Safety and Immunogenicity of a Novel Vaccine Formulation MV-ZIKA-RSP (V187-001)

Phase 1

Completed

Conditions: Zika Virus Infection

Interventions: Biological: Two MV-ZIKA-RSP vaccination (low dose)
Other: Two placebo injection
Biological: Two MV-ZIKA-RSP vaccinations (high dose)
Biological: One MV-ZIKA-RSP vaccination (high dose) and one placebo

Registration Number: NCT04033068

Lead Sponsor: Themis Bioscience GmbH

Brief Summary: This study is designed to investigate, at first, safety and tolerability of a novel liquid vaccine formulation named MV-ZIKA-RSP, in healthy adults aged 18 to 55 years

Detailed Description: This is an observer-blinded, block-randomized, dose-finding, phase I trial, comparing different dose levels of MV-ZIKA-RSP to evaluate the safety, tolerability, and immunogenicity, of this novel ZIKA-RSP vaccine. Placebo (physiological saline solution) will be applied to blind the different treatment schedules.

After the screening procedures, 48 healthy male and female volunteers aged 18-55 years will be randomly assigned to one of four treatment groups (A, B, C or D). Participants will be assessed for immunogenicity on days 0, 28 and 56 (treatment period), as confirmed by the presence of functional anti-zika-rsp antibodies determined by (PRNT50) and by ELISA, at the same time safety will be also assessed. After the treatment period, participants will be called by phone (day 182) for evaluation of safety follow-up.

The investigator and site personnel assessing AEs, all participants, as well as one of the sponsor's representatives involved in the monitoring and conduct of the study will be blinded to which vaccine was administered. Only the unblinded monitor, site personnel performing randomization, preparation and administration of IMP will be unblinded.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 48

Inclusion Criteria

Signed informed consent obtained before any trial-related activities
Healthy men or women aged 18 to 55 years on the day of consenting
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
All female participants must have a negative urine pregnancy serum pregnancy test at screening
Willingness not to become pregnant or to father a child during the entire study period by practising reliable methods of contraception as specified in protocol section 8.11.4
Availability during the duration of the trial
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 (including exposure to an investigational medicinal product or device) within one month before the screening visit or planned concurrent participation in another clinical study before completion of the treatment period (day 56)
History of immunodeficiency, known human immunodeficiency virus (HIV) infection or current hepatitis B/C infection
Strong anamnestic evidence for or confirmed the history of or current infection with Zika- or Dengue-virus
History of drug addiction including alcohol dependence within the last 2 years
Inability or unwillingness to avoid intake of more than around 20g alcohol per day during 48 hours after each vaccination (equals roughly 0.5 L beer or 0.25 L of wine)
Vaccination within 4 weeks prior to first vaccination or planning to receive any non-study vaccine until the end of the treatment period (day 56)
Prior receipt of any Zika or Chikungunya vaccine
History of moderate or severe arthritis or arthralgia within the past 3 months prior to Screening Visit
Recent infection within 1 week prior to Screening Visit (possibility of deferral)
Blood donations including plasma donations, 90 days prior to Screening Visit and anticipated blood, plasma, tissue, sperm or organ donation, throughout the study until the end of the treatment period (day 56)
Clinically relevant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine, inflammatory, autoimmune or neurological diseases or clinically relevant abnormal laboratory values, 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 haematological malignancy
Behavioural, cognitive, or psychiatric condition 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 other allergic reactions, which the investigator considers compromising the safety of the volunteer
Abnormal laboratory values which, at the discretion of the investigator should lead to the exclusion of the subject
Use of medication during 2 weeks before the first vaccination and throughout the study, which the investigator considers affecting the validity of the study, except hormonal contraception or hormonal replacement therapy in female participants. (Prior to taking any medication within 72 h before study vaccination, the subject should consult the investigator)
Use of immunosuppressive drugs like corticosteroids (excluding topical preparations) within 30 days prior to first IMP administration, or anticipated use until completion of the end of treatment visit Receipt of blood products or immunoglobulins within 120 days prior to the Screening Visit or anticipated receipt of any blood product or immunoglobulin before completion of the treatment period (day 56)
Pregnancy (positive pregnancy test at screening or during the treatment period) or lactation at screening, or planning to become pregnant during the treatment period
Unreliable contraception methods (for details please refer to protocol section 8.11.4)
Persons in a direct relationship with the sponsor, an investigator or other study team members. Direct dependent relationships include close relatives (i.e. children, parents, partner/spouse, siblings) as well as employees of the study site or the sponsor

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Two MV-ZIKA-RSP vaccination (low dose)	Two MV-ZIKA-RSP vaccination (low dose)	14 Participants will receive MV-ZIKA-RSP 2,5 x10E4 /dose on day 0 and day 28
Two placebo injection	Two placebo injection	8 Participants will receive placebo on day 0 and placebo on day 28
Two MV-ZIKA-RSP vaccinations (high dose)	Two MV-ZIKA-RSP vaccinations (high dose)	14 Participants will receive MV-ZIKA-RSP 1 x10E5/dose on day 0 and day 28
One MV-ZIKA-RSP vaccination (high dose) and one placebo	One MV-ZIKA-RSP vaccination (high dose) and one placebo	12 Participants will receive MV-ZIKA-RSP 1 x10E5/dose on day 0 and placebo on day 28

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced an Adverse Event (AE) up to Day 56	Up to Day 56	An AE is any untoward medical occurrence in a participant to whom an investigational medicinal product has been administered, not necessarily caused by or related to that product. As specified by the protocol, the percentage of participants who experience an AE up to study Day 56 was presented.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced an Unsolicited AE up to Day 182	Up to Day 182	An AE is any untoward medical occurrence in a participant to whom an investigational medicinal product has been administered, not necessarily caused by or related to that product. Unsolicited or spontaneous AEs were recorded in a diary by the participant and verified by the investigator. As specified by the protocol, the percentage of participants who experienced an unsolicited AE up to study Day 182 was presented.
GMT of Anti-ZIKA-RSP Antibodies by Enzyme Linked Immunosorbent Assay (ELISA) on Days 0, 28 and 56	Day 0, Day 28 and Day 56	The induction of functional anti-ZIKA-RSP antibodies by V187 was investigated in sera from participants by means of Immunoglobulin G (IgG) ELISA, an immunoassay that quantifies anti-ZIKA-RSP IgG. As specified by the protocol, the GMT of anti-ZIKA-RSP antibodies by ELISA on Day 0 (first dose), Day 28 (second dose) and Day 56 (follow-up assessment) was presented. Values below the LLOQ were set to the half of the true LLOQ value and values above the ULOQ were set to the true ULOQ value for calculations.
T-Cell Immune Response Assessed by Number of Spot Forming Cells (SFC) Per Million Peripheral Blood Mononuclear Cells (PBMCs) Measured by Interferon (IFN)-γ Enzyme-linked Immune Adsorbent Spot (ELISpot) Assay on Day 56	Day 56	Immune response mediated by functional T-cells was investigated using an IFNγ enzyme-linked immune adsorbent spot (ELISpot) assay. This is an immunoassay that quantifies IFNγ producing cells by assessing the number of SFCs per 10\^6 PBMCs stimulated with a peptide pool containing the viral protein prM\*; a precipitate forms and appears as spots at the sites of cytokine localization, with each individual spot representing an individual cytokine-secreting cell. As specified by the protocol, median of the number of IFNγ SFCs per 10\^6 PBMCs on Day 56 was presented. Values below the LLOQ were set to the half of the true LLOQ value and values above the ULOQ were set to the true ULOQ value for calculations.
T-Cell Immune Response Assessed by Number of SFC Per Million PBMCs Measured by Interleukin-2 (IL-2) ELISpot Assay on Day 56	Day 56	Immune response mediated by functional T-cells was investigated using an IL-2 ELISpot assay. This is an immunoassay that quantifies IL-2 producing cells by assessing the number of SFCs per 10\^6 PBMCs stimulated with a peptide pool containing the viral protein prM\*; a precipitate forms and appears as spots at the sites of cytokine localization, with each individual spot representing an individual cytokine-secreting cell. As specified by the protocol, median of the number of IL-2 SFCs per 10\^6 PBMCs on Day 56 was presented. Values below the LLOQ were set to the half of the true LLOQ value and values above the ULOQ were set to the true ULOQ value for calculations.
Laboratory Parameter (Hematology): Concentration of Hematocrit on Days 28 and 56	Day 28 and Day 56	Hematological parameters were investigated in blood samples from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of hematocrit on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Percentage of Participants Who Experienced a Solicited AE up to Day 182	Up to Day 182	An AE is any untoward medical occurrence in a participant to whom an investigational medicinal product has been administered, not necessarily caused by or related to that product. Solicited AEs include local solicited AEs (e.g. injection site pain, tenderness, erythema/redness, swelling, itching and induration) and systemic solicited AEs (e.g. nausea, vomiting, arthralgia, headache, fatigue, myalgia, fever, pain in limb, rash and flu-like symptoms). Solicited AEs were recorded in a diary by the participant and verified by the investigator. As specified by the protocol, the percentage of participants who experience a solicited AE up to study Day 182 was presented.
Geometric Mean Titer (GMT) of Anti-ZIKA-RSP (Zikavirus Recombinant Subviral Particle) Antibodies by Virus Neutralization Test (VNT) on Days 0, 28 and 56	Day 0, Day 28 and Day 56	The induction of functional anti-ZIKA-RSP antibodies by V187 was investigated in sera from participants by means of a VNT, an immunoassay that detects and quantifies antibodies in serum samples that can neutralize infectious Zika virions. As specified by the protocol, the GMT of anti-ZIKA-RSP antibodies by the VNT on Day 0 (first dose), Day 28 (second dose) and Day 56 (follow-up assessment) was presented. Values below the lower limit of quantification (LLOQ) were set to the half of the true LLOQ value and values above the upper limit of quantification (ULOQ) were set to the true ULOQ value for calculations.
Laboratory Parameters (Clinical Chemistry): Concentration of Alanine Aminotransferase, Alkaline Phosphatase and Aspartate Aminotransferase on Days 28 and 56	Day 28 and Day 56	Clinical chemistry parameters were investigated in sera from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameters (Clinical Chemistry): Concentration of Sodium, Calcium and Potassium on Days 28 and 56	Day 28 and Day 56	Clinical chemistry parameters were investigated in sera from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of sodium, calcium and potassium on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameter (Urinalysis): Specific Gravity on Days 28 and 56	Day 28 and Day 56	Urinalysis parameters were investigated in urine samples from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the specific gravity on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameters (Hematology): Concentration of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets on Days 28 and 56	Day 28 and Day 56	Hematological parameters were investigated in blood samples from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameters (Urinalysis): Percentage of Participants Negative for Bilirubin, Erythrocytes, Ketones, Leukocytes, Nitrite and Protein on Days 28 and 56	Day 28 and Day 56	Urinalysis parameters were investigated in urine samples from participants by means of clinical laboratory assays and evaluated by the investigator. Bilirubin, erythrocytes, ketones, leukocytes, nitrite and protein levels were defined as negative by the local laboratory and reported at the study site. As specified by the protocol, the percentage of participants negative for bilirubin, erythrocytes, ketones, leukocytes, nitrite and protein on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameters (Urinalysis): Percentage of Participants Normal for Glucose and Urobilinogen on Days 28 and 56	Day 28 and Day 56	Urinalysis parameters were investigated in urine samples from participants by means of clinical laboratory assays and evaluated by the investigator. Glucose and urobilinogen were defined as normal by the local laboratory and reported at the study site. As specified by the protocol, the percentage of participants normal for glucose and urobilinogen on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Percentage of Participants Who Experienced a Serious Adverse Event (SAE) up to Day 182	Up to Day 182	An SAE is any untoward medical occurrence that results in death, is life-threatening, requires or prolongs existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect or is another important medical event deemed as much by medical or scientific judgement. As specified by the protocol, the percentage of participants who experience an SAE up to study Day 182 was presented.
Laboratory Parameter (Hematology): Concentration of Erythrocytes on Days 28 and 56	Day 28 and Day 56	Hematological parameters were investigated in blood samples from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of erythrocytes on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameter (Hematology): Concentration of Hemoglobin on Days 28 and 56	Day 28 and Day 56	Hematological parameters were investigated in blood samples from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of hemoglobin on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameters (Clinical Chemistry): Concentration of Bilirubin and Creatinine on Days 28 and 56	Day 28 and Day 56	Clinical chemistry parameters were investigated in sera from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the concentration of bilirubin and creatinine on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.
Laboratory Parameter (Urinalysis): pH on Days 28 and 56	Day 28 and Day 56	Urinalysis parameters were investigated in urine samples from participants by means of clinical laboratory assays and evaluated by the investigator. As specified by the protocol, the pH on Day 28 (second dose) and Day 56 (follow-up assessment) was presented.