TAK-003 (Tetravalent Dengue Vaccine Candid

23 February 2023Senior Medical Director – Clinical Development Dengu

e

Shibadas Biswal, MDTakeda Vaccines

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

VV-MEDMAT-82307

9
• TAK-003 is an investigational compound that has not been approved for use by the U

Administration 

• There is no guarantee TAK-003 will be approved in any country or countries for use i

investigation in the trials or studies discussed herein 

• Regulatory approval and use of TAK-003 is dependent on review by relevant local au

– Currently, TAK-003 is approved for use in Indonesia, the EU, and UK

ACIP, Advisory Committee on Immunization Practices.

Disclaimers

10 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)
• Construct of the vaccine

• Immune response profile• Overview of the clinical development• Efficacy profile from the pivotal efficacy trial• Safety profile from an integrated analysis of placebo-controlled trials• Immunogenicity data from the pivotal efficacy trial• SummaryTopics to be covered

11 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)
C, capsid; DENV, dengue virus; E, envelope; NS, non-structural; prM, pre-membrane; TDV, tetravalent dengue vaccine. 

1. Osorio JE, et al. Expert Rev Vaccines 2016;15:497–508; 2. Osorio JE, et al. Vaccine 2015;33:7112–7120; 3. Patel SS, et al. Clin Infect Dis 2022. doi:10.1093/cid/ciac418 [Epub ahead of print].

TAK-003 is based on a live, attenuated DENV-2 virus backbonexpressing E and prM proteins of all four DENV serotypes

Genetic structure and design of TAK-0031–3

Substitution with prM and E genes 

from DENV-1, -3, and -4

Three attenuating mutations2

Attenuated TDV-2 

TDV-1TDV-3TDV-4

12 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)
Humoral-mediated immunity

• TAK-003 elicited neutralizing antibodies against each of DENV-1,-2,-3,-41,2• TAK-003 elicited cross-reactive antibodies that blocked the activity of DENV NS1 pr• TAK-003 elicited type-specific memory B cells that target DENV-1, -2, -3, -4*4Cell-mediated immunity• TAK-003 stimulated cross-reactive CD4+ and CD8+ T-cell responses5Innate immunity• TAK-003 stimulated production of T cells capable of producing IFNγ, TNFα, and IL-2

*These data were gathered from non-human primates and humans.CD, cluster of differentiation; DENV, dengue virus; IFN, interferon; IL, interleukin; NS, non-structural; TNF, tumor necrosis factor.1. Biswal S, et al. Lancet 2020;395:1423–1433; 2. Tricou V, et al. Lancet 2020;395:1434–1443; 3. Sharma M, et al. J Infect Dis 2020;221:867–877; 4. Michlmayr D, et al. J Infect Dis 2021;233:247–2

5. Tricou V, et al. Vaccine 2022;40:1143–1151.

In clinical trials, TAK-003 activated multiple facets of immunity 

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

A broad spectrum of immune responses may contribute to protection again

virus clearance, and prevention of severe disease1–5

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Ab, antibody; CMI, cell-mediated immunity; HepA, hepatitis A; HPV9, human papillomavirus 9 vaccine; S&I, safety and immunogenicity. 

1. ClinicalTrials.gov NCT01110551. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01110551 (accessed January 2023); 2. ClinicalTrials.gov NCT01224639. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01224639 (accessed January 2023); 3. ClinicalTrials.gov NCT017654

https://www.clinicaltrials.gov/ct2/show/NCT01765426 (accessed January 2023); 4. ClinicalTrials.gov NCT01542632. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01542632 (accessed January 2023); 5. ClinicalTrials.gov NCT01728792. Available at: https://www.clinicaltrials.gov/

January 2023); 6. ClinicalTrials.gov NCT02193087. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02193087 (accessed January 2023); 7. ClinicalTrials.gov NCT01511250. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01511250 (accessed January 2023); 8. ClinicalTrials.https://www.clinicaltrials.gov/ct2/show/NCT02302066 (accessed January 2023); 9. ClinicalTrials.gov NCT02425098. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02425098 (accessed January 2023); 10. ClinicalTrials.gov NCT02747927. Available at: https://www.clinicaltrials.govJanuary 2023); 11. ClinicalTrials.gov NCT02948829. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02948829 (accessed January 2023); 12. ClinicalTrials.gov NCT03999996. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03999996 (accessed January 2023); 13. ClinicalTr

https://www.clinicaltrials.gov/ct2/show/NCT03423173 (accessed January 2023); 14. ClinicalTrials.gov NCT03341637. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03341637 (accessed January 2023); 15. ClinicalTrials.gov NCT03771963. Available at: https://www.clinicaltrials.go

January 2023); 16. ClinicalTrials.gov NCT03746015. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03746015 (accessed January 2023); 17. ClinicalTrials.gov NCT03342898. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03342898 (accessed January 2023); 18. ClinicalTr

https://www.clinicaltrials.gov/ct2/show/NCT03525119 (accessed January 2023); 19. ClinicalTrials.gov NCT04313244. Available at: https://www.clinicaltrials.gov/ct2/show/NCT04313244 (accessed January 2023).

Overview of the clinical development program

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

• 19 clinical trials conducted in 13 dengue endemic and non-endemic countries

• Over 28,000 children/adults (aged 1.5–60 years) participated in Phase I–III clinical st• Clinical development included both baseline seronegative and seropositive participa

• ~20,000 participants received at least one dose of TAK-003

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RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious adverse event.

1. ClinicalTrials.gov NCT02747927. Available at: https://clinicaltrials.gov/ct2/show/NCT02747927 (accessed January 2023); 2. Biswal S, et al. N Engl J Med 2019;281:2009–2019. TIDES (DEN-301): Pivotal Phase III trial designEfficacy and safety of a tetravalent dengue vaccine (TAK-003)20,071 children (aged 4–16 years) received either TAK-003 or placebo in a 2:1 ratio1,2

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Baseline serostatus data were available for 6684 and 13,375 safety set participants in the placebo and TAK-003 groups, respectively. 

n refers to number of participants in the safety analysis set. Seronegative at baseline: seronegative to all four DENV serotypes. Seropositive at baseline: reciprocal neutralizing titer ≥10 for one or more DENV serotypes. DENV, dengue virus; SD, standard deviation.Takeda. Data on file. Demographic and baseline characteristics: Safety setEfficacy and safety of a tetravalent dengue vaccine (TAK-003)

Characteristic Placebo n=6687 

n

Seronegative, n (%) 1832 (27.4) 3Mean age, years (SD) 9.6 (3.34) 9

4–5 years, n (%) 846 (12.7) 16–11 years, n (%) 3697 (55.3) 712–16 years, n (%) 2144 (32.1) 4

Asia, n (%) 2993 (44.8) 5

Latin America, n (%) 3694 (55.2) 7

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APAC, Asia-Pacific; DENV, dengue virus; LATAM, Latin America; VCD, virologically confirmed dengue.

1. 1. Tricou V, et al. Efficacy and safety of Takeda’s tetravalent dengue vaccine candidate (TAK-003) after 4.5 years of follow-up. Presented at NECTM, Rotterdam, Netherlands, 8–10 June 2022; Trial sites and background dengue cases in the placebo groupEfficacy and safety of a tetravalent dengue vaccine (TAK-003)

Panama

Colombia

Brazil

Philippine

Sri Lanka

Dominican 

Nicaragua Republic

Thailand

Up to 57 months post 1st dose: Safety set1

LATAM2 

Cases of VCD, n

Serotype of infection 

17
Primary and secondary efficacy endpoint analysis

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

Vaccine efficacy = 1 – hazard ratio (TAK-003 vs. placebo). Hazard ratio estimated from Cox proportional hazards model with aage and stratified by region.

