A Phase-I Study of a Nanoparticle-based Peptide Vaccine Against Dengue Virus

• ClinicalTrials.gov Identifier: NCT04935801
• Recruitment Status: Completed
• First Posted: June 23, 2021
• Last Update Posted: December 5, 2022
• Sponsor: Emergex Vaccines Holding Ltd.
• Collaborators: Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland; University of Lausanne Hospitals
• Information provided by (Responsible Party): Emergex Vaccines Holding Ltd.

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:

1. 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.
2. As the SARS-CoV-2 pandemic devastates the world, the need for highly efficient and scalable vaccines is desperately required.
3. Peptide vaccines have high potential as a rapidly scalable modular platform for emerging diseases requiring targeted immunological responses.
4. 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:

1. candidate vaccine for the prevention of Dengue
2. proof-of-concept for a rapidly scalable modular peptide vaccine platform, which will be followed by a COVID-19 construct after interim analyses.

Secondary:

1. 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.
2. 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 nanoparticle-based peptide vaccine against Dengue (Master protocol) Stage 2: naNO-COVID A Phase-I study of a nanoparticle-based peptide vaccine against SARS-CoV2 (Sub-protocol)

Study Design

• Study Type: Interventional (Clinical Trial)
• 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 thus no shielding of the solution colour is needed.

• Primary Purpose: Prevention
• Official Title: naNO-DENGUE: A Phase I Double-blind, Randomized, 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: August 2, 2021
• Actual Primary Completion Date: March 11, 2022
• Actual Study Completion Date: September 15, 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 :

1. Safety: Solicited local & Systemic AEs [ Time Frame: 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
2. Safety: Unsolicited AEs [ Time Frame: 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
3. Safety: SAEs [ Time Frame: 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)
4. Safety: Adverse Events of Special Interest (AESI) [ Time Frame: 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)
5. Safety: Haemoglobin blood levels measurement [ Time Frame: Screening, Days 7, 14, 28, 35 ]

   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

6. Safety: Alkaline Phosphate Blood levels measurement [ Time Frame: Screening, Days 7, 14, 28, 35 ]

   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 :

1. Immunogenicity: Proportion of participants with CD8-T cell specific to PepGNP-Dengue [ Time Frame: Study Days 0-180 or through termination visit, if terminated early ]
   Frequency of CD8+ T cells specific peptides by cytometry ex vivo, using staining with dengue specific dextramers and activation-induced markers (AIM)
2. Proportion of participants becoming seropositive (antibodies against Dengue virus) [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Switzerland

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

Investigators

• Principal Investigator: Blaise Genton, Prof; Center for Primary Care and Public Health (Unisante), University of Lausanne, Switzerland

More Information

• Responsible Party: Emergex Vaccines Holding Ltd.
• ClinicalTrials.gov Identifier: NCT04935801
• Other Study ID Numbers: naNO-DENGUE
• First Posted: June 23, 2021
• Last Update Posted: December 5, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

The Investigators will be involved in writing and/or reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising from the study.

Apart from obvious flaws to the conduct of the study, which may preclude data publication, safety and efficacy data will be published under the supervision and authorization of PI and Sponsor.

Publication will include as much individual level data as possible to ensure reproducibility of results without compromising participant privacy.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Within 12 months of study completion
• Access Criteria: Peer-reviewed publication

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Emergex Vaccines Holding Ltd.:

Dengue; peptide vaccine; T-cell; nanoparticle; Dengue vaccine; T cell vaccine

Additional relevant MeSH terms:

Dengue; Arbovirus Infections; Vector Borne Diseases; Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral