Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Although the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been assayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease

Vaccines represent one of the most effective measures of public health medicine, saving countless lives and preventing lifelong disabilities. Vaccines are extremely safe, however, no vaccine is completely free from risks and adverse events can occur following vaccination. An adverse event following immunization (AEFI) may be a true adverse reaction caused by the vaccine or an event that temporally occurred after immunization but is not caused by it. Among the adverse reactions to vaccines, one of the most feared is the triggering of autoimmune diseases, which are a heterogeneous group of disorders characterized by dysregulation of the immune system. Currently, no mechanisms have been demonstrated that could explain the correlation between vaccination and the development of autoimmune diseases. Furthermore, epidemiological studies do not support the hypothesis that vaccines cause systemic autoimmune diseases. The only confirmed associations, although very rare, are those between the flu vaccine and Guillain-Barré syndrome, especially with old vaccine preparations, and measles-mumps-rubella (MMR) vaccine and thrombocytopenia. Due to the SARS-CoV2 pandemic, new types of vaccines have been developed and are now available. Close vaccine safety-surveillance is currently underway for these new vaccines.

Many studies have shed light on the mechanisms underlying both immunoprotection and immune dysregulation arising after Trypanosoma cruzi infection. However, little is known about the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide), the drug available for clinical treatment of the infection, on the immune system in the infected host. In the present study we investigated the effect of benznidazole therapy on the lymphoid compartment during the course of experimental T. cruzi infection. Although amelioration of a variety of clinical and parasitological signs was observed in treated mice, amelioration of splenocyte expansion was not detected. Interestingly, this sustained splenomegaly observed in benznidazole-treated mice showed a preferential expansion of CD8 ؉ T lymphocytes. Moreover, although benznidazole treatment blocked the expansion of recently activated CD4؉ and CD8 ؉ T cells seen in infected hosts, benznidazole treatment led to a selective expansion of effector and memory CD8 ؉ T lymphocytes in association with a lower rate of apoptosis. In addition, the surviving treated animals were protected from reinfection. Together, these data suggest that, in addition to its well-known direct role in blocking parasite replication in vivo, benznidazole appears to directly affect immune regulation in T. cruzi-infected hosts.Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is a human parasitosis affecting 16 million to 18 million people in Latin America (42). This disease is characterized by an acute phase with detectable parasitemia and acute myocarditis in 8% of cases (20) and a longlasting chronic phase in which most infected people remain asymptomatic. However, approximately 36% of chronically infected individuals develop digestive problems and/or cardiomyopathy (42) in association with parasitemia and some parasitism in tissues.

Creatine kinase (CK total and CK-MB) were studied as markers of lesion progression induced by Trypanosoma cruzi infection. After 3 weeks mice infected with 10(4) parasites showed an increase in both enzyme levels and in their frequency distribution. A trend to increase was already detected in the 2nd week. A short duration per os treatment with benznidazole (Bz) prevented the occurrence of tissue lesions, since no changes were observed in enzymes. However, in the 4th week, about 40% of Bz-treated mice showed an increase in CK-MB, as did those that survived until the 8th week. Long-term treatment with Bz in drinking water of mice infected with 10(2) parasites showed, after 32 weeks, a partial reversion of the occurrence of high CK-MB levels from 85.7% to 50%. We found a positive correlation between inflammatory infiltrates and CK-MB levels, indicating that this marker could be useful to monitor the occurrence of experimental chagasic myocarditis.

A comparative study was performed between the trypanocidal efficacy of and associated immune response to benznidazole and posaconazole in a murine model of Chagas disease. Both drugs led to 100% survival, suppression of parasitaemia and reduction of specific anti-Trypanosoma cruzi antibodies following chronic infection. All posaconazole-treated animals had negative haemocultures at 54 days post infection, whilst 50% of those treated with benznidazole had positive results. Although both drugs were effective in reducing parasitism and inflammation in the heart, posaconazole-treated animals had plasma enzymatic levels of cardiac lesion that were indistinguishable from those of uninfected mice, whilst for benznidazole the enzyme levels were significantly higher than those of uninfected controls 31 days after the start of treatment. Posaconazole was more effective than benznidazole in controlling spleen enlargement and unspecific splenocyte proliferation in the early acute phase, but allowed higher levels of activation of CD4(+) and CD8(+) T-cells in the late acute phase when the adaptive immune response takes control of the infection. These results support the notion that posaconazole could be superior to benznidazole for the treatment of T. cruzi infection in humans.