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VCD (per 100 per

Endpoint

Placebo

n=6317

30 days to 12 months post 2nd dose (primary endpoint)

VCD by any serotype 149 (2.6) 

30 days to 18 months post 2nd dose (secondary endpoint)

VCD leading to hospitalization (key secondary endpoint) 66 (0.8) 

VCD by any serotype 206 (2.4) 

Baseline seropositive 150 (2.4) Baseline seronegative 56 (2.4) 

VCD by DENV-1 62 (0.7) VCD by DENV-2 80 (0.9) VCD by DENV-3 60 (0.7) VCD by DENV-4 5 (<0.1) DCAC-defined severe VCD 1 (<0.1) 

DHF 7 (<0.1) 

VE against VCD by any serotype in the 30 days to 18 months post 2nd dose time frame was an exploratory endpoint; Seronegative at baseline: seronegative to all four DENV serotypes; seropositive at baseline: reciprocal neutralizing titer ≥10 for one or more DENV serotypes.CI, confidence interval; DCAC, Dengue Case Adjudication Committee; DENV, dengue virus; DHF, dengue hemorrhagic fever; VCD, virologically confirmed dengue; VE, vaccine efficacy.

1. Biswal S, et al. Lancet 2020;395:1423–1433; 2. Biswal S, et al. N Engl J Med 2019;381:2009–2019; 3. Takeda. Data on File.

DEN-301: Primary and secondary endpoints 

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

Primary and secondary endpoints per protocol set data; placebo to TAK-003 1:2 r

VE (%)

-80 -60 -40 -20 0 20 40 60 80 100

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Cumulative efficacy results over ~57 months 

(safety set data)

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

Vaccine efficacy = 1 – hazard ratio (TAK-003 vs. placebo). Hazard ratio estimated from Cox proportional hazards model with aage and stratified by region.

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Safety set data truncated at 57 months post 1st dose. Seronegative at baseline: seronegative to all four DENV serotypes; seropositive at baseline: reciprocal neutralizing titer ≥10 for one or mor

CI, confidence interval; DENV, dengue virus; VCD, virologically confirmed dengue.1. Tricou V, et al. Efficacy and safety of Takeda’s tetravalent dengue vaccine candidate (TAK-003) after 4.5 years of follow-up. Presented at NECTM, Rotterdam, Netherlands, 8–10 June 2022.TAK-003 was efficacious against VCD over 57 months regardlebaseline serostatusEfficacy and safety of a tetravalent dengue vaccine (TAK-003)

Cumulative incidence of participants 

with VCD (%)

02468

10

0 3 6 9 12 15 18 21 24 33 42 51 27 36 45 54 30 39 48 57

Time since 1st dose (months)

PlaceboTAK-003PlaceboTAK-003

SeropositiveSeronegative

Cumulat

Overall Seronegative Seropositive 

21
Cumulative incidence of participants 

with hospitalized VCD (%)

Safety set data truncated at 57 months post 1st dose. Seronegative at baseline: seronegative to all four DENV serotypes; seropositive at baseline: reciprocal neutralizing titer ≥10 for one or morCI, confidence interval; DENV, dengue virus; VCD, virologically confirmed dengue.1. Tricou V, et al. Efficacy and safety of Takeda’s tetravalent dengue vaccine candidate (TAK-003) after 4.5 years of follow-up. Presented at NECTM, Rotterdam, Netherlands, 8–10 June 2022.TAK-003 was efficacious against hospitalized VCD over 57 moregardless of baseline serostatusEfficacy and safety of a tetravalent dengue vaccine (TAK-003)

0.00.51.01.52.02.5

0 3 6 9 12 15 18 21 24 33 42 51 27 36 45 54 30 39 48 57

PlaceboTAK-003PlaceboTAK-003

SeropositiveSeronegative

Time since 1st dose (months)

Cumulat

Overall Seronegative Seropositive 

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n refers to number of participants in the safety set. Numbers of VCD (per 100 person-years) are based on the number of participants evaluated. 

Repeat episodes of VCD were excluded from efficacy analysis at VCD or serotype level as applicable.Seronegative at baseline: seronegative to all four DENV serotypes. Seropositive at baseline: reciprocal neutralizing titer ≥10 for one or more DENV serotypes.CI, confidence interval; DENV, dengue virus; VCD, virologically confirmed dengue; VE, vaccine efficacy.1. Tricou V, et al. Efficacy and safety of Takeda’s tetravalent dengue vaccine candidate (TAK-003) after 4.5 years of follow-up. Presented at NECTM, Rotterdam, Netherlands, 8–10 June 2022; 2. T

Efficacy against VCD: By baseline serostatus and serotype

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

Placebo

n=6687

TAK-003

n=13,380 

VCD, n (per 100 person-years) 

Seropositive

DENV-1DENV-2DENV-3DENV-4

151 (0.7)135 (0.6)

97 (0.4)

20 (<0.1)

133 (0.3)

54 (0.1)96 (0.2)

12 (<0.1)

Seronegative

DENV-1DENV-2DENV-3DENV-4

79 (1.0)58 (0.7)16 (0.2)

3 (<0.1)

89 (0.5)

14 (<0.1)

36 (0.2)

12 (<0.1)

−

−1

1st dose to end of Part 3: Safety set (~57 months)1,2

23
Placebo

n=6687

TAK-003

n=13,380 

Hospitalized VCD, n (per 100 person-years) 

Seropositive

DENV-1DENV-2DENV-3DENV-4

24 (0.1)59 (0.3)

15 (<0.1)

3 (<0.1)

16 (<0.1)

5 (<0.1)8 (<0.1)

0 (0.0)

6971

Seronegative

DENV-1DENV-2DENV-3DENV-4

14 (0.2)23 (0.3)3 (<0.1)1 (<0.1)

6 (<0.1)

0 (0.0)

11 (<0.1)

0 (0.0)

71

−8

1

Rate of hospitalization among VCD cases in placebo group: The Philippines, 17/191 (8.9%); Sri Lanka, 70/103 (68.0%); Thailand, 25/64 (39.1%); Brazil, 2/24 (8.3%); Colombia, 14/87 (16.1%);Dominican Republic, 4/22 (18.2%); Nicaragua, 8/24 (33.3%); Panama, 2/45 (4.4%).

n refers to number of participants in the safety set. Numbers of hospitalized VCD (per 100 person-years) are based on the number of participants evaluated.

Seronegative at baseline: seronegative to all four DENV serotypes. Seropositive at baseline: reciprocal neutralizing titer ≥10 for one or more DENV serotypes. CI, confidence interval; DENV, dengue virus; NE, non-estimable; VCD, virologically confirmed dengue; VE, vaccine efficacy.

1. Tricou V, et al. Efficacy and safety of Takeda’s tetravalent dengue vaccine candidate (TAK-003) after 4.5 years of follow-up. Presented at NECTM, Rotterdam, Netherlands, 8–10 June 2022; 2. T

Efficacy against hospitalized VCD: By baseline serostatus and serotype

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)1st dose to end of Part 3: Safety set (~57 months)1,2

24
VCD, virologically confirmed dengue.

1. Tricou V, et al. Efficacy and safety of Takeda’s tetravalent dengue vaccine candidate (TAK-003) after 4.5 years of follow-up. Presented at NECTM, Rotterdam, Netherlands, 8–10 June 2022; 2. T

Rate of hospitalization among VCD cases by country

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

0

1020304050607080

1 2 3 4 5 6 7 8

Rate of hospitalization among VCD cases 

in placebo group (%)

8.9

68.0

39.1

8.3

16.1 18.2

33.3

4.4

Placebo group analysis 1st dose to end of Part 3 safety set (~57 months)1,2

25
Rate of hospitalization among VCD cases in placebo group: The Philippines, 17/191 (8.9%); Sri Lanka, 70/103 (68.0%); Thailand, 25/64 (39.1%); Brazil, 2/24 (8.3%); Colombia, 14/87 (16.1%); Do

(18.2%); Nicaragua, 8/24 (33.3%); Panama, 2/45 (4.4%).

n refers to number of participants in the safety set. Numbers of hospitalized VCD (per 100 person-years) are based on the number of participants evaluated.

Seronegative at baseline: seronegative to all four DENV serotypes. Seropositive at baseline: reciprocal neutralizing titer ≥10 for one or more DENV serotypes. CI, confidence interval; DENV, dengue virus; NE, non-estimable; VCD, virologically confirmed dengue; VE, vaccine efficacy.

1. Takeda. Data on File.Efficacy against hospitalized VCD: by baseline serostatus and serotypeEfficacy and safety of a tetravalent dengue vaccine (TAK-003)

Placebo

n=5987

TAK-003

n=11,986 VE (95% C

Hospitalized VCD, n (per 100 person-years) Seropositive

DENV-1DENV-2DENV-3DENV-4

22 (0.1)

18 (<0.1)11 (<0.1)

2 (<0.1)

11 (<0.1)

2 (<0.1)5 (<0.1)

0 (0.0)

75.1 (48.7, 87.9)94.4 (76.0, 98.7)78.3 (37.4, 92.4)100 (NE, NE)

Seronegative

DENV-1DENV-2DENV-3DENV-4

12 (0.2)3 (<0.1)3 (<0.1)1 (<0.1)

5 (<0.1)

0 (0.0)

5 (<0.1)

0 (0.0)

78.9 (40.1, 92.6)100 (NE, NE)15.3 (−254.4, 79100 (NE, NE)

1st dose to end of Part 3: Safety set (~57 months)1

Sensitivity analysis excluding data from Sri Lanka

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Safety: Integrated analysis of placebo-controlled trials 

27 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)
• Solicited reactions occurred more frequently in the TAK-003 arm

• Similar reporting of unsolicited AEs in the TAK-003 and placebo arms• Most frequent TAK-003-related unsolicited AEs: injection-site pruritus (0.7%), bruising (0.6%), and pyrexia 

*Injection-site pain, erythema, and swelling; †For adults and children ≥6 years old: headache, myalgia, malaise, asthenia, and fever; for children <6 years old: irritability/fussiness, drowsiness, loAE, adverse event.Solicited AEs: n=3783 (TAK-003) and n=1703 (placebo); Unsolicited AEs: n=3830 (TAK-003) and n=1725 (placebo). 1. Patel S. Presented at ASTMH 2021, National Harbor, MD, US, 17–21 November 2021; 2. Takeda. Data on File: Integrated safety analysis of placebo-controlled trials, Takeda. 

Integrated safety analysis

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

43.4 46.1

21.3

3.0

25.7

40.1

22.8

0

102030405060708090

100

1 2 3 4

Participants (%)

Series1 Series2

AEs after any dose

Solicited local (within 7 days), systemic (within 14 days), and unsolicited (within 28 dayin participants aged 4–60 years old1,2

28
*Placebo-controlled trials pool; includes SAEs up to 54 months post 2nd dose in DEN-301; †As reported by investigators: not necessarily virologically confirmed dengue fever or meeting WHO 97 

‡As per local practice in Sri Lanka and Thailand, symptomatic and asymptomatic COVID-19-positive participants were isolated in designated centers/hospitals, and therefore, cases met SAE crite

