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Bulut O, Baydemir I, Kilic G, Domínguez-Andrés J, Netea MG. Resveratrol potentiates BCG-induced trained immunity in human monocytes. J Leukoc Biol 2025; 117:qiae241. [PMID: 39492706 DOI: 10.1093/jleuko/qiae241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/01/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024] Open
Abstract
Resveratrol is a natural polyphenol derived from plants such as grapes and berries. In addition to its role in plants during injury and infection, various cardioprotective, neuroprotective, and longevity-promoting effects were reported in diverse model organisms. The primary target of resveratrol is the deacetylase Sirtuin 1, which regulates many immunological processes, including BCG-induced trained immunity response in humans. We, therefore, investigated the effect of resveratrol on trained immunity induced by BCG, β-glucan (BG), Candida albicans, or oxidized low-density lipoprotein (oxLDL). Using an in vitro model of trained immunity with monocytes obtained from healthy donors, we demonstrate that resveratrol amplifies BCG-induced trained immunity regarding IL-6 and TNFα production after a secondary challenge. Although resveratrol did not improve and even limited glycolysis, oxidative phosphorylation, and reactive oxygen species production, it enhanced the permissive epigenetic mark H3K27Ac on IL-6 and TNFα promoters. In contrast to BCG-induced trained immunity, resveratrol potently inhibited training induced by BG, C. albicans, oxLDL, and muramyl dipeptide, a peptidoglycan component of BCG. Resveratrol's unique boosting effect on BCG training depended on BCG being alive and metabolically active. These results suggest that resveratrol might amplify the effects of BCG vaccination, which should be mechanistically characterized further. In addition, resveratrol could alleviate oxLDL-induced training of innate immune cells in atherosclerosis, and in vivo studies of trained immunity combined with resveratrol are warranted to explore these therapeutic possibilities.
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Affiliation(s)
- Ozlem Bulut
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 8, GA 6525 Nijmegen, Netherlands
| | - Ilayda Baydemir
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 8, GA 6525 Nijmegen, Netherlands
| | - Gizem Kilic
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 8, GA 6525 Nijmegen, Netherlands
| | - Jorge Domínguez-Andrés
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 8, GA 6525 Nijmegen, Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 8, GA 6525 Nijmegen, Netherlands
- Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Carl-Troll-Straße 31, 53115 Bonn, Germany
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Jiang G, Zou Y, Zhao D, Yu J. Optimising vaccine immunogenicity in ageing populations: key strategies. THE LANCET. INFECTIOUS DISEASES 2025; 25:e23-e33. [PMID: 39326424 DOI: 10.1016/s1473-3099(24)00497-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/17/2024] [Accepted: 07/25/2024] [Indexed: 09/28/2024]
Abstract
Vaccination has been shown to be the most effective means of preventing infectious diseases, although older people commonly have a suboptimal immune response to vaccines and thus impaired protection against subsequent adverse outcomes. This Review provides an overview of the existing mechanistic insights into compromised vaccine response for respiratory infectious diseases in older people, defined as aged 65 years and older, including immunosenescence, epigenetic regulation, trained immunity, and gut microbiota. We further summarise the latest proven or potential strategies to strengthen weakened immunogenicity. Insights from these analyses will be conducive to the development of the next generation of vaccines.
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Affiliation(s)
- Guangzhen Jiang
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yushu Zou
- Department of Biomedical Informatics, School of Basic Medical Sciences and State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Dongyu Zhao
- Department of Biomedical Informatics, School of Basic Medical Sciences and State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jingyou Yu
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China.
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Romero-Rodríguez DP, Díaz-Alvarado CA, Rocha-González HI, Juárez E. Control of Mycobacterium tuberculosis infection in the elderly: Is there a role for epigenetic reprogramming reversal? Biofactors 2025; 51:e2151. [PMID: 39888304 DOI: 10.1002/biof.2151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/25/2024] [Indexed: 02/01/2025]
Abstract
With the increase in the elderly population worldwide, the number of subjects suffering from tuberculosis (TB) has shown an increased prevalence in this group. Immunosenescence is essential in this phenomenon because it may reactivate the lesions and render their adaptive immunity dysfunctional. In addition, inflammation in the lungs of the elderly subjects is also dysfunctional. Although effective drugs are available, they are often tolerated inadequately, reducing adherence to the therapy and leading to therapeutic failure. Comorbidities, poor general health status, and other medications may lead to increased drug adverse reactions and reduced adherence to treatment in the elderly. Hence, older adults require an individualized approach for better outcomes. Trained immunity, which involves epigenetic reprogramming, may contribute to balancing the dysfunction of innate and adaptive immunity in older people. This review analyzes the relationship between inflammation, age, and Mycobacterium tuberculosis. Moreover, we hypothesize that immunomodulation using trained immunity activators will help reduce inflammation while enhancing antimicrobial responses in the elderly. Understanding immunomodulation's molecular and physiological effects will lead to informed decisions about TB prevention and treatment strategies uniquely designed for the elderly.
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Affiliation(s)
- Dámaris P Romero-Rodríguez
- Laboratorio Nacional Conahcyt de Investigación y Diagnóstico por Inmunocitofluorometría (LANCIDI), Laboratorio de Citometría de Flujo, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, Mexico
| | | | - Héctor Isaac Rocha-González
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Esmeralda Juárez
- Laboratorio BSL3, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, Mexico
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4
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Carrero Longlax S, Koster KJ, Kamat AM, Lozano M, Lerner SP, Hannigan R, Nishiguchi T, Abhimanyu, Sheikh D, Ladki M, Portillo A, Koirala A, Patel TD, Spieler Z, Benjamin AB, Lebedev M, Ofili TU, Hutchison RW, Udeani G, Opperman LA, Neal G, Mandalakas AM, Netea MG, Arditi M, Avalos P, Grimm SL, Coarfa C, Cirillo JD, DiNardo AR. BCG-Induced DNA Methylation Changes Improve Coronavirus Disease 2019 Vaccine Immunity Without Decreasing the Risk for Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Open Forum Infect Dis 2025; 12:ofaf007. [PMID: 39872813 PMCID: PMC11770274 DOI: 10.1093/ofid/ofaf007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 01/03/2025] [Indexed: 01/30/2025] Open
Abstract
Background The BCG vaccine induces trained immunity, an epigenetic-mediated increase in innate immune responsiveness. Therefore, this clinical trial evaluated if BCG-induced trained immunity could decrease coronavirus disease 2019 (COVID-19)-related frequency or severity. Methods A double-blind, placebo-controlled clinical trial of healthcare workers randomized participants to vaccination with BCG TICE or placebo (saline). Enrollment included 529 healthcare workers randomized to receive BCG or placebo. Primary analysis evaluated COVID-19 disease frequency, while secondary analysis evaluated coronavirus immunity in a subset of participants. Study enrollment ceased early in December 2020 following introduction of COVID-19-specific vaccines. Results Study enrollment was halted early, prior to reaching the targeted recruitment, and was not powered to detect a decrease in COVID-19 frequency. Symptomatic COVID-19 occurred in 21 of 263 and 10 of 266 participants in the BCG and placebo arms, respectively (P = .50, Fisher exact test). Participants vaccinated with BCG, but uninfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrated increased coronavirus vaccine immunity (increase spike-inducible levels of tumor necrosis factor, interleukin 6, and interleukin 1β) 12 months after BCG vaccination compared to participants receiving placebo. Immune responsiveness to SARS-CoV-2 antigens correlated with BCG-induced DNA methylation changes. Conclusions Due to early study closure, the study was not powered to evaluate COVID-19 frequency. Secondary analysis demonstrated that 12 months following vaccination, BCG increased coronavirus vaccine immunity compared to those who did not receive BCG. This increase in COVID-19 vaccine immunity correlated with BCG-induced DNA methylation changes.
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Affiliation(s)
- Santiago Carrero Longlax
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Kent J Koster
- Center for Airborne Pathogen Research and Imaging, Texas A&M School of Medicine, Bryan, Texas, USA
| | - Ashish M Kamat
- Urology Department, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marisa Lozano
- Urology Department, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Seth P Lerner
- Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA
| | - Rebecca Hannigan
- Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA
| | - Tomoki Nishiguchi
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Abhimanyu
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Daanish Sheikh
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Malik Ladki
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Alexandra Portillo
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Amrit Koirala
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Tajhal D Patel
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Zoe Spieler
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Aaron B Benjamin
- Center for Airborne Pathogen Research and Imaging, Texas A&M School of Medicine, Bryan, Texas, USA
| | - Maxim Lebedev
- Center for Airborne Pathogen Research and Imaging, Texas A&M School of Medicine, Bryan, Texas, USA
| | - Theresa U Ofili
- Department of Pharmacy Practice, Texas A&M School of Pharmacy, College Station, Texas, USA
| | - Robert W Hutchison
- Department of Pharmacy Practice, Texas A&M School of Pharmacy, College Station, Texas, USA
| | - George Udeani
- Department of Pharmacy Practice, Texas A&M School of Pharmacy, College Station, Texas, USA
| | - Lynne A Opperman
- Department of Biomedical Sciences and Center for Craniofacial Research and Diagnosis, Texas A&M School of Dentistry, Dallas, Texas, USA
| | - Gabriel Neal
- Primary Care and Rural Medicine, Texas A&M School of Medicine, Bryan, Texas, USA
| | - Anna M Mandalakas
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
- Clinical Infectious Diseases, Research Centre Borstel, Borstel, Germany
- Clinical Tuberculosis Unit, German Centre for Infection Research, Borstel, Germany
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Moshe Arditi
- Departments of Pediatrics and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Pablo Avalos
- Departments of Pediatrics and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Sandra L Grimm
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Cristian Coarfa
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Jeffrey D Cirillo
- Center for Airborne Pathogen Research and Imaging, Texas A&M School of Medicine, Bryan, Texas, USA
| | - Andrew R DiNardo
- Global Tuberculosis Program, William T. Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
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Mora VP, Quero FB, Troncoso-Bravo T, Orellana C, Pereira P, Mackern-Oberti JP, Funes SC, Soto JA, Bohmwald K, Bueno SM, Kalergis AM. Partial long-term clinical improvement after a BCG challenge in systemic lupus erythematosus-prone mice. Autoimmunity 2024; 57:2380465. [PMID: 39034498 DOI: 10.1080/08916934.2024.2380465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 07/07/2024] [Indexed: 07/23/2024]
Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that causes a breakdown of immune tolerance. Current treatments mainly involve general immunosuppression, increasing the risk of infections. On the other hand, Bacillus Calmette-Guérin (BCG) has been investigated as a potential therapy for autoimmune diseases in recent years, prompting an ongoing investigation. This study aimed to evaluate the effect of BCG vaccination on early and late clinical presentation of SLE in a murine disease model. MRL/MPJ-Faslpr mice were immunized with BCG or treated with PBS as a control. The progress of the disease was evaluated at 27 days post-immunization (dpi) (early) and 56 dpi (late). Clinical parameters and proteinuria were monitored. Blood samples were collected for measurement of antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), and cytokine determination was performed using ELISA. Samples collected from mice were analyzed by flow cytometry and histopathology. We observed a clinical improvement in BCG-treated mice, reduced proteinuria in the latter stages of the disease, and decreased TNF-α. However, BCG did not elicit significant changes in ANAs, anti-dsDNA, histopathological scores, or immune cell infiltration. BCG was only partially beneficial in an SLE mouse model, and further research is needed to determine whether the immunity induced by this vaccine can counteract lupus's autoimmune response.
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Affiliation(s)
- Valentina P Mora
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Francisco B Quero
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Tays Troncoso-Bravo
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Ingeniería Química y Bioprocesos, Facultad de Ingeniería, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia Orellana
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia Pereira
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan P Mackern-Oberti
- Instituto de Medicina y Biología Experimental de Cuyo, CONICET, Mendoza, Argentina
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Samanta C Funes
- Instituto Multidisciplinario de Investigaciones Biológicas-San Luis (IMIBIO-SL), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de San Luis (UNSL), San Luis, Argentina
| | - Jorge A Soto
- Millennium Institute of Immunology and Immunotherapy. Departamento de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile
| | - Karen Bohmwald
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute of Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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6
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Dulfer EA, Föhse K, Taks EJM, Moorlag SJCFM, Koekenbier EL, van de Maat JS, Ten Oever J, Hoogerwerf JJ, van Werkhoven CH, Bonten MJM, van Hylckama Vlieg A, Rosendaal FR, Netea MG. The effect of BCG vaccination in the elderly on infectious and non-infectious immune-mediated diseases. J Infect 2024; 89:106344. [PMID: 39515666 DOI: 10.1016/j.jinf.2024.106344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVES Previous research has suggested beneficial heterologous effects of the Bacillus Calmette-Guérin (BCG) vaccine on non-mycobacterial infections and other immune-mediated diseases. During the COVID-19 pandemic, randomized controlled trials BCG-PRIME (n = 5349) and BCG-CORONA-ELDERLY (n = 1907) investigated the impact of BCG on SARS-CoV-2 infections in older individuals. We extended the follow-up in these studies by one year (BCG-Long Term study), to assess the overall effects of BCG vaccination on infectious and immune-mediated diseases in individuals aged over 60. METHODS Prior participants were invited to complete a one-year follow-up survey after their completion of the original trial. Data on vaccinations, hospital admissions, infectious episodes, and new medical diagnoses were collected and compared between BCG- and placebo-vaccinated participants. Variables of interest were combined with the previous trial databases and analyzed using relative risks (RR) and an adjusted Cox regression model accounting for participation probability. RESULTS The response in the follow-up survey was 60%, including 4238 individuals in the final analysis (2317 had received BCG and 1921 placebo). Incidence and severity of infectious diseases and other diagnoses, including cardiovascular diseases and cancer, did not differ between the groups. The proportion of individuals hospitalized for cardiac arrhythmias after BCG was two-fold higher than reported after placebo (1.6% versus 0.8%, RR 2.0 (95% confidence interval 1.1-3.6)). Cardiac arrhythmia-related hospitalizations were primarily due to exacerbation of pre-existing arrhythmias. CONCLUSION The results of the present study confirm that BCG has no relevant effect on non-mycobacterial infectious diseases and other immune-mediated diseases in a population of generally mycobacteria-naïve older Dutch individuals in the two years following vaccination. However, our study suggests that BCG may aggravate pre-existing cardiac arrhythmia, which warrants further investigation.
