Immune Response to Different Schedules of a Tetravalent Dengue Vaccine Given With or Without Yellow Fever Vaccine

Phase 2

Completed

• Conditions: Dengue; Dengue Fever; Dengue Hemorrhagic Fever; Yellow Fever
• Interventions: Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, and 4 virus; Biological: Yellow Fever

• Registration Number: NCT01488890
• Lead Sponsor: Sanofi Pasteur, a Sanofi Company

Brief Summary

The aim of this study was to evaluate the administration of CYD dengue vaccine serotypes (1, 2, 3 and 4) following a compressed schedule in 3 different populations.

Primary Objectives:

* To describe the humoral immune response to each of the 4 parental dengue virus serotypes at baseline and 28 days after CYD dengue vaccine Dose 3 in Group 1 (Month \[M\] 13) and Group 2 (M07), irrespective of whether or not Yellow Fever (YF) vaccine has been previously administered.

* To describe the persistence of the humoral immune response to each of the 4 parental dengue virus serotypes 6 months after CYD dengue vaccine Dose 3 in Group 1 (M18) and Group 2 (M12), irrespective of whether or not YF vaccine has been previously administered.

Secondary Objective:

* To describe the humoral immune response to each of the 4 parental dengue virus serotypes at baseline and 28 days after CYD dengue vaccine Dose 1 and Dose 2 in Groups 1 and 2, irrespective of whether or not YF vaccine has been previously administered.

* To describe the humoral immune response to each of the 4 parental dengue virus serotypes at baseline and 28 days after CYD dengue Dose 1 in the combined YF-participants in Group 1 (N=60) and Group 2 (N=60), and in Group 3 (N=120).

* To describe by FV status at baseline the humoral immune response to each of the 4 parental dengue virus serotypes at baseline and 28 days after each injection of CYD dengue vaccine in Groups 1, 2, and 3.

* To describe the safety profile after each injection of CYD dengue vaccine and/or YF vaccine.

Detailed Description

Participants were randomized to 4 different groups to receive either CYD dengue vaccine and/or YF vaccine. Participants who already received YF vaccine prior to enrolment were randomized to one of the 2 groups receiving CYD dengue vaccine alone. Participants were evaluated for immunogenicity, antibody persistence, reactogenicity and safety.

Study Timeline

• Study Start: 2011-12-06
• Study First Submitted: 2011-12-06
• Study First Submitted QC: 2011-12-07
• Study First Posted: 2011-12-08
• Primary Completion: 2013-09-27
• Study Completion: 2013-09-27
• Disposition First Submitted: 2014-04-08
• Disposition First Submitted QC: 2014-04-08
• Disposition First Posted: 2014-05-02
• Results First Submitted: 2019-05-24
• Results First Submitted QC: 2019-05-24
• Results First Posted: 2019-06-14
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-15
• Last Update Posted: 2022-03-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 390

Inclusion Criteria

• Aged >= 18 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
• For participants classified as YF positive (+) to be included in Groups 1 and 2, previous vaccination (3 months to 10 years) with YF vaccine confirmed by acceptable documentation.

Exclusion Criteria

• Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, surgically sterile, or using 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 of any vaccine in the 4 weeks preceding the first trial vaccination or planned receipt of any vaccine in the 4 weeks following each trial vaccination
• For all participants classified as YF negative (-), any previous vaccination against Flavivirus (FV) diseases (including Japanese Encephalitis [JE], tick-borne encephalitis, and YF)
• For participants classified as YF+, previous vaccination against FV diseases except YF (including JE and tick-borne encephalitis)
• For all participants, any FV vaccination planned during the trial period outside the study protocol
• 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)
• Self-reported seropositivity for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
• Self-reported history of FV infection (e.g., JE, Dengue, YF, West Nile), confirmed either clinically or serologically
• Known systemic hypersensitivity to any of the vaccine components, 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
• Current alcohol abuse or drug addiction
• Chronic illness that, in the opinion of the investigator, is 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
• Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature >= 38.0°C [>=100.4°F]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided
• Previous residence (> 12 months) in, or travel in the last 30 days to FV endemic regions
• History of thymic pathology (thymoma), thymectomy, or myasthenia.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CYD Dengue and Yellow Fever vaccine: Group 3	Yellow Fever	Participants received 3 doses of CYD dengue vaccine; one each at 0, 2 and 6 months, and single dose of YF vaccine at Day 0.
CYD Dengue vaccine: Group 1	Live, attenuated, recombinant dengue serotypes 1, 2, 3, and 4 virus	Participants received 3 doses of CYD dengue vaccine; one each at 0, 6 and 12 months.
CYD Dengue vaccine: Group 2	Live, attenuated, recombinant dengue serotypes 1, 2, 3, and 4 virus	Participants received 3 doses of CYD dengue vaccine; one each at 0, 2 and 6 months.
CYD Dengue and Yellow Fever vaccine: Group 3	Live, attenuated, recombinant dengue serotypes 1, 2, 3, and 4 virus	Participants received 3 doses of CYD dengue vaccine; one each at 0, 2 and 6 months, and single dose of YF vaccine at Day 0.
Yellow Fever vaccine: Group 4	Yellow Fever	Participants received single dose of YF vaccine at Day 0.

