Phase II Study to Evaluate Safety and Immunogenicity of a Chikungunya Vaccine

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the immunogenicity and safety of a novel vaccine against Chikungunya virus after one or two vaccinations by comparison of two different dose levels.

Detailed Description
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This is a double blinded, block-randomized, active- and placebo controlled, phase II trial, comparing two dose levels by assessing immunogenicity, safety and tolerability of MV-CHIK (a novel vaccine against Chikungunya virus). Healthy male and female subjects aged 18-55 years will be randomized to one of six treatment groups (A, B, C. D, M1 or M2) differing in dosage and scheduling of vaccinations. Group A-D will be split in one arm receiving MV-CHIK and one control-arm receiving Priorix®. All subjects of group A. B, C and D will receive three i.m. injections on study day 0, 28 and 196. Subjects of group A and B will receive MV-CHIK low dose or control-vaccine Priorix® (or equivalent measles vaccine) and subjects of group C and D will be treated with MV-CHIK high dose or control-vaccine (Priorix® or equivalent measles vaccine). All subjects of group A, B, C and D additionally will be randomized to one of two treatment sequences: group A and C will receive MV-CHIK or control-vaccine Priorix® on study day 0 and 28, followed by placebo on day 196, and group B and D receive placebo on day 0 and MV-CHIK or Priorix® on day 28, followed by an additional vaccination of the same product on day196 (boosting vaccination). All subjects of the measles booster group M1 and M2 will receive five i.m. injections on study day -28, 0, 28, 168 and 196. The first vaccination will be Priorix® (or equivalent measles vaccine) on study day -28. Group M1 will receive MV-CHIK vaccinations on day 0 and day 28 and placebo on day 168 and 196. Group M2 will receive placebo on day 0 and 28 and MV-CHIK on day 168 and on day 196. All subjects will be followed for safety and immunogenicity evaluation until day 224. Study duration per subject is estimated to be 33-37 weeks ( 8 months), respectively.

Official Title
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Double Blinded, Randomized, Priorix®- and Placebo-controlled, Trial to Evaluate the Optimal Dose of MV-CHIK Vaccine (Against Chikungunya Virus) in Regard to Immunogenicity, Safety and Tolerability in Healthy Volunteers

Conditions
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Chikungunya Virus Infection

Intervention / Treatment
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* Biological: MV-CHIK low dose
* Biological: MV-CHIK high dose
* Biological: Priorix®
* Biological: physiological saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent obtained before any trial-related activities. Ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to cooperate with the investigator and to comply with the requirements of the entire study Available for the duration of the trial Healthy men or women aged >18 and <55 years In female subjects either childbearing potential terminated by surgery or one year post-menopausal, or a negative urine pregnancy test during screening and the willingness not to become pregnant during the entire study period by practicing reliable methods of contraception as specified in protocol Normal findings in medical history and physical examination or the investigator considers all abnormalities to be clinically irrelevant Normal laboratory values or the investigator considers all abnormalities to be clinically irrelevant (unless otherwise specified in exclusion criteria) Exclusion Criteria: Participation in another clinical study within the past month in which the subject has been exposed to an investigational product (pharmaceutical product or placebo or device) or planned concurrent participation in another clinical study during the study period History of immunodeficiency, known human immunodeficiency virus (HIV) infection, current hepatitis B/C infection, Drug addiction including alcohol dependence Inability or unwillingness to avoid more than the usual intake of alcohol during the 48 hours after vaccination (not more than 20g alcohol per day, which equals 0.5 L beer or 0.25 L of wine) Persons who are accommodated in an institution on court or official order. Persons in direct relationship with the sponsor, an Investigator or other study site staff. Direct relationship