Trained Immunity: RoadMap for drug discovery and development

1 NCT ID NCT06257212 Title Live Vaccines and Innate Immunity Training in COPD Dates 2024/02/28 to 2025/09 Phase Phase 4 Enrolment 60 (Estimated) Condition(s) COPD Intervention(s) BCG vaccine
MMR vaccine Primary Outcome Innate immune training measured by fold-changes in cytokine production capacity of innate immune cells following pro-inflammatory stimulation. Measured from inclusion in the trial to 4 months’ post-inclusion. Cytokines include: IL-1β, IL-10, TNF-α, IFN-γ 2 NCT ID NCT06266754 Title The Non-Specific Immunological Effects of Providing Oral Polio Vaccine to Seniors in Guinea-Bissau Dates 2024/01/29 to 2024/12/31 Phase Phase 4 Enrolment 80 (Estimated) Condition(s) Vaccine Reaction Intervention(s) Oral Polio vaccine Primary Outcome

1. Levels of proinflammatory cytokines (including IL1-β, TNF-α, IFN-γ) after stimulation of PBMCs with non-OPV antigens and mitogens 1 month after intervention

2. Levels of plasma markers of systemic inflammation (e.g. TWEAK and SIRT2) 1 month after intervention

3. Investigating epigenetic changes in PBMCs by single-cell ATAC-sequencing and whole-genome methylation assays 1 month after intervention

4. Investigate transcriptional effects on immune cells by single-cell RNA-sequencing 1 month after intervention. Identifying proportions of immune cell subsets

3 NCT ID NCT05208060 Title Study to Evaluate the Ability of Sublingual MV130 to Induce the Expression of Trained Immunity in Peripheral Blood Cells Dates 2023/09/01 to 2025/12/31 Phase Phases 1 and 2 Enrolment 48 (Estimated) Condition(s) Immune Response Intervention(s) MV130 vaccine Primary Outcome Increase in ex vivo PBMCs cytokine response (TNF-α, IL-6, IL-1β) to secondary restimulation compared to placebo at days 15, 45, and 70 with respect to baseline Selected Secondary Outcomes relevant to Trained Immunity

1. Epigenetic and metabolic changes in purified monocytes from PBMCs, including specific Trained Immunity-associated miRNAs (miR155, miR146, miR21), lactate production, glucose consumption, and mitochondrial activity at day 45 with respect to baseline

2. Change in proportions of immune cells (including T cells, B cells, NK cells, and subsets of monocytes) in peripheral blood at days 15, 45, and 70 with respect to baseline

4 NCT ID NCT02403505 Title Early Phase Clinical Trial About Therapeutic Biological Product Mix for Treating CEA Positive Rectal Cancer Dates 2021/12/28 to 2025/02/28 Phase Phase 1 Enrolment 20 (Estimated) Condition(s) Rectal Cancer Intervention(s) CEA protein antigen and BCG vaccine mix for percutaneous use Primary Outcome Timeframe: up to 90 days

1. Participants with positive CEA blood test

2. Participants with positive IGRA blood test with CEA protein antigen after percutaneous use

3. Participants with IGRA blood test with TB antigens (negative before percutaneous use, positive after percutaneous use)

5 NCT ID NCT05507671 Title The Role of BCG Vaccine in the Clinical Evolution of COVID-19 and in the Efficacy of Anti-SARS-CoV-2 Vaccines Dates 2021/05/27 to 2023/12/31 Phase Phase 3 Enrolment 556 (Estimated) Condition(s) COVID-19 Intervention(s) BCG vaccine Primary Outcome

1. Incidence of SARS-CoV-2 infection. Timeframe: 6 months from recruitment day

2. Incidence of COVID-19 symptoms. Timeframe: 6 months from recruitment day

3. Intensity of efficacy of first dose of vaccine against COVID-19. Timeframe: 6 months from recruitment day

4. Duration of efficacy of the second vaccine dose against COVID-19. Timeframe: 1 year from recruitment day

Selected Secondary Outcomes relevant to Trained Immunity Serum concentrations of cytokines TNF-α, IFN-γ, IL-1β, IL-4, IL-6, and IL-10 in 50 participants of BCG group versus 50 participants of placebo group 2 months after recruitment 6 NCT ID NCT06628544 Title Trained Immunity in Fungal Infection and Its Mechanism Dates 2020/09/01 to 2023/12/01 Phase Early Phase 1 Enrolment 79 (Actual) Condition(s) BCG vaccination Intervention(s) BCG vaccine
Metformin Primary Outcome IL-6 and TNF-α cytokine production by PBMCs isolated after 5 days of continuous medication and restimulated with C. albicans or Mycobacterium tuberculosis 7 NCT ID NCT03296423 Title Bacillus Calmette-Guérin Vaccination to Prevent Infections of the Elderly Dates 2017/09/21 to 2020/11/30 Phase Phase 4 Enrollment 200 (Actual) Condition(s) Infection
Hospitalization
Mortality Intervention(s) BCG vaccine Primary Outcome Time to first infection. Timeframe: 12 months Selected Secondary Outcomes relevant to Trained Immunity

