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Item does not contain fulltext, BACKGROUND AND OBJECTIVE: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs). METHODS: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h). RESULTS: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods. CONCLUSION: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

01 juni 2023, Item does not contain fulltext, BACKGROUND: Novel mRNA-based vaccines have been used to protect against SARS-CoV-2, especially in vulnerable populations who also receive an annual influenza vaccination. The TACTIC study investigated potential immune interference between the mRNA COVID-19 booster vaccine and the quadrivalent influenza vaccine, and determined if concurrent administration would have effects on safety or immunogenicity. METHODS: TACTIC was a single-blind, placebo-controlled randomized clinical trial conducted at the Radboud University Medical Centre, the Netherlands. Individuals ≥60 years, fully vaccinated against COVID-19 were eligible for participation and randomized into one of four study groups: 1) 0.5 ml influenza vaccination Vaxigrip Tetra followed by 0.3 ml BNT162b2 COVID-19 booster vaccination 21 days later, (2) COVID-19 booster vaccination followed by influenza vaccination, (3) influenza vaccination concurrent with the COVID-19 booster vaccination, and (4) COVID-19 booster vaccination only (reference group). Primary outcome was the geometric mean concentration (GMC) of IgG against the spike (S)-protein of the SARS-CoV-2 virus, 21 days after booster vaccination. We performed a non-inferiority analysis of concurrent administration compared to booster vaccines alone with a predefined non-inferiority margin of -0.3 on the log10-scale. FINDINGS: 154 individuals participated from October, 4, 2021, until November, 5, 2021. Anti-S IgG GMCs for the co-administration and reference group were 1684 BAU/ml and 2435 BAU/ml, respectively. Concurrent vaccination did not meet the criteria for non-inferiority (estimate -0.1791, 95% CI -0.3680 to -0.009831) and antibodies showed significantly lower neutralization capacity compared to the reference group. Reported side-effects were mild and did not differ between study groups. INTERPRETATION: Concurrent administration of both vaccines is safe, but the quantitative and functional antibody responses were marginally lower compared to booster vaccin

01 juli 2023, Item does not contain fulltext

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Item does not contain fulltext, 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 BC

Item does not contain fulltext, Earlier studies showed that BCG vaccination improves antibody responses of subsequent vaccinations. Similarly, in older volunteers we found an increased IgG receptor-binding domain (RBD) concentration after SARS-CoV-2 infection if they were recently vaccinated with BCG. This study aims to assess the effect of BCG on the serum antibody concentrations induced by COVID-19 vaccination in a population of adults older than 60 years. Serum was collected from 1,555 participants of the BCG-CORONA-ELDERLY trial a year after BCG or placebo, and we analyzed the anti-SARS-CoV-2 antibody concentrations using a fluorescent-microsphere-based multiplex immunoassay. Individuals who received the full primary COVID-19 vaccination series before serum collection and did not test positive for SARS-CoV-2 between inclusion and serum collection were included in analyses (n = 945). We found that BCG vaccination before first COVID-19 vaccine (median 347 days [IQR 329-359]) did not significantly impact the IgG RBD concentration after COVID-19 vaccination in an older European population.

Contains fulltext : 282363.pdf (Publisher’s version ) (Open Access), BACKGROUND: Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses. RESULTS: The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval, .65-2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval, .71-1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine. CONCLUSIONS: BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection. CLINICAL TRIALS REGISTRATION: EU Clinical Trials Register 2020-001591-15 Clinic

Contains fulltext : 252950.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 282367.pdf (Publisher’s version ) (Open Access), OBJECTIVES: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Guérin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. METHODS: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). RESULTS: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication. CONCLUSIONS: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19.

Contains fulltext : 282310.pdf (Publisher’s version ) (Open Access), Trained immunity is defined as the de facto memory characteristics induced in innate immune cells after exposure to microbial stimuli after infections or certain types of vaccines. Through epigenetic and metabolic reprogramming of innate immune cells after exposure to these stimuli, trained immunity induces an enhanced nonspecific protection by improving the inflammatory response upon restimulation with the same or different pathogens. Recent studies have increasingly shown that trained immunity can, on the one hand, be induced by exposure to viruses; on the other hand, when induced, it can also provide protection against heterologous viral infections. In this review we explore current knowledge on trained immunity and its relevance for viral infections, as well as its possible future uses.