includes relatives or close dependents (children, spouse/partner, siblings or parents), as well as employees (site or sponsor). Non-study licensed vaccines: vaccination within 4 weeks prior to first vaccination or planning to receive any non-study vaccine during the study period. Measles vaccination or booster within the last 5 years or during the clinical study Prior receipt of any Chikungunya vaccine Blood donations during 1 month prior to Screening Visit and throughout the study Recent infection (within 1 week prior to Screening Visit) (If non-serious, can be basis for temporary deferral) Relevant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, hematological, endocrine, inflammatory or neurological diseases, that in the opinion of the investigator may interfere with the aim of the study History of neoplastic disease (excluding non-melanoma skin cancer that was successfully treated) within the past 5 years or a history of any hematological malignancy. History of autoimmune disease (e.g. rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroid disease). History of moderate or severe arthritis or arthralgia within the past 3 months prior to Screening Visit. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand and cooperate with the study protocol. History of severe adverse reactions to vaccine administration, including anaphylaxis and related symptoms, such as urticaria, respiratory difficulty, angioedema and abdominal pain to vaccines, or history of allergic reaction likely to be exacerbated by any component of the vaccine. History of anaphylaxis to drugs or major allergic reactions in general, which the investigator considers may compromise the safety of the volunteers Clinically relevant abnormal laboratory values indicative of physical illness Hematology: hemoglobin, hematocrit, erythrocyte count, differential white blood count, platelets Chemistry: creatinine (≥1.7 mg/dL), potassium, sodium, calcium, aspartate transaminase/alanine aminotransferase (AST/ALT) ≥ 2.6 upper limit of normal (ULN), alkaline phosphatase, bilirubin Coagulation parameter: prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen according to the evaluation of the principle investigator Urinalysis according to the evaluation of the principle investigator Use of medication during 2 weeks before the first vaccination and throughout the study, which the investigator considers may affect the validity of the study except hormonal contraception in female subjects; prior to taking any medication during 72 h prior to the first vaccination, the study center should be consulted. Immunosuppressive drugs: use of corticosteroids (excluding topical preparations) or immunosuppressive drugs within 30 days prior to vaccination, or anticipated use during the trial. Receipt of blood products or immunoglobulins within 120 days prior to Screening Visit or anticipated receipt of any blood products or immunoglobulin during the trial. Pregnancy (positive pregnancy test at screening or during study phase), lactation or unreliable contraception in female subjects with child-bearing potential (for details please refer to section 8.3.6) Subjects with any condition which in the opinion of the investigator makes the subject unsuitable for inclusion Individuals who are living and/or working with severely immunocompromised people, children under 15 months old or pregnant women. Inability or unwillingness to provide informed consent and to abide by the requirements of the study Refusal to allow storage of specimens for future research. Regular blood plasma donations

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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group A; MV-CHIK low<br>60 subjects will receive i.m. vaccinations with MV-CHIK low dose (5xE4 (± 0.5 log) TCID50 per 0.3 mL) on study day 0 and 28, placebo on day 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: MV-CHIK low dose<br>* recombinant measles virus vaccine expressing Chikungunya virus antigens, powder for suspension for injection, 5xE4 (± 0.5 log) TCID50/dose<br>* Other names: vaccine against Chikungunya;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Active Comparator: Treatment Group A/C; Priorix®<br>20 subjects will receive i.m. vaccinations with Priorix® on study day 0 and 28, placebo on day 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: Priorix®<br>* lyophilized mixed preparation containing the attenuated Schwarz measles virus strain, the RIT 4385 strain of mumps virus (derived from the Jeryl Lynn strain) and the Wistar RA 27/3 rubella virus strain. Powder and solvent for suspension for injection<br>* Other names: vaccine against Measles, Mumps and Rubella;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Experimental: Treatment Group B; MV-CHIK low<br>60 subjects will receive i.m. vaccinations with placebo on study day 0. MV-CHIK low dose (5xE4 (± 0.5 log) TCID50 per 0.3 mL) on day 28 and MV-CHIK boosting dose on day 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: MV-CHIK low dose<br>* recombinant measles virus vaccine expressing Chikungunya virus antigens, powder for suspension for injection, 5xE4 (± 0.5 log) TCID50/dose<br>* Other names: vaccine against Chikungunya;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Active Comparator: Treatment Group B/D; Priorix®<br>20 subjects will receive i.m. vaccinations with placebo on study day 0, Priorix® on day 28 and one boosting dose with Priorix® on day 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: Priorix®<br>* lyophilized mixed preparation containing the attenuated Schwarz measles virus strain, the RIT 4385 strain of mumps virus (derived from the Jeryl Lynn strain) and the Wistar RA 27/3 rubella virus strain. Powder and solvent for suspension for injection<br>* Other names: vaccine against Measles, Mumps and Rubella;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Experimental: Treatment Group C; MV-CHIK high<br>60 subjects will receive i.m. vaccinations with MV-CHIK high dose (5xE5 (± 0.5 log) TCID50 per 0.3 mL) on study day 0 and 28, placebo on day 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: MV-CHIK high dose<br>* recombinant measles virus vaccine expressing Chikungunya virus antigens, powder for suspension for injection; 5xE5 (± 0.5 log) TCID50/dose<br>* Other names: vaccine against Chikungunya;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Experimental: Treatment Group D; MV-CHIK high<br>60 subjects will receive i.m. vaccinations with placebo on study day 0, MV-CHIK high dose (5xE5 (± 0.5 log) TCID50 per 0.3 mL) on study day 28 and MV-CHIK boosting dose on day 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: MV-CHIK high dose<br>* recombinant measles virus vaccine expressing Chikungunya virus antigens, powder for suspension for injection; 5xE5 (± 0.5 log) TCID50/dose<br>* Other names: vaccine against Chikungunya;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Experimental: Measles Booster Group 1<br>20 subjects will receive i.m. vaccinations with Priorix® on study day -28, MV-CHIK on day 0 and 28 and placebo on day 168 and 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: MV-CHIK low dose<br>* recombinant measles virus vaccine expressing Chikungunya virus antigens, powder for suspension for injection, 5xE4 (± 0.5 log) TCID50/dose<br>* Other names: vaccine against Chikungunya;Biological: Priorix®<br>* lyophilized mixed preparation containing the attenuated Schwarz measles virus strain, the RIT 4385 strain of mumps virus (derived from the Jeryl Lynn strain) and the Wistar RA 27/3 rubella virus strain. Powder and solvent for suspension for injection<br>* Other names: vaccine against Measles, Mumps and Rubella;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|
| Experimental: Measles Booster Group 2<br>20 subjects will receive i.m. vaccinations with Priorix® on study day -28, placebo on day 0 and 28 and MV-CHIK on day 168 and 196. Physical examinations, vital signs, pregnancy tests for females, inquiry of adverse events and collection of immunogenicity blood samples will be performed during all visits. | Biological: MV-CHIK low dose<br>* recombinant measles virus vaccine expressing Chikungunya virus antigens, powder for suspension for injection, 5xE4 (± 0.5 log) TCID50/dose<br>* Other names: vaccine against Chikungunya;Biological: Priorix®<br>* lyophilized mixed preparation containing the attenuated Schwarz measles virus strain, the RIT 4385 strain of mumps virus (derived from the Jeryl Lynn strain) and the Wistar RA 27/3 rubella virus strain. Powder and solvent for suspension for injection<br>* Other names: vaccine against Measles, Mumps and Rubella;Biological: physiological saline solution<br>* sterile physiological saline solution 0.9% used as placebo<br>* Other names: 0.9% sodium chloride (NaCl);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Anti-chikungunya Antibody Titers on Day 56 (28 Days Post Immunisation) Confirmed by Plaque Reduction Neutralization Test (PRNT50) | Immunogenicity on day 56 confirmed by the presence of functional anti-chikungunya antibodies as determined by the plaque reduction neutralization test (PRNT50). This means immunogenicity 28 days after primary immunization regime, comprising one or two vaccinations. | Study day 56 (28 days after one or two vaccinations depending on treatment group). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Anti-Chikungunya Antibody Titers on Days 0, 28, 196 and 224 (M1/M2 Groups Day 168) Confirmed by Plaque Reduction Neutralization Test (PRNT50) | Evaluation of immunogenicity on day 0, 28, 196 and 224; additionally for group M1 and M2 on day 168 as confirmed by the presence of functional anti-chikungunya antibodies, determined by the plaque reduction neutralization test (PRNT50). | Baseline until study day 224 | 
| Measurement of Anti-measles Antibody Titer by Enzyme Linked Immunosorbent Assay | Determination of anti-measles antibodies on day 0, 28, and 56; additionally for group M1 and M2 on day -28 by enzyme linked immunosorbent assay (ELISA). | Baseline until study day 56 | 
| Number of Participants With Solicited Local and Systemic Adverse Events | Evaluation of solicited local and systemic adverse events as recorded in the subjects' diaries for 7 days after each vaccination. As per the protocol, adverse events were analyzed per treatment group but were not assessed with respect to individual vaccinations. | Solicited adverse events were recorded for 7 days after each vaccination | 
| Number of Participants Who Experienced Treatment Emergent Adverse Events | Evaluation of all treatment emergent adverse events (TEAEs) occurred throughout the clinical study. Clinically relevant abnormal safety laboratory values were recorded as TEAEs. As per the protocol, adverse events were analyzed per treatment group but were not assessed with respect to individual vaccinations. | First vaccination until study day 224 | 
| Number of Participants With Shedding of Live Recombinant Virus in Urine Until Day 196 | Shedding was observed in a subset of subjects at one Austrian study site, by qualitative determination of live recombinant measles virus in urine by polymerase chain reaction (PCR). | Baseline until study day 196; assessed on days 0, 7, 10, 14, 28 and 196 | 
| Number of Participants With Shedding of Live Recombinant Virus in Saliva Until Day 196 | Shedding was observed in a subset of subjects at one Austrian study site, by qualitative determination of live recombinant measles virus in saliva by polymerase chain reaction (PCR). | Baseline until study day 196; assessed on days 0, 7, 10, 14, 28 and 196 | 
| Chikungunya Virus Specific T Cell Responses | Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood to determine functional IL-2-producing T cells on day 0, 28, 56 and 224 in a subset of subjects. ELISpots were performed using peptides covering the CHIK proteins E1, E2 and C for re-stimulation, thereby producing three values per sample representing the number of spots per 1 x 10^6 PBMCs. If one or more of the three values was greater than 50, the sample was considered positive and the highest of the three values was used in the analysis. If all three values were below 50, the sample was considered negative and a value of 0.0 was used for analysis. | Baseline until study day 224 | 
| Immunogenicity Confirmed by the Presence of Humoral Anti-chikungunya Antibodies, Determined by Enzyme Linked Immunosorbent Assay (ELISA) | Evaluation of immunogenicity mediated by serum IgG antibodies against Chikungunya on days 0, 28, 196 and 224; additionally for group M1 and M2 on day 168, determined by enzyme linked immunosorbent assay (ELISA). | Baseline until study day 224; assessed on days 0, 28, 168, 196 and 224 | 
| Functional Anti-chikungunya Antibody Titers on Day 56 (28 Days Post Immunization) by Baseline Measles Titer | To determine the potential impact of pre-existing antibodies against measles on MV-CHIK immunogenicity, participants from treatment Groups A to D were divided into quartiles according to serum IgG concentrations against measles virus on Day 0. Functional anti-chikungunya antibodies as determined by PRNT50 were compared between groups. | Study day 56 (28 days after one or two vaccinations depending on treatment group) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chikungunya, infectious disease