteins with statistical significance relative to the reactivity against the same antigens by the sera from healthy donors, patients with autoimmune diseases or patients suffering from tuberculosis, leprosy or malaria. Shortly after benznidazole treatment, a statistically significant decrease in reactivity against KMP11, HSP70 and PFR2 was observed (six or nine month). It was also observed that, following benznidazole treatment, the differential reactivity against these antigens co-relates with the clinical status of the patients.</p> <p>Conclusions</p> <p>The recombinant antigens KMP11, PFR2, Tgp63 and HSP70 are recognized by Chagas disease patients' sera at any clinical stage of the disease. Shortly after benznidazole treatment, a drop in reactivity against three of these antigens is produced in an antigen-specific manner. Most likely, analysis of the reactivity against these recombinant antigens may be useful for monitoring the effectiveness of benznidazole treatment.</p

Clinical Outcomes of Thirteen Patients with Acute Chagas Disease Acquired through Oral Transmission from Two Urban Outbreaks in Northeastern Brazil

Chagas disease is caused by a parasitic protozoan transmitted to humans by the contaminated feces of blood-feeding assassin bugs from the Triatominae subfamily. It may also be transmitted from mother to baby during pregnancy, by breastfeeding, blood transfusion or organ transplant. In rare cases, the disease can also be caused by accidental ingestion of contaminated food (sugar cane or açaí juice, drinking water, etc.). Acute Chagas disease often presents itself as a mononucleosis-like syndrome, with symptoms including fever, lymph node enlargement and muscle pain. The mortality rate of acute Chagas disease is high, mainly due to heart failure as a consequence of cardiac fiber lesions. There are few studies describing clinical outcomes and the disease progression of patients who receive therapeutic treatment, especially with regard to cardiac exam findings. In this report, the authors describe clinical findings from two micro-outbreaks occurring in impoverished towns in northeastern Brazil. Prior to receiving treatment, patient mortality rate was 28.6% in one of the outbreaks, and one pregnant woman experienced a spontaneous abortion due to the disease in the other outbreak. Most patients complained of fever, dyspnea, myalgia and periorbital edema. After receiving a two-month course of treatment, clinical symptoms improved and the number of abnormalities in cardiac exams decreased

Differential Regional Immune Response in Chagas Disease

Following infection, lymphocytes expand exponentially and differentiate into effector cells to control infection and coordinate the multiple effector arms of the immune response. Soon after this expansion, the majority of antigen-specific lymphocytes die, thus keeping homeostasis, and a small pool of memory cells develops, providing long-term immunity to subsequent reinfection. The extent of infection and rate of pathogen clearance are thought to determine both the magnitude of cell expansion and the homeostatic contraction to a stable number of memory cells. This straight correlation between the kinetics of T cell response and the dynamics of lymphoid tissue cell numbers is a constant feature in acute infections yielded by pathogens that are cleared during the course of response. However, the regional dynamics of the immune response mounted against pathogens that are able to establish a persistent infection remain poorly understood. Herein we discuss the differential lymphocyte dynamics in distinct central and peripheral lymphoid organs following acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. While the thymus and mesenteric lymph nodes undergo a severe atrophy with massive lymphocyte depletion, the spleen and subcutaneous lymph nodes expand due to T and B cell activation/proliferation. These events are regulated by cytokines, as well as parasite-derived moieties. In this regard, identifying the molecular mechanisms underlying regional lymphocyte dynamics secondary to T. cruzi infection may hopefully contribute to the design of novel immune intervention strategies to control pathology in this infection

Differential Phenotypic and Functional Profiles of TcCA-2 -Specific Cytotoxic CD8+ T Cells in the Asymptomatic versus Cardiac Phase in Chagasic Patients

It has been reported that the immune response mediated by T CD8+ lymphocytes plays a critical role in the control of Trypanosoma cruzi infection and that the clinical symptoms of Chagas disease appear to be related to the competence of the CD8+ T immune response against the parasite. Herewith, in silico prediction and binding assays on TAP-deficient T2 cells were used to identify potential HLA-A*02:01 ligands in the T. cruzi TcCA-2 protein. The TcCA-2-specific CD8+ T cells were functionality evaluated by Granzyme B and cytokine production in peripheral blood mononuclear cells (PBMC) from Chagas disease patients stimulated with the identified HLA-A*02:01 peptides. The specific cells were phenotypically characterized by flow cytometry using several surface markers and HLA-A*02:01 APC-labeled dextramer loaded with the peptides. In the T. cruzi TcCA-2 protein four T CD8+ epitopes were identified which are processed and presented during Chagas disease. Interestingly, a differential cellular phenotypic profile could be correlated with the severity of the disease. The TcCA-2-specific T CD8+ cells from patients with cardiac symptoms are mainly effector memory cells (TEM and TEMRA) while, those present in the asymptomatic phase are predominantly naive cells (TNAIVE). Moreover, in patients with cardiac symptoms the percentage of cells with senescence features is significantly higher than in patients at the asymptomatic phase of the disease. We consider that the identification of these new class I-restricted epitopes are helpful for designing biomarkers of sickness pathology as well as the development of immunotherapies against T. cruzi infection.This work was supported by grants SAF2012-35777 and SAF2013-48527-R from Programa Estatal I+D+i (MINECO); Network of Tropical Diseases Research RICET, grants RD12/0018/0021 and RD12/0018/0018 (MSSSI, Spain) and FEDER. MS and BC were also supported by grant FIS, 2009SGR385 from ISCIII (MSSSI, Spain). Coauthor Concepción Marañón is employed by Genomic Medicine Department, GENYO. Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government. Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government provided support in the form of salaries for author Concepción Marañón, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the author contributions section.Peer reviewe

Is 20/20 vision good enough? Visual acuity differences within the normal range predict contour element detection and integration

Contour integration (CI) combines appropriately aligned and oriented elements into continuous boundaries. Collinear facilitation (CF) occurs when a low-contrast oriented element becomes more visible when flanked by collinear high-contrast elements. Both processes rely at least partly on long-range horizontal connections in early visual cortex, and thus both have been extensively studied to understand visual cortical functioning in aging, development, and clinical disorders. Here, we ask: Can acuity differences within the normal range predict CI or CF? To consider this question, we measured binocular visual acuity and compared subjects with 20/20 vision to those with better-than-20/20 vision (SharpPerceivers) on two tasks. In the CI task, subjects located an integrated shape embedded in varying amounts of noise; in the CF task, subjects detected a low-contrast element flanked by collinear or orthogonal high-contrast elements. In each case, displays were scaled in size to modulate element visibility and spatial frequency (4-12 cycles/deg). SharpPerceivers could integrate contours under noisier conditions than the 20/20 group (p=.0002) especially for high spatial frequency displays. Moreover, although the two groups exhibited similar collinear facilitation, SharpPerceivers could detect the central target with lower contrast at high spatial frequencies (p<.05). These results suggest that small acuity differences within the normal range—corresponding to about a one line difference on a vision chart—strongly predict element detection and integration. Furthermore, simply ensuring that subjects have normal or corrected-to-normal vision is not sufficient when comparing groups on contour tasks; visual acuity confounds also need to be ruled out