Immunity and Safety of Covid-19 Synthetic Minigene Vaccine

Study Overview
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Brief Summary
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In December 2019, viral pneumonia caused by a novel beta-coronavirus (Covid-19) broke out in Wuhan, China. Some patients rapidly progressed and suffered severe acute respiratory failure and died, making it imperative to develop a safe and effective vaccine to treat and prevent severe Covid-19 pneumonia. Based on detailed analysis of the viral genome and search for potential immunogenic targets, a synthetic minigene has been engineered based on conserved domains of the viral structural proteins and a polyprotein protease. The infection of Covid-19 is mediated through binding of the Spike protein to the ACEII receptor, and the viral replication depends on molecular mechanisms of all of these viral proteins. This trial proposes to develop and test innovative Covid-19 minigenes engineered based on multiple viral genes, using an efficient lentiviral vector system (NHP/TYF) to express viral proteins and immune modulatory genes to modify dendritic cells (DCs) and to activate T cells. In this study, the safety and efficacy of this LV vaccine (LV-SMENP) will be investigated.

Detailed Description
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Background: The 2019 discovered new coronavirus, Covid-19, is an enveloped positive strand single strand RNA virus. The number of Covid-19 infected people has increased rapidly and WHO has warned that the spread of Covid-19 may soon become pandemic and have disastrous outcomes. Covid-19 could pose a serious threat to human health and global economy. There is no vaccine available or clinically approved antiviral therapy as yet. This study aims to evaluate the safety and efficacy of treating Covid-19 infections with a novel lentiviral based DC and T cell vaccines. Objective: Primary study objectives: Injection and infusion of LV-SMENP DC and antigen-specific cytotoxic T cell vaccines to healthy volunteers and Covid-19 infected patients to evaluate the safety. Secondary study objectives: To evaluate the anti- Covid-19 efficacy of the LV-SMENP DC and antigen-specific cytotoxic T cell vaccines. Design: Based on the genomic sequence of the new coronavirus Covid-19, select conserved and critical structural and protease protein domains to engineer lentiviral SMENP minigenes to express Covid-19 antigens. LV-SMENP-DC vaccine is made by modifying DC with lentivirus vectors expressing Covid-19 minigene SMENP and immune modulatory genes. CTLs will be activated by LV-DC presenting Covid-19 specific antigens. LV-DC vaccine and antigen-specific CTLs are prepared in 7 21 days. Subject will receive total 5x10^6 cells of LV-DC vaccine and 1x10^8 antigen-specific CTLs via sub-cutaneous injection and IV infusion, respectively. Patients are followed weekly for one month after the infusion, monthly for 3 months, and then every 3 months until the trial ends.

Official Title
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Phase I/II Multicenter Trial of Lentiviral Minigene Vaccine (LV-SMENP) of Covid-19 Coronavirus

Conditions
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Pathogen Infection Covid-19 Infection

Intervention / Treatment
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* Biological: Injection and infusion of LV-SMENP-DC vaccine and antigen-specific CTLs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Laboratory (RT-PCR) confirmed Covid-19 infection in throat swab and/or sputum and/or lower respiratory tract samples; The interval between the onset of symptoms and randomized is within 7 days. The onset of symptoms is mainly based on fever. If there is no fever, cough or other related symptoms can be used; White blood cells ≥ 3,500 / μl, lymphocytes ≥ 750 / μl; Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or tuberculosis (TB) test is negative; Sign the Informed Consent Form on a voluntary basis; Exclusion Criteria: Subject infected with HCV (HCV antibody positive), HBV (HBsAg positive), HIV (HIV antibody positive), or HTLV (HTLV antibody positive). Subject is albumin-intolerant. Subject with life expectancy less than 4 weeks. Subject participated in other investigational somatic cell therapies within past 30 days. Subject with positive pregnancy test result. Researchers consider unsuitable.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pathogen-specific DC and CTLs<br>Patients will receive approximately 5x10^6 LV-DC vaccine and 1x10^8 CTLs via sub-cutaneous injections and iv infusions, respectively. | Biological: Injection and infusion of LV-SMENP-DC vaccine and antigen-specific CTLs<br>* Patients will receive approximately 5x10^6 LV-DC vaccine and 1x10^8 CTLs via sub-cutaneous injections and iv infusions, respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement based on the 7-point scale | A decline of 2 points on the 7-point scale from admission means better outcome. The 7-category ordinal scale that ranges from 1 (discharged with normal activity) to 7 (death). | 28 days after randomization | 
| Lower Murray lung injury score | Murray lung injury score decrease more than one point means better outcome. The Murray scoring system range from 0 to 4 according to the severity of the condition. | 7 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | Number of deaths during study follow-up | Measured from Day 0 through Day 28 | 
| Duration of mechanical ventilation | Duration of mechanical ventilation use in days. Multiple mechanical ventilation durations are summed up. | Measured from Day 0 through Day 28 | 
| Duration of hospitalization | Days that a participant spent at the hospital. Multiple hospitalizations are summed up. | Measured from Day 0 through Day 28 | 
| Proportion of patients with negative RT-PCR results | Proportion of patients with negative RT-PCR results of virus in upper and/or lower respiratory tract samples. | 7 and 14 days after randomization | 
| Proportion of patients in each category of the 7-point scale | Proportion of patients in each category of the 7-point scale, the 7-category ordinal scale that ranges from 1 (discharged with normal activity) to 7 (death). | 7,14 and 28 days after randomization | 
| Proportion of patients with normalized inflammation factors | Proportion of patients with different inflammation factors in normalization range. | 7 and 14 days after randomization | 
| Frequency of vaccine/CTL Events | Frequency of vaccine/CTL Events | Measured from Day 0 through Day 28 | 
| Frequency of Serious vaccine/CTL Events | Frequency of Serious vaccine/CTL Events | Measured from Day 0 through Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lentiviral vector, LV-DC vaccine, Covid-19 CTL