Targeting innate #immunity for #tuberculosis #vaccination (J Clin Invest., abstract)

[Source: Journal of Clinical Investigation, full page: (LINK). Abstract, edited.]

Targeting innate immunity for tuberculosis vaccination

Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea, and on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group

First published September 3, 2019



Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.

Keywords: Tuberculosis; Vaccines.


Effectiveness of #BCG #vaccination against Mycobacterium #tuberculosis #infection in #adults: a cross-sectional analysis of a #UK-based cohort (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: a cross-sectional analysis of a UK-based cohort

Anthea L Katelaris, Charlotte Jackson, Jo Southern, Rishi K Gupta,Francis Drobniewski, Ajit Lalvani, Marc Lipman, Punam Mangtani, Ibrahim Abubakar

The Journal of Infectious Diseases, jiz430,

Published: 29 August 2019




BCG appears to reduce acquisition of Mycobacterium tuberculosis (Mtb) infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of Mtb infection in adults.


We conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored.


Of 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (aOR=0.70, 95% CI 0.56-0.87, p=0.0017) yielding a VE of 30%. VE declined with time since vaccination, but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with non-vaccinated participants.


BCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against Mtb infection as well as disease. This has implications for immunisation programmes, vaccine development and tuberculosis control efforts worldwide.

BCG, Bacille Calmette-Guérin vaccine, tuberculosis, vaccine effectiveness

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© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail:

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (

Keywords: Mycobacterium tuberculosis; Vaccines; BCG.


Live-attenuated Mycobacterium #tuberculosis #vaccine MTBVAC versus #BCG in #adults and #neonates: a randomised controlled, double-blind dose-escalation trial (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Michele Tameris, MBChB *, Helen Mearns, PhD *, Adam Penn-Nicholson, PhD, Yolande Gregg, NDip, Nicole Bilek, PhD, Simbarashe Mabwe, BSc, Hennie Geldenhuys, MBChB, Justin Shenje, MBChB, Angelique Kany Kany Luabeya, MBChB, Ingrid Murillo, BD, Juana Doce, PhD, Nacho Aguilo, PhD, Dessislava Marinova, PhD, Eugenia Puentes, PhD, Esteban Rodríguez, VD, Jesús Gonzalo-Asensio, PhD, Bernard Fritzell, MD, Jelle Thole, PhD, Prof Carlos Martin, MD, Prof Thomas J Scriba, DPhil †, Prof Mark Hatherill, MD  † and theMTBVAC Clinical Trial Team

Published: August 12, 2019 / DOI:




Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high.


We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-γ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 10 5colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 10 5 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 10 5 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 10 3 CFU, 2·5 × 10 4 CFU, and 2·5 × 10 5 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with, number NCT02729571.


Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 10 3 CFU MTBVAC group, nine to the 2·5 × 10 4 CFU group, and ten to the 2·5 × 10 5 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 10 5 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 10 3 CFU MTBVAC group, two in the 2·5 × 10 4 CFU MTBVAC group, and two in the 2·5 × 10 5 CFU MTBVAC group), including one infant in the 2·5 × 10 3 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 10 5 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 10 3 CFU MTBVAC group, six (75%) of eight in the 2·5 × 10 4 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 10 3 CFU MTBVAC group, four (67%) of the six in the 2·5 × 10 4 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 10 5 CFU MTBVAC group.


MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition.


Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri.

Keywords: Tuberculosis; Vaccines; BCG.


Boosting #BCG with proteins or #rAd5 does not enhance #protection against #tuberculosis in rhesus macaques (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 28 May 2019

Boosting BCG with proteins or rAd5 does not enhance protection against tuberculosis in rhesus macaques

Patricia A. Darrah, Robert M. DiFazio, Pauline Maiello, Hannah P. Gideon, Amy J. Myers, Mark A. Rodgers, Joshua A. Hackney, Thomas Lindenstrom, Thomas Evans, Charles A. Scanga, Victor Prikhodko, Peter Andersen, Philana Ling Lin, Dominick Laddy, Mario Roederer, Robert A. Seder & JoAnne L. Flynn

npj Vaccines 4, Article number: 21 (2019)



Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

Keywords: Tuberculosis; BCG; Vaccines; Animal models.


#Outcomes of controlled #human #malaria infection after #BCG #vaccination (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 20 February 2019

Outcomes of controlled human malaria infection after BCG vaccination

Jona Walk, L. Charlotte J. de Bree, Wouter Graumans, Rianne Stoter, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Karina Teelen, Cornelus C. Hermsen, Rob J. W. Arts, Marije C. Behet, Farid Keramati, Simone J. C. F. M. Moorlag, Annie S. P. Yang, Reinout van Crevel, Peter Aaby, Quirijn de Mast, André J. A. M. van der Ven, Christine Stabell Benn, Mihai G. Netea & Robert W. Sauerwein

Nature Communications, volume 10, Article number: 874 (2019)



Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed ‘trained immunity’. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.

Keywords: Malaria; BCG; Vaccines.


Early #BCG #vaccination, #hospitalizations and hospital #deaths: Analysis of a secondary outcome in three #RCTs from Guinea-Bissau (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Early Bacille Calmette-Guérin vaccination, hospitalizations and hospital deaths: Analysis of a secondary outcome in three randomized trials from Guinea-Bissau

F Schaltz-Buchholzer, MD, PhD, S Biering-Sørensen, PhD, N Lund, MD, PhD, I Monteiro, P Umbasse, A Bærent Fisker, MD, PhD, A Andersen, PhD, A Rodrigues, MD, PhD, P Aaby, DMSc, C S Benn, DMSc

The Journal of Infectious Diseases, jiy544,

Published: 18 September 2018




To examine effects of early Bacille Calmette-Guérin (BCG) vaccination on the risk, cause and severity of infant hospitalizations.


Analysis of three trials randomizing low-weight neonates to early-BCG(intervention) versus no-BCG(usual practice in low-weight neonates, control), with hospitalizations as secondary outcome.


Hospitalization data was collected at the pediatric ward of the National Hospital. Effects of BCG on hospitalization risk were assessed in Cox-models providing overall and major disease-group incidence rate ratios(IRRs). Severity was assessed by in-hospital case-fatality rates and compared by group as cohort study risk ratios(RRs).


Among 6,583 infants (3,297 BCG; 3,286 controls), there were 908 infant hospitalizations (450 BCG; 458 controls) and 135 in-hospital deaths (56 BCG; 79 controls). The neonatal(28days), 6-week and infant(1year) BCG versus control hospitalization IRRs were 0.97(95% CI 0.72-1.31), 0.95(0.73-1.24) and 0.96(0.84-1.10). Corresponding BCG versus control case-fatality RRs were 0.58(0.35-0.94), 0.56(0.35-0.90) and 0.72(0.53-0.99). BCG tended to reduce neonatal and infant sepsis hospitalization rates, IRRs being 0.75(0.50-1.13) and 0.78(0.55-1.11), and reduced in-hospital neonatal sepsis mortality, RR=0.46(0.22-0.98). There were no confirmed tuberculosis hospitalizations.


BCG did not affect hospitalization rates but reduced in-hospital mortality significantly, primarily by preventing fatal cases of sepsis. The observed beneficial effects of BCG on in-hospital mortality were entirely non-specific.

Bacille Calmette-Guérin, infant mortality, infant morbidity, in-hospital case-fatality, neonatal mortality, neonatal morbidity, non-specific (heterologous) effects of vaccines, sepsis, tuberculosis

Issue Section: Major Article

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail:

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (

Keywords: BCG; Vaccines; Guinea-Bissau.


#BCG-Induced Trained #Immunity Is Not Protective for Experimental #Influenza A/Anhui/1/2013 (#H7N9) Infection in Mice (Front Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Immunol. 2018 Apr 30;9:869. doi: 10.3389/fimmu.2018.00869. eCollection 2018.

Bacillus Calmette-Guérin-Induced Trained Immunity Is Not Protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice.

de Bree CLCJ1,2,3,4, Marijnissen RJ5, Kel JM5, Rosendahl Huber SK5, Aaby P3, Benn CS3,4, Wijnands MVW5, Diavatopoulos DA2,6, van Crevel R1,2, Joosten LAB1,2, Netea MG1,2,7, Dulos J8.

Author information: 1 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands. 2 Radboud Centre for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. 3 Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. 4 Odense Patient Data Explorative Network, University of Southern Denmark, Odense University Hospital, Odense, Denmark. 5 Department of Immunology, Triskelion B.V., Zeist, Netherlands. 6 Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 7 Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. 8 Aduro Biotech Europe, Oss, Netherlands.



Avian influenza A of the subtype H7N9 has been responsible for almost 1,600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre-existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette-Guérin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex vivo peripheral blood mononuclear cell restimulation. We investigated whether BCG (Statens Serum Institut-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here, we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model.

KEYWORDS: avian influenza A/Anhui/1/2013 (H7N9); bacillus Calmette–Guérin; innate immune memory; oseltamivir; trained immunity

PMID: 29760700 PMCID: PMC5936970 DOI: 10.3389/fimmu.2018.00869

Keywords: Avian Influenza; H7N9; Immunotherapy; BCG; Animal Models.