A Phase-I Study of a Nanoparticle-based Peptide Vaccine Against SARS-CoV-2

Study Overview
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Brief Summary
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This trial is Stage 2 of a 2-part adaptive trial. The study aims to investigate the safety of 2 doses of a T-cell priming specific cocktail of Coronaviruses peptides mounted on a gold nanoparticle. Note: Stage 1 of the 2-part adaptive trial, testing a specifically selected mix of Dengue virus peptides, commenced Aug 2021. This is now in follow up (NCT04935801).

Detailed Description
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Despite drastic quarantine measures, SARS-CoV-2 continues to propagate and threaten global economies and healthcare systems. There is universal consensus on the need for vaccination to protect against complications, reduce viral shedding and therefore prevent severe manifestation of disease and reduce hospitalisations. Coronavirus harbours the potential to become a seasonal disease. It is moving towards being a ''new flu'' with potential perennial circulation and continuously evolving Variants of Concern (VOCs), needing diverse vaccines to control it. The Global Vaccine Alliance, GAVI, has specifically advocated for vaccine diversity as a means to ensure equality and access as well as a means of maximising scalability. 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 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: The scale of the COVID-19 pandemic requires multiple vaccine candidates to ensure democratic and rapid access to protection by: Providing a range of vaccine choices tailored to variations in immunological profiles across demographics as well as suited to environments with various levels of resources (cold chain etc). Distributing and parallelizing manufacture, to speed up scale, avoid reagent stock limitations and dilute monopolies. The ability for SARS-CoV-2 to mutate, requires multiple vaccine candidates to ensure robust and sustainable protection. Vaccines with a range of epitopes and immune targets provide immunological diversity and reduce vulnerability to mutant escape. Nanotechnology fulfils the needs of a COVID vaccine by being a rapidly scalable and modular platform. Humoral immunity may be transient and insufficient against emerging variants of SARS-CoV-2. Cellular immunity against SARS-CoV-2 is lasting and associated with recovery in COVID-19. The proposed vaccine of this trial specifically seeks to diversify the immunological target response by carefully curating an MHC-I binding antigen cocktail from the SARS viruses ligandome and loading it onto a robust nanoparticle for controlled release and coupled T-cell immunostimulation. It also specifically seeks to avoid generating a humoral response, which has the potential to be transient and even detrimental in certain cases. For this second stage of the trial, the objectives are are follows: Primary: To evaluate the safety and reactogenicity of two intradermal injections of two different doses of the investigational COVID peptide T-cell inducing vaccine (PepGNP-Covid19) administered to healthy volunteers in Switzerland as a: candidate vaccine for the prevention of COVID-19 proof-of-concept for a rapidly scalable modular peptide vaccine platform. Secondary: To assess the evidence of a CD8 T-cell mediated immune response as a surrogate of protection against severe COVID-19 disease using a novel peptide set-point vaccine in healthy adults. To assess the presence of an antibody mediated response. For naNO-COVID, a total of 26 eligible participants will be randomised into the following groups: Group 1 (n=13) 10 low dose (LD) PepGNP-Covid19 (2.5nmol peptide +12.8ug) + 3 Comparator. Group 2 (n=13) 10 high dose (HD) PepGNP-Covid19 (7.5nmol + 38.3ug) + 3 Comparator. Thus, 20/26 vaccine and 6/26 Comparator controls. Allocations of vaccine vs bpC 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 second stage of a 2-stage study investigating the safety of 2 vaccines from a T-cell priming vaccine platform for emerging diseases. (stage 1 = naNO-Dengue, stage 2 = naNO-COVID).

Official Title
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A Phase-I, Double-blind, Randomized, Vehicle-controlled, Dose-finding, Safety Study of a Synthetic Nanoparticle-based, T Cell Priming Peptide Vaccine Against SARS-CoV-2 in Healthy Adults in Switzerland

Conditions
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Coronavirus, SARS-CoV-2 Infection, COVID-19

Intervention / Treatment
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* Biological: LD Vehicle-GNP
* Biological: LD PepGNP-Covid19
* Biological: HD Vehicle-GNP
* Biological: HD PepGNP-Covid19


Participation Criteria
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Eligibility Criteria
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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 (including vaccine against COVID) in the 4 weeks preceding the first trial vaccination (excluding influenza vaccination which may be received 2 weeks prior to the first vaccination), or planned receipt of any vaccine in the 4 weeks following each trial vaccination. Positive SARS-CoV2 test in the 4 weeks preceding the first trial vaccination. Receipt of immunoglobins, 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. Known systemic hypersensitivity to any of the vaccine components (e.g gold,) or history of a life-threatening reaction to vaccines. 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 Unisante). 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 (defined as the presence of a moderate or severe illness with or without fever according to investigator's judgment. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e. axillary temperature of ≤ 37.5°C).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: LD Vehicle GNP<br>Low dose (LD) comparator (2.5nmol) - gold nanoparticle (12.8ug) without peptides | Biological: LD Vehicle-GNP<br>* Two intradermal injections in the upper arm spaced 21 days apart<br>|
| Experimental: LD PepGNP-Covid19<br>Low dose (LD) peptide vaccine (2.5nmol) - gold nanoparticle (12.8ug) plus peptides | Biological: LD PepGNP-Covid19<br>* Two intradermal injections in the upper arm spaced 21 days apart<br>|
| Sham Comparator: HD Vehicle GNP<br>High dose (HD) comparator (7.5nmol) - gold nanoparticle (38.3ug) without peptides | Biological: HD Vehicle-GNP<br>* Two intradermal injections in the upper arm spaced 21 days apart<br>|
| Experimental: HD PepGNP-Covid19<br>High Dose (HD) peptide vaccine (7.5nmol) - gold nanoparticle (38.3ug) plus peptides | Biological: HD PepGNP-Covid19<br>* Two intradermal injections in the upper arm spaced 21 days apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Solicited local & systemic AEs | 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 | Through 14 days after prime or boost vaccination | 
| Safety: Unsolicited AEs | Number of volunteers overall and in each dose group with unsolicited vaccine-associated adverse events (AEs) in each dose group | Study Days 0-180 or through termination visit, if terminated early | 
| Safety: SAEs | Number of volunteers overall and in each dose group with vaccine-associated serious adverse events (SAEs) | Study Days 0-180 or through termination visit, if terminated early | 
| Safety: Adverse Events of Special Interest (AESI) | Number of volunteers overall and in each dose group with vaccine-associated adverse events of special interest (AESIs) | Study Days 0-180 or through termination visit, if terminated early | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity: Proportion of participants with CD8-T cell specific to PepGNP-Covid19 | Frequency of CD8+ T cells specific for individual CTL peptides by flow cytometry, using ex vivo MHC I dextramer staining and activation-induced markers (AIM) | Study Days 0-180 or through termination visit, if terminated early | 
| Proportion of participants becoming seropositive (antibodies against SARS-CoV-2) | Geometric mean titre and geometric mean fold rise of antibodies against SARS-CoV2 as determined by Enzyme-linked Immunosorbent Assay (ELISA) | Study Days 0-180 or through termination visit, if terminated early | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus, SARS-CoV-2, COVID-19, T-cell priming, COVID vaccine, nanoparticle, T-cell vaccine