Safety, Tolerability and Immunogenicity of Vaccine Candidate MVA-MERS-S

Study Overview
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Brief Summary
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The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially fatal disease with a reported lethality of up to 40% that is under tight epidemiologic control by the World Health Organization (WHO) and currently without registered prevention or treatment option. In this phase I first-in-human clinical trial, healthy volunteers in two different dose cohorts will be vaccinated twice with the candidate vaccine MVA-MERS-S. A subgroup will additionally receive a late booster vaccination. The aim of the study is to assess the safety and tolerability of the candidate vaccine and to characterize its immunogenicity.

Detailed Description
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The vaccine contains a Modified Vaccinia Virus Ankara (MVA) vector expressing the MERS-CoV spike glycoprotein (S). A total of 24 participants will receive the following vaccine regime: 12 participants will receive 10^7 plaque-forming units (PFU) of MVA-MERS-S on days 0 and 28. 12 participants will receive 10^8 PFU of MVA-MERS-S on days 0 and 28. Safety and immunogenicity data will be collected throughout the study, which concludes at day 180. Update March 2019: A subgroup of participants from both dose cohorts will receive a late booster immunization of 10^8 PFU MVA-MERS-S 12 months (+/- 4 months) after prime immunization.

Official Title
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An Open, Single Center Phase I Trial to Assess the Safety, Tolerability and Immunogenicity of Two Ascending Doses of the Candidate Vaccine MVA-MERS-S

Conditions
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MERS (Middle East Respiratory Syndrome)

Intervention / Treatment
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* Biological: vaccine candidate MVA-MERS-S


