Date

2021-03-30

Protocol

Protocol changed

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Secondary outcome(s)

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VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline VE of Two Doses of TDV in Preventing Hospitalization due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype Percentage of Participants with Solicited Local Injection Site Adverse Events (AEs) in the Safety Subset Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination. Severity of Solicited Local Injection Site Adverse Events (AEs) in the Safety Subset Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination. Percentage of Participants with Solicited Systemic Adverse Events (AEs) in the Safety Subset Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (? 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (? 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. Percentage of Participants with Any Unsolicited Adverse Events (AEs) in the Safety Subset Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study. Percentage of Participants with Serious Adverse Events (SAEs) During Parts 1 and 2 A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. Percentage of Participants with Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3 A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. Percentage of Participants with a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset Seropositive response is defined as a reciprocal neutralizing titer ? 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. Percentage of Participants with a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset Seropositive response is defined as a reciprocal neutralizing titer ? 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset GMTs of neutralizing antibodies will be measured via microneutralization test (MNT). The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. [VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype [Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (additional 6 months following the completion of Part 1)] VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline [Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (additional 6 months following the completion of Part 1)] VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline [Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (additional 6 months following the completion of Part 1)] VE of Two Doses of TDV in Preventing Hospitalization due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype [Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (additional 6 months following the completion of Part 1)] VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype [Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (additional 6 months following the completion of Part 1)] Percentage of Participants with Solicited Local Injection Site Adverse Events (AEs) in the Safety Subset [Time Frame: Days 1 through 7 after each vaccination] Severity of Solicited Local Injection Site Adverse Events (AEs) in the Safety Subset [Time Frame: Days 1 through 7 after each vaccination] Percentage of Participants with Solicited Systemic Adverse Events (AEs) in the Safety Subset [Time Frame: Days 1 through 14 after each vaccination] Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset [Time Frame: Days 1 through 14 after each vaccination] Percentage of Participants with Any Unsolicited Adverse Events (AEs) in the Safety Subset [Time Frame: Days 1 through 28 after each vaccination] Percentage of Participants with Serious Adverse Events (SAEs) During Parts 1 and 2 [Time Frame: From Day 1 until the end of Parts 1 and 2 (approximately 21 months)] Percentage of Participants with Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3 [Time Frame: For 3 years (18 month halves) beginning at the end of Part 2 (approximately 21 months after the first vaccination)] Percentage of Participants with a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset [Time Frame: Day 1 and Months 1, 3, 4, 9, 15 and then annually] Percentage of Participants with a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset [Time Frame: Day 1 and Months 1, 3, 4, 9, 15 and then annually] Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset [Time Frame: Day 1 and Months 1, 3, 4, 9, 15 and then annually]]

