Long-Term Safety and Antibody Persistence of TDV and the Impact of a Booster Dose

Study Overview
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Brief Summary
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The purpose of this study is to describe antibody persistence for each of the 4 dengue serotypes for up to 63 months after the first vaccination in the primary vaccination series for participants from parent trial DEN-315 (NCT03341637) (Mexico) and for up to 36 months after the first vaccination in the primary vaccination series for participants from parent trial DEN-304 (NCT03423173) (United States [US]) and to describe the impact of a tetravalent dengue vaccine (TDV) booster dose vs placebo on antibody response for each of the 4 dengue serotypes at 1 month and 6 months post administration of the TDV booster or placebo.

Detailed Description
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The vaccine tested in this study is Takeda's Dengue Tetravalent Vaccine (Live, Attenuated) (TDV). This study will look at the long-term antibody persistence and safety of Takeda's TDV in healthy adolescents and adults and will assess the impact of a booster dose. The study has enrolled 365 healthy participants. Participants who previously received TDV in two parent trials (DEN-304 [NCT03423173] and DEN-315 [NCT03341637]), will be invited to participate in this follow-up trial. Participants will be assessed for antibody persistence and safety from Baseline (Month 0) through Month 15 (for participants from parent trial DEN-304 [US]) or Month 42 (for participants from parent trial DEN-315 [Mexico]). At Month 15 (for participants from parent trial DEN-304 [US]) or at Month 42 (for participants from parent trial DEN-315 [Mexico]), eligible participants will be randomized in 1:1 ratio to one of two trial groups to receive TDV or placebo: A. Group 1- TDV 0.5 mL subcutaneous (SC) injection at Month 15 for participants from parent trial DEN-304 (US) or at Month 42 for participants from parent trial DEN-315 (Mexico]). B. Group 2- Takeda's tetravalent dengue placebo (dummy SC injection - this is a liquid that looks like the study drug but has no active ingredient), 0.5 mL, subcutaneous injection at Month 15 for participants from parent trial DEN-304 (US) or at Month 42 for participants from parent trial DEN-315 (Mexico). This multi-centre trial will be conducted in US and Mexico. The overall time to participate in this study is up to 21 months for parent trial DEN-304 (US) and up to 48 months for parent trial DEN-315 (Mexico). Participants from parent trial DEN-304 (US) and participants from parent trial DEN-315 (Mexico) will come for 5 visits to the clinic which includes a final visit (Visit 5) 6 months after the booster dose for a follow-up assessment.

Official Title
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A Phase 3, Follow-Up Trial to Evaluate Long-Term Safety and Antibody Persistence, and the Impact of a Booster Dose of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescents and Adults in Areas Non-Endemic for Dengue

Conditions
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Dengue Fever

Intervention / Treatment
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* Biological: Takeda's Dengue Tetravalent Vaccine (Live, Attenuated) (TDV)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Male or female participants (irrespective of serostatus at baseline in the parent trials (DEN-304 [(NCT03423173)] and DEN-315 [NCT03341637]) who received at least one dose of Takeda's tetravalent dengue vaccine candidate (TDV) in the parent trials and have data from at least one blood draw post-vaccination. Exclusion Criteria: Participants with a prolonged period of habitation (≥1 year) in a dengue endemic area within the 2 years prior to Visit 1 Day 1 (Month 0). Previous and planned vaccination (during the trial conduct), against any flavivirus including dengue (other than Takeda's TDV), yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne encephalitis. Booster Exclusion Criteria: Participants for whom baseline serostatus is not defined in the parent trials (DEN-304 [(NCT03423173)] and DEN-315 [NCT03341637]). Participants with any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (eg, Guillain-Barré syndrome). Known or suspected impairment/alteration of immune function, including: Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Month 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US); use of inhaled, intranasal, or topical corticosteroids is allowed. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Month 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US). Administration of immunoglobulins and/or any blood products within the 3 months prior to administration of the TDV booster or placebo at Month 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US); consider whether applicable as an exclusion criterion or criterion for delay. Receipt of immunostimulants within 60 days prior to Month 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US). Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Month 42 for participants from parent trial DEN-315 (Mexico) / Month 15 for participants from parent trial DEN-304 (US). Known human immunodeficiency virus (HIV) infection or HIV-related disease. Hepatitis C virus infection. Genetic immunodeficiency. Abnormalities of splenic or thymic function. Participants with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time. Participants with history of current or previous infection with a flavivirus such as dengue, Zika, YF, JE, West Nile fever, tick-borne encephalitis or Murray Valley encephalitis and participants with a prolonged period of habitation (≥1 year) in a dengue endemic area during trial conduct.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 63 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Takeda's Dengue Tetravalent Vaccine (Live, Attenuated) (TDV)<br>TDV 0.5 mL, injection, subcutaneously, once at Month 15 for participants from parent trials DEN-304 (US) or once at Month 42 for participants from parent trial DEN-315 (Mexico). | Biological: Takeda's Dengue Tetravalent Vaccine (Live, Attenuated) (TDV)<br>* TDV subcutaneous injection<br>|
| Placebo Comparator: Placebo<br>TDV placebo-matching 0.5 mL injection, subcutaneously, once at Month 15 for participants from parent trial DEN-304 (US) or once at Month 42 for participants from parent trial DEN-315 (Mexico). | Biological: Placebo<br>* Normal Saline (0.9% NaCl) subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 0 (Day 1) | GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | Month 0 (Day 1) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 12 | GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | Month 12 | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 15 (US) | GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | Month 15 (US) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 42 (Mexico) | GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | Month 42 (Mexico) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 0 (Day 1) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 0 (Day 1) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 12 | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 12 | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 15 (US) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 15 (US) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 42 (Mexico) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 42 (Mexico) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose at Month 0 (Day 1) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 0 (Day 1) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose at Month 12 | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 12 | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose Month 15 (US) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 15 (US) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose at Month 42 (Mexico) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trials (DEN-304 and DEN-315). | Month 42 (Mexico) | 
| GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at 1 Month Post-Booster Dose at Month 16 (US) | GMTs of neutralizing antibodies will be measured by MNT50 for each of the 4 Dengue Serotypes for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post-booster dose at Month 16 (US) | 
| GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at 1 Month Post-Booster Dose at Month 43 (Mexico) | GMTs of neutralizing antibodies will be measured by MNT50 for each of the 4 Dengue Serotypes for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post-booster dose at Month 43 (Mexico) | 
| GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at 6 Months Post-Booster Dose at Month 21 (US) | GMTs of neutralizing antibodies will be measured by MNT50 for each of the 4 Dengue Serotypes for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | 6 months post-booster dose at Month 21 (US) | 
| GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at 6 Months Post-Booster Dose at Month 48 (Mexico) | GMTs of neutralizing antibodies will be measured by MNT50 for each of the 4 Dengue Serotypes for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | 6 months post-booster dose at Month 48 (Mexico) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes at 1 Month Post-Booster Dose at Month 16 (US) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for participants from parent trials DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trials DEN-304 (US) and DEN-315 (Mexico). | 1 month post-booster dose at Month 16 (US) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes at 1 Month Post-Booster Dose at Month 43 (Mexico) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for participants from parent trials DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trials DEN-304 (US) and DEN-315 (Mexico). | 1 month post-booster dose at Month 43 (Mexico) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes at 6 Months Post-Booster Dose at Month 21 (US) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for participants from parent trials DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trials DEN-304 (US) and DEN-315 (Mexico). | 6 months post-booster dose at Month 21 (US) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes at 6 Months Post-Booster Dose at Month 48 (Mexico) | Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for participants from parent trials DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trials DEN-304 (US) and DEN-315 (Mexico). | 6 months post-booster dose at Month 48 (Mexico) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes at 1 Month Post-Booster Dose at Month 16 (US) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). | 1 month post-booster dose at Month 16 (US) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 43 (Mexico) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). | 1 month post-booster dose at Month 43 (Mexico) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 21 (US) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). | 6 months post-booster dose at Month 21 (US) | 
| Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-booster Dose at 6 Months Post-Booster Dose at Month 48 (Mexico) | Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for participants from parent trial DEN-304 (US) and DEN-315 (Mexico) randomized to Groups 1 and 2 by current trial group, and by current trial group and serostatus at baseline in the parent trial DEN-304 (US) and DEN-315 (Mexico). | 6 months post-Booster dose at Month 48 (Mexico) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Ratio (GMR) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes for all Participants Prior to the Booster Dose | GMR of neutralizing antibodies will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at baseline in the parent trial (DEN-304 and DEN-315). | Month 0 vs Month 12 in the current trial, Month 4 in the parent trials vs Month 15 (US) and Month 42 (Mexico) in the current trials, Month 9 in the parent trials vs Month 0 and Month 12 in the current trial | 
| GMR of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Post-booster Dose | GMR of neutralizing antibodies will be calculated for participants randomized to Groups 1 and 2 by current trial group, by current trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at baseline in the parent trial (DEN-304 and DEN-315). | Month 4 in the parent trials vs 1 and 6 months post-booster dose in the current trial; Month 15 (US)/Month 42 (Mexico) vs 1 month post-booster dose; Month 15 (US)/Month 42 (Mexico) vs 6 month post-booster dose; 1 vs 6 month post-booster dose | 
| Percentage of Participants with Solicited Local Injection Site Adverse Events (AEs) by Severity, Post-booster Dose | Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days post-booster dose at Month 15 (US) and Month 42 (Mexico). | Days 1 through 7 post-booster dose at Month 15 (US) and Month 42 (Mexico) | 
| Percentage of Participants with Solicited Systemic AEs by Severity Post-booster Dose | Solicited systemic AEs are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days post-booster dose at Month 15 (US) and Month 42 (Mexico). | Days 1 through 14 post-booster dose at Month 15 (US) and Month 42 (Mexico) | 
| Percentage of Participants with any Unsolicited AEs Post-booster Dose | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a trial vaccine or placebo; it does not necessarily have to have a causal relationship with this treatment. | Days 1 through 28 post-booster dose at Month 15 (US) and Month 42 (Mexico) | 
| Percentage of Participants with any Medically Attended AEs (MAAEs) Post-booster Dose | MAAEs are defined as AEs leading to an unscheduled visit to or by a healthcare professional including visits to an emergency department, but not fulfilling seriousness criteria. | Month 15 post-booster dose through Month 21 (US); Month 42 post-booster dose through Month 48 (Mexico) | 
| Percentage of Participants with any Serious Adverse Events (SAEs) Prior to the Booster Dose | A SAE is defined as 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. | Month 0 through Month 15 (US) and Month 42 (Mexico) | 
| Percentage of Participants with any SAEs Post-Booster Dose | A SAE is defined as 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. | Month 15 post-booster dose after vaccination through Month 21 (US); Month 42 post-booster dose after vaccination through Month 48 (Mexico) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccine