Work Group Summary and 

Interpretation of TAK- Interpretation of TAK-003 Effic

003 Effic

Safety, and Immunogenicity D

Gabriela Paz-Bailey, MD, PhD, MSc

Dengue Branch Chief

Division of Vector Borne Diseases, NCEZID, CDC
Phase 3 Study (DEN-301)

• Design: double-blind, placebo-controlled study

• Randomized to TAK-003 or placebo in a 2:1 ratio

• Ages: children 4–16 years

• Sites: conducted across 5 countries in Latin America and 3 

in Asia

• Duration: ~57 months after first dose
DEN-301 population and outcomes ev

• Safety set included 20,071 participants.

• 28% of participants were seronegative at baseline.

• Primary endpoint was virologically-confirmed dengue (VCD) fr

serotype one year after the second dose.*

• Secondary endpoints, stratified by serotype and serostatus, in

• VCD• Hospitalization for dengue• Dengue hemorrhagic fever (1997 WHO definition)• Trial-specific severe dengue definition

*Exploratory endpoints were analyzed using the per protocol set (19,021 participants; 28% seronegative). Biswal, Lancet 2020.
All VE data shown in the following summa

~57 months follow-up

and

include all RCT trial sites*

*Participants included from the safety set.
VE for VCD
Overall VE

61.2% (56.0, 65.8%)

VE in Seropositives

64.2% (58.4, 69.2%)

VE in Serone

53.5% (41.6–

VE in Seropositives by Serotype

DENV-1 56.1% (44.6, 65.2%)DENV-2 80.4% (73.1, 85.7%)DENV-3 52.3% (36.7, 64.0%)DENV-4 70.6% (39.9, 85.6%)

VE in Seronegative

DENV-1 45.4% DENV-2 88.1% DENV-3 -15.5% DENV-4 -105.6% 

Vaccine Efficacy* Outcome: Virologically Confirme

Unpublished d

*57 months after first dose, significant results bolded. Number for seropositive placebo 

participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.
Summary: Virologically Confirmed Den

Summary: 

• Seropositives

• Protection against all 4 serotypes.

• Seronegatives

• Protection against DENV-1 and -2.• No efficacy for DENV-3 and -4.

• Data insufficient to rule out an increased risk of VCD among 
VE for hospitalization
Overall VE

84.1% (77.8, 88.6%)

VE in Seropositives

85.9% (78.7, 90.7%)

VE in Sero

79.3% (63

VE in Seropositives by SerotypeDENV-1 66.8% (37.4, 82.3%)DENV-2 95.8% (89.6, 98.3%)DENV-3 74.0% (38.6, 89.0%)DENV-4 100% (NE, NE)†

VE in Seronegati

DENV-1 78.4DENV-2 100DENV-3 -87.9DENV-4 100 

Vaccine Efficacy* Outcome: Hospitalization

†DENV-4 Placebo events: 3 TAK-003 events: 0

§DENV-2 Placebo even¶DENV-3 Placebo even

**DENV-4 Placebo even

*57 months after first dose, significant results bolded. Number for seropositive placebo 

participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. Unpublished d
Hospitalization for DENV-3 and DENV-4 among sero

children was low

Placebo

n=1832

Incidence

density/100

person-years

TAK-003

n=3714

Incidence

density/100

person-years

VE 

DENV-1 14 0.17 6 0.03 78.4% DENV-2 23 0.28 0 0.0 100% DENV-3 3 0.04 11 0.07 –87.9% DENV-4 1 0.01 0 0.0 100% 
Summary: Hospitalizations Summary

• Seropositives

• Protection against all 4 serotypes.• Few hospitalizations for DENV-4.

• Seronegatives

• Protection against DENV-1, and -2.

• One hospitalization due to DENV-4.

• No efficacy for DENV-3

• Data insufficient to rule out an increased risk of hospitalizat

vaccinated children with DENV-3.
VE for Severe Dengue
Overall VE

70.0% (31.5, 86.%)

VE in Seropositives

80.9% (46.3, 93.2%)

VE in Serone

-3.4% (-464.7, 

Vaccine Efficacy* Outcome: Dengue Hemorrhagic 

(1997 Definitio

VE by serostatus 

Events by Serotype

Placebo TAK-003

DENV-1 3 2DENV-2 7 0DENV-3 2 3DENV-4 1 0Total 13 5

Events by Se

Placebo 

DENV-1 1 DENV-2 0 DENV-3 1 DENV-4 0 Total 2 

*57 months after first dose, significant results for vaccine efficacy bolded. Number for seropositive 

placebo participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.
Overall VE