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant must not be enrolled before all inclusion criteria (including test results) are confirmed. Subjects meeting all of the criteria listed below will be included in the study: Ability to understand the subject information and to personally sign and date the informed consent to participate in the study, before completing any study related procedures. Provided written informed consent. Healthy male and female participants aged 18 - 55 years inclusive at the time of consent. The date of signing informed consent is defined as the beginning of the screening period. This inclusion criterion will only be assessed at the first screening visit. No clinically significant health problems as determined during medical history and physical examination at screening visit. Body weight in defined relation to height. Body mass index 18.5 - 30.0 kg/m2 and weight >50 kg at screening. Females of child-bearing potential who agree to apply effective contraception methods (defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly ) from at least 7 days prior to vaccination until the end of the study or females who are permanently sterilized (at least 6 weeks post-sterilization). Males who agree to apply effective contraception methods from day 0 through day 56. Be willing to refrain from blood donation during the course of the study. The subject is co-operative and available for the entire study. Exclusion Criteria: Participants are excluded from the study if any of the following criteria are met at screening or at day -1: Prior receipt of a MERS vaccine or MVA immunizations. Receipt of any vaccine in the 2 weeks prior to 1st trial vaccination (4 weeks for live vaccines) or planned receipt of any vaccine in the 3 weeks following the 2nd trial vaccination. Known allergy to the components of the MVA-MERS-S vaccine product as eggs, chicken proteins, and gentamycin or history of life-threatening reactions to vaccine containing the same substances. Participation in a clinical trial or use of an investigational product within 30 days or five times the half-life of the investigational drug -whichever is longer- prior to receiving the first dose within this study. Evidence in the subject's medical history or in the medical examination that might influence either the safety of the subject or the absorption, distribution, metabolism or excretion of the investigational product under investigation. Any positive result for human immunodeficiency virus (HIV)1/2 antibody, hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg) testing. Any confirmed or suspected immunosuppressive or immunodeficient condition, cytotoxic therapy in the previous 5 years, and/or diabetes. Participants with inflammatory, infectious and neuroinflammatory underlying disease which could cause an expected impairment of the blood brain barrier such as meningitis, multiple sclerosis, epilepsy, or Alzheimer's disease. Any chronic or active neurologic disorder, including migraines, seizures, and epilepsy, excluding a single febrile seizure as a child. Known history of Guillain-Barré Syndrome. Active malignancy or history of metastatic or hematologic malignancy. Suspected or known alcohol and/or illicit drug abuse within the past 5 years. Moderate or severe illness and/or fever >38°C within 1 week prior to vaccination. Administration of immunoglobulins and/or any blood products within the 120 days preceding study entry or planned administration during the study period. History of blood donation within 60 days of enrollment or plans to donate within the treatment phase (until the 2nd vaccination). Receipt of chronic (defined as more than 14 days) immune suppressants or other immune-modifying drugs within 6 months of study inclusion (screening). For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 0.5 mg/kg/day. Intranasal and topical steroids are allowed. Participants with skin lesions close to the injection site or active oral lesions will be excluded. Thrombocytopenia, contraindicating intramuscular vaccination based on investigator's judgment. Participants with a significant infection or known inflammation. History of relevant cardiovascular disorders or evidence of hyper- (sitting blood pressure systolic >140 or diastolic >90 mmHg) or hypotension (sitting blood pressure systolic <90 or diastolic <40 mmHg) at screening. Subjects who are known or suspected not to comply with the study directives. Any other significant finding that in the opinion of the investigator would increase the risk of the individual having an adverse outcome from participating in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccination with 10^7 PFU MVA-MERS-S<br>Vaccinations occur on days 0 and 28 A subgroup will additionally receive a late booster immunization with 10^8 PFU MVA-MERS-S 12 months (+/- 4 months) after prime immunization. | Biological: vaccine candidate MVA-MERS-S<br>* vaccination with MVA-MERS-S in two escalating dose regimes<br>|
| Experimental: Vaccination with 10^8 PFU MVA-MERS-S<br>Vaccinations occur on days 0 and 28 A subgroup will additionally receive a late booster immunization with 10^8 PFU MVA-MERS-S 12 months (+/- 4 months) after prime immunization. | Biological: vaccine candidate MVA-MERS-S<br>* vaccination with MVA-MERS-S in two escalating dose regimes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Solicited Local or Systemic Reactogenicity as Defined by the Study Protocol | The solicited local adverse events for this study include: Swelling, erythema, induration, hematoma and pain at site of injection The solicited systemic adverse events for this study include: Fever Chills Myalgia (described to the subject as generalized muscle aches) Arthralgia (described to the subject as generalized joint aches) Fatigue/Malaise Headache Gastrointestinal symptoms The reactogenicity (adverse events) will be assessed via a trained physician taking into account a patient diary. The severity of the adverse event will be measured as specified in the study protocol (grade 0=none, grade 1=mild, grade 2=moderate, grade 3=severe). The adverse event will furthermore be categorized in related vs. not related. | 14 days after each vaccination | 
| Percentage of Participants Who Experienced an Unsolicited Adverse Event | The unsolicited adverse events will be assessed via a trained physician taking into account a patient diary. The severity of the adverse event will be measured as specified in the study protocol (grade 0=none, grade 1=mild, grade 2=moderate, grade 3=severe). The adverse event will furthermore be categorized in related vs. not related. | 28 days after each vaccination | 
| Change of Mean C-reactive Protein (CRP) Levels (Measured in [mg/l]) From Baseline (Day -1 ) as Compared to the End of the Study (D180) | The safety laboratory measures include: - Clinical Chemistry: CRP in miligrams per liter [mg/l] | Throughout the study up to conclusion | 
| Change of Mean White Blood Cell (WBC) Counts (Measured in [Billion Cells/L]) From Baseline (Day -1) as Compared to the End of the Study (D180) | The safety laboratory measures include Hematology: WBC count in billions per liter [billion cells/L] | Throughout the study up to conclusion | 
| Percentage of Participants Experiencing a Serious Adverse Event up to Day 180 (Study Completion) | Serious adverse events are defined as any untoward medical occurrence (whether considered to be related to investigational medicinal product or not) that at any dose: results in death is life-threatening requires inpatient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity is a congenital abnormality/birth defect is an Important Medical Event, i.e., an event that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. | Throughout the study up to conclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity: Number of Participants Who Seroconverted Throughout the Study (up to Study Completion at Day 180) | Humoral immunity: The magnitude of MVA-MERS-S antibody responses as assessed by neutralization assay and ELISA. | Throughout the study up to conclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine, clinical phase 1, modified vaccinia Ankara vector, MERS-CoV