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

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.

Time frame: During the 21-day (Days 0-20) follow-up after Dose 1 of the study vaccine

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after Dose 1 of the study vaccine

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: At 30 days (Month 7) after Dose 2 of the study vaccine

Population: The analysis was performed on the Primary ATP cohort for immunogenicity, which included all evaluable subjects for whom data concerning immunogenicity outcome measures were available.

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.

Time frame: At 5 to 12 months post-Dose 2 of the study vaccine

Population: The analysis was performed on the Booster ATP cohort for immunogenicity, which included all evaluable subjects who completed the primary vaccination course, who had received the booster dose according to their random assignment and for whom data concerning immunogenicity outcome measures were available.

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.

Time frame: At Month 1 post-booster dose of the study vaccine

Population: The analysis was performed on the Booster ATP cohort for immunogenicity, which included all evaluable subjects who completed the primary vaccination course, who had received the booster dose according to their random assignment and for whom data concerning immunogenicity outcome measures were available.

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.

Time frame: During the 31-day (Days 0-30) follow-up after each vaccine dose and across doses

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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 \[pre-vaccination, study Visit 12 post-booster vaccination (Days 2, 5, 8 or 12), Visit 13 post-booster vaccination (Days 5, 8, 12 or 14) and at Months 1 and 6 post-booster vaccination\].

Time frame: At Month 1 post-booster vaccination

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

Among assessed haematological and biochemical parameters were: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), hematocrit (HC), absolute neutrophil count (NEU) and platelet count (Platelet).

Time frame: During the 31-day (Days 0-30) follow-up after the study vaccine booster dose

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

Among assessed haematological and biochemical parameters were: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), hematocrit (HC), absolute neutrophil count (NEU) and platelet count (Platelet).

Time frame: During the 31-day (Days 0-30) follow-up after each vaccine dose (Month 1 and Month 7)

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: Before (PRE) and one month after the booster vaccination (Month 1)

Population: The analysis was performed on the Booster ATP cohort for immunogenicity, which included all evaluable subjects who completed the primary vaccination course, who had received the booster dose according to their random assignment and for whom data concerning immunogenicity outcome measures were available.

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.

Time frame: At Months 0, 1 and 7

Population: The analysis was performed on the Primary ATP cohort for immunogenicity, which included all evaluable subjects for whom data concerning immunogenicity outcome measures were available.

The antibody titers and pre-vaccination status were determined by MN50 with a cut-off value equal to 1:10.

Time frame: At Months 1 and 7

Population: The analysis was performed on the Primary ATP cohort for immunogenicity, which included all evaluable subjects for whom data concerning immunogenicity outcome measures were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after Dose 2 of the study vaccine

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) with the symptom sheet filled in and for whom data were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after each dose of the study vaccine

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after the study vaccine booster dose

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) with the symptom sheet filled in and for whom data were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after each dose of the study vaccine

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after the study vaccine booster dose

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) with the symptom sheet filled in and for whom data were available.

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.

Time frame: During the 21-day (Days 0-20) follow-up after Dose 2 of the study vaccine

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) with the symptom sheet filled in and for whom data were available.

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.

Time frame: During the 31-day (Days 0-30) follow-up after the study vaccine booster dose

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

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.

Time frame: 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]

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

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.

Time frame: During the 31-day (Days 0-30) follow-up after each vaccine dose

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

The number of subjects with measurable dengue viremia at specified timepoints.

Time frame: 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)

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Time frame: During the whole booster phase of the study (from pre-vaccination up to Month 6 post-vaccination with the booster dose)

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

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.

Time frame: During the 31-day (Days 0-30) follow-up after each vaccine dose (Month 1 and Month 7)

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

SAEs assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Time frame: During the whole primary phase of the study (from Day 0 up to Month 9)

Population: The analysis was performed on the Primary Total Vaccinated Cohort, included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: At Months 1 and 7

Population: The analysis was performed on the Primary ATP cohort for immunogenicity, which included all evaluable subjects for whom data concerning immunogenicity outcome measures were available.

The number of subjects with suspected and confirmed Dengue post-vaccination.

Time frame: During the 31-day (Days 0-30) follow-up after each vaccine dose and across doses

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

The number of subjects with suspected and confirmed Dengue post-booster vaccination.

Time frame: During the 31-day (Days 0-30) follow-up after the study vaccine booster dose

Population: The analysis was performed on the Booster Total Vaccinated Cohort, which included all vaccinated subjects (with documented booster dose administration) for whom data were available.

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.

Time frame: During the 31-day (Days 0-30) follow-up after any study vaccine dose

Population: The analysis was performed on the Primary Total Vaccinated Cohort, which included all vaccinated subjects (with at least one vaccine administration documented) for whom data were available.

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.

Time frame: At Month 0 and Month 1

Population: The analysis was performed on the Primary ATP cohort for immunogenicity, which included all evaluable subjects for whom data concerning immunogenicity outcome measures were available.