Study to Evaluate the Ability of Sublingual MV130 to Induce the Expression of Trained Immunity in Peripheral Blood Cells

Study Overview
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Brief Summary
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A mechanistic clinical trial with the aim to evaluate whether MV130 can induce the expression of a particular immune response (trained immunity) in peripheral blood cells. Therefore, the investigators are not evaluating efficacy in any disease or medical condition but rather assessing the immunological effect in immunogenicity of MV130 in healthy volunteers.

Detailed Description
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Bacillus Calmette-Guérin (BCG) has been postulated as a strategy to prevent transmission and reduce the incidence of infectious diseases due to its ability to induce trained immunity. However, it is not recommended to vaccinate with live-attenuated vaccines, such as BCG, to certain vulnerable populations including immunocompromised patients. This issue can be overcome with inactivated preparations that mediate trained immunity such as MV130. The safety of MV130 in pilot studies in patients with immunodeficiency or solid organ recipients, has been highlighted in recent studies. Based on the principles of trained immunity, it has recently been suggested that this concept can be further exploited in a next generation of anti-infectious vaccines: Trained immunity-based vaccines (TIbV). Thus, these vaccines may confer a broad protection far beyond to the nominal antigens they contain.

Official Title
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A Phase I/II Randomized, Prospective, Double-blind, Placebo-controlled, Single-center Study to Evaluate the Ability of Sublingual MV130 to Induce the Expression of Trained Immunity in Peripheral Blood Cells

Conditions
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Immune Response

Intervention / Treatment
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* Biological: MV130
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects that have provided written informed consent. Healthy males and females 18 to 65 years, both included, at the time of enrolment. Subjects who are able to provide cooperation and comply with dosing regimen. Women of childbearing age (from menarche) should submit a urine pregnancy test with a negative result at the time of enrolment in the trial. Exclusion Criteria: Simultaneous participation in another clinical trial. Females who are pregnant or breast-feeding, or potential pregnant or breast-feeding females. Subjects who are allergic to any of the components included in MV130. Subjects with any concomitant disease or treatment that, according to the investigator criteria, may affect the development of this study, such as immunodeficiencies, malignancies involving bone marrow or lymphoid systems, medical treatment affecting the immune system (including corticosteroids, immunosuppressants, biological agents,…), human immunodeficiency virus, - - Subjects who have been vaccinated (flu, pneumococcal or any other vaccine different from COVID-19 vaccine) within 6 months before inclusion, or who have planned to be vaccinated during the clinical trial (excluding the COVID-19 vaccine). Subjects who have had an infection that included fever and/or diarrhoea within 3 months before inclusion. Subjects under metformin treatment during the last month before inclusion in Subjects under statins treatment during the last month before inclusion in the clinical trial or during *. these drugs interfere with metabolic pathways involved in trained immunity induction

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MV130<br>Suspension of 6 inactivated whole bacteria concentrates, that contains 90% of Gram positive bacteria (V104 S. pneumoniae 60%, V102 S. aureus 15%, V101 S. epidermidis 15%) and 10% of Gram negative bacteria (V113 K. pneumoniae 4%, V105 M. catarrhalis 3%, V103 H. influenzae 3%), at a concentration of 300 FTU/mL, equivalent to   10^9 bacteria/mL. | Biological: MV130<br>* Treatment administered sublingually<br>|
| Placebo Comparator: Placebo<br>Sodium chloride 9 mg/mL and water for injection s.q. f 1 mL. | Other: Placebo<br>* Treatment administered sublingually<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase ex vivo in cytokine response | The primary outcome is the change ex vivo in cytokine response (TNF-alfa, IL-6 and/or IL-1beta) in PBMCs upon secondary restimulation (MV130, lipopolysaccharide [LPS], inactivated Candida albicans, Resiquimod-R848, Poly I:C and/or phytohemagglutinin [PHA]) in MV130 vaccinated subjects compared to placebo group, at days 15, 45 and/or 70, with respect to baseline. | 70 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in epigenetic markers (miRNA) in purified monocytes from PBMCs in a subgroup of MV130 vaccinated (n=12) versus placebo (n=12), at day 45 with respect to baseline. | Changes in specific miRNA from total RNA associated to trained immunity (miR155, miR146 and/or miR21, etc.) by real time quantitative polymerase chain reaction (RT-qPCR) measured as expression levels. | 70 days | 
| Changes in epigenetic markers (active chromatin histone marks) in purified monocytes from PBMCs, in a subgroup of MV130 vaccinated (n=12) versus placebo (n=12), at day 45 with respect to baseline, including: | Changes in active chromatin histone marks (H3K4me3 and/or H3K27me3, among others) by chromatin immunoprecipitation (ChIP) analysis, measured as relative expression. | 70 days | 
| Metabolic changes in purified monocytes from PBMCs, in a subgroup of vaccinated (n=12) versus placebo (n=12), at day 45 with respect to baseline, including: | Changes in concentration of lactate production by using a colorimetric assay kit. Changes in glucose consumption (concentration), determined by using a glucose assay kit. Changes in mitochondrial activity, measured by using a fluorescence probe kit. | 70 days | 
| Changes in percentages of immune populations in peripheral blood | Changes in percentages of immune populations in peripheral blood including T and B cells, NK cells and subsets of monocytes, in MV130 group compared to placebo at days 15, 45 and/or 70, with respect to baseline. | 70 days | 
| Change in MV130 non-specific response | Change in MV130 non-specific response (T and B cells from PBMCs) in MV130 treated group compared to placebo including: T cell proliferation (days 15, 45 and/or 70) by labelling T cells with carboxyfluorescein succinimidyl ester (CFSE) prior to restimulation with PHA and/or inactivated C. albicans. Also, change of cytokine production (such as IFN-gamma, IL-17 and/or IL-10) from T cells upon restimulation (LPS, inactivated Candida albicans, Resiquimod-R848, Poly I:C, viral peptides/proteins and/or PHA) (days 15, 45 and/or 70 with respect to baseline) [27]. Antibody production: Cross-reactive serum IgG against viral components. Different viral proteins/peptides will be tested (days 45 and 70 with respect to baseline). | 70 days | 
| MV130 specific response | MV130 specific response (T and B cell responses from PBMCs) in MV130 vaccinated group compared to placebo, including: T cell proliferation and cytokine production (IFN-gamma, IL-17 and/or IL-10) following restimulation with MV130 (days 15, 45 and/or 70 with respect to baseline) Antibody production: MV130 specific IgG and IgA levels in serum and IgA levels in saliva (days 45 and/or 70 with respect to baseline). Individual bacteria contained in MV130 (i.e., S. pneumoniae) will be further tested for specific antibody production. | 70 days | 
| Changes in baseline oral microbiota composition in MV130 treated group | Changes in baseline oral microbiota composition in MV130 treated group (days 45 and 70 with respect to baseline) compared to placebo, based o¬n the 16S rRNA sequence phylogeny | 70 days | 
| Rates of adverse events | The overall rate of adverse events in both groups | 70 days | 
| Classification of the Adverse events | Classification of the Adverse events during the trial | 70 days | 
| Rates of adverse reactions | The overall rate of adverse reactions in both groups | 70 days | 
| Classification of the Adverse reactions | Classification of the Adverse reactions during the trial | 70 days | 
| Percentage by type of adverse events | Percentage by type of adverse events occurred during the trial | 70 days | 
| Percentage of subject with adverse reactions | Percentage of subject experiencing adverse reactions during the trial | 70 days | 
| Timing of reaction appearance | Time from the first administration to appearance of the reaction | 70 days | 
| Classification of the adverse reaction according to the place of appearance | Classification of the adverse reaction in local or systemic, depending on the place of appearance | 70 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trained immunity, Innate immune system, MV130, Sublingual vaccine, Trained immunity-based vaccines