1. Cytokine stimulation from PBMCs. Timeframe: month 3

2. Epigenetic changes of circulating monocytes. Timeframe: month 3

8 NCT ID NCT02114255 Title Effects of BCG on Influenza Induced Immune Response Dates 2014/05 to 2014/09 Phase Phases 2 and 3 Enrolment 40 (Actual) Condition(s) Influenza virus infection
Trained Immunity Intervention(s) BCG vaccine Primary Outcome

1. Difference in influenza antibody titers at days 14, 21, 28, and 42

2. Difference in thrombocyte function at days 0, 14, 21, 28, and 42

Selected Secondary Outcomes relevant to Trained Immunity

1. IFN-γ, IL-10, type 1 IFN, IL-17, IL-22 production by ex vivo leukocytes stimulated with inactivated/live influenza virus at days 0, 14, 28, and 42

2. Production of inflammatory mediators (including TNFα, IL-1β, IFN-γ, IL-10, IL-17, and IL-22) by ex vivo leukocytes stimulated with different stimuli (including M. tuberculosis, S. aureus, C. albicans, and inactivated influenza) at days 0, 21, 28, and 42

3. qPCR/microarray of inflammatory transcriptional pathways at days 0, 14, 21, 28, and 42.

4. Granzyme B production by ex vivo leukocytes stimulated with inactivated/live influenza virus at days 0, 14, 21, 28, and 42

9 NCT ID NCT01734811 Title Efficacy and Safety Evaluation in Recurrent Wheezing Attacks (MV130) Dates 2012/10 to 2017/02 Phase Phase 3 Enrolment 120 (Actual) Condition(s) Bronchospasm
Bronchiolitis
Bronchitis Intervention(s) MV130 vaccine Primary Outcome Number of Recurrent Bronchospasm (Wheezing Attacks) (b) Trials investigating modulation of Trained Immunity for therapeutic benefit 10 NCT ID NCT06624436 Title Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia Dates 2024/10/24 to 2025/12 Phase Phase 4 Enrolment 52 (Estimated) Condition(s) Sepsis
Neuroinflammatory Response
Immunosuppression
Endotoxemia Intervention(s) Dexamethasone
Tocilizumab
Anakinra Primary Outcome

1. Plasma TNF concentrations upon second LPS challenge

2. Cerebrospinal fluid TNF concentrations during repeated experimental human endotoxemia

Selected Secondary Outcomes relevant to Trained Immunity

1. Plasma cytokine (IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1β, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) concentrations (plasma and cerebrospinal fluid), other inflammatory protein biomarkers (Olink Target 96 inflammation panel) (plasma and cerebrospinal fluid), and mHLA-DR during first and second LPS challenges

2. Blood leukocyte single-cell and bulk mRNA profiles/transcriptomic pathways upon LPS challenges

3. Cytokine production of ex vivo leukocyte cultures

11 NCT ID NCT03332225 Title A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis Dates 2017/12/15 to 2019/12/31 Phase Phase 2 Enrolment 36 (Actual) Condition(s) Sepsis
Macrophage Activation Syndrome Intervention(s) Anakinra
Recombinant human IFN-γ Primary Outcome Mortality. Timeframe: 28 days Selected Secondary Outcomes relevant to Trained Immunity

1. Cytokine stimulation from PBMCs. Timeframe: 4 and 7 days

2. Gene expression of PBMCs. Timeframe: 7 days

3. Epigenetic changes of circulating monocytes. Timeframe: 7 days

(c) Trials investigating inhibition of Trained Immunity for therapeutic benefit 12 NCT ID NCT05790499 Title LDL-c Level Variability and Trained Immunity Dates 2023/03/20 to 2024/01/31 Phase N/A Enrollment 12 (Estimated) Condition(s) Cholesterol Variability
Trained Immunity Intervention(s) Atorvastatin Primary Outcome Changes in LDL-C levels between baseline and atorvastatin treatment cycles. Timeframe: 16 weeks Selected Secondary Outcomes relevant to Trained Immunity Timeframe: 16 weeks

1. PBMCs subgroup percentage and activation status

2. PBMCs secreting cytokines

3. PBMCs change in gene expression

4. Levels of hs-CRP, IL-6, IL-18, and sVCAM-1

13 NCT ID NCT05210725 Title Trained Immunity by Dual-pathway Inhibition in Coronary Artery Disease Dates 2022/03/01 to 2022/07/01 Phase Phase 4 Enrolment 20 (Actual) Condition(s) Coronary Artery Disease Intervention(s) Rivaroxaban and Acetylsalicylic acid Primary Outcome Whole blood immune responsiveness to LPS stimulation when switching from acetylsalicylic acid monotherapy to acetylsalicylic acid and low-dose rivaroxaban dual pathway inhibition. Timeframe: 12 weeks Selected trial outcomes relevant to Trained Immunity

1. White blood cell count and distribution. Timeframe: 3 months

2. Monocyte immune responsiveness to LPS stimulation. Timeframe: 3 months

3. Enrichment of epigenetic gene marks. Timeframe: 3 months