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Affiliation(s)
- Elisabeth A Dulfer
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Konstantin Föhse
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Esther J M Taks
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Simone J C F M Moorlag
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Eva L Koekenbier
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Josephine S van de Maat
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jaap Ten Oever
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jacobien J Hoogerwerf
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Cornelis H van Werkhoven
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Marc J M Bonten
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
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Devaleenal Daniel B, Venkatesan M, Padmapriyadarsini C. Safety profile of BCG revaccination for COVID prevention among elderly individuals in India. Indian J Tuberc 2024; 71:380-382. [PMID: 39278669 DOI: 10.1016/j.ijtb.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 04/16/2024] [Accepted: 05/09/2024] [Indexed: 09/18/2024]
Abstract
BCG vaccination is known to be safe in infants and a part of immunization schedule in high tuberculosis (TB) burden countries. In the conquest to bring down the severity of the COVID 19 pandemic, many drugs were repurposed in research mode including BCG vaccination/revaccination in various populations. We did a study among the elderly population (>60 years of age) to assess the role of BCG revaccination in preventing the severity of COVID 19 disease. Live attenuated BCG vaccine was given to the willing participants and were followed up for 6 months to estimate COVID19 incidence, understand severity and immunogenicity profile. A total of 48 serious adverse events (SAE) were reported among 1566 elders, none of them had more than one SAE. None of the SAEs were related to the BCG revaccination. Among the 372 adverse events reported, 96% were local reactions at the vaccine site and resolved on its own. BCG revaccination appeared to be safe and could be explored further if repurposing studies were planned for other diseases.
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Affiliation(s)
- Bella Devaleenal Daniel
- Department of Clinical Research, ICMR-National Institute for Research in Tuberculosis, 1, Mayor Satyamoorthy Road, Chetpet, Chennai, 600031, Tamil Nadu, India.
| | - Mythily Venkatesan
- Department of Statistics, ICMR-National Institute for Research in Tuberculosis, Chennai, India
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Pandiarajan AN, Kumar NP, Rajamanickam A, Bhavani PK, Jeyadeepa B, Selvaraj N, Asokan D, Tripathy S, Padmapriyadarsini C, Babu S. Enhanced Antimicrobial Peptide Response Following Bacillus Calmette-Guerin Vaccination in Elderly Individuals. Vaccines (Basel) 2024; 12:1065. [PMID: 39340094 PMCID: PMC11436028 DOI: 10.3390/vaccines12091065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Antimicrobial peptides are an important component of host defense against Mycobacterium tuberculosis. However, the ability of BCG to induce AMPs as part of its mechanism of action has not been investigated in detail. METHODS We investigated the impact of Bacillus Calmette-Guerin (BCG) vaccination on circulating plasma levels and TB-antigen stimulated plasma levels of AMPs in a healthy elderly population. We assessed the association of AMPs, including Human Beta Defensin 2 (HBD-2), Human Neutrophil Peptide 1-3 (HNP1-3), Granulysin, and Cathelicidin (LL37), in circulating plasma and TB-antigen stimulated plasma (using IGRA supernatants) at baseline (pre-vaccination) and at Month 1 and Month 6 post vaccination. RESULTS Post BCG vaccination, both circulating plasma levels and TB-antigen stimulated plasma levels of AMPs significantly increased at Month 1 and Month 6 compared to pre-vaccination levels in the elderly population. However, the association of AMP levels with latent TB (LTB) status did not exhibit statistical significance. CONCLUSION Our findings indicate that BCG vaccination is linked to heightened circulating levels of AMPs in the elderly population, which are also TB-antigen-specific. This suggests a potential mechanism underlying the immune effects of BCG in enhancing host defense against TB.
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Affiliation(s)
| | | | | | | | - Bharathi Jeyadeepa
- International Center for Excellence in Research, NIAID, Chennai 600031, India
| | - Nandhini Selvaraj
- International Center for Excellence in Research, NIAID, Chennai 600031, India
| | - Dinesh Asokan
- ICMR-National Institute for Research in Tuberculosis, Chennai 600031, India
| | - Srikanth Tripathy
- ICMR-National Institute for Research in Tuberculosis, Chennai 600031, India
| | | | - Subash Babu
- International Center for Excellence in Research, NIAID, Chennai 600031, India
- Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
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9
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Nathella PK, Padmapriyadarsini C, Nancy A, Karunanithi K, Selvaraj N, Renji RM, Shrinivasa B, Babu S. BCG vaccination is associated with longitudinal changes in systemic eicosanoid levels in elderly individuals: A secondary outcome analysis. Heliyon 2024; 10:e32643. [PMID: 38975122 PMCID: PMC11226842 DOI: 10.1016/j.heliyon.2024.e32643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/06/2024] [Accepted: 06/06/2024] [Indexed: 07/09/2024] Open
Abstract
We investigated how BCG vaccination affects the levels of certain eicosanoids, namely Leukotriene B4, 15-epimer of LXA4, prostaglandin F2, Lipoxin A4, Prostaglandin E2 and Resolvin D1 in the plasma of healthy elderly individuals (aged 60-80) before vaccination, one month post-vaccination (M1), and six months post-vaccination (M6). This study is part of the clinical trial "BCG Vaccine Study: Reducing COVID-19 Impact on the Elderly in Indian Hotspots," registered in the clinical trial registry (NCT04475302). While some primary outcomes have been previously reported, this analysis delves into the immunological outcomes. Our findings indicate that BCG vaccination leads to reduced plasma levels of 15-epi-LXA4, LXA4, PGE2, and Resolvin D1 at both M1 and M6. In contrast, there is a notable increase in circulating levels of LTB4 at these time points following BCG vaccination. This underscores the immunomodulatory effects of BCG vaccination and hints at its potential to modulate immune responses by dampening inflammatory reactions.
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Affiliation(s)
| | | | - Arul Nancy
- ICMR-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India
| | | | - Nandhini Selvaraj
- ICMR-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India
| | - Rachel Mariam Renji
- ICMR-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India
| | - B.M. Shrinivasa
- ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | - Subash Babu
- ICMR-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India
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10
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Bulut O, Kilic G, Debisarun PA, Röring RJ, Sun S, Kolkman M, van Rijssen E, Ten Oever J, Koenen H, Barreiro L, Domínguez-Andrés J, Netea MG. Alendronate modulates cytokine responses in healthy young individuals after BCG vaccination. Immunol Lett 2024; 267:106851. [PMID: 38479480 PMCID: PMC11806412 DOI: 10.1016/j.imlet.2024.106851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 02/28/2024] [Accepted: 03/10/2024] [Indexed: 05/31/2024]
Abstract
Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by epigenetic and metabolic reprogramming. Cholesterol synthesis plays an amplifying role in trained immunity through mevalonate release. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, can inhibit cholesterol synthesis. We explored their effects on trained immunity induced by BCG in a placebo-controlled clinical study (NL74082.091.20) in young, healthy individuals. Participants receiving single-dose oral alendronate on the day of BCG vaccination had more neutrophils and plasma cells one month after treatment. Alendronate led to reduced proinflammatory cytokine production by PBMCs stimulated with heterologous bacterial and viral stimuli one month later. Furthermore, the addition of alendronate transcriptionally suppressed multiple immune response pathways in PBMCs upon stimulation. Our findings indicate that N-BPs modulate the long-lasting effects of BCG vaccination on the cytokine production capacity of innate immune cells.
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Affiliation(s)
- Ozlem Bulut
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gizem Kilic
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Priya A Debisarun
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rutger Jan Röring
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sarah Sun
- Committee on Immunology, University of Chicago, Chicago, IL, USA; Medical Scientist Training Program, University of Chicago, Chicago, IL, USA
| | - Manon Kolkman
- Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Esther van Rijssen
- Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jaap Ten Oever
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans Koenen
- Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Luis Barreiro
- Committee on Immunology, University of Chicago, Chicago, IL, USA; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Jorge Domínguez-Andrés
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
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11
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Gupta S, Yadav S, Kumar P. Efficacy of Bacillus Calmette-Guérin in Cancer Prevention and Its Putative Mechanisms. J Cancer Prev 2024; 29:6-15. [PMID: 38567111 PMCID: PMC10982520 DOI: 10.15430/jcp.23.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/31/2024] [Accepted: 02/13/2024] [Indexed: 04/04/2024] Open
Abstract
Bacillus Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis. Although it was developed as a prophylactic vaccine against tuberculosis (TB), researchers have also evaluated it for preventing cancer development or progression. These studies were inspired by the available data regarding the protective effects of microbial infection against cancers and an inverse relationship between TB and cancer mortality. Initial studies demonstrated the efficacy of BCG in preventing leukemia, melanoma and a few other cancers. However, mixed results were observed in later studies. Importantly, these studies have led to the successful use of BCG in the tertiary prevention of non-muscle invasive bladder cancer, wherein BCG therapy has been found to be more effective than chemotherapy. Moreover, in a recently published 60-year follow-up study, childhood BCG vaccination has been found to significantly prevent lung cancer development. In the present manuscript, we reviewed the studies evaluating the efficacy of BCG in cancer prevention and discussed its putative mechanisms. Also, we sought to explain the mixed results of BCG efficacy in preventing different cancers.
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Affiliation(s)
- Sakshi Gupta
- Department of Preventive Oncology (Dr. BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Yadav
- Department of Preventive Oncology (Dr. BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
| | - Pawan Kumar
- Department of Preventive Oncology (Dr. BRA-IRCH), All India Institute of Medical Sciences, New Delhi, India
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12
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Mitroulis I, Hajishengallis G, Chavakis T. Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities. Cardiovasc Res 2024; 119:2801-2812. [PMID: 36655373 PMCID: PMC10874275 DOI: 10.1093/cvr/cvad003] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/08/2022] [Accepted: 08/01/2022] [Indexed: 01/20/2023] Open
Abstract
Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia, and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favour chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for the development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.
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Affiliation(s)
- Ioannis Mitroulis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
- First Department of Internal Medicine and Department of Haematology, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
- Centre for Cardiovascular Science, QMRI, University of Edinburgh, Edinburgh EH16 4TJ, UK
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13
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Noble CCA, Messina NL, Pittet LF, Curtis N. Interpreting the Results of Trials of BCG Vaccination for Protection Against COVID-19. J Infect Dis 2023; 228:1467-1478. [PMID: 37558650 PMCID: PMC10640778 DOI: 10.1093/infdis/jiad316] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/21/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023] Open
Abstract
BCG vaccination has beneficial off-target ("nonspecific") effects on nonmycobacterial infections. On this premise, trials set out to investigate whether BCG provides off-target protection against coronavirus disease 2019 (COVID-19). A literature search identified 11 randomized "BCG COVID-19" trials, with conflicting results. These trials and the differences in their study design are discussed using the PICOT (participants, intervention, control, outcome, and timing) framework to highlight the factors that likely explain their inconsistent findings. These include participant age, sex and comorbid conditions, BCG vaccination strain and dose, outcome measure and duration of follow-up. Understanding how to control these factors to best exploit BCG's off-target effects will be important in designing future trials and intervention strategies.
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Affiliation(s)
- Christie C A Noble
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
- Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Nicole L Messina
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
- Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Laure F Pittet
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
- Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Paediatric Infectious Diseases Unit, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Nigel Curtis
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
- Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Infectious Diseases, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
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14
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Ziogas A, Bruno M, van der Meel R, Mulder WJM, Netea MG. Trained immunity: Target for prophylaxis and therapy. Cell Host Microbe 2023; 31:1776-1791. [PMID: 37944491 DOI: 10.1016/j.chom.2023.10.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 07/27/2023] [Accepted: 10/15/2023] [Indexed: 11/12/2023]
Abstract
Trained immunity is a de facto memory for innate immune responses, leading to long-term functional reprogramming of innate immune cells. In physiological conditions, trained immunity leads to adaptive states that enhance resistance against pathogens and contributes to immunosurveillance. Dysregulated trained immunity can however lead either to defective innate immune responses in severe infections or cancer or to inflammatory and autoimmune diseases if trained immunity is inappropriately activated. Here, we review the immunological and molecular mechanisms that mediate trained immunity induction and propose that trained immunity represents an important target for prophylactic and therapeutic approaches in human diseases. On the one hand, we argue that novel approaches that induce trained immunity may enhance vaccine efficacy. On the other hand, induction of trained immunity in cancer, and inhibition of exaggerated induction of trained immunity in inflammatory disorders, are viable targets amenable for new therapeutic approaches.
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Affiliation(s)
- Athanasios Ziogas
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, the Netherlands.
| | - Mariolina Bruno
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Roy van der Meel
- Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Willem J M Mulder
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, the Netherlands; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, the Netherlands; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands; Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
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15
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Ahmed A, Tripathi H, van Meijgaarden KE, Kumar NC, Adiga V, Rakshit S, Parthiban C, Eveline J S, D’Souza G, Dias M, Ottenhoff TH, Netea MG, Joosten SA, Vyakarnam A. BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways. iScience 2023; 26:107889. [PMID: 37817935 PMCID: PMC10561055 DOI: 10.1016/j.isci.2023.107889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/22/2023] [Accepted: 09/07/2023] [Indexed: 10/12/2023] Open
Abstract
This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in HLA-DR+CD16-CD14hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4+ T cell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR+CD16-CD14hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1β, and IL-6 to "heterologous" fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes: CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.
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Affiliation(s)
- Asma Ahmed
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
| | - Himanshu Tripathi
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
| | | | - Nirutha Chetan Kumar
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
| | - Vasista Adiga
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
- Department of Biotechnology, PES University, Bangalore, India
| | - Srabanti Rakshit
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
| | - Chaitra Parthiban
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
| | - Sharon Eveline J
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - George D’Souza
- Department of Pulmonary Medicine, St. John’s Medical College, Bangalore, India
| | - Mary Dias
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
| | - Tom H.M. Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Simone A. Joosten
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
| | - Annapurna Vyakarnam
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
- Department of Immunobiology, School of Immunology & Microbial Sciences, Faculty of Life Science & Medicine, King’s College, London, UK
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16
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Yedke NG, Arthur R, Kumar P. Bacillus calmette gaurine vaccine ameliorates the neurotoxicity of quinolinic acid in rats via the modulation of antioxidant, inflammatory and apoptotic markers. J Chem Neuroanat 2023; 131:102287. [PMID: 37172828 DOI: 10.1016/j.jchemneu.2023.102287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/06/2023] [Accepted: 05/09/2023] [Indexed: 05/15/2023]
Abstract
A mutation in the Huntingtin gene causes 'Huntington's disease, which presents as a motor and behavioral impairment. Due to the limited drug therapy for this disease, scientists are constantly searching for newer and alternative drugs that may either retard or prevent the progress of the disease. This study aims to explore the neuroprotective potential of Bacillus Calmette Gaurine (BCG) vaccine against quinolinic acid-induced (QA) neurotoxicity in rats. QA (200 nmol/2 µl, i.s) was injected bilaterally into the rat striatum, after which a single dose of BCG (2 × 10^7, cfu) was given to the rats. Animals were assessed for behavioral parameters on the 14th and 21st days. On the 22nd day, animals were sacrificed, brains were harvested, and striatum was separated to evaluate biochemical, inflammatory, and apoptotic mediators. Histopathological studies were performed using Hematoxyline and Eosin staining to assess neuronal morphology. BCG treatment reversed motor abnormalities, reduced oxidative stress and neuroinflammatory markers, apoptotic mediators and striatal lesions induced by QA treatment. In conclusion, treat' 'ing rats with BCG vaccine (2 × 10^7, cfu) mitigated the quinolinic acid-induced Huntington's disease-like symptoms. Hence, BCG vaccine (2 ×10^7, cfu) could be used as an adjuvant in managing HD.
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Affiliation(s)
- Narhari Gangaram Yedke
- Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda 151001, Punjab, India; Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Richmond Arthur
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India.
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17
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Kim H, Choi HG, Shin SJ. Bridging the gaps to overcome major hurdles in the development of next-generation tuberculosis vaccines. Front Immunol 2023; 14:1193058. [PMID: 37638056 PMCID: PMC10451085 DOI: 10.3389/fimmu.2023.1193058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Although tuberculosis (TB) remains one of the leading causes of death from an infectious disease worldwide, the development of vaccines more effective than bacille Calmette-Guérin (BCG), the only licensed TB vaccine, has progressed slowly even in the context of the tremendous global impact of TB. Most vaccine candidates have been developed to strongly induce interferon-γ (IFN-γ)-producing T-helper type 1 (Th1) cell responses; however, accumulating evidence has suggested that other immune factors are required for optimal protection against Mycobacterium tuberculosis (Mtb) infection. In this review, we briefly describe the five hurdles that must be overcome to develop more effective TB vaccines, including those with various purposes and tested in recent promising clinical trials. In addition, we discuss the current knowledge gaps between preclinical experiments and clinical studies regarding peripheral versus tissue-specific immune responses, different underlying conditions of individuals, and newly emerging immune correlates of protection. Moreover, we propose how recently discovered TB risk or susceptibility factors can be better utilized as novel biomarkers for the evaluation of vaccine-induced protection to suggest more practical ways to develop advanced TB vaccines. Vaccines are the most effective tools for reducing mortality and morbidity from infectious diseases, and more advanced technologies and a greater understanding of host-pathogen interactions will provide feasibility and rationale for novel vaccine design and development.
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Affiliation(s)
- Hongmin Kim
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Han-Gyu Choi
- Department of Microbiology and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Sung Jae Shin
- Department of Microbiology, Institute for Immunology and Immunological Diseases, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
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18
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Netea MG, Ziogas A, Benn CS, Giamarellos-Bourboulis EJ, Joosten LAB, Arditi M, Chumakov K, van Crevel R, Gallo R, Aaby P, van der Meer JWM. The role of trained immunity in COVID-19: Lessons for the next pandemic. Cell Host Microbe 2023; 31:890-901. [PMID: 37321172 PMCID: PMC10265767 DOI: 10.1016/j.chom.2023.05.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 05/03/2023] [Accepted: 05/08/2023] [Indexed: 06/17/2023]
Abstract
Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks.
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Affiliation(s)
- Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany.
| | - Athanasios Ziogas
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Christine Stabell Benn
- Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark, Copenhagen, Denmark; Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
| | | | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Moshe Arditi
- Departments of Pediatrics and Biomedical Sciences, Guerin Children's and Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Konstantin Chumakov
- Office of Vaccines Research and Review, Food and Drug Administration, Global Virus Network Center of Excellence, Silver Spring, MD, USA
| | - Reinout van Crevel
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Robert Gallo
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Global Virus Network, Baltimore, MD, USA
| | - Peter Aaby
- Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark, Copenhagen, Denmark
| | - Jos W M van der Meer
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
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19
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Ijaz MU, Vaziri F, Wan YJY. Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases ⋆. LIVER RESEARCH 2023; 7:116-123. [PMID: 38223885 PMCID: PMC10786626 DOI: 10.1016/j.livres.2023.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 02/22/2023] [Accepted: 05/16/2023] [Indexed: 01/16/2024]
Abstract
Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.
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Affiliation(s)
- Muhammad Umair Ijaz
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Farzam Vaziri
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
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20
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Grifoni A, Alonzi T, Alter G, Noonan DM, Landay AL, Albini A, Goletti D. Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis. Front Immunol 2023; 14:1146704. [PMID: 37292210 PMCID: PMC10246744 DOI: 10.3389/fimmu.2023.1146704] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/11/2023] [Indexed: 06/10/2023] Open
Abstract
Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.
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Affiliation(s)
- Alba Grifoni
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, United States
| | - Tonino Alonzi
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
| | - Galit Alter
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard, Cambridge, MA, United States
| | - Douglas McClain Noonan
- Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Alan L. Landay
- Department of Internal Medicine, Rush Medical College, Chicago, IL, United States
| | | | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
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21
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Benn CS, Schaltz-Buchholzer F, Nielsen S, Netea MG, Aaby P. Randomized clinical trials of COVID-19 vaccines: Do adenovirus-vector vaccines have beneficial non-specific effects? iScience 2023; 26:106733. [PMID: 37163200 PMCID: PMC10125209 DOI: 10.1016/j.isci.2023.106733] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 01/24/2023] [Accepted: 04/20/2023] [Indexed: 05/11/2023] Open
Abstract
We examined the possible non-specific effects of novel mRNA- and adenovirus-vector COVID-19 vaccines by reviewing the randomized control trials (RCTs) of mRNA and adenovirus-vector COVID-19 vaccines. We calculated mortality risk ratios (RRs) for mRNA COVID-19 vaccines vs. placebo recipients and compared them with the RR for adenovirus-vector COVID-19 vaccine recipients vs. controls. The RR for overall mortality of mRNA vaccines vs. placebo was 1.03 (95% confidence interval [CI]: 0.63-1.71). In the adenovirus-vector vaccine RCTs, the RR for overall mortality was 0.37 (0.19-0.70). The two vaccine types differed significantly with respect to impact on overall mortality (p = 0.015). The RCTs of COVID-19 vaccines were unblinded rapidly, and controls were vaccinated. The results may therefore not be representative of the long-term effects. However, the data argue for performing RCTs of mRNA and adenovirus-vector vaccines head-to-head comparing long-term effects on overall mortality.
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Affiliation(s)
- Christine S Benn
- Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau
- OPEN, Odense Patient Data Explorative Network, Institute of Clinical Research Odense University Hospital/ University of Southern Denmark, Odense, Denmark
- Danish Institute of Advanced Science, University of Southern Denmark, Odense, Denmark
| | - Frederik Schaltz-Buchholzer
- Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau
- OPEN, Odense Patient Data Explorative Network, Institute of Clinical Research Odense University Hospital/ University of Southern Denmark, Odense, Denmark
| | - Sebastian Nielsen
- Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau
- OPEN, Odense Patient Data Explorative Network, Institute of Clinical Research Odense University Hospital/ University of Southern Denmark, Odense, Denmark
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Immunology and Metabolism, Life and Medical Science Institute, University of Bonn, Bonn, Germany
| | - Peter Aaby
- Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau
- OPEN, Odense Patient Data Explorative Network, Institute of Clinical Research Odense University Hospital/ University of Southern Denmark, Odense, Denmark
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22
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Geckin B, Zoodsma M, Kilic G, Debisarun PA, Rakshit S, Adiga V, Ahmed A, Parthiban C, Kumar NC, D’Souza G, Baltissen MP, Martens JHA, Domínguez-Andrés J, Li Y, Vyakarnam A, Netea MG. Differences in Immune Responses in Individuals of Indian and European Origin: Relevance for the COVID-19 Pandemic. Microbiol Spectr 2023; 11:e0023123. [PMID: 36779734 PMCID: PMC10100912 DOI: 10.1128/spectrum.00231-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/14/2023] Open
Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, large differences in susceptibility and mortality due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported between populations in Europe and South Asia. While both host and environmental factors (including Mycobacterium bovis BCG vaccination) have been proposed to explain this, the potential biological substrate of these differences is unknown. We purified peripheral blood mononuclear cells from individuals living in India and the Netherlands at baseline and 10 to 12 weeks after BCG vaccination. We compared chromatin accessibility between the two populations at baseline, as well as gene transcription profiles and cytokine production capacities upon stimulation. The chromatin accessibility of genes important for adaptive immunity was higher in the Indians than in the Europeans, while the latter had more accessible chromatin regions in genes of the innate immune system. At the transcriptional level, we observed that the Indian volunteers displayed a more tolerant immune response to stimulation, in contrast to a more exaggerated response in the Europeans. BCG vaccination strengthened the tolerance program in the Indians but not in the Europeans. These differences may partly explain the different impact of COVID-19 on the two populations. IMPORTANCE In this study, we assessed the differences in immune responses in individuals from India and Europe. This aspect is of great relevance, because of the described differences in morbidity and mortality between India and Europe during the pandemic. We found a significant difference in chromatin accessibility in immune cells from the two populations, followed by a more balanced and effective response in individuals from India. These exciting findings represent a very important piece of the puzzle for understanding the COVID-19 pandemic at a global level.