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1. VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype 2. VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline 3. VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline 4. VE of Two Doses of TDV in Preventing Hospitalization due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype 5. VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype 6. Percentage of Participants with Solicited Local Injection Site Adverse Events (AEs) in the Safety Subset Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination. 7. Severity of Solicited Local Injection Site Adverse Events (AEs) in the Safety Subset Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination. 8. Percentage of Participants with Solicited Systemic Adverse Events (AEs) in the Safety Subset Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (? 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. 9. Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (? 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. 10. Percentage of Participants with Any Unsolicited Adverse Events (AEs) in the Safety Subset Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study. 11. Percentage of Participants with Serious Adverse Events (SAEs) During Parts 1 and 2 A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. 12. Percentage of Participants with Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3 A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. 13. Percentage of Participants with a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset Seropositive response is defined as a reciprocal neutralizing titer ? 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. 14. Percentage of Participants with a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset Seropositive response is defined as a reciprocal neutralizing titer ? 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. 15. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset GMTs of neutralizing antibodies will be measured via microneutralization test (MNT). The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. Booster Phase (Parts 4 and 5) Efficacy All subjects in the booster phase: • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by any dengue serotype from 30 days post-booster vaccination (Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by each dengue serotype from 30 days post-booster vaccination (Day 30b [Month 1b]) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by any and each dengue serotype in dengue seronegative subjects at baseline from 30 days post-booster vaccination (Day 30b [Month 1b]) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by any and each dengue serotype in dengue seropositive subjects at baseline from 30 days post-booster vaccination (Day 30b [Month 1b]) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • VE of a TDV booster dose in preventing hospitalization due to virologically confirmed dengue fever induced by any dengue serotype from 30 days post-booster vaccination (Day 30b [Month 1b]) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • VE of a TDV booster dose in preventing virologically confirmed severe dengue fever induced by any dengue serotype from 30 days post-booster vaccination (Day 30b [Month 1b]) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined. Safety Booster immunogenicity subset: • Frequency and severity of solicited local (injection site) AEs for 7 days (day of booster vaccination + 6 subsequent days) and solicited systemic AEs for 14 days (day of booster vaccination + 13 subsequent days) post-vaccination. • Percentage of subjects with any unsolicited AEs for 28 days (day of booster vaccination + 27 subsequent days) post-vaccination. All subjects in the booster phase: • Percentage of subjects with SAEs during Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • Percentage of subjects with fatal SAEs and related SAEs during Part 4 and Part 5 separately, and for Parts 4 and 5 combined. Booster immunogenicity subset: • Seropositivity rate (% of seropositive subjects) for each of the 4 dengue serotypes at prebooster vaccination on Day 1b (Month 0b) and post-booster vaccination on Day 30b (Month 1b), Day 180b (Month 6b), Day 395b (Month 13b), and Day 760b (Month 25b). • Seropositivity rate (% of seropositive subjects) for multiple (any 2, 3 or 4) dengue serotypes at pre-booster vaccination on Day 1b (Month 0b) and post-booster vaccination on Day 30b (Month 1b), Day 180b (Month 6b), Day 395b (Month 13b), and Day 760b (Month 25b). Note: Seropositivity is defined as a reciprocal neutralizing titer ?10. • GMTs of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination on Day 1b (Month 0b) and post-booster vaccination on Day 30b (Month 1b), Day 180b (Month 6b), Day 395b (Month 13b), and Day 760b (Month 25b). • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination on Day 1b (Month 0b) versus post-booster vaccination on Day 30b (Month 1b). • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination on Day 1b (Month 0b) versus post-booster vaccination on Day 180b (Month 6b). • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination on Day 1b (Month 0b) versus post-booster vaccination on Day 395b (Month 13b). • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination on Day 1b (Month 0b) versus post-booster vaccination on Day 760b (Month 25b). Post-booster vaccination: • To examine the relationship between dengue neutralizing antibodies (MNT50) and protection from dengue infection (correlate of protection). • To describe the profiles of IgG, IgM and NS1 antigen during episodes of hospitalized febrile illness. Booster Phase (Parts 4 and 5) Efficacy All subjects in the booster phase: • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by any dengue serotype from 30 days post-booster vaccination [Time frame-(Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined.] • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by each dengue serotype from 30 days post-booster vaccination [Time frame-(Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined.] • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by any and each dengue serotype in dengue seronegative subjects at baseline from 30 days post-booster vaccination [Time frame-(Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined.] • VE of a TDV booster dose in preventing virologically confirmed dengue fever induced by any and each dengue serotype in dengue seropositive subjects at baseline from 30 days post-booster vaccination [Time frame-(Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined.] • VE of a TDV booster dose in preventing hospitalization due to virologically confirmed dengue fever induced by any dengue serotype from 30 days post-booster vaccination [Time frame-(Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined.] • VE of a TDV booster dose in preventing virologically confirmed severe dengue fever induced by any dengue serotype from 30 days post-booster vaccination [Time frame-(Day 30 booster [b] (Month 1b)) until the end of Part 4 and Part 5 separately, and for Parts 4 and 5 combined.] Safety Booster immunogenicity subset: • Frequency and severity of solicited local (injection site) AEs [time frame-7 days (day of booster vaccination + 6 subsequent days)] and solicited systemic AEs [time frame14 days (day of booster vaccination + 13 subsequent days) post-vaccination.] • Percentage of subjects with any unsolicited AEs [time frame 28 days (day of booster vaccination + 27 subsequent days) post-vaccination.] All subjects in the booster phase: • Percentage of subjects with SAEs during Part 4 and Part 5 separately, and for Parts 4 and 5 combined. • Percentage of subjects with fatal SAEs and related SAEs during Part 4 and Part 5 separately, and for Parts 4 and 5 combined. Booster immunogenicity subset: • Seropositivity rate (% of seropositive subjects) for each of the 4 dengue serotypes at prebooster vaccination [time frame-Day 1b (Month 0b) and post-booster vaccination on Day 30b (Month 1b), Day 180b (Month 6b), Day 395b (Month 13b), and Day 760b (Month 25b).] • Seropositivity rate (% of seropositive subjects) for multiple (any 2, 3 or 4) dengue serotypes at pre-booster vaccination [time frame- Day 1b (Month 0b) and post-booster vaccination on Day 30b (Month 1b), Day 180b (Month 6b), Day 395b (Month 13b), and Day 760b (Month 25b).] Note: Seropositivity is defined as a reciprocal neutralizing titer ?10. • GMTs of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination [time frame- Day 1b (Month 0b) and post-booster vaccination on Day 30b (Month 1b), Day 180b (Month 6b), Day 395b (Month 13b), and Day 760b (Month 25b).] • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination [time frame- Day 1b (Month 0b) versus post-booster vaccination on Day 30b (Month 1b).] • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination [time frame- Day 1b (Month 0b) versus post-booster vaccination on Day 180b (Month 6b).] • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination [time frame- Day 1b (Month 0b) versus post-booster vaccination on Day 395b (Month 13b).] • GMR of neutralizing antibodies (MNT50) for each dengue serotype at pre-booster vaccination [time frame-Day 1b (Month 0b) versus post-booster vaccination on Day 760b (Month 25b).] Post-booster vaccination: • To examine the relationship between dengue neutralizing antibodies (MNT50) and protection from dengue infection (correlate of protection). • To describe the profiles of IgG, IgM and NS1 antigen during episodes of hospitalized febrile illness.