A Trial of a Walter Reed Army Institute of Research (WRAIR) Live Attenuated Virus Tetravalent Dengue Vaccine in Healthy US Adults

Study Overview
=================
Brief Summary
-----------------
This descriptive study will evaluate the safety and immunogenicity of 5 different formulations of the WRAIR dengue vaccine compared to a placebo.

Detailed Description
-----------------
Subjects will be randomized into one of 6 groups. One group will receive a placebo vaccine and the others will receive one of 5 different dengue vaccine formations. Each subject will receive two doses six months apart. Study subjects who elect to participate in a mosquito transmissibility component of the study will undergo mosquito feedings during each of the two assigned follow-up visits after vaccine dose 1. All subjects will have 11 venipunctures during 11 visits (i.e., screening plus 10 study visits) over a period of nine months.

Official Title
-----------------
Observer-blind, Single Center, Controlled Study of 2 Doses of Various Formulations of the WRAIR Live Attenuated Tetravalent Dengue Vaccine Compared to a Placebo Control, Administered on a 0-6-month Schedule, to Healthy Adults

Conditions
-----------------
Dengue

Intervention / Treatment
-----------------
* Biological: Live attenuated tetravalent dengue vaccine
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: Healthy male or female adult 18-45 years at the time of vaccination Free of obvious health problems as established by medical history and physical examination before entering into the study Written informed consent obtained from the subject Able to read the Subject Information Sheet and Consent Form Subjects who the investigator believes can and will comply with the requirements of the protocol Females must be of non-childbearing potential, or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions as defined in the protocol for 30 days prior to vaccination, have a negative pregnancy test within 48 hours prior to vaccination and must agree to continue such precautions for 60 days after completion of the vaccination series Exclusion: History of: recurrent migraine headache any neurological or behavioral disorder or seizures drug abuse or alcohol consumption (more than 2 drinks per day) allergic disease/reaction likely to be exacerbated by vaccine urticaria related to mosquito bites requiring medical attention Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, renal, hematologic or endocrine functional defect Any confirmed or suspected immunosuppressive or immunodeficient condition; Seropositive for HBsAg, anti-HCV or anti-HIV Acute disease at the time of enrollment Chronic hepatomegaly or splenomegaly Use of any investigational or non-registered drug or vaccine within 30 days preceding study or planned use Planned administration of a vaccine not foreseen by the study protocol 30 days ±each vaccine dose Planned move during study Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs or administration of immunoglobulins and/or blood products, within 90 days preceding the first dose or planned administration during the study period Any chronic systemic drug therapy to be continued during the study period

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DENGUE FORMULATION 17A GROUP<br>Healthy male or female subjects, between and including 18-45 years of age, who received two doses of Dengue vaccine Formulation 17a, administered subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm, at Months 0 and 6. | Biological: Live attenuated tetravalent dengue vaccine<br>* Live attenuated tetravalent dengue vaccine<br>|
| Experimental: DENGUE FORMULATION 17B GROUP<br>Healthy male or female subjects, between and including 18-45 years of age, who received two primary doses of Dengue vaccine Formulation 17b, administered subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm, at Months 0 and 6, and one booster dose approximately 5-12 months after the second dose. | Biological: Live attenuated tetravalent dengue vaccine<br>* Live attenuated tetravalent dengue vaccine<br>|
| Experimental: DENGUE FORMULATION 19 GROUP<br>Healthy male or female subjects, between and including 18-45 years of age, who received two primary doses of Dengue vaccine Formulation 19, administered subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm, at Months 0 and 6 and one booster dose approximately 5-12 months after the second dose. | Biological: Live attenuated tetravalent dengue vaccine<br>* Live attenuated tetravalent dengue vaccine<br>|
| Placebo Comparator: PLACEBO GROUP<br>Healthy male or female subjects, between and including 18-45 years of age, who received two doses of Placebo, administered subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm, at Months 0 and 6. | Biological: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site. | During the 21-day (Days 0-20) follow-up after Dose 1 of the study vaccine | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were abdominal pain, arthralgia, fatigue, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], headache, muscle aches, nausea, pain behind the eyes, photophobia, pruritus, rash and vomiting. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the 21-day (Days 0-20) follow-up after Dose 1 of the study vaccine | 
| Titers for DEN Neutralizing Antibodies Types 1, 2, 3 and 4 | Titers for DEN-1, DEN-2, DEN-3 and DEN-4 neutralizing antibodies, expressed as Geometric Mean Titers (GMTs), with cut-off values greater than or equal to (≥) 10 estimated dose giving 50% (ED50) signal reduction when compared to a control without serum. | At 30 days (Month 7) after Dose 2 of the study vaccine | 
| Titers for DEN Neutralizing Antibodies Types 1, 2, 3 and 4 Based on Priming Status | Titers for DEN-1, DEN-2, DEN-3 and DEN-4 neutralizing antibodies, expressed as Geometric Mean Titers (GMTs), with cut-off values greater than or equal to (≥) 10 estimated dose giving 50% (ED50) signal reduction when compared to a control without serum. Not primed = Not primed by MN50; Primed = Primed by MN50. Primed subject is a subject with neutralizing antibody titer ≥ 10 ED50 at pre-vaccination for at least one DEN type. Not primed subject is a subject with neutralizing antibody titer <10 ED50 for any DEN type at pre-vaccination. | At 5 to 12 months post-Dose 2 of the study vaccine | 
| Titers for DEN Neutralizing Antibodies Types 1, 2, 3 and 4 Based on Priming Status | Titers for DEN 1, DEN 2, DEN 3 and DEN 4 neutralizing antibodies, expressed as Geometric Mean Titers (GMTs), with cut-off values greater than or equal to (≥) 10 estimated dose giving 50% (ED50) signal reduction when compared to a control without serum. Not primed = Not primed by MN50; Primed = Primed by MN50. Primed subject is a subject with neutralizing antibody titer ≥ 10 ED50 at pre-vaccination for at least one DEN type. Not primed subject is a subject with neutralizing antibody titer <10 ED50 for any DEN type at pre-vaccination. | At Month 1 post-booster dose of the study vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site. | During the 21-day (Days 0-20) follow-up after Dose 2 of the study vaccine | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were abdominal pain, arthralgia, fatigue, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], headache, muscle aches, nausea, pain behind the eyes, photophobia, pruritus, rash and vomiting. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the 21-day (Days 0-20) follow-up after Dose 2 of the study vaccine | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site. | During the 21-day (Days 0-20) follow-up after each dose of the study vaccine | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were abdominal pain, arthralgia, fatigue, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], headache, muscle aches, nausea, pain behind the eyes, photophobia, pruritus, rash and vomiting. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the 21-day (Days 0-20) follow-up after each dose of the study vaccine | 
| Number of Subjects With Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 31-day (Days 0-30) follow-up after any study vaccine dose | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the whole primary phase of the study (from Day 0 up to Month 9) | 
| Number of Subjects With Alert Values for Safety Laboratory Determinations | Among assessed haematological and biochemical parameters were: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), hematocrit (HC), absolute neutrophil count (NEU) and platelet count (Platelet). | During the 31-day (Days 0-30) follow-up after each vaccine dose (Month 1 and Month 7) | 
| Number of Subjects With Abnormal Findings at Dengue Physical Examination | The abnormal findings at Dengue physical examination included: Rash, Generalized Rash, Skin Hemorrhage, Conjunctival Hemorrhage, Conjunctival Injection, Mucosal Hemorrhage, Lymphadenopathy, Generalized Lymphadenopathy, Hepatomegaly and Splenomegaly. Rash involved < 50% of the body surface; Generalized rash involved at least 50% of the body surface. Generalized lymphadenopathy was defined as palpable lymph nodes in four or more of the following locations: cervical, axillary, inguinal or other, with right and left sides considered as separate locations. | During the 31-day (Days 0-30) follow-up after each vaccine dose and across doses | 
| Number of Subjects With Suspected and Confirmed Dengue | The number of subjects with suspected and confirmed Dengue post-vaccination. | During the 31-day (Days 0-30) follow-up after each vaccine dose and across doses | 
| Number of Subjects With Measurable Dengue Viremia | The number of subjects with measurable dengue viremia at specified timepoints. Negative = Genome equivalent (GEQ)/µL result is equal to zero; Undetermined = GEQ/µL result is below limit of detection (LOD); Positive = GEQ/µL result is ≥ LOD. | During the 31-day (Days 0-30) follow-up after each vaccine dose | 
| Number of Subjects With Safety Laboratory Determinations Outside the Normal Ranges | Among assessed haematological and biochemical parameters were: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), hematocrit (HC), absolute neutrophil count (NEU) and platelet count (Platelet). Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter. | During the 31-day (Days 0-30) follow-up after each vaccine dose (Month 1 and Month 7) | 
| Titers for DEN Neutralizing Antibodies Types 1, 2, 3 and 4 | Titers for DEN-1, DEN-2, DEN-3 and DEN-4 neutralizing antibodies, expressed as Geometric Mean Titers (GMTs), with cut-off values greater than or equal to (≥) 10 estimated dose giving 50% (ED50) signal reduction when compared to a control without serum. | At Month 0 and Month 1 | 
| Number of Subjects With Antibody Titers Above the Assay Cut-off Value for Each DEN Serotype | Assay cut-off values were greater than or equal to (≥) 10 estimated dose giving 50% (ED50) signal reduction when compared to a control without serum. | At Months 0, 1 and 7 | 
| Number of Subjects With Antibody Titers Above the Assay Cut-off Value (Tetravalent Response) for All Dengue Serotypes | The antibody titers and pre-vaccination status were determined by MN50 with a cut-off value equal to 1:10. | At Months 1 and 7 | 
| Number of Subjects With Sero-response to Each DEN Type | Sero-response defined as: For initially seronegative subjects (antibody titer < 10 ED50 for neutralizing antibodies to DEN 1, DEN 2, DEN 3, DEN 4 prior to vaccination), antibody titer ≥ 10 ED50 at post-vaccination; For initially seropositive subjects (antibody titer ≥ 10 ED50 for neutralizing antibodies to DEN 1, DEN 2, DEN 3, DEN 4 prior to vaccination), antibody titer at post-vaccination ≥ 4 fold the pre-vaccination antibody titer. | At Months 1 and 7 | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site. | During the 21-day (Days 0-20) follow-up after the study vaccine booster dose | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were abdominal pain, arthralgia, fatigue, fever [defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)], headache, muscle aches, nausea, pain behind the eyes, photophobia, pruritus, rash and vomiting. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = oral fever > 39.0 °C. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the 21-day (Days 0-20) follow-up after the study vaccine booster dose | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited AEs | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 31-day (Days 0-30) follow-up after the study vaccine booster dose | 
| Number of Subjects With SAEs | SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the whole booster phase of the study (from pre-vaccination up to Month 6 post-vaccination with the booster dose) | 
| Number of Subjects With Hematological and Biochemical Determinations Within and Outside the Normal Ranges | Among assessed haematological and biochemical parameters were: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), hematocrit (HC), absolute neutrophil count (NEU) and platelet count (Platelet). Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter. Note: No blood sample was taken for these laboratory tests at Month 6 post-booster vaccination. | At each booster phase visit [pre-booster vaccination (PRE), study Visit 12 post-booster vaccination (Days 2, 5, 8 or 12) (FU1), study Visit 13 post-booster vaccination (Days 5, 8, 12 or 14) (FU2) and at Months 1 and 6 post-booster vaccination] | 
| Number of Subjects With Alert Values for Safety Laboratory Determinations | Among assessed haematological and biochemical parameters were: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), hematocrit (HC), absolute neutrophil count (NEU) and platelet count (Platelet). | During the 31-day (Days 0-30) follow-up after the study vaccine booster dose | 
| Number of Subjects With Abnormal Findings at Dengue Physical Examination | The abnormal findings at Dengue physical examination included: Conjunctival hemorrhage, Conjunctival injection, Generalized lymphadenopathy, Generalized rash, Hepatomegaly, Lymphadenopathy, Mucosal hemorrhage, Rash, Skin hemorrhage and Splenomegaly. Rash involved < 50% of the body surface; Generalized rash involved at least 50% of the body surface. Generalized lymphadenopathy was defined as palpable lymph nodes in four or more of the following locations: cervical, axillary, inguinal or other, with right and left sides considered as separate locations. Note: Results only available during the 31-day follow-up period (Month 1) after the booster dose, instead of at each booster phase visit [pre-vaccination, study Visit 12 post-booster vaccination (Days 2, 5, 8 or 12), Visit 13 post-booster vaccination (Days 5, 8, 12 or 14) and at Months 1 and 6 post-booster vaccination]. | At Month 1 post-booster vaccination | 
| Number of Subjects With Suspected and Confirmed Dengue | The number of subjects with suspected and confirmed Dengue post-booster vaccination. | During the 31-day (Days 0-30) follow-up after the study vaccine booster dose | 
| Number of Subjects With Measurable Dengue Viremia | The number of subjects with measurable dengue viremia at specified timepoints. | At study Visit 12 (Days 2, 5, 8 or 12) (FU1), study Visit 13 post-booster vaccination (Days 5, 8, 12 or 14) (FU2) and at study Visit 14 (Month 1 post-booster vaccination) | 
| Number of Subjects With Antibody Titers Above the Assay Cut-off Value for Each DEN Serotype | Assay cut-off values were greater than or equal to (≥) 10 estimated dose giving 50% (ED50) signal reduction when compared to a control without serum. Not primed = Not primed by MN50; Primed = Primed by MN50. Primed subject is a subject with neutralizing antibody titer ≥ 10 ED50 at pre-vaccination for at least one DEN type. Not primed subject is a subject with neutralizing antibody titer <10 ED50 for any DEN type at pre-vaccination. | Before (PRE) and one month after the booster vaccination (Month 1) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dengue infection