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Affiliation(s)
- Büsra Geckin
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn Zoodsma
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Gizem Kilic
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Priya A. Debisarun
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Srabanti Rakshit
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Vasista Adiga
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Asma Ahmed
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Chaitra Parthiban
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Nirutha Chetan Kumar
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - George D’Souza
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Marijke P. Baltissen
- Department of Molecular Biology, Radboud University, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Joost H. A. Martens
- Department of Molecular Biology, Radboud University, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Jorge Domínguez-Andrés
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Yang Li
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
- Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Annapurna Vyakarnam
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, Guy’s Hospital, King’s College London, London, United Kingdom
| | - Mihai G. Netea
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
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23
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Joseph J. Trained Immunity as a Prospective Tool against Emerging Respiratory Pathogens. Vaccines (Basel) 2022; 10:1932. [PMID: 36423027 PMCID: PMC9695339 DOI: 10.3390/vaccines10111932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/12/2022] [Accepted: 11/14/2022] [Indexed: 04/07/2025] Open
Abstract
Although parental vaccines offer long-term protection against homologous strains, they rely exclusively on adaptive immune memory to produce neutralizing antibodies that are ineffective against emerging viral variants. Growing evidence highlights the multifaceted functions of trained immunity to elicit a rapid and enhanced innate response against unrelated stimuli or pathogens to subsequent triggers. This review discusses the protective role of trained immunity against respiratory pathogens and the experimental models essential for evaluating novel inducers of trained immunity. The review further elaborates on the potential of trained immunity to leverage protection against pathogens via the molecular patterns of antigens by pathogen recognition receptors (PPRs) on innate immune cells. The review also focuses on integrating trained innate memory with adaptive memory to shape next-generation vaccines by coupling each one's unique characteristics.
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Affiliation(s)
- John Joseph
- Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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24
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Jalalizadeh M, Buosi K, Dionato FAV, Dal Col LSB, Giacomelli CF, Ferrari KL, Pagliarone AC, Leme PAF, Maia CL, Yadollahvandmiandoab R, Trinh Q, Franchini KG, Bajgelman MC, Reis LO. Randomized clinical trial of BCG vaccine in patients with convalescent COVID-19: Clinical evolution, adverse events, and humoral immune response. J Intern Med 2022; 292:654-666. [PMID: 35599154 PMCID: PMC9347570 DOI: 10.1111/joim.13523] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND The Bacillus Calmette-Guérin (BCG) vaccine may confer cross-protection against viral diseases in adults. This study evaluated BCG vaccine cross-protection in adults with convalescent coronavirus disease 2019 (COVID-19). METHOD This was a multicenter, prospective, randomized, placebo-controlled, double-blind phase III study (ClinicalTrials.gov: NCT04369794). SETTING University Community Health Center and Municipal Outpatient Center in South America. PATIENTS a total of 378 adult patients with convalescent COVID-19 were included. INTERVENTION single intradermal BCG vaccine (n = 183) and placebo (n = 195). MEASUREMENTS the primary outcome was clinical evolution. Other outcomes included adverse events and humoral immune responses for up to 6 months. RESULTS A significantly higher proportion of BCG patients with anosmia and ageusia recovered at the 6-week follow-up visit than placebo (anosmia: 83.1% vs. 68.7% healed, p = 0.043, number needed to treat [NNT] = 6.9; ageusia: 81.2% vs. 63.4% healed, p = 0.032, NNT = 5.6). BCG also prevented the appearance of ageusia in the following weeks: seven in 113 (6.2%) BCG recipients versus 19 in 126 (15.1%) placebos, p = 0.036, NNT = 11.2. BCG did not induce any severe or systemic adverse effects. The most common and expected adverse effects were local vaccine lesions, erythema (n = 152; 86.4%), and papules (n = 111; 63.1%). Anti-severe acute respiratory syndrome coronavirus 2 humoral response measured by N protein immunoglobulin G titer and seroneutralization by interacting with the angiotensin-converting enzyme 2 receptor suggest that the serum of BCG-injected patients may neutralize the virus at lower specificity; however, the results were not statistically significant. CONCLUSION BCG vaccine is safe and offers cross-protection against COVID-19 with potential humoral response modulation. LIMITATIONS No severely ill patients were included.
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Affiliation(s)
- Mehrsa Jalalizadeh
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Keini Buosi
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Franciele A. V. Dionato
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Luciana S. B. Dal Col
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Cristiane F. Giacomelli
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Karen L. Ferrari
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Ana Carolina Pagliarone
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Patrícia A. F. Leme
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Cristiane L. Maia
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Reza Yadollahvandmiandoab
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
| | - Quoc‐Dien Trinh
- Brigham and Women's Center for Surgery and Public HealthHarvard Medical SchoolBostonMassachusettsUSA
| | - Kleber G. Franchini
- Brazilian Center for Research in Energy and MaterialsCNPEMBrazilian Biosciences National Laboratory—LNBioCampinasBrazil
| | - Marcio C. Bajgelman
- Brazilian Center for Research in Energy and MaterialsCNPEMBrazilian Biosciences National Laboratory—LNBioCampinasBrazil
| | - Leonardo O. Reis
- Department of UroScienceSchool of Medical SciencesState University of Campinas—UNICAMPCampinasBrazil
- Center for Life SciencesPontifical Catholic University of CampinasCampinasBrazil
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25
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Kulesza J, Kulesza E, Koziński P, Karpik W, Broncel M, Fol M. BCG and SARS-CoV-2-What Have We Learned? Vaccines (Basel) 2022; 10:1641. [PMID: 36298506 PMCID: PMC9610589 DOI: 10.3390/vaccines10101641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/22/2022] [Accepted: 09/24/2022] [Indexed: 11/19/2022] Open
Abstract
Despite controversy over the protective effect of the BCG (Bacille Calmette-Guérin) vaccine in preventing pulmonary tuberculosis (TB) in adults, it has been used worldwide since 1921. Although the first reports in the 1930s had noted a remarkable decrease in child mortality after BCG immunization, this could not be explained solely by a decrease in mortality from TB. These observations gave rise to the suggestion of nonspecific beneficial effects of BCG vaccination, beyond the desired protection against M. tuberculosis. The existence of an innate immunity-training mechanism based on epigenetic changes was demonstrated several years ago. The emergence of the pandemic caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in 2019 revived the debate about whether the BCG vaccine can affect the immune response against the virus or other unrelated pathogens. Due to the mortality of the coronavirus disease (COVID-19), it is important to verify each factor that may have a potential protective value against the severe course of COVID-19, complications, and death. This paper reviews the results of numerous retrospective studies and prospective trials which shed light on the potential of a century-old vaccine to mitigate the pandemic impact of the new virus. It should be noted, however, that although there are numerous studies intending to verify the hypothesis that the BCG vaccine may have a beneficial effect on COVID-19, there is no definitive evidence on the efficacy of the BCG vaccine against SARS-CoV-2.
