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

Immune Response Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05208060
• Other study ID #: MV130-SLG-039
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: June 1, 2022
• Est. completion date: December 31, 2023

Study information

• Verified date: March 2022
• Source: Inmunotek S.L.
• Contact: Miguel Casanovas Verges, MD, PhD
• Phone: 664277223
• Email: mcasanovas[@]inmunotek.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 48
• Est. completion date: December 31, 2023
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Immune Response

Intervention

Biological:
• MV130
Treatment administered sublingually

Other:
• Placebo
Treatment administered sublingually

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Inmunotek S.L.

References & Publications (11)

Alecsandru D, Valor L, Sánchez-Ramón S, Gil J, Carbone J, Navarro J, Rodríguez J, Rodríguez-Sainz C, Fernández-Cruz E. Sublingual therapeutic immunization with a polyvalent bacterial preparation in patients with recurrent respiratory infections: immunomodulatory effect on antigen-specific memory CD4+ T cells and impact on clinical outcome. Clin Exp Immunol. 2011 Apr;164(1):100-7. doi: 10.1111/j.1365-2249.2011.04320.x. — View Citation

Cirauqui C, Benito-Villalvilla C, Sánchez-Ramón S, Sirvent S, Diez-Rivero CM, Conejero L, Brandi P, Hernández-Cillero L, Ochoa JL, Pérez-Villamil B, Sancho D, Subiza JL, Palomares O. Human dendritic cells activated with MV130 induce Th1, Th17 and IL-10 responses via RIPK2 and MyD88 signalling pathways. Eur J Immunol. 2018 Jan;48(1):180-193. doi: 10.1002/eji.201747024. Epub 2017 Sep 14. — View Citation

Del Fresno C, García-Arriaza J, Martínez-Cano S, Heras-Murillo I, Jarit-Cabanillas A, Amores-Iniesta J, Brandi P, Dunphy G, Suay-Corredera C, Pricolo MR, Vicente N, López-Perrote A, Cabezudo S, González-Corpas A, Llorca O, Alegre-Cebollada J, Garaigorta U, Gastaminza P, Esteban M, Sancho D. The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity. Front Immunol. 2021 Nov 18;12:748103. doi: 10.3389/fimmu.2021.748103. eCollection 2021. — View Citation

García González LA, Arrutia Díez F. Mucosal bacterial immunotherapy with MV130 highly reduces the need of tonsillectomy in adults with recurrent tonsillitis. Hum Vaccin Immunother. 2019;15(9):2150-2153. doi: 10.1080/21645515.2019.1581537. Epub 2019 Apr 17. — View Citation

Guevara-Hoyer K, Saz-Leal P, Diez-Rivero CM, Ochoa-Grullón J, Fernández-Arquero M, Pérez de Diego R, Sánchez-Ramón S. Trained Immunity Based-Vaccines as a Prophylactic Strategy in Common Variable Immunodeficiency. A Proof of Concept Study. Biomedicines. 2020 Jul 9;8(7). pii: E203. doi: 10.3390/biomedicines8070203. — View Citation

Molero-Abraham M, Sanchez-Trincado JL, Gomez-Perosanz M, Torres-Gomez A, Subiza JL, Lafuente EM, Reche PA. Human Oral Epithelial Cells Impair Bacteria-Mediated Maturation of Dendritic Cells and Render T Cells Unresponsive to Stimulation. Front Immunol. 2019 Jun 28;10:1434. doi: 10.3389/fimmu.2019.01434. eCollection 2019. — View Citation

Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020 Jun;20(6):375-388. doi: 10.1038/s41577-020-0285-6. Epub 2020 Mar 4. Review. — View Citation

Nieto A, Mazón A, Nieto M, Calderón R, Calaforra S, Selva B, Uixera S, Palao MJ, Brandi P, Conejero L, Saz-Leal P, Fernández-Pérez C, Sancho D, Subiza JL, Casanovas M. Bacterial Mucosal Immunotherapy with MV130 Prevents Recurrent Wheezing in Children: A Randomized, Double-Blind, Placebo-controlled Clinical Trial. Am J Respir Crit Care Med. 2021 Aug 15;204(4):462-472. doi: 10.1164/rccm.202003-0520OC. — View Citation

Ochoa-Grullón J, Benavente Cuesta C, González Fernández A, Cordero Torres G, Pérez López C, Peña Cortijo A, Conejero Hall L, Mateo Morales M, Rodríguez de la Peña A, Díez-Rivero CM, Rodríguez de Frías E, Guevara-Hoyer K, Fernández-Arquero M, Sánchez-Ramón S. Trained Immunity-Based Vaccine in B Cell Hematological Malignancies With Recurrent Infections: A New Therapeutic Approach. Front Immunol. 2021 Feb 12;11:611566. doi: 10.3389/fimmu.2020.611566. eCollection 2020. — View Citation

Sánchez-Ramón S, Conejero L, Netea MG, Sancho D, Palomares Ó, Subiza JL. Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations. Front Immunol. 2018 Dec 17;9:2936. doi: 10.3389/fimmu.2018.02936. eCollection 2018. Review. — View Citation

Vázquez A, Fernández-Sevilla LM, Jiménez E, Pérez-Cabrera D, Yañez R, Subiza JL, Varas A, Valencia J, Vicente A. Involvement of Mesenchymal Stem Cells in Oral Mucosal Bacterial Immunotherapy. Front Immunol. 2020 Nov 19;11:567391. doi: 10.3389/fimmu.2020.567391. eCollection 2020. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Rates of adverse events	The overall rate of adverse events in both groups	70 days
Secondary	Classification of the Adverse events	Classification of the Adverse events during the trial	70 days
Secondary	Rates of adverse reactions	The overall rate of adverse reactions in both groups	70 days
Secondary	Classification of the Adverse reactions	Classification of the Adverse reactions during the trial	70 days
Secondary	Percentage by type of adverse events	Percentage by type of adverse events occurred during the trial	70 days
Secondary	Percentage of subject with adverse reactions	Percentage of subject experiencing adverse reactions during the trial	70 days
Secondary	Timing of reaction appearance	Time from the first administration to appearance of the reaction	70 days
Secondary	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