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In this paper we examine several definitions of vaccine efficacy (VE) that we found in the literature, for diseases that express themselves in outbreaks, that is, when the force of infection grows in time, reaches a maximum and then vanishes. The fact that the disease occurs in outbreaks results in several problems that we analyse. We propose a mathematical model that allows the calculation of VE for several scenarios. Vaccine trials usually needs a large number of volunteers that must be enrolled. Ideally, all volunteers should be enrolled in approximately the same time, but this is generally impossible for logistic reasons and they are enrolled in a fashion that can be replaced by a continuous density function (for example, a Gaussian function). The outbreak can also be replaced by a continuous density function, and the use of these density functions simplifies the calculations. Assuming, for example Gaussian functions, one of the problems one can immediately notice is that the peak of the two curves do not occur at the same time. The model allows us to conclude: First, the calculated vaccine efficacy decreases when the force of infection increases; Second, the calculated vaccine efficacy decreases when the gap between the peak in the force of infection and the peak in the enrollment rate increases; Third, different trial protocols can be simulated with this model; different vaccine efficacy definitions can be calculated and in our simulations, all result are approximately the same. The final, and perhaps most important conclusion of our model, is that vaccine efficacy calculated during outbreaks must be carefully examined and the best way we can suggest to overcome this problem is to stratify the enrolled volunteer's in a cohort-by-cohort basis and do the survival analysis for each cohort, or apply the Cox proportional hazards model for each cohort.
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BACKGROUND Butantan–Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically con firmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine effi cacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) — 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine effi cacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regard less of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.)
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BACKGROUND: Cardiovascular disease is associated with severe COVID-19. Our aim was to describe clinical and laboratory features (including electrocardiographic and echocardiographic ones) and outcomes of patients with cardiac disease hospitalized with COVID-19. METHODS: This is an observational retrospective study of consecutive adult patients admitted, between March and September of 2020, with confirmed SARSCoV-2 infection. Data were collected as per the ISARIC case report form and complemented with variables related to heart disease. RESULTS: One hundred twenty-one patients were included. Mean age was 60 SD 15.2 years and 80/121(66.1%) were male. Two-thirds of the patients (80/121, 66.1%) had COVID-19 at the time of hospital admission and COVID-19 was the reason for hospitalization in 42 (34.7%). Other reasons for hospital admission were acute coronary syndrome (26%) and decompensated heart failure (14.8%). Chronic cardiac diseases were found in 106/121 (87.6%), mostly coronary artery disease (62%) or valve disease (33.9%). A transthoracic echocardiogram was performed in 93/121(76.8%) and enlarged cardiac chambers were found in 71% (66/93); admission ECG was done in 93 cases (93/121, 76.8%), and 89.2% (83/93) were abnormal. Hospital-acquisition of COVID-19 occurred in 20 (16.5%) of patients and their mortality was 50%. On bivariate analysis for mortality, BNP levels and troponin levels were NOT associated with mortality. On multivariate analysis, only C reactive protein levels and creatinine levels were significant. CONCLUSIONS: COVID-19 impacted the profile of hospital admissions in cardiac patients. BNP and troponin levels were not associated with mortality and may not be good prognostic discriminators in cardiac patients.