70.2% (-24.7, 92.9%)

VE in Seropositives

90.2% (16.4, 98.9%)

VE in Seroneg

-999.0% (NE

Vaccine Efficacy* Outcome: Severe Dengue Trial-specific Definitio

VE by serostatus 

Events by Serotype

Placebo TAK-003

DENV-1 1 0DENV-2 1 0DENV-3 3 1DENV-4 0 0Total 5 1

Events by Se

Placebo 

DENV-1 0 DENV-2 0 DENV-3 0 DENV-4 0 Total 0 

*57 months after first dose, significant results for vaccine efficacy bolded. Number for seropositive 

placebo participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.
Summary: Severe Dengue Summary

• Small number of events, difficult to stratify by serotype.• Seropositives:

• Offered protection against dengue hemorrhagic fever and trialspecific definition of severe dengue due to any serotype.

• Seronegatives:

• Few events.• No efficacy for dengue hemorrhagic fever and trial-specific 

definition of severe dengue due to any serotype.
Immunogenicity and Safety
Immunogenicity

• Subset of 2,518 TAK-003 and 1,247 placebo recipients (28

seronegative in each arm)

• GMTs highest for DENV-2 serotype among TAK-003 recipie

• GMTs remained stable until 51 months after 1st dose for DENV-1

• GMTs for DENV-2 decreased over time but remained higher tha

serotypes at 51 months after 1st dose.

Geometric mean titers (GMTs) calculated using PRNT50Seropositivity = reciprocal neutralizing titers ≥10
Vaccine safety

• Solicited AEs were higher among recipients of TAK-003 c

placebo.*

• Local: TAK-003 43%; placebo 26%• General: TAK-003 46%; placebo 40%

• Unsolicited AEs were similar between recipients of TAK-0

placebo.*

• Common TAK-003 unsolicited AEs:

• injection site pruritus (0.7%)• bruising (0.6%)• pyrexia (0.2%)

*Adverse events were analyzed using the safety set.
Vaccine safety: serious adverse events 

• SAEs were similar among recipients of TAK-003 (8%) and 

(10%).

• 1 TAK-003 and 4 placebo recipients had SAEs related to the inte

• Common SAEs (>0.2%) among recipients included:

• Dengue fever (TAK-003: 0.5%; placebo: 2%).• Dengue hemorrhagic fever (TAK-003: 0.1%; placebo 0.5%).

• Incidence of death was 0.1% in both TAK-003 (n=16) and p

(n=9) recipients.

• No deaths attributed to TAK-003.
Summary

Findings for TAK-003• Protects seropositive recipients against VCD and hospitalization due to • Protects seronegative recipients against VCD and hospitalization for DE• Does NOT protect seronegative recipients against VCD and hospitalizat• DENV-4 assessment among seronegative children is limited by low num

• No protection against VCD for DENV-4. • Only one DENV-4 hospitalization limits efficacy assessment.

• Unsolicited, serious adverse events, and deaths similar in vaccine and p
Summary

Pending Questions/Observations• Vaccine efficacy against hospitalizations for DENV-4 among seronegativ

unknown.

• No efficacy against hospitalizations for DENV-3 among seronegative v

compared to placebo (-87.9%; 95% CI: -573.4–47.6%).

• Data insufficient to rule out an increased risk among vaccine recipie

• Unclear significance of immunogenicity data because no clearly define

immune protection exists.
ACIP Dengue Vaccines Workgroup

ACIP MembersWilbur Chen (Chair)Kathy PoehlingBeth BellVeronica McNallyCDC Co-LeadGabriela Paz-BaileyLaura AdamsEx Officio MembersKaitlyn Morabito (NIH)Ralph LeBlanc (FDA)Ihid Carneiro Leao (FDA)Kirk Prutzman (FDA)Srihari Seshadri (DOD)

Liaison Representatives

Elizabeth Barnett (AAP)Rob Schechter (AIM)ConsultantsEdwin AsturiasRobert AtmarAlan BarrettIris CardonaAnna DurbinTony MarfinKristen PierceAnita Shet

CDC ContributorsJosh WongMimi EckertRachel EidexAlfonso HernandeSusan HillsTerri HydeMike McNeilJorge MunozErin StaplesCindy WeinbaumRita Helfand