Background The bacille Calmette–Guérin (BCG) vaccine has immunomodulatory “off-target” effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). Methods In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. Results A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], −0.7 to 5.5; P=0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, −1.2 to 3.5; P=0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. Conclusions Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206 .)

IntroductionBCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysisThis international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and disseminationEthical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registrationClinicalTrials.gov NCT04327206

Background and objectives Because of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using samples from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2. Methods This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry. Results BCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS‐CoV‐2. Conclusions The immunomodulatory signature of BCG’s off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19.

ix Publicações xi Lista de Figuras xiii A Lista de Materiais 85 Dedicatórià A minha mãe, Maria Cecília Jardim, que sempre me motivou a acreditar nos meus sonhos e me ensinou o valor da educação. Ao meu filho,Ítalo, que me dá força para vencer os desafios e buscar novos sonhos. A todos que sonham e trabalham por um mundo melhor. Agradecimentos Ao orientador e amigo Prof. Dr. Adriano Almeida Gonçalves Siqueira, pela confiança depositada, orientação, tempo dedicado a este trabalho e pelas inestimáveis experiências transmitidas em nossas conversas. Aos professores e funcionários do Departamento de Engenharia Mecânica da Escola de Engenharia de São Carlos, pelas contribuições durante o mestrado. Aos técnicos do Departamento de Engenharia Mecânica por contribuir com o desenvolvimento do projeto. Aos alunos de Iniciação Científica, Heitor de Araujo Martins, Guilherme Machado Lara Silveira, Danilo Santos, Paulo Roberto Chiarolanza Vilela e Tiago Furlan Winter, pela dedicação ao projeto. Aos amigos do Rotary Club de Campinas, especialmente ao Sr. Carlos Roberto de Mattos Rocha que muito contribuiu para minha formação. Aos amigos do Departamento de Engenharia Mecânica pela amizade, paciência, companheirismo e colaborações durante a realização das disciplinas e deste trabalho. A minha noiva Maria Helena por estar sempre ao meu lado. Ao Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) pela concessão da bolsa de mestrado.vii Resumo Esta dissertação apresenta o projeto e a construção de atuadores elásticos em série para o acionamento das juntas de um exoesqueleto para membros inferiores, baseado em umaórtese comercial. Inicialmente, considerou-se como dispositivo de testes a parte do exoesqueleto referenteà junta do tornozelo, ou seja, a construção de umaórtese tornozelo-pé ativa. Atuadores elásticos em série são considerados neste trabalho, pois tais dispositivos apresentam características ideais para a sua utilização emórteses ativas: controle de força, controle de impedância (possibilidade de impedância baixa), absorção de impactos, baixo atrito e largura de banda que se aproxima da movimentação muscular. Um primeiro protótipo do atuador elástico em série foi construído e resultados experimentais de controle de força, impedância e posição foram obtidos com sucesso, através de uma interface de acionamento e controle entre o atuador, os sensores (encoders e sensores de força) e o computador. Também foi construída umaórtese tornozelopé ativa acionada pelo atuador elástico em série construído, sendo apresentados os primeiros resultados experimentais obtidos com este dispositivo. Palavras-chave: Atuadores elásticos em série, exoesqueleto, controle de impedância, reabilitação. viii ix Abstract This dissertation deals with the design and construction of series elastic actuators for driving the joints of an exoskeleton for lower limbs, based on a commercial orthosis. Initially, it was considered the construction of the exoskeleton's ankle joint, that is, the construction of an active ankle-foot orthosis. Series ...

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