Immunologic Mechanisms of Immune Interference and/or Cross-Neutralizing Immunity After CYD Tetravalent Dengue Vaccine

Phase 2

Completed

• Conditions: Dengue Fever; Dengue; Dengue Hemorrhagic Fever
• Interventions: Biological: CYD Dengue Vaccine; Biological: Japanese Encephalitis Vaccine

• Registration Number: NCT01943825
• Lead Sponsor: Sanofi Pasteur, a Sanofi Company

Brief Summary

The aim of the study was to evaluate a compressed dosing schedule and the immunologic effects of co-administration of a CYD dengue vaccine with a licensed flavivirus (FV) with Japanese encephalitis (JE) vaccine.

Primary Objectives:

* To describe and compare the humoral immune response to each of the 4 parental dengue virus serotypes at baseline and 28 days after each CYD dengue vaccine dose.

* To describe the persistence of the humoral immune response to each of the 4 parental dengue virus serotypes 6 after CYD dengue vaccine Dose 3, irrespective of whether or not JE vaccine had been previously administered.

Secondary Objectives:

* To describe the safety profile after each injection of CYD dengue vaccine.

* To describe the humoral immune response to each of the 4 parental dengue virus serotypes at baseline and 28 days after each CYD dengue vaccine dose when administered with or after JE virus vaccine in Groups 3 and 4.

* To describe the persistence of the humoral immune response to each of the 4 parental dengue virus serotypes at 6 months post-dose 3 in all four groups and at 12 months post-dose 3 in Groups 1 and 3 with the compressed schedule.

* To determine the level of viremia on Day (D)0, D3, D5, D7 and D14 following each CYD vaccine dose administered in Groups 1-4.

* To describe the JE humoral immune response at baseline and 28 days after each injection of CYD dengue vaccine in Groups 3 and 4.

Detailed Description

Study participants were randomly assigned to one of the four groups to receive assigned study vaccine and were evaluated for neutralizing antibody titers; markers of cell-mediated immunity.

Study Timeline

• Study First Submitted: 2013-09-12
• Study First Submitted QC: 2013-09-12
• Study First Posted: 2013-09-17
• Study Start: 2013-11-05
• Primary Completion: 2015-11-25
• Study Completion: 2015-11-25
• Disposition First Submitted: 2017-04-28
• Disposition First Submitted QC: 2017-04-28
• Disposition First Posted: 2017-05-01
• Results First Submitted: 2019-12-19
• Results First Submitted QC: 2020-01-24
• Results First Posted: 2020-02-05
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-15
• Last Update Posted: 2022-03-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

• Aged greater than or equal to (>=)18 to less than or equal to (<=) 45 years on the day of inclusion.
• Informed consent form had been signed and dated.
• Able to attend all scheduled visits and complied with all trial procedures.
• Participant was in good health, based on medical history and physical examination.

Exclusion Criteria

• Participant was pregnant, or lactating, or of childbearing potential (were considered of non-childbearing potential, a female had to be post- menopausal for at least 1 year, surgically sterile, or used an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination).
• Participation in the 4 weeks preceding the first trial vaccination, or planned participation during the present trial period, in another clinical trial investigating a vaccine, drug, medical device, or medical procedure.
• Receipt or planned receipt of any vaccine, outside the study protocol in the 4 weeks preceded or followed trial vaccinations. (If influenza activity warranted vaccination of healthy young adults, influenza vaccination was encouraged and did not lead to study exclusion).
• Any history of FV vaccination, or planned FV vaccination during the trial period.
• Previous residence (greater than [>]12 months) in, or travel in the last 30 days to dengue endemic regions.
• Receipt of immune globulins, blood or blood-derived products in the 3 months prior to first vaccination or planned use during the study period.
• Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceded 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
• Known systemic hypersensitivity to any of the vaccine components (including protamine sulfate), or history of a life-threatening reaction to the vaccine(s) used in the trial or to a vaccine containing any of the same substances, including dry natural latex.
• Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Excessive alcohol consumption 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.
• Identified as an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members (i.e., immediate, husband, wife and their children, adopted or natural) of the employee or the Investigator.
• Temporary Exclusion Criteria: Moderate or severe acute illness/infection (according to Investigator judgment) on the day of vaccination or febrile illness (temperature >= 38.0 degree Celsius [>= 100.4 degree fahrenheit]). A prospective participant was not included in the study until the condition had resolved or the febrile event had subsided. If the delay for the febrile illness exceeded the window between screening and vaccination, or if deemed necessary by the Investigator, a prospective participant might be re-screened once the fever had resolved.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CYD Dengue Vaccine: Group 1	CYD Dengue Vaccine	Participants received 3 doses of CYD dengue vaccine, one each at 0, 2 and 6 months, respectively.
CYD Dengue Vaccine: Group 2	CYD Dengue Vaccine	Participants received 3 doses of CYD dengue vaccine, one each at 0, 6 and 12 months, respectively.
CYD Dengue and JE Vaccine: Group 3	CYD Dengue Vaccine	Participants received 3 doses of CYD dengue vaccine, one each at 0, 2 and 6 months, and 2 doses of JE (IXIARO) vaccine at 0 and 1 months, respectively.
CYD Dengue and JE Vaccine: Group 4	Japanese Encephalitis Vaccine	Participants received 2 doses of JE (IXIARO) vaccine at 0 and 1 months; and 3 doses of CYD dengue vaccine at 7, 9 and 13 months, respectively.
CYD Dengue and JE Vaccine: Group 3	Japanese Encephalitis Vaccine	Participants received 3 doses of CYD dengue vaccine, one each at 0, 2 and 6 months, and 2 doses of JE (IXIARO) vaccine at 0 and 1 months, respectively.
CYD Dengue and JE Vaccine: Group 4	CYD Dengue Vaccine	Participants received 2 doses of JE (IXIARO) vaccine at 0 and 1 months; and 3 doses of CYD dengue vaccine at 7, 9 and 13 months, respectively.

Primary Outcome Measures

Name	Time	Method
Geometric Means Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Strains	Pre-injection 1, 2 and 3; 28 days post-injection 1, 2 and 3; and 6 months post-injection 3	GMTs of antibodies against each dengue virus serotype (parental strains 1, 2, 3 and 4) were measured by plaque reduction neutralization test (PRNT). The lower limit of quantitation (LLOQ) of the assay was a titer of 10 (1/dilution).
Number of Participants With Antibody Titers Greater Than or Equal to (>=)10 (1/Dilution) Against Each Dengue Virus Serotype Strains	Pre-injection 1, 2 and 3; 28 days post-injection 1, 2 and 3; and 6 months post-injection 3	Antibody titers against each dengue virus serotype (parental strains 1, 2, 3 and 4) were measured by PRNT.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Detectable Non Serotype-Specific Vaccine Viremia	3, 5, 7 and 14 days post-injection 1, 2 and 3	Viremia was determined by reverse transcriptase (RT) polymerase chain reaction (PCR) using primer/probes specific to a non serotype-specific part of the dengue vaccine.
Geometric Means Titers of Antibodies Against Each Dengue Virus Serotype Strains	6 months and 12 months post-injection 3	GMTs of antibodies against each dengue virus serotype (parental strains 1, 2, 3 and 4) were measured by PRNT.
Number of Participants With Solicited Injection Site Reactions	Within 7 days after any CYD dengue vaccine and/or JE vaccine	A solicited reaction was defined as an adverse reaction observed and reported under the conditions (symptom and onset) pre-listed (i.e., solicited) in the electronic case report form (eCRF) and considered as related to vaccination. Solicited injection site reactions: pain, erythema, and swelling.
Number of Participants With Solicited Systemic Reactions	Within 14 days after any CYD dengue vaccine and/or JE vaccine	A solicited reaction was defined as an adverse reaction observed and reported under the conditions (symptom and onset) pre-listed (i.e., solicited) in the eCRF and considered as related to vaccination. Solicited systemic reactions: fever, headache, malaise, myalgia, and asthenia.
Geometric Means Titers of Antibodies Against Each Dengue Virus Serotype Strains in Participants Who Received Japanese Encephalitis Vaccine - Groups 3 and 4	Pre-injection 1, 2 and 3, and 28 days post-injection 1, 2 and 3	GMTs of antibodies against each dengue virus serotype (parental strains 1, 2, 3 and 4) were measured by PRNT. The LLOQ of the assay was a titer of 10 (1/dilution).
Geometric Means Titers of Antibodies Against Japanese Encephalitis - Groups 3 and 4	Pre-injection 1, and 28 days post-injection 1, 2 and 3	GMTs of antibodies against JE were measured by JE micro neutralization assay. The LLOQ of the assay was a titer of 10 (1/dilution).
Number of Participants With Detectable Serotype-Specific Vaccine Viremia	3, 5, 7 and 14 days post-injection 1; 3 and 14 days post-injection 2 and 7 days post-injection 3	Viremia was determined by RT PCR using primer/probes specific to each dengue vaccine serotypes.