A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection

Counoupas, Claudio; Johansen, Matt D.; Stella, Alberto Ospina; Nguyen, Duc Hai; Ferguson, Angela; Aggarwal, Anupriya; Bhattacharyya, Nayan D.; Grey, Alice; Hutchings, Owen; Patel, Karishma; Siddiquee, Rezwan; Stewart, Erica L.; Feng, Carl G.; Hansbro, Nicole G.; Palendira, Umaimainthan; Steain, Megan; Saunders, Bernadette M.; Low, Jason K. K.; Mackay, J.P.; Kelleher, Anthony D.; Britton, Warwick J.; Turville, Stuart; Hansbro, Philip M.; Triccas, James A.

doi:10.1038/s41541-021-00406-4

Cited by 55 publications

(69 citation statements)

References 42 publications

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“…Such non-specific protection by BCG against non-mycobacterial infections and perhaps other non-infectious disorders include induction of: (i) a heterologous TH1, TH17, and CD8+ lymphocytic response and (ii) a non-specific memory in innate immune cells (natural killer cells, monocytes, and macrophages) through epigenetic effects and metabolic rewiring in a paradigm known as "trained immunity" [33]. Of contemporary note is the investigation of BCG in the COVID-19 pandemic; BCG benefit has been shown in both animal COVID-19 studies and humans where BCG demonstrated a "synergy" with COVID-19 vaccination [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.

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Section: Discussionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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“…This concept, which remains controversial, is currently being formally tested in a number of clinical trials ( Junqueira-Kipnis et al, 2020 ; Pépin et al, 2021 ; Tsilika et al, 2021 Preprint ). In addition, recent preclinical work has demonstrated the use of BCG as an adjuvant to boost SCV2-specific vaccine-induced protection ( Counoupas et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

Hilligan

Namasivayam

Clancy

et al. 2021

Journal of Experimental Medicine

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In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer nonspecific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here, we demonstrate that intravenous, but not subcutaneous, inoculation of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 (SCV2) and results in reduced viral loads in non-transgenic animals infected with an α variant. The observed increase in host resistance was associated with reductions in SCV2-induced tissue pathology, inflammatory cell recruitment, and cytokine production that multivariate analysis revealed as only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and ensuing immunopathology. While intravenous BCG vaccination is not a clinically acceptable practice, our findings provide an experimental model for identifying mechanisms by which nonspecific stimulation of the pulmonary immune response promotes host resistance to SCV2 lethality.

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“…While BCG vaccination is routinely used in most countries as a TB prevention, the vaccine is generally given intradermally, and recent human studies showing protection by BCG against COVID-19 disease also used intradermal BCG (13). Like other animal studies using BCG in animal models of SCV2 (28) we used the intravenous route based on literature that IV BCG is far more potent against tuberculosis in non-human primates, and evidence that IV BCG reprograms bone marrow hematopoietic stem cells towards a more protective state against bacterial challenge (22). Nevertheless, SCV2 animal studies using percutaneous BCG have shown significant immunologic benefits at the level of flow cytometry (29), and we anticipate that many of the scRNAseq shifts which we observed in IV BCG vaccinated hamsters would be present following intradermal BCG albeit potentially at a lower level.…”

Section: Discussionmentioning

confidence: 99%

Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation

Singh

Wang

Lombardo

et al. 2022

Preprint

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COVID-19 continues to exact a toll on human health despite the availability of several vaccines. Bacillus Calmette Guerin (BCG) has been shown to confer heterologous immune protection against viral infections including COVID-19 and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model together with immune profiling and single cell RNA sequencing (scRNAseq). We observed that BCG reduced both lung SCV2 viral load and bronchopneumonia. This was accompanied by an increase in lung alveolar macrophages, a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. Single cell transcriptome profiling showed that BCG uniquely recruits immunoglobulin-producing plasma cells to the lung suggesting accelerated antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, and differentially expressed gene (DEG) analysis showed a transcriptional shift away from exhaustion markers and towards antigen presentation and repair. Similarly, BCG enhanced lung recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, with both cell-types also showing reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

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A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection

Cited by 55 publications

References 42 publications

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation

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