Primary Outcome Measures

Name	Time	Method
Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Following Injection (Inj.) With CYD Dengue Vaccine Dose 3: Group 1 and Group 2	Pre-injection 1, 28 days and 6 months post-injection 3	GMTs of antibodies against each dengue virus serotype (parental strain) was assessed using the dengue plaque reduction neutralization test (PRNT).
Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following Injection With CYD Dengue Vaccine Dose 3: Group 1 and Group 2	Pre-injection 1, 28 days and 6 months post-injection 3	Seropositivity against each dengue virus serotypes (parental strains) was assessed using the dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titer \>=10 (1/dilution).

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following Each Injection With CYD Dengue Vaccine: Group 1, Group 2 and Group 3 (FV Non-Immune Participants)	Pre injection 1, 2, 3 and 28 days post injection 1, 2 and 3	Seropositivity against each dengue virus serotypes (parental strains) was assessed using the dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titer \>=10 (1/dilution). FV non-immune participants were defined as participants with titer \< 10 (1/dilution) for all serotypes with parental dengue virus strains (sera tested by PRNT) and with titer \<10 (1/dilution) for YF virus (using sera with PRNT80 result).
Number of Participants Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Any Vaccination With CYD Dengue Vaccine (Administered With or Without Yellow Fever Vaccine) or Yellow Fever Vaccine	Within 7 days after any injection	Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 reactions: Pain: significant; prevents daily activity; Erythema and Swelling: \>100 mm.
Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following Each Injection With CYD Dengue Vaccine: Group 1, Group 2 and Group 3 (FV Immune Participants)	Pre Injection 1, 2 and 3 and 28 days post injection 1, 2 and 3	GMTs of antibodies against each dengue virus serotype (parental strain) was assessed using the dengue PRNT. FV immune participants were defined as participants with titer \>= 10 (1/dilution) for at least 1 serotype with parental dengue virus strain (sera tested by PRNT) or with titer \>= 10 (1/dilution) for YF virus (sera with PRNT80 result).
Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following Each Injection With CYD Dengue Vaccine: Group 1, Group 2 and Group 3 (FV Non-Immune Participants)	Pre-injection 1, 2, 3 and 28 days post-injection 1, 2 and 3	GMTs of antibodies against each dengue virus serotype (parental strain) was assessed using the dengue PRNT. FV non-immune participants were defined as participants with titer \< 10 (1/dilution) for all serotypes with parental dengue virus strains (sera tested by PRNT) and with titer \<10 (1/dilution) for YF virus (using sera with PRNT80 result).
Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following Each Injection With CYD Dengue Vaccine: Group 1, Group 2 and Group 3 (FV Immune Participants)	Pre-injection 1, 2, 3 and 28 days post-injection 1, 2 and 3	Seropositivity against each dengue virus serotypes (parental strains) was assessed using the dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titer \>=10 (1/dilution). FV immune participants at baseline were defined as participants with titer \>= 10 (1/dilution) for at least 1 serotype with parental dengue virus strain (sera tested by PRNT) or with titer \>=10 (1/dilution) for YF virus (sera with PRNT80 result).
Number of Participants Reporting Solicited Systemic Reactions (Fever, Headache, Malaise, Myalgia, Asthenia) Following Any Vaccination With CYD Dengue Vaccine (Administered With or Without Yellow Fever Vaccine) or Yellow Fever Vaccine	Within 14 days after any injection	Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions: Fever: \>= 39.0°C; Headache, Malaise, Myalgia, and Asthenia: significant; prevents daily activity.
Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following Injection With CYD Dengue Vaccine Dose 1 and Dose 2: Group 1 and Group 2	Pre-injection 1 and 2 and 28 days post-injection 1 and 2	GMTs of antibodies against each dengue virus serotype (parental strain) was assessed using the dengue PRNT.
Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following Injection With CYD Dengue Vaccine Dose 1 and Dose 2: Group 1 and Group 2	Pre-injection 1 and 2 and 28 days post-injection 1 and 2	Seropositivity against each dengue virus serotypes (parental strains) was assessed using the dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titer \>=10 (1/dilution).
Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following Injection With CYD Dengue Vaccine Dose 1 In YF Non-Immune Participants: Group 1 and Group 2 (Pooled) and Group 3	Pre-injection 1 and 28 days post-injection 1	GMTs of antibodies against each dengue virus serotype (parental strain) was assessed using the dengue plaque reduction neutralization test-50 (PRNT50). Groups 1 and 2 data was reported as pooled data. YF-non immune participants were defined as participants with YF baseline titer PRNT80 \< 10 (1/dilution).
Percentage of YF Non-Immune Participants With Seropositivity Against Each Dengue Virus Serotype Following Injection With CYD Dengue Vaccine Dose 1: Group 1 and Group 2 (Pooled) and Group 3	Pre-injection 1 and 28 days post-injection 1	Seropositivity against each dengue virus serotypes (parental strains) was assessed using the dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titer \>=10 (1/dilution). Groups 1 and 2 data was reported as pooled data. YF-non immune participants were defined as participants with YF baseline titer dengue plaque reduction neutralization test-80 (PRNT80) \<10 (1/dilution).