This proof-of-concept study tested if prior BCG revaccination can qualitatively and quantitively enhance antibody and T-cell responses induced by Oxford/AstraZeneca ChAdOx1nCoV-19 or COVISHIELD (TM... Show moreThis proof-of-concept study tested if prior BCG revaccination can qualitatively and quantitively enhance antibody and T-cell responses induced by Oxford/AstraZeneca ChAdOx1nCoV-19 or COVISHIELD (TM), an efficacious and the most widely distributed vaccine in India. We compared COVISHIELD (TM) induced longitudinal immune responses in 21 BCG re-vaccinees (BCG-RV) and 13 BCG-non-revaccinees (BCG-NRV), all of whom were BCG vaccinated at birth; latent tuberculosis negative and SARS-CoV-2 seronegative prior to COVISHIELD (TM) vaccination. Compared to BCG-NRV, BCG-RV displayed significantly higher and persistent spike-specific neutralizing (n) Ab titers and polyfunctional CD4+ and CD8+ T-cells for eight months post COVISHIELD (TM) booster, including distinct CD4+IFN-gamma+ and CD4+IFN-gamma- effector memory (EM) subsets co-expressing IL-2, TNF-alpha and activation induced markers (AIM) CD154/CD137 as well as CD8+IFN-gamma+ EM,TEMRA (T cell EM expressing RA) subset combinations co-expressing TNF-alpha and AIM CD137/CD69. Additionally, elevated nAb and T-cell responses to the Delta mutant in BCG-RV highlighted greater immune response breadth. Mechanistically, these BCG adjuvant effects were associated with elevated markers of trained immunity, including higher IL-1 beta and TNF-alpha expression in CD14+HLA-DR+monocytes and changes in chromatin accessibility highlighting BCG-induced epigenetic changes. This study provides first in-depth analysis of both antibody and memory T-cell responses induced by COVISHIELD (TM) in SARS-CoV-2 seronegative young adults in India with strong evidence of a BCG-induced booster effect and therefore a rational basis to validate BCG, a low-cost and globally available vaccine, as an adjuvant to enhance heterologous adaptive immune responses to current and emerging COVID-19 vaccines. Show less
Doesschate, T. ten; Vaart, T.W. van der; Debisarun, P.A.; Taks, E.; Moorlag, S.J.C.F.M.; Paternotte, N.; ... ; Werkhoven, C.H. van 2022
Objectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Gue?rin (BCG) vaccine may provide non-specific protection against respiratory infections... Show moreObjectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Gue?rin (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. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. Show less
Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is a globally prevalent infectious disease with significant animal welfare and economic impact. Difficulties in implementing test-and... Show moreBovine tuberculosis (bTB), caused by Mycobacterium bovis, is a globally prevalent infectious disease with significant animal welfare and economic impact. Difficulties in implementing test-and-slaughter measures in low- and middle-income countries (LMICs) and the underperformance of the current diagnostics establish a clear need to develop improved diagnostics. Adaptive immunity biomarkers other than IFN gamma could be useful as suggested by various gene expression studies; however, a comprehensive assessment at the protein level is lacking. Here, we screened a range of chemokines and cytokines for their potential as biomarkers in samples from M. bovis experimentally challenged or naive animals. Although serum concentrations for most proteins were low, the pro-inflammatory markers, IL-2, CXCL-9, IP-10 and CCL4, in addition to IFN gamma, were found to be significantly elevated in bovine tuberculin (PPDb)-stimulated whole blood supernatants. Further assessment of these molecules in BCG-vaccinated with or without subsequent M. bovis challenge or naive animals revealed that PPDb-specific IL-2 and IP-10, in addition to IFN gamma, could discriminate naive and BCG-vaccinated from M. bovis challenged animals. Moreover, these proteins, along with CCL4, showed DIVA potential, i.e., enabling differentiation of M. bovis-infected animals from BCG-vaccinated animals. Combined analysis of cytokines and chemokines could also accurately identify M. bovis infection with strong correlations observed between PPDb-specific IFN gamma, IL-2 and IP-10 levels. This provides proof of concept for utilizing multiple biomarker signatures for discrimination of animals with respect to M. bovis infection or BCG vaccination status. Show less
Gela, A.; Murphy, M.; Rodo, M.; Hadley, K.; Hanekom, W.A.; Boom, W.H.; ... ; Delayed BCG Study Team 2022
Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CDI, MRI, and butyrophilin 3AI. Such T cells, referred to as donor... Show moreBackground: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CDI, MRI, and butyrophilin 3AI. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MRI-restricted MAIT cells, CDth-restricted glucose monomycolate (GMM)-specific T cells, CDth-restricted NKT cells, and gamma delta T cells, in vaccination against Mycobacterium tuberculosis. Methods: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. Findings: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CDth-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CDId-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of gamma delta T cells as well as a novel subset of CD26(+)CDI6I(+)TRAVI-2(-) IFN-gamma-expressing CD4(+) T cells in infants. Interpretation: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. Copyright (C) 2022 The Authors. Published by Elsevier B.V. Show less
