key: cord-0031592-tzshjp1e
authors: Scharfstein, Julio
title: Brazilian immunology in Caxambu: beyond vaccination, a tribute to the pioneers of basic research in Chagas disease
date: 2022-05-09
journal: Mem Inst Oswaldo Cruz
DOI: 10.1590/0074-02760210314chgsb
sha: d6a8d98dc023014bcc6b23685f637b7bae0258b5
doc_id: 31592
cord_uid: tzshjp1e

nan

dogenously, they become immunologically tolerant to these self-structures. This is the reason why rodents are not able to produce anti-α-Gal antibodies when challenged by α-Gal bearing pathogens. In contrast, humans and OWPs naturally produce anti-α-Gal antibodies, and this immune response is usually potentiated upon infection by different pathogens, including T. cruzi and Leishmania spp. The perception that the antibody repertoire of wild type mice lacks a fundamental component of immune response (anti-α-Gal) of humans and OWP was the starting point of a productive line of immunology research (7, 8) launched by Luiz RG Travassos (EPM/UNIFESP), a pioneer in the field of parasite and fungal glycobiology. Systematic investigations carried out by Igor Almeida (at USP and University of Texas-El Paso) (9, 10) have paved the way for the design of synthetic vaccines and chemotherapy biomarkers for followup based on α-Gal-bearing neoglycoproteins (NGPs). With a US patent recently assigned to the University of Texas System, (11) the PhD studies that Igor Almeida initiated in Travassos's lab resulted in an innovative approach in human vaccination against T. cruzi, Leishmania spp. and other pathogens. Of further interest, these synthetic α-Gal-NGPs are being currently validated as biomarkers for early assessment of cure following chemotherapy with benznidazole or nifurtimox in an ongoing NIH-funded phase-2 trial (https://clinicaltrials.gov/ct2/show/NCT03981523). If successful, these molecular assays will serve as prognostic tools of therapeutic cure, hence translating to the clinical settings a biological phenomenon (lytic antibodies) originally described by Antoniana Krettli, J Romeu Cançado, and Zigman Brenner. (12) Collectively, these classic discoveries illustrate how systematic investigations in basic Chagas disease may have broader application in translational Medicine.

As pondered by Alexander R Precioso, the prevalence of vectorial transmission of Chagas disease in Brazil is low and limited to distant geographic regions. Hence, the high cost and the complexity of logistics required for large scale clinical trials of an immunoprophylactic vaccine might be an obstacle to this pretense. Clinical studies with therapeutic vaccines (perhaps associated to chemotherapy with lower doses of benznidazole) might be safely conducted in hospital units under supervision of medical staff. However, this initiative must be preceded by preclinical studies convincingly showing that the chronic Chagas disease cardiomyopathy (CCC) is either prevented or markedly attenuated by therapeutic interventions. Another complication is that therapeutic vaccination in animals that are chronically infected with T. cruzi must be evaluated with parasite strains/isolates representative of various DTUs.

As mentioned earlier, there is a second reason why preclinical studies in wild-type mice may not be the ideal model for testing vaccine efficacy (prophylactic or therapeutic) against Chagas disease. For reasons that are still unclear, chronically infected mice do not consistently develop the dilated form of cardiomyopathy observed in patients. Future attempts to evaluate the cardioprotective effect of immunoprophylactic or therapeutic vaccines in chronically infected animals should be preferably performed in colonies of OWP or dogs. Considering that vaccination studies in chronically infected dogs will be operationally complex, it might be preferable to test vaccine efficacy in transgenic mice deficient of the alpha-galactosyltransferasec gene, or, alternatively, in hamsters in which this key gene will be eventually ablated. In a study published several years ago, Edécio Cunha Neto and co-workers (13) demonstrated that a significant proportion of chronically infected hamsters developed a dilated cardiomyopathy that closely resembles human CCC. Although the hamster is known for decades as a rodent species that is highly susceptible to infection by Leishmania spp., immunologists comprehensibly showed low interest to investigate immunity mechanisms in hamsters because there is limited availability of tools (monoclonal antibodies) to phenotype leukocytes and tissue cells. Regarding transgenesis, so far there is only a single report, published by Chinese groups, describing CRISP/Cas-9-dependent generation of transgenic lines of hamsters. Recently, however, awareness that the Syrian hamster is highly susceptible to acute infection by Ebola and coronaviruses, including SARS-Cov-2 (14) has prompted iniciatives in R&D to supply immunoreagents for hamster research. (15) The history of vaccination against neglected parasitic diseases is still nascent, reflecting the difficulty to cross the "valley of death" of vaccine development. While sharing his own experience as the director of WHO-TDR (1998), Carlos Morel reproduced fragments of a conversation he held in his Geneve office with Barry Bloom, an influential immunologist of the second half of the 20th century. While not minimising the hardships that immunoparasitologists faced throughout decades, we recently learned that a phase-2b randomised clinical trial to evaluate the efficacy of a modified CS-based vaccine (R21 in adjuvant Matrix-M) against malaria was concluded in Burkina Faso. (16) The results showed 77% efficacy in a cohort study involving seasonal vaccine administration to 450 children. Although the results of phase 3 trials are still to come, this human vaccine against malaria is the outcome of a life-time project headed by Ruth and Victor Nussenzweig. Joined by several brilliant co-workers, these Brazilian-born immunoparasitologists should be credited for being the first to cross the "valley of death" in vaccine development. More importantly, millions of lives in Africa might be spared as result of their milestone discoveries. (17) Without fear of being nostalgic, my final note goes to a conversation that I held in the early 80's in Caxambu (Hotel Gloria) with Maurício M Rodrigues, my first scientific initiation (IC) student. One night, under the fresh evening breeze of November, over a beer, we stopped laughing about the funny scenes that Isaac Roitman created for his famous Award at the end of the Annual Meetings to discuss distant prospects of a vaccine against Chagas' disease. With excitement on his bright eyes, the young Maurício first learned about the strategies that the NYU team was developing to produce a malarial vaccine based on CS antigen. Back to the future, after spending a post doc Trypanosoma cruzi, a flagellated protozoan seeking shelter from the inflammatory storm. with Fidel Zavala at NYU, Maurício Rodriguez developed a productive career at Universidade Federal De São Paulo (UNIFESP), mostly focused on the development of an experimental vaccine against Chagas disease. Irrespective of the outcome of vaccination against Chagas disease, the mysteries behind T. cruzi successful adaptation in immunocompetent mammals will still defy the imagination (Figure) of multiple generations of students attending Sociedade Brasileira de Protozoologia (SBPZ) and the Annual Meetings of Basic Research on Chagas Disease.

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