Item does not contain fulltext, BACKGROUND/OBJECTIVES: Obesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. We investigated whether obesity is associated with differences in inflammatory, respiratory, and clinical outcome parameters in critically ill COVID-19 patients. SUBJECTS/METHODS: Sixty-seven COVID-19 ICU patients were divided into obese (BMI ≥ 30 kg/m(2), n = 18, 72% class I obesity, 28% class II obesity) and non-obese (BMI < 30 kg/m(2), n = 49) groups. Concentrations of circulating interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and IL-1 receptor antagonist (RA) were determined from ICU admission until 10 days afterward, and routine laboratory and clinical parameters were collected. RESULTS: BMI was 32.6 [31.2-34.5] and 26.0 [24.4-27.7] kg/m(2) in the obese and non-obese group, respectively. Apart from temperature, which was significantly lower in obese patients (38.1 [36.9-38.9] vs. 38.7 [38.0 -39.5] °C, p = 0.02), there were no between-group differences on ICU admission. Plasma cytokine concentrations declined over time (p < 0.05 for all), but no differences between obese and non-obese patients were observed. Also, BMI did not correlate with the cytokine response (IL-6 r = 0.09, p = 0.61, TNF-α r = 0.03, p = 0.99, IP-10 r = 0.28, p = 0.11). The kinetics of clinical inflammatory parameters and respiratory mechanics were also similar in both groups. Finally, no differences in time on ventilator, ICU length of stay or 40-day mortality between obese and non-obese patients were apparent. CONCLUSIONS: In COVID-19 patients requiring mechanical ventilation in the ICU, a higher BMI is not related to a different immunological response, unfavorable respiratory mechanics, or impaired outcome.

Contains fulltext : 240766.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 232398.pdf (Publisher’s version ) (Open Access), BACKGROUND: Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications, and mortality rate. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown. METHODS: A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. RESULTS: Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (P < .05). These complement factors were especially elevated in intensive care unit patients during the entire disease course (P < .005 for C3a and TCC). More intense complement activation was observed in patients who died and in those with thromboembolic events. CONCLUSIONS: Patients with COVID-19 demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated proinflammatory response associated with increased mortality rate and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19.

Contains fulltext : 220582.pdf (publisher's version ) (Open Access), OBJECTIVES: The objectives of these two separate trials are: (1) to reduce health care workers (HCWs) absenteeism; and (2) to reduce hospital admission among the elderly during the COVID-19 pandemic through BCG vaccination. TRIAL DESIGN: Two separate multi-centre placebo-controlled parallel group randomized trials PARTICIPANTS: (1) Health care personnel working in the hospital or ambulance service where they will take care of patients with the COVID-19 infection and (2) elderly >/=60 years. The HCW trial is being undertaken in 9 hospitals. The elderly trial is being undertaken in locations in the community in Nijmegen, Utrecht, and Veghel, in the Netherlands, using senior citizen organisations to facilitate recruitment. INTERVENTION AND COMPARATOR: For both trials the intervention group will be randomized to vaccination with 0.1 ml of the licensed BCG vaccine (Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated M. bovis). The placebo group consists of 0.1 ml 0.9% NaCl, which is the same amount, and has the same colour and appearance as the suspended BCG vaccine. MAIN OUTCOMES: (1) Number of days of unplanned work absenteeism in HCWs for any reason which can be continuously measured on a bi-weekly basis, and (2) the cumulative incidence of hospital admission due to documented COVID-19. RANDOMISATION: Participants will be randomized to BCG vaccine or placebo (1;1) centrally using a computer- based system, stratified by study centre. BLINDING (MASKING): Subjects, investigators, physicians and outcome assessors are blinded for the intervention. Only the pharmacist assistant that prepares- and research personnel that administers- study medicines are unblinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): (1) The sample size for the first trial is N=1500 HCWs randomised 1:1 to either BCG vaccine (n=750) and placebo (n=750) and (2) The sample size for the second trial is N=1600 elderly persons randomised to BCG vaccine (n=800) and the placebo group (n=800). TRIA

Contains fulltext : 225381.pdf (publisher's version ) (Open Access), Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio [AOR] 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.

Contains fulltext : 220045.pdf (publisher's version ) (Open Access)