97. Tetravalent Dengue Vaccine (TAK-003) Development Program: A Bird’s Eye View

Abstract Background Dengue fever is a mosquito-borne viral disease endemic in 128 countries. An unmet clinical need remains for an effective vaccine that can be used more broadly than the vaccine presently available. A clinical development program has evaluated the long-term safety, immunogenicity, and vaccine efficacy (VE) of TAK-003, a live attenuated tetravalent dengue vaccine with a DENV-2 backbone engineered to elicit immune responses to all 4 dengue serotypes. Methods 18 clinical trials in 13 countries have involved 28,175 seropositive/seronegative participants aged from 1.5-60 years from endemic/non-endemic regions. In the ongoing pivotal phase III study, 4–16-year-old healthy children (N=20,099) were randomized 2:1 to receive two doses of TAK-003 or placebo, 3 months apart for an evaluation of VE and safety over a multi-year period stratified pre-vaccination dengue serostatus. Active surveillance throughout the trial detected symptomatic dengue. The trial will continue up to 4–4.5 years post 2nd dose, and for another 25 months after a booster dose. Data up to 3 years after the second vaccination are currently available. Results Safety and immunogenicity data from Phase I/II studies established the final formulation and dosing schedule. Overall VE in the pivotal phase III study was 80.2% [95% CI: 73.3–85.3] against virologically confirmed dengue (VCD) at 12 months post 2nd dose. At 18 months, VE was 66.2% (95% CI: 49.1–77.5) in dengue-naive and 76.1% (95% CI: 68.5–81.9) in dengue pre-exposed participants, with VE of 90.4% (95% CI: 82.6–94.7) and 85.9% (95% CI: 31.9–97.1) for prevention of hospitalized VCD and dengue hemorrhagic fever, respectively. Cumulative VE against VCD from first dose to 3 years post 2nd dose was 62.0% (95% CI: 56.6–66.7) and 83.6% (95% CI: 76.8–88.4) in prevention of hospitalized VCD. Some decline in VE was observed over time mainly driven by outpatient dengue. Two doses of TAK-003 3 months apart were well-tolerated with no important safety risks identified up to 3 years after completion of the vaccination schedule. Conclusion TAK-003 is immunogenic against all 4 dengue serotypes and continues to be efficacious, well-tolerated, and with no evidence of disease enhancement in seronegative population up to 3 years post-vaccination. Disclosures Vianney Tricou, D Phil, Takeda Pharmaceuticals International (Employee) Shibadas Biswal, MD, Takeda Vaccines, Inc (Employee) Sanjay S. Patel, PhD, Takeda Pharmaceuticals International AG (Employee) Olaf Zent, MD, Takeda Pharmaceuticals International AG (Employee) Martina Rauscher, PhD, Takeda Pharmaceuticals International AG (Employee) Gonzalo Perez, MD, Takeda group companies (Employee) Walid Kandeil, MD, Takeda Pharmaceuticals International AG (Employee) Nicolas Folschweiller, PhD, Takeda (Employee)

Background. Changes in the influenza hemagglutinin protein during replication of influenza in eggs during vaccine production may contribute to low vaccine effectiveness (VE). This phenomenon, egg adaptation, can explain VE differences between egg-based (QIVe-SD) and cell-based (QIVc) quadrivalent influenza vaccines. This research evaluated the relative vaccine effectiveness (rVE) of QIVc versus QIVe-SD in the reduction of influenza-related and any respiratory-related hospitalizations/emergency room (ER) visits among subjects 4-64 years old during the 2019/20 influenza season.

Methods.
A retrospective cohort analysis was conducted among subjects 4-64 years old vaccinated with QIVc or QIVe-SD using administrative claims data in the U.S. (IQVIA PharMetrics ® Plus). The adjusted number of events and rates of influenza-related hospitalizations/ER visits and respiratory-related hospitalizations/ER visits were assessed using inverse probability of treatment weighting (IPTW). Poisson regression was used to estimate relative vaccine effectiveness (rVE). In the main analysis, the study period was from Aug 4, 2019 to Mar 7, 2020 (ending early to avoid any influenza outcome misclassification with COVD-19 infection). In the assessment of the high influenza activity period (HIAP), the analysis period was restricted to Dec 8, 2019 to Mar 7, 2020.
Conclusion. QIVc was more effective in preventing influenza-related and respiratory-related hospitalizations/ER visits compared to QIVe-SD, using either a broad influenza season definition or restricting to the HIAP.
Disclosures Background. Dengue fever is a mosquito-borne viral disease endemic in 128 countries. An unmet clinical need remains for an effective vaccine that can be used more broadly than the vaccine presently available. A clinical development program has evaluated the long-term safety, immunogenicity, and vaccine efficacy (VE) of TAK-003, a live attenuated tetravalent dengue vaccine with a DENV-2 backbone engineered to elicit immune responses to all 4 dengue serotypes.
Methods. 18 clinical trials in 13 countries have involved 28,175 seropositive/seronegative participants aged from 1.5-60 years from endemic/non-endemic regions. In the ongoing pivotal phase III study, 4-16-year-old healthy children (N=20,099) were randomized 2:1 to receive two doses of TAK-003 or placebo, 3 months apart for an evaluation of VE and safety over a multi-year period stratified pre-vaccination dengue serostatus. Active surveillance throughout the trial detected symptomatic dengue. The trial will continue up to 4-4.5 years post 2 nd dose, and for another 25 months after a booster dose. Data up to 3 years after the second vaccination are currently available.
Conclusion. TAK-003 is immunogenic against all 4 dengue serotypes and continues to be efficacious, well-tolerated, and with no evidence of disease enhancement in seronegative population up to 3 years post-vaccination.