Immunogenicity and Safety of a Purified Vero Rabies Vaccine

Phase 2

Completed

Conditions: Rabies Virus

Interventions: Biological: VRVg 2
Biological: Imovax Rabies
Biological: VRVg 1
Biological: Human Rabies Immunoglobulins (HRIG)

Registration Number: NCT03145766

Lead Sponsor: Sanofi Pasteur, a Sanofi Company

Brief Summary: This multicenter, observer-blind, controlled, randomized, Phase II study was designed to evaluate different formulations of the Purified Vero Rabies Cell vaccine VRVg.

Detailed Description: This study assessed different formulations of the modified formulation of VRVg (VRVg 2- formulations 1 \[low\], 2 \[medium\] and 3 \[high\]) tested in parallel to the initial VRVg formulation (VRVg-1) and Imovax Rabies. Immune responses were assessed at Day 14, Day 28, Day 42, and at Month 7. Safety events were also reported.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 320

Inclusion Criteria

An individual must fulfill all of the following criteria in order to be eligible for trial enrollment:

Aged 18 to less than 65 years on the day of inclusion.
Informed consent form had been signed and dated.
Able to attend all scheduled visits and to complied with all trial procedures.
Body Mass Index (BMI): 18.5 kilograms per meter square (Kg/m^2) less than or equal to (<=) BMI <= 30 Kg/m^2.

Exclusion Criteria

An individual fulfilling any of the following criteria was to be excluded from trial enrollment:

Participant was pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 4 weeks after the last vaccination. To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, or surgically sterile.
Participation at the time of study enrollment 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 in the 4 weeks (28 days) preceding the first trial vaccination or planned receipt of any vaccine prior to Visit 6.
Previous vaccination against rabies (in pre- or post-exposure regimen) with either the trial vaccine or another vaccine.
Receipt of immune globulins, blood or blood-derived products in the past 3 months.
Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
At high risk for rabies infection during the trial (e.g., veterinarians and staff, animal handlers, rabies researchers, or any others whose activities may bring them into frequent contact with rabies virus or animals who had the rabies virus).
Known systemic hypersensitivity to any of the vaccine or human rabies immunoglobulins (HRIG) components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances.
Self-reported thrombocytopenia, contraindicating IM vaccination.
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating IM vaccination.
Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
Current alcohol abuse or drug addiction.
Chronic illness that, in the opinion of the investigator, was at a stage where it might interfere with trial conduct or completion (e.g., cardiac disorders, renal disorders, auto immune disorders, diabetes, psychiatric disorders or chronic infection).
Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature greater than or equal to [>=] 100.4 Fahrenheit >=38.0 Celsius). A prospective participant should not be included in the study until the condition had resolved or the febrile event had subsided.
Identified as an Investigator or employee of the Investigator or study center 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.
History of Guillain-Barré syndrome.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 2: VRVg-2 Formulation 2	VRVg 2	VRVg-2 formulation 2, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 1: VRVg-2 Formulation 1	VRVg 2	VRVg-2 formulation 1, intramuscular (IM) injection on Days 0, 3, 7, 14 and 28. Concomitant administration of human rabies immunoglobulins (HRIG) on Day 0.
Group 3: VRVg-2 Formulation 3	VRVg 2	VRVg-2 formulation 3, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 1: VRVg-2 Formulation 1	Human Rabies Immunoglobulins (HRIG)	VRVg-2 formulation 1, intramuscular (IM) injection on Days 0, 3, 7, 14 and 28. Concomitant administration of human rabies immunoglobulins (HRIG) on Day 0.
Group 4: VRVg-1	Human Rabies Immunoglobulins (HRIG)	VRVg-1 initial formulation, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 5: Imovax Rabies	Imovax Rabies	Imovax Rabies, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 3: VRVg-2 Formulation 3	Human Rabies Immunoglobulins (HRIG)	VRVg-2 formulation 3, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 5: Imovax Rabies	Human Rabies Immunoglobulins (HRIG)	Imovax Rabies, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 2: VRVg-2 Formulation 2	Human Rabies Immunoglobulins (HRIG)	VRVg-2 formulation 2, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.
Group 4: VRVg-1	VRVg 1	VRVg-1 initial formulation, IM injection on Days 0, 3, 7, 14 and 28. Concomitant administration of HRIG on Day 0.

Primary Outcome Measures

Name	Time	Method
Rabies Virus Neutralizing Antibody Geometric Mean Titers Against Rabies Virus at Day 42	Day 42	RVNA GMT against rabies virus was assessed using the RFFIT assay method.
Rabies Virus Neutralizing Antibody Geometric Mean Titers Against Rabies Virus at Month 7	Month 7	RVNA GMT against rabies virus was assessed using the RFFIT assay method.
Rabies Virus Neutralizing Antibody Geometric Mean Titers Against Rabies Virus at Day 14	Day 14	RVNA GMT against rabies virus was assessed using the RFFIT assay method.
Rabies Virus Neutralizing Antibody (RVNA) Geometric Mean Titers (GMTs) Against Rabies Virus at Day 0	Day 0	RVNA GMT against rabies virus was assessed using the rapid fluorescent focus inhibition test (RFFIT) assay method.
Rabies Virus Neutralizing Antibody Geometric Mean Titers Against Rabies Virus at Day 28	Day 28	RVNA GMT against rabies virus was assessed using the RFFIT assay method.
Percentage of Participants With Rabies Virus Neutralizing Antibody Titer Greater Than or Equal to (>=) 0.2 IU/mL and >=0.5 IU/mL at Day 0	Day 0	RVNA titer against rabies virus was assessed using the RFFIT assay method. Participants with RVNA titer \>=0.2 IU/mL were considered as seropositive.
Percentage of Participants With RVNA Titers >=0.2 IU/mL and >=0.5 IU/mL at Day 28	Day 28	RVNA titer against rabies virus was assessed using the RFFIT assay method. Participants with RVNA titer \>=0.2 IU/mL were considered as seropositive.
Percentage of Participants With RVNA Titers >=0.2 IU/mL and >=0.5 IU/mL at Day 42	Day 42	RVNA titer against rabies virus was assessed using the RFFIT assay method. Participants with RVNA titer \>=0.2 IU/mL were considered as seropositive.
Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody 7 Days Following Vaccination 3 (Day 14/Day 0)	Day 0 (pre-dose) and Day 14 (7 days post-dose 3)	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs 7 days post 3rd vaccination (i.e., on Day 14) and pre-vaccination on Day 0.
Number of Participants With at Least One Solicited Systemic Reactions	Within 7 Days After any and each vaccination (Vaccination 1, 2, 3, 4 and 5)	A solicited reaction was an AR observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. An AR was all noxious and unintended responses to a medicinal product related to any dose. Solicited systemic reactions included fever, headache, malaise and myalgia.
Number of Participants With at Least One Unsolicited Adverse Events	Within 28 Days After any vaccination	An AE was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRF in terms of diagnosis and/or onset post-vaccination.
Number of Participants With Serious Adverse Events (SAEs)	From Day 0 up to Month 7	An AE was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. An SAE was any untoward medical occurrence that at any dose resulted in death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect or a medically important event.
Percentage of Participants With Complete Virus Neutralization at Starting Dilution (1/5) of Rapid Fluorescent Focus Inhibition Test Assay at Day 0	Day 0	Complete virus neutralization was defined as absence of fluorescent cells at the participant/time point level at the starting dilution (1/5) of the RFFIT assay. Percentage of participants with complete virus neutralization were reported.
Percentage of Participants With Complete Virus Neutralization at Starting Dilution (1/5) of Rapid Fluorescent Focus Inhibition Test Assay at Month 7	Month 7	Complete virus neutralization was defined as absence of fluorescent cells at the participant/time point level at the starting dilution (1/5) of the RFFIT assay. Percentage of participants with complete virus neutralization were reported.
Number of Participants With Immediate Unsolicited Adverse Events	Within 30 Minutes After any Vaccination	An adverse event was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the case report form (CRF) in terms of diagnosis and/or onset post-vaccination. All participants were observed for 30 minutes after any vaccination, and any unsolicited AEs occurred during that time were recorded as immediate unsolicited AEs in the CRF. Immediate AEs considered as related to vaccination were recorded as immediate unsolicited adverse reactions (ARs).
Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL and >=0.5 IU/mL at Day 14	Day 14	RVNA titer against rabies virus was assessed using the RFFIT assay method. Participants with RVNA titer \>=0.2 IU/mL were considered as seropositive.
Percentage of Participants With Complete Virus Neutralization at Starting Dilution (1/5) of Rapid Fluorescent Focus Inhibition Test Assay at Day 14	Day 14	Complete virus neutralization was defined as absence of fluorescent cells at the participant/time point level at the starting dilution (1/5) of the RFFIT assay. Percentage of participants with complete virus neutralization were reported.
Percentage of Participants With Complete Virus Neutralization at Starting Dilution (1/5) of Rapid Fluorescent Focus Inhibition Test Assay at Day 28	Day 28	Complete virus neutralization was defined as absence of fluorescent cells at the participant/time point level at the starting dilution (1/5) of the RFFIT assay. Percentage of participants with complete virus neutralization were reported.
Percentage of Participants With Complete Virus Neutralization at Starting Dilution (1/5) of Rapid Fluorescent Focus Inhibition Test Assay at Day 42	Day 42	Complete virus neutralization was defined as absence of fluorescent cells at the participant/time point level at the starting dilution (1/5) of the RFFIT assay. Percentage of participants with complete virus neutralization were reported.
Number of Participants With at Least One Solicited Injection Site Reactions	Within 7 Days After any and each vaccination (Vaccination 1, 2, 3, 4 and 5)	A solicited reaction (SR) was an AR observed and reported under conditions (symptoms and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. An AR was all noxious and unintended responses to a medicinal product related to any dose. Solicited injection site reactions included pain, erythema and swelling at and around the injection site.
Percentage of Participants With RVNA Titers >=0.2 IU/mL and >=0.5 IU/mL at Month 7	Month 7	RVNA titer against rabies virus was assessed using the RFFIT assay method. Participants with RVNA titer \>= 0.2 IU/mL were considered as seropositive.
Geometric Mean Titer Ratio of Rabies Virus Neutralizing Antibody 14 Days Following Vaccination 4 (Day 28/Day 0)	Day 0 (pre-dose) and Day 28 (14 days post-dose 4)	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs 14 days post 4th vaccination (i.e., on Day 28) and pre-vaccination on Day 0.
Geometric Mean Titer Ratio of Rabies Virus Neutralizing Antibody 14 Days Following Vaccination 5 (Day 42/Day 0)	Day 0 (Pre-dose) and Day 42 (14 days Post-dose 5)	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs 14 days post 5th vaccination (i.e., on Day 42) and pre-vaccination on Day 0.
Geometric Mean Titer Ratio of Rabies Virus Neutralizing Antibody 6 Months Following Last Vaccination (Month 7/Day 0)	Day 0 (Pre-dose) and Month 7 (6 Months Post Last Vaccination)	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs 6 month post last vaccination on Month 7 and pre-vaccination on Day 0.