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Affiliation(s)
- Jakub Kulesza
- Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Kniaziewicza 1/5, 91-347 Lodz, Poland
| | - Ewelina Kulesza
- Department of Rheumatology and Internal Diseases, Medical University of Lodz, Żeromskiego 113, 90-549 Lodz, Poland
| | - Piotr Koziński
- Tuberculosis and Lung Diseases Outpatient Clinic, Health Facility Unit in Łęczyca, Zachodnia 6, 99-100 Łęczyca, Poland
| | - Wojciech Karpik
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Marlena Broncel
- Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Kniaziewicza 1/5, 91-347 Lodz, Poland
| | - Marek Fol
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
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26
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Olmo-Fontánez AM, Turner J. Tuberculosis in an Aging World. Pathogens 2022; 11:pathogens11101101. [PMID: 36297158 PMCID: PMC9611089 DOI: 10.3390/pathogens11101101] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/18/2022] [Accepted: 09/22/2022] [Indexed: 11/29/2022] Open
Abstract
Tuberculosis (TB) is one of the leading causes of death due to its being an infectious disease, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb). Approximately one-fourth of the world’s population is infected with latent M.tb, and TB is considered a global threat killing over 4000 people every day. The risk of TB susceptibility and mortality is significantly increased in individuals aged 65 and older, confirming that the elderly represent one of the largest reservoirs for M.tb infection. The elderly population faces many challenges that increase their risk of developing respiratory diseases, including TB. The challenges the elderly face in this regard include the following: decreased lung function, immuno-senescence, inflammaging, adverse drug effects, low tolerance to anti-TB drugs, lack of suitable diagnoses/interventions, and age-associated comorbidities. In order to find new therapeutic strategies to maintain lung homeostasis and resistance to respiratory infections as we age, it is necessary to understand the molecular and cellular mechanisms behind natural lung aging. This review focuses primarily on why the elderly are more susceptible to TB disease and death, with a focus on pulmonary function and comorbidities.
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Affiliation(s)
- Angélica M. Olmo-Fontánez
- Host Pathogen Interactions and Population Health Programs, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- Integrated Biomedical Sciences Program, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Joanne Turner
- Host Pathogen Interactions and Population Health Programs, Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- Correspondence:
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27
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Ning H, Kang J, Lu Y, Liang X, Zhou J, Ren R, Zhou S, Zhao Y, Xie Y, Bai L, Zhang L, Kang Y, Gao X, Xu M, Ma Y, Zhang F, Bai Y. Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice. Front Immunol 2022; 13:943667. [PMID: 36081510 PMCID: PMC9445367 DOI: 10.3389/fimmu.2022.943667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Bacillus Calmette-Guérin (BCG) is a licensed prophylactic vaccine against tuberculosis (TB). Current TB vaccine efforts focus on improving BCG effects through recombination or genetic attenuation and/or boost with different vaccines. Recent years, it was revealed that BCG could elicit non-specific heterogeneous protection against other pathogens such as viruses through a process termed trained immunity. Previously, we constructed a recombinant BCG (rBCG-DisA) with elevated c-di-AMP as endogenous adjuvant by overexpressing di-adenylate cyclase of Mycobacterium tuberculosis DisA, and found that rBCG-DisA induced enhanced immune responses by subcutaneous route in mice after M. tuberculosis infection. In this study, splenocytes from rBCG-DisA immunized mice by intravenous route (i.v) elicited greater proinflammatory cytokine responses to homologous and heterologous re-stimulations than BCG. After M. tuberculosis infection, rBCG-DisA immunized mice showed hallmark responses of trained immunity including potent proinflammatory cytokine responses, enhanced epigenetic changes, altered lncRNA expressions and metabolic rewiring in bone marrow cells and other tissues. Moreover, rBCG-DisA immunization induced higher levels of antibodies and T cells responses in the lung and spleen of mice after M. tuberculosis infection. It was found that rBCG-DisA resided longer than BCG in the lung of M. tuberculosis infected mice implying prolonged duration of vaccine efficacy. Then, we found that rBCG-DisA boosting could prolong survival of BCG-primed mice over 90 weeks against M. tuberculosis infection. Our findings provided in vivo experimental evidence that rBCG-DisA with c-di-AMP as endogenous adjuvant induced enhanced trained immunity and adaptive immunity. What’s more, rBCG-DisA showed promising potential in prime-boost strategy against M. tuberculosis infection in adults.
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Affiliation(s)
- Huanhuan Ning
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
| | - Jian Kang
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
| | - Yanzhi Lu
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
| | - Xuan Liang
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- College of Life Sciences, Northwest University, Xi’an, China
| | - Jie Zhou
- Department of Endocrinology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ren
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
| | - Shan Zhou
- Department of Clinical Laboratory, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Yong Zhao
- Laboratory Animal Center, Air Force Medical University, Xi’an, China
| | - Yanling Xie
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- School of Life Sciences, Yan’an University, Yan’an, China
| | - Lu Bai
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- School of Life Sciences, Yan’an University, Yan’an, China
| | - Linna Zhang
- Department of Physiology, Basic Medical School, Ningxia Medical University, Yinchuan, China
| | - Yali Kang
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- Department of Physiology, Basic Medical School, Ningxia Medical University, Yinchuan, China
| | - Xiaojing Gao
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- Department of Physiology, Basic Medical School, Ningxia Medical University, Yinchuan, China
| | - Mingze Xu
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
| | - Yanling Ma
- College of Life Sciences, Northwest University, Xi’an, China
| | - Fanglin Zhang
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- *Correspondence: Yinlan Bai, ; Fanglin Zhang,
| | - Yinlan Bai
- Department of Microbiology and Pathogen Biology, School of Preclinical Medicine, Air Force Medical University, Xi’an, China
- *Correspondence: Yinlan Bai, ; Fanglin Zhang,
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28
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Dionato FAV, Jalalizadeh M, Buosi K, Visacri MB, Dal Col LSB, Giacomelli CF, Leme PAF, Maia CL, Moriel P, Reis LO. BCG vaccine safety in COVID-19 convalescent adults: BATTLE a randomized controlled trial. Vaccine 2022; 40:4603-4608. [PMID: 35738969 PMCID: PMC9212358 DOI: 10.1016/j.vaccine.2022.06.039] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/04/2022] [Accepted: 06/12/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION The safety of BCG revaccination is uncertain and there is no data on its use in patients with COVID-19. METHODS COVID-19 convalescent adults confirmed by SARS-CoV-2 RT-PCR in South-America were 1:1 randomized in the first 14 days of symptoms to BCG intradermal vaccine or placebo and evaluated for adverse events on days 7, 14, 21, and beyond 40 days. CLINICAL TRIAL REGISTRATION NCT04369794. RESULTS 151 placebo and 148 BCG patients were included in the final analysis, with an average age of 40.7 years. No severe adverse event to BCG was reported. On day 7, 130 (87.8%) of the BCG recipients had local reaction, average size of 10.6 ± 6.4 mm, compared to only 2 (1.3%) placebos. Lesions gradually shrunk in size (mean 10.5 mm, 9.7 mm, and 6.8 mm at 14, 21, and beyond 40 days, respectively. The number of symptoms in any of the visits was not different between groups, and anosmia resolved earlier (25.7% vs. 37.1% at 7 days, OR = 1.70, 1.01-2.89, p = 0.035) in the BCG recipients. CONCLUSION The BCG revaccination is safe in convalescent COVID-19 adults of a tuberculosis endemic region, regardless of tuberculin or IGRA test results. Local adverse events were similar though occurred earlier to that previously reported in children.
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Affiliation(s)
- Franciele A V Dionato
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Mehrsa Jalalizadeh
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Keini Buosi
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Marília B Visacri
- Department of Pharmacology, School of Medical Sciences, University of Campinas, Campinas (SP), Brazil
| | - Luciana S B Dal Col
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Cristiane F Giacomelli
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Patricia A F Leme
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Cristiane L Maia
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil
| | - Patricia Moriel
- Department of Pharmacology, School of Medical Sciences, University of Campinas, Campinas (SP), Brazil
| | - Leonardo O Reis
- UroScience, School of Medical Sciences, University of Campinas, UNICAMP, and the Pontifical Catholic University of Campinas, PUC-Campinas, Brazil; Center of Life Sciences, Pontifical Catholic University of Campinas, PUC-Campinas, Brazil.
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29
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Fiction and Facts about BCG Imparting Trained Immunity against COVID-19. Vaccines (Basel) 2022; 10:vaccines10071006. [PMID: 35891168 PMCID: PMC9316941 DOI: 10.3390/vaccines10071006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/17/2022] [Accepted: 06/21/2022] [Indexed: 02/05/2023] Open
Abstract
The Bacille Calmette-Guérin or BCG vaccine, the only vaccine available against Mycobacterium tuberculosis can induce a marked Th1 polarization of T-cells, characterized by the antigen-specific secretion of IFN-γ and enhanced antiviral response. A number of studies have supported the concept of protection by non-specific boosting of immunity by BCG and other microbes. BCG is a well-known example of a trained immunity inducer since it imparts ‘non-specific heterologous’ immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the recent pandemic. SARS-CoV-2 continues to inflict an unabated surge in morbidity and mortality around the world. There is an urgent need to devise and develop alternate strategies to bolster host immunity against the coronavirus disease of 2019 (COVID-19) and its continuously emerging variants. Several vaccines have been developed recently against COVID-19, but the data on their protective efficacy remains doubtful. Therefore, urgent strategies are required to enhance system immunity to adequately defend against newly emerging infections. The concept of trained immunity may play a cardinal role in protection against COVID-19. The ability of trained immunity-based vaccines is to promote heterologous immune responses beyond their specific antigens, which may notably help in defending against an emergency situation such as COVID-19 when the protective ability of vaccines is suspicious. A growing body of evidence points towards the beneficial non-specific boosting of immune responses by BCG or other microbes, which may protect against COVID-19. Clinical trials are underway to consider the efficacy of BCG vaccination against SARS-CoV-2 on healthcare workers and the elderly population. In this review, we will discuss the role of BCG in eliciting trained immunity and the possible limitations and challenges in controlling COVID-19 and future pandemics.
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Gong W, Mao Y, Li Y, Qi Y. BCG Vaccination: A potential tool against COVID-19 and COVID-19-like Black Swan incidents. Int Immunopharmacol 2022; 108:108870. [PMID: 35597119 PMCID: PMC9113676 DOI: 10.1016/j.intimp.2022.108870] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/07/2022] [Accepted: 05/12/2022] [Indexed: 12/17/2022]
Abstract
The severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus
disease 2019 (COVID-19), and its variants have brought unprecedented
impacts to the global public health system, politics, economy, and other
fields. Although more than ten COVID-19 specific vaccines have been
approved for emergency use, COVID-19 prevention and control still face
many challenges. Bacille Calmette–Guérin (BCG) is the only authorized
vaccine used to fight against tuberculosis (TB), it has been hypothesized
that BCG may prevent and control COVID-19 based on BCG-induced
nonspecific immune responses. Herein, we summarized: 1) The nonspecific
protection effects of BCG, such as prophylactic protection effects of BCG
on nonmycobacterial infections, immunotherapy effects of BCG vaccine, and
enhancement effect of BCG vaccine on unrelated vaccines; 2) Recent
evidence of BCG's efficacy against SARS-COV-2 infection from ecological
studies, analytical analyses, clinical trials, and animal studies; 3)
Three possible mechanisms of BCG vaccine and their effects on COVID-19
control including heterologous immunity, trained immunity, and
anti-inflammatory effect. We hope that this review will encourage more
scientists to investigate further BCG induced non-specific immune
responses and explore their mechanisms, which could be a potential tool
for addressing the COVID-19 pandemic and COVID-19-like “Black Swan”
events to reduce the impacts of infectious disease outbreaks on public
health, politics, and economy.
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Affiliation(s)
- Wenping Gong
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8(th) Medical Center of PLA General Hospital, Beijing 100091, China
| | - Yingqing Mao
- Huadong Research Institute for Medicine and Biotechniques, Nanjing 210002, Jiangsu Province, China
| | - Yuexi Li
- Huadong Research Institute for Medicine and Biotechniques, Nanjing 210002, Jiangsu Province, China.
| | - Yong Qi
- Huadong Research Institute for Medicine and Biotechniques, Nanjing 210002, Jiangsu Province, China.
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De Zuani M, Frič J. Train the Trainer: Hematopoietic Stem Cell Control of Trained Immunity. Front Immunol 2022; 13:827250. [PMID: 35154147 PMCID: PMC8828730 DOI: 10.3389/fimmu.2022.827250] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/12/2022] [Indexed: 01/14/2023] Open
Abstract
Recent evidence shows that innate immune cells, in addition to B and T cells, can retain immunological memory of their encounters and afford long-term resistance against infections in a process known as 'trained immunity'. However, the duration of the unspecific protection observed in vivo is poorly compatible with the average lifespan of innate immune cells, suggesting the involvement of long-lived cells. Accordingly, recent studies demonstrate that hematopoietic stem and progenitor cells (HSPCs) lay at the foundation of trained immunity, retaining immunological memory of infections and giving rise to a "trained" myeloid progeny for a long time. In this review, we discuss the research demonstrating the involvement of HSPCs in the onset of long-lasting trained immunity. We highlight the roles of specific cytokines and Toll-like receptor ligands in influencing HSPC memory phenotypes and the molecular mechanisms underlying trained immunity HSPCs. Finally, we discuss the potential benefits and drawbacks of the long-lasting trained immune responses, and describe the challenges that the field is facing.
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Affiliation(s)
- Marco De Zuani
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
| | - Jan Frič
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
- Institute of Hematology and Blood Transfusion, Prague, Czechia
- *Correspondence: Jan Frič,
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Koeken VACM. Controlling inflammation in the elderly with BCG vaccination. SCIENCE ADVANCES 2021; 7:eabk1668. [PMID: 34348906 PMCID: PMC8336952 DOI: 10.1126/sciadv.abk1668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 07/06/2021] [Indexed: 05/04/2023]
Abstract
The tuberculosis vaccine BCG may protect against inflammation in the elderly as well as offer an option for protection from SARS-CoV-2 in developing countries.
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Affiliation(s)
- Valerie A C M Koeken
- Radboud Center for Infectious Diseases and Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany.
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