**All trials pool: n=16,919 (TAK-003), n=8381 (placebo).DHF, dengue hemorrhagic fever; SAE, serious adverse event; WHO, World Health Organization.Takeda. Data on File: Integrated safety analysis of placebo-controlled trials including data from DEN-301 up to end of Part 3. Integrated safety analysis: SAEs

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

Participants with event, n (%)* TAK-003 n=14,627 Placebo n=7167Any SAE 1169 (7.99) 691 (9.64)Any related SAE 1 (<0.01) 4 (0.06)

SAEs (by preferred term) experienced by >0.2% of participants

Appendicitis 104 (0.71) 48 (0.67)Dengue fever† 77 (0.53) 144 (2.01)Gastroenteritis 52 (0.36) 21 (0.29)Viral infection 41 (0.28) 40 (0.56)Asymptomatic COVID-19‡ 37 (0.25) 13 (0.18)Pneumonia 36 (0.25) 24 (0.33)Urinary tract infection 34 (0.23) 21 (0.29)COVID-19‡ 32 (0.22) 11 (0.15)Influenza 31 (0.21) 20 (0.28)DHF† 14 (0.10) 37 (0.52)

One SAE was TAK-003, comfive related SrecipientsDeaths**• 16 (0.09%• 9 (0.11%) • None wer

the invest

• No fatal ca

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Immunogenicity in baseline seronegative participants 

30 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)
PPSI: number of participants evaluated at each time point may vary. Percentages are based on the number of participants evaluated.

Seropositive: reciprocal neutralizing titer ≥10.DENV, dengue virus; M, month; PPSI, per protocol set of immunogenicity.Takeda. Data on File.Immunogenicity data: Seropositivity rate

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)PPSI – participants seronegative at baseline in pivotal efficacy trial (TIDES)

94.1

99.5 98.6 100.0 96.1 100.0

90.5

99.8

85.3

0

20406080

100

1 2 3 4 5 6 7 8 9 

Seropositivity rate (%)

Seropositivity rate across serotypes at Month 1 and Month 4 in the TAK-003 grou

(n=702)

31
PPSI: number of participants evaluated at each time point may vary. Percentages are based on the number of participants evaluated.

*Titers expressed as the reciprocal of the highest dilution of test serum that shows a 50% reduction in plaque counts compared with that of virus controls. DENV, dengue virus; GMT, geometric mean titer; PPSI, per protocol set of immunogenicity.Takeda. Data on File.

Immunogenicity data: GMT* 

Efficacy and safety of a tetravalent dengue vaccine (TAK-003)

Months after 1st vaccination

PPSI analysiBaseline sero

10,000

1000

100

10

1

0 3 4 9 15 27 39 51 1

Baseline seronegative

GMT

PPSI – participants seronegative at baseline in pivotal efficacy trial (TIDES)

DENV-1 placebo DENV-1 TAK-003 DENV-2 placebo DENV-2 TAK-003 DENV-3 placebo DENV-3 TAK-003 D

TAK-003 group

Placebo group

32
• Data from the TIDES pivotal trial showed: – Long-term efficacy of TAK-003 in both baseline seronegative and seropositive participa

– TAK-003 is immunogenic against each of DENV-1, -2,-3, -4 serotypes

• Data from pivotal trial suggested varying TAK-003 efficacy profiles by serotype – Efficacious against all four serotypes in baseline seropositive participants – Efficacious against DENV-1 and DENV-2 in baseline seronegative participants – Among baseline seronegative participants:

o Data suggested lack of efficacy against DENV-3o The trial did not allow assessment of DENV-4 due to low incidenceo Long-term follow-up did not conclude a higher risk of hospitalized or severe forms of dengue 

and DENV-3 or -4 serotype

o Totality of data did not indicate harm

• Safety data from integrated analysis of placebo-controlled trials showed: – TAK-003 had an acceptable safety profile

DENV, dengue virus. Takeda. Data on File.

Summary

33 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)
Thank you

34 Efficacy and safety of a tetravalent dengue vaccine (TAK-003)