Hooij, A. van; Eeden, S.J.F. van den; Khatun, M.; Soren, S.; Franken, K.L.M.C.; Roy, J.C.; ... ; Geluk, A. 2021
Leprosy is an infectious disease caused by Mycobacterium leprae leading to irreversible disabilities along with social exclusion. Leprosy is a spectral disease for which the clinical outcome after... Show moreLeprosy is an infectious disease caused by Mycobacterium leprae leading to irreversible disabilities along with social exclusion. Leprosy is a spectral disease for which the clinical outcome after M. leprae infection is determined by host factors. The spectrum spans from anti-inflammatory T helper-2 (Th2) immunity concomitant with large numbers of bacteria as well as antibodies against M. leprae antigens in multibacil-lary (MB) leprosy, to paucibacillary (PB) leprosy characterised by strong pro-inflammatory, Th1 as well as Th17 immunity. Despite decades of availability of adequate antibiotic treatment, transmission of M. leprae is unabated. Since individuals with close and frequent contact with untreated leprosy patients are particularly at risk to develop the disease themselves, prophylactic strategies currently focus on household contacts of newly diagnosed patients. It has been shown that BCG (re)vaccination can reduce the risk of leprosy. However, BCG immunopro-phylaxis in contacts of leprosy patients has also been reported to induce PB leprosy, indicating that BCG (re)vaccination may tip the balance between protective immunity and overactivation immunity causing skin/nerve tissue damage. In order to identify who is at risk of developing PB leprosy after BCG vaccination, amongst individuals who are chronically exposed to M. leprae, we analyzed innate and adaptive immune markers in whole blood of household contacts of newly diagnosed leprosy patients in Bangladesh, some of which received BCG vaccination. As controls, individuals from the same area without known contact with leprosy patients were similarly assessed. Our data show the added effect of BCG vaccination on immune markers on top of the effect already induced by M. leprae exposure. Moreover, we identified BCG-induced markers that differentiate between protective and disease prone immunity in those contacts. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Intravesical bacillus Calmette-Guerin (BCG) is widely used for high-risk, non-muscle-invasive bladder cancer. This report describes four cases that illustrate the spectrum of BCG-induced... Show moreIntravesical bacillus Calmette-Guerin (BCG) is widely used for high-risk, non-muscle-invasive bladder cancer. This report describes four cases that illustrate the spectrum of BCG-induced complications, varying from granulomatous prostatitis to sepsis. There is considerable debate regarding whether inflammation or infection is the predominant mechanism in the pathogenesis of BCG disease. In two patients with a systemic illness, the symptoms first resolved after adding prednisone, indicating a principal role for inflammation in systemic disease. In vitro testing of T-cell responses and a mycobacterial growth inhibition assay were performed for these patients with systemic disease. The patient with mild symptoms showed more effective in vitro growth reduction of BCG, while the patient with sepsis and organ involvement had high T-cell responses but ineffective killing. While these findings are preliminary, it is believed that immunological assays, as described in this report, may provide a better insight into the pathogenesis of BCG disease in individual patients, justifying further research. (C) 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Dam, A.D. van; Bekkering, S.; Crasborn, M.; Beek, L. van; Berg, S.M. van den; Vrieling, F.; ... ; Berbee, J.F.P. 2016
Conclusions: BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an... Show moreConclusions: BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
There is no effective vaccine against tuberculosis (TB). The only available TB-vaccine, M. bovis BCG, induces only limited, and highly variable protection. TB-vaccine efficacy would have to include... Show moreThere is no effective vaccine against tuberculosis (TB). The only available TB-vaccine, M. bovis BCG, induces only limited, and highly variable protection. TB-vaccine efficacy would have to include protection against active pulmonary TB, since this is the transmissible form of the disease, in the adult population; an effective vaccine would have an enormous impact on the TB-epidemic. This thesis has aimed to characterize the M. bovis BCG-reactive human T-cell response, in order to identify cellular responses that may account for the variable and poorly understood protective efficacy of BCG-vaccination. The studies presented in this thesis describe three BCG-induced cellular immune responses in adults: (i) the induction of CD8+ regulatory T-cells (Tregs), that suppress immunity partly via the ectoenzyme CD39, (ii) a dichotomous pro-inflammatory response, consisting of either induction of polyfunctional CD4+ T-cells in vaccinees with high skin inflammation of the vaccine lesion, or virtually no induction of cytokines with concomitant induction of CD8+ Tregs in vaccinees with low skin inflammation, and (iii) induction of inhibitory KLRG1+ CD8+ T-cells. This network of inter-related and partly opposing regulatory, pro-inflammatory and inhibitory immune responses may impact vaccine-induced protective immunity against TB and this could assist in guiding future TB-vaccine design. Show less
