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SS Saa aff fee ett tyy y,, ,aa ann ndd dII Imm mmm muu unn noo ogg gee enn nii icc cii itt tyy yDD Daa att taa aWork Group Summary and
Interpretation of TAK-003 Efficacy,
Safety, and Immunogenicity Data
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 countries
in Asia
• Duration : ~57 months after first dose
DEN-301 population and outcomes evaluated
• Safety set included 20,071 participants.
• 28% of participants were seronegative at baseline.
• Primary endpoint was virologically-confirmed dengue (VCD) from any
serotype one year after the second dose.*
• Secondary endpoints, stratified by serotype and serostatus, included:
• 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 summary are for:
~57 months follow-up
and
include all RCT trial sites*
*Participants included from the safety set.
VE for VCD
DENV-2 80.4% (73.1, 85.7%)
DENV-3 52.3% (36.7, 64.0%)
DENV-4 70.6% (39.9, 85.6%)
Overall VE
61.2% (56.0, 65.8%)
VE in Seronegatives
53.5% (41.6–62.9%)
VE in Seropositives by Serotype VE in Seronegatives by Serotype
DENV-1 45.4% (26.1, 5 9.7%) Vaccine Efficacy* Outcome : Virologically Confirmed Dengue
VE in Seropositives
64.2% (58.4, 69.2%)
DENV- 2 88.1% (78.6, 93.3%)
DENV-3 -15.5% (-108.2, 35.9%)
DENV-4 -105.6% (-628.7, 42.0%)
*57 months after first dose, s ignificant results bolded. Number for seropositive placebo
participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. Unpublished data presented by Takeda to ACIP WG DENV-1 56.1% (44.6, 65.2%)
SS Suu umm mmm maa arr ryy y:: : Summary: Virologically Confirmed Dengue
• 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 vaccinees.
VE for hospitalization
DENV-2
95.8% (89.6, 98.3%)
DENV-3
DENV-4 74.0% (38.6, 89.0%)
NE)† 100% (NE,DENV
-2 100% NE)§ (NE,
DENV-3 -87.9% 47.6%)¶ (-573.4,
DENV-4 100 % (NE, NE)**
Overall VE
84.1% (77.8, 88.6%)
VE in Seropositives by Serotype VE in Seronegatives by Serotype Vaccine Efficacy* Outcome : Hospitalization
VE in Seropositives
85.9% (78.7, 90.7%)
†DENV-4 Placebo events: 3 TAK-003 events: 0
*57 months after first dose, s ignificant results bolded. Number for seropositive placebo
participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. §DENV-2 Placebo events: 23 TAK-003 events: 0
¶DENV-3 Placebo events: 3 TAK-003 events: 11
**DENV-4 Placebo events: 1 TAK-003 events: 0
Unpublished data presented by Takeda to ACIP WG DENV-1 66.8% (37.4, 82.3%) VE in Seronegatives
79
.3% (63.5, 88.2%)
DENV-1 78. 4% (43.9, 91.7%)
Hospitalization for DENV-3 and DENV-4 among seronegative
children was low
Incidence
de
nsity/100
person -years Incidence
density/100
person -years Placebo
n =1832 TAK -003
n =3714 VE (95% CI)
DENV
-1 14 0.17 6 0.03 78.4% (43.9, 91.7%)
DENV-2 23 0.28 0 0.0 100% (NE, NE)
DENV-3 3 0.04 11 0.07 –87.9% (–573.4, 47.6%)
DENV-4 1 0.01 0 0.0 100% (NE, NE)
SS Suu umm mmm maa arr ryy y Summary: Hospitalizations
• 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 hospitalization among
vaccinated children with DENV-3.
VE for Severe Dengue
Vaccine Efficacy* Outcome: Dengue Hemorrhagic Fever
(1997 Definition)
Overall VE
70.0% (31.5, 86.%)
VE in Seropositives
80.9% (46.3, 93.2%)
Events by Serotype
Placebo TAK-003 Events by Serotype
Placebo TAK-003 VE in Seronegatives
-3.4% (-464.7, 81.1%)
DENV-1 3 2 DENV-1 1 0
DENV-2 7 0 DENV-2 0 0
DENV-3 2 3 DENV-3 1 4
DENV-4 1 0 DENV-4 0 0
Total 1 5 Total 2 4
*57 months after first dose, s ignificant results for vaccine efficacy bolded. Number for seropositive
placebo participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. VE by serostatus from unpublished data from Takeda.
Vaccine Efficacy* Outcome: Severe Dengue
Trial-specific Definition
Overall VE
70.2% (-24.7, 92.9%)
VE in Seropositives
90.2% (16.4, 98.9%)
Events by Serotype
Plac
ebo TAK-003 Events by Serotype
Plac
ebo TAK-003 VE in Seronegatives
-999.0% (NE, NE)
DENV-1 1 0 DENV-1 0 0
DENV-2 1 0 DENV-2 0 0
DENV-3 3 1 DENV-3 0 2
DENV-4 0 0 DENV-4 0 0
Total 5 1 Total 0 2
*57 months after first dose, s ignificant results for vaccine efficacy bolded. Number for seropositive
placebo participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. VE by serostatus from unpublished data from Takