Efficacy and Safety of BCG Revaccination With M. bovis BCG Moscow to Prevent COVID-19 Infection in Health Care Workers: A Randomized Phase II Clinical Trial.

The Bacillus Calmette-Guérin (BCG) vaccine, which is widely used to protect children against tuberculosis, can also improve immune response against viral infections. This unicentric, randomized-controlled clinical trial assessed the efficacy and safety of revaccination with BCG Moscow in reducing the positivity and symptoms of COVID-19 in health care workers (HCWs) during the COVID-19 pandemic. HCWs who had negative COVID-19 IgM and IgG and who dedicated at least eight hours per week in facilities that attended to individuals suspected of having COVID-19 were included in the study and were followed for 7, 15, 30, 60, and 180 days by telemedicine. The HCWs were randomly allocated to a revaccinated with BCG group, which received the BCG vaccine, or an unvaccinated group. Revaccination with BCG Moscow was found to be safe, and its efficacy ranged from 30.0% (95.0%CI -78.0 to 72.0%) to 31.0% (95.0%CI -74.0 to 74.0%). Mycobacterium bovis BCG Moscow did not induce NK cell activation at 15-20 days post-revaccination. As hypothesized, revaccination with BCG Moscow was associated with a lower incidence of COVID-19 positivity, though the results did not reach statistical significance. Further studies should be carried out to assess whether revaccination with BCG is able to protect HCWs against COVID-19. The protocol of this clinical trial was registered on August 5th, 2020, at REBEC (Registro Brasileiro de Ensaios Clínicos, RBR-4kjqtg - ensaiosclinicos.gov.br/rg/RBR-4kjqtg/1) and the WHO (# U1111-1256-3892). The clinical trial protocol was approved by the Comissão Nacional de ética de pesquisa- CONEP (CAAE 31783720.0.0000.5078).

Correction to: BCG revaccination of health workers in Brazil to improve innate immune responses against COVID-19: A structured summary of a study protocol for a randomised controlled trial.

An amendment to this paper has been published and can be accessed via the original article.

BCG revaccination of health workers in Brazil to improve innate immune responses against COVID-19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The BCG vaccine, widely used in Brazil in new-borns, induces adjuvant protection for several diseases, including childhood virus infections. BCG activates monocytes and innate memory NK cells which are crucial for the antiviral immune response. Therefore, strategies to prevent COVID-19 in health workers (HW) should be carried out to prevent them becoming unwell so that they can continue to work during the pandemic. The hypothesis is that BCG will improve the innate immune response and prevent symptomatic infection or COVID-19 severity. The primary objective is to verify the effectiveness and safety of the BCG vaccine to prevent or reduce incidence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the city of Goiânia (Brazil) among HW previously vaccinated with BCG and also its severity and mortality during the pandemic of the disease. Secondary objectives are to estimate the incidence of COVID-19 among these professionals and the innate immune response elicited to BCG. TRIAL DESIGN: This a phase II trial for repositioning BCG as a preventive strategy against COVID-19. The trial is an open-label, parallel-group randomised clinical trial, comparing HW vaccinated with BCG and HW not vaccinated. PARTICIPANTS: The trial will recruit 800 HW of Goiânia - Goiás, Brazil to reach a total of 400 HW included after comorbidities questioning and laboratorial evaluation. Eligibility criteria: Any HW presenting BCG vaccination scar with direct contact with suspected COVID-19 patients for at least 8 hours per week, whether in hospital beds, ICU, or in transportation or admission (nurses, doctors, physiotherapists, nutritionists, receptionists, etc.) who have negative IgM and IgG COVID-19 test. Participants with any of the following characteristics will be excluded: - Have had in the last fifteen days any signs or symptoms of virus infection, including COVID-19; - Have had fever in the last fifteen days; - Have been vaccinated fifteen days before the inclusion; - Have a history or confirmation of any immunosuppressive disease such as HIV, presented solid tumour in the last two years or autoimmune diseases; - Are under preventive medication with antibiotics, steroid anti-inflammatories, or chemotherapy; - Have less than 500 neutrophils per mL of blood; - Have previously been diagnosed with tuberculosis; - Are breastfeeding or pregnant; - Are younger than 18 years old; - Are participating as an investigator in this clinical trial. INTERVENTION AND COMPARATOR: HW will be randomized into the BCG vaccinated group or the BCG unvaccinated control group. The BCG vaccinated group will receive in the right arm, intradermally, a one off dose of 0.1 mL corresponding to approximately 2 x105 to 8 x105 CFU of live, freeze-dried, attenuated BCG Moscow 361-I, Bacillus Calmette Guerin vaccine (Serum Institute of India PVT. LTD.). The unvaccinated control group will not be vaccinated. The HW allocated in both groups will be followed up at specific times points until 180 days post inclusion. The vaccinated and control groups will be compared according to COVID-19 related outcomes. MAIN OUTCOMES: The primary outcomes are the incidence coefficient of infection by SARS-CoV-2 determined by RT-PCR of naso-oropharyngeal swab specimen or rapid lateral flow IgG and IgM test, and presence of general COVID-19 symptoms, disease severity and admission to hospital during the 180 days of follow up. The secondary outcome is the innate immune response elicited 15-20 days after vaccination. RANDOMISATION: The vaccine vial contains approximately 10 doses. In order to optimize the vaccine use, the randomisation was performed in blocks of 20 participants using the platform randomization.com [ http://www.jerrydallal.com/random/permute.htm ]. The randomization was prepared before any HW inclusion. The results were printed and inserted in sealed envelopes that were numbered with BCG-001 to BCG-400. The printed results as well the envelopes had the same numbers. At the time of the randomisation, each participant that meets the inclusion criteria will receive a consecutive participant number [BCG-001-BCG-400]. The sealed envelope with the assigned number, blinded to the researchers, will be opened in front of the participant and the arm allocation will be known. BLINDING (MASKING): There is no masking for the participants or for the healthcare providers. The study will be blinded to the laboratory researchers and to those who will be evaluating the outcomes and performing the statistical analyses. In this case, only the participant identification number will be available. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Four hundred heath workers will be randomised in two groups. Two hundred participants will be vaccinated, and 200 participants will not be vaccinated. TRIAL STATUS: The protocol approved by the Brazilian Ethical Committee is the seventh version, number CAAE: 31783720.0.0000.5078. The trial has been recruiting since September 20th, 2020. The clinical trial protocol was registered on August 5th, 2020. It is estimated that recruitment will finish by March 2021. TRIAL REGISTRATION: The protocol number was registered on August 5th, 2020 at REBEC (Registro Brasileiro de Ensaios Clínicos). Register number: RBR-4kjqtg and WHO trial registration number UTN: U1111-1256-3892. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Medication adherence in patients in treatment for rheumatoid arthritis and systemic lupus erythematosus in a university hospital in Brazil.

Medication adherence is essential for the control of symptoms and progression of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The aim of the study was to investigate medication adherence in outpatients in treatment for RA and SLE in a university hospital in Brazil. This was a quantitative, cross-sectional analytical study. A total of 92 patients (55 RA patients and 37 SLE patients) were included in the study. A structured questionnaire for patients' interview and a form for collecting data from medical records were used for data collection. Adherence to drug treatment was assessed by the Morisky scale questionnaire. Data storage and analysis were performed using Epi Info 3.5.4 and statistical analysis by Stata/SE 12.0. The Pearson's chi-squared test and Fisher's exact test were applied for statistical and bivariate analyses. For multivariate data analysis the Poisson regression and the Wald test were used. The prevalence of adherence to drug treatment was 16.4% in RA patients and 45.9% in SLE patients. The final model of the multivariate analysis demonstrated associations between medication adherence and the following covariates for both RA and SLE groups: duration of therapy for rheumatic disease at the institution greater than 15 years and presence of more than six chronic comorbidities. The parameter "acquisition of medication at the high-cost pharmacy" was differently associated with medication adherence by group, and for the SLE group, living outside the city of Goiânia was a protective factor associated with adherence. This study demonstrated a low prevalence of medication adherence in patients in treatment for RA and SLE treated at this institution. These findings will serve as a base for future studies to elucidate what factors may positively or negatively affect medication adherence in this population. In addition, multidisciplinary approaches are needed to enhance adherence to drug treatment in patients in treatment for rheumatic disease.