naNO-DENGUE: Evaluation of Safety and Immunogenicity of a T-Cell Priming Peptide Vaccine Against Dengue

Sponsor

Emergex Vaccines Holding Ltd. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04935801

Collaborator

Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland (Other), University of Lausanne Hospitals (Other)

Enrollment

Location

Arms

10.9

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This trial aims to test the safety of 2 doses of a T-cell priming specific cocktail of Dengue viruses peptides representing all 4 DENV serotypes and mounted on a gold nanoparticle.

NOTE: This is the master protocol of a prospective 2-stage adaptive trial, which aims to add and test a Coronavirus vaccine candidate as well, in an identical trial design.

Condition or Disease	Intervention/Treatment	Phase
Dengue	Biological: LD vehicle-GNP Biological: LD PepGNP-Dengue Biological: HD vehicle-GNP Biological: HD PepGNP-Dengue	Phase 1

Detailed Description

A critical limitation for Dengue vaccines is their association with antibody-dependent enhancement, where poorly formed immune responses predispose the individual to severe disease during a second infection. Thus, a more targeted vaccine (inducing / priming T cells and not producing antibodies) could be the best alternative and most successful preventive method in the fight against severe manifestations of the disease.

Nanoparticle antigen delivery systems have been developed to enrich specific targeting of immune receptors. These carrier systems are designed to facilitate antigen uptake and processing by antigen presenting cells (APCs), as well as to control antigen release and protect them from premature proteolytic degradation. This more targeted response also allows us to reduce the effective antigen dose (to nanomoles) and mimic a replicating infection with zero risk of developing the infectious disease.

The hypotheses are listed below:

During the COVID-19 pandemic, Dengue virus disease is likely to cause significant diagnostic confusion and it risks further progression due to disrupted control measures.
As the SARS-CoV-2 pandemic devastates the world, the need for highly efficient and scalable vaccines is desperately required.
Peptide vaccines have high potential as a rapidly scalable modular platform for emerging diseases requiring targeted immunological responses.
Dengue viruses and Coronaviruses (e.g. COVID-19 causing viruses) are particularly well suited to this approach.

For this initial naNO-DENGUE part of the trial, the objectives are as follows:

Primary:

To evaluate the safety and reactogenicity of two intradermal injections of two different doses of the investigational Dengue peptide T cell inducing vaccine (PepGNP-Dengue) administered to healthy volunteers as a:

candidate vaccine for the prevention of severe Dengue disease
proof-of-concept for a rapidly scalable modular peptide vaccine platform, which will be followed by a Coronavirus construct after interim analyses.

Secondary:

To assess the evidence of a T-cell mediated immune response as a surrogate of protection against severe dengue disease using a novel peptide set-point vaccine in healthy adults.
To check the absence of an antibody mediated response

For naNO-DENGUE, a total of 26 eligible participants will be randomized into the following groups:

Group 1 (n=13): 10 Low Dose (LD) PepGNP-Dengue (2.5 nmol) + 3 Comparator
Group 2 (n=13): 10 High Dose (HD) PepGNP-Dengue (7.5 nmol) + 3 Comparator, Thus, 20/26 vaccine vera and 6/26 Comparator controls. Allocations of vaccine vera vs Comparator for each group are double-blinded. Each arm will be staggered into a "Pioneer" group (3/13 participants) followed a week later after a safety review by the remaining 10/13 "Followers".

This is the master protocol for a 2-stage study investigating the safety of 2 vaccines from a

T Cell priming vaccine platform for emerging diseases:

Stage 1: naNO-DENGUE A Phase-I study of a peptide T cell vaccine against Dengue virus (Master protocol) Stage 2: naNO-COVID A Phase-I study of a peptide T cell vaccine against Coronavirus (Sub-protocol)

Study Design

Study Type:

Interventional

Actual Enrollment :

26 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This trial is double-blinded (blinded to investigators and participants) Blinding will be maintained for the duration of the study All allocations will remain coded to all volunteers and investigators. An independent pharmacy team at CHUV will label the Vaccine and Comparator doses with coded participant numbers but will not have access to the identifier list linking the code to the participant identity. All Vaccine and Comparator doses will be prepared and labelled away form investigators and stored in identical conditions. The appearance of the comparators and doses will be identical. The solutions of both are indistinguishable within the dosage group and this no shielding of the solution colour is needed.

Primary Purpose:

Prevention

Official Title:

naNO-DENGUE: A Phase I Double-blind, Randomised, Vehicle-controlled, Dose-finding, Safety Study of a Synthetic Nanoparticle-based T-Cell Priming Peptide Vaccine Against Dengue Virus in Healthy Adults in Switzerland

Actual Study Start Date :

Aug 2, 2021

Actual Primary Completion Date :

Mar 11, 2022

Anticipated Study Completion Date :

Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Sham Comparator: LD Vehicle_GNP Low dose (LD) comparator (2.5nmol) - gold nanoparticle (14.8ug) without peptides	Biological: LD vehicle-GNP Two intradermal injections in the upper arm spaced 21 days apart
Experimental: LD PepGNP-Dengue Low dose (LD) peptide vaccine (2.5nmol) - gold nanoparticle (14.8ug) plus peptides	Biological: LD PepGNP-Dengue Two intradermal injections in the upper arm spaced 21 days apart
Sham Comparator: HD vehicle-GNP High dose (HD) comparator (7.5nmol) - gold nanoparticle (44.5ug) without peptides	Biological: HD vehicle-GNP Two intradermal injections in the upper arm spaced 21 days apart
Experimental: HD PepGNP-Dengue High dose (HD) peptide vaccine (7.5nmol) - gold nanoparticle (44.5ug) plus peptides	Biological: HD PepGNP-Dengue Two intradermal injections in the upper arm spaced 21 days apart

Outcome Measures

Primary Outcome Measures

Safety: Solicited local and systemic AEs [Through 14 days after prime or boost vaccination]
Number of volunteers overall and in each dose group with local or systemic vaccine reactogenicity, based on evaluation of solicited adverse events (AEs) recorded on subject memory aids or during clinical assessments
Safety: Unsolicited AEs [Study Days 0-180 or through termination visit, if terminated early]
Number of volunteers overall and in each dose group with unsolicited vaccine-associated adverse events (AEs) in each dose group
Safety: SAEs [Study Days 0-180 or through termination visit, if terminated early]
Number of volunteers overall and in each dose group with vaccine-associated serious adverse events (SAEs)
Safety: Adverse Events of Special Interest (AESI) [Study Days 0-180 or through termination visit, if terminated early]
Number of volunteers overall and in each dose group with vaccine-associated adverse events of special interest (AESIs)
Safety: Haemoglobin blood levels measurement [Days 0 (pre-prime dose), 7, 14, 21 (pre-booster dose), 28, 35, 90 and 180]
Number of volunteers overall and in each dose group with abnormal results in blood test regarding haemoglobin (Hb) measured in g/l. Reference range (from "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" - https://www.fda.gov/media/73679/download): Female 117-157 g/l / Male: 133-177 g/l) Anaemia reported as: GRADE 1: <117 - 100 g/l GRADE 2: <100 - 80 g/l GRADE 3: < 80 g/l
Safety: Alkaline phosphate blood levels measurement [Days 0 (pre-prime dose), 7, 14, 21 (pre-booster dose), 28, 35, 90 and 180]
Number of volunteers overall and in each dose group with abnormal results in blood test regarding Alkaline phosphate measured in U/L. Reference ranges (from "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" - https://www.fda.gov/media/73679/download): 36-120 U/L Elevation in Alkaline phosphate reported as: GRADE 1: 121 - 300 U/L GRADE 2: >300 - 600 U/L GRADE 3: >600 U/L

Secondary Outcome Measures

Immunogenicity: Proportion of participants with CD8-T cell specific to PepGNP-Dengue [Study Days 0-180 or through termination visit, if terminated early]
Specific CD8 T cell responses: Assessment of memory CD8 T cell response performed by primarily measuring: CCR7lo / CD62Llo / CD27- / CD45RA- Assessment of T and B cell responses: CD8 Activation-Induced Markers (AIM) CD8+/CD69+/CD137+ and CD8+/CD107a+ Activation markers: The induction of cell activation by ex vivo quantification of activation markers on various cell subsets by flow cytometry.
Proportion of participants becoming seropositive (antibodies against Dengue virus) [Study Days 0-180 or through termination visit, if terminated early]
Dengue serology rapid test: Serology to detect antibodies against the four dengue serotypes by rapid test Anti-DENV2 Ig: Serology to detect antibodies against natural DENV (lysate or inactivated viral particles), by ELISA

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Aged 18 to 45 years on the day of inclusion
Participant signed informed consent
Residing in Switzerland

Exclusion Criteria:

Participant is pregnant, lactating, or of childbearing potential
Participation in the 4 weeks preceding the first trial vaccination or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure
Receipt of any vaccine in the 4 weeks preceding the first trial vaccination (excepting influenza vaccination, which may be received up to 2 weeks before first study vaccine) or planned receipt of any vaccine in the 4 weeks following each trial vaccination.
Previous vaccination against Japanese encephalitis (JE), Yellow Fever (YF), or any dengue virus vaccine (monovalent or tetravalent) at any time in the past with either a trial vaccine or another vaccine (commercial or investigational) based on medical history
Self-reported or documented history of flavivirus (FV) infection (e.g. DENV, YF, WNV, JE, TBE), confirmed either clinically or serologically
Receipt of immunoglobulins, blood or blood-derived products in the past 3 months
Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy
Self-reported or documented seropositivity for human immunodeficiency virus (HIV), hepatitis B natural infection (HBcAb positive serology), or hepatitis C
Previous residence for more than 12 months in, or travel in the last 30 days to FV-endemic regions (excluding TBE and WNV)
At high risk for dengue infection during the trial
Known systemic hypersensitivity to any of the vaccine components (e.g. gold), or history of a life-threatening reaction to vaccines, or to a vaccine containing any of the same substances
Current alcohol abuse or drug addiction (reported or suspected)
Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
Thrombocytopenia or any coagulation disorder
Identified as an Investigator or employee of the Investigator or study centre with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study (i.e. in the employment of the Tropivac clinic or DFRI unit at Unisanté).
Refusal to be informed in the event that relevant results concerning the participant's health are revealed.

The following events constitute contraindications to the administration of the investigational product on the day of planned vaccination.

The participant must be followed until resolution of the event as with any medical event and may be considered for vaccination at a later date (maximum 14 days later) or withdrawn at the discretion of the Investigator. Delays due to these events do not constitute a protocol deviation.

Temperature of >37.5°C at the time of vaccination
Acute disease at the time of vaccination
If there is a clinical/epidemiological suspicion of COVID-19 (according to the clinician's judgement), the participant will be asked to first take a PCR/rapid test for SARS-CoV2, and the vaccination will be delayed until the result comes back negative and the symptoms have resolved.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Primary Care and Public Health, (Unisante)	Lausanne	Vaud	Switzerland	1004

Sponsors and Collaborators

Emergex Vaccines Holding Ltd.
Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland
University of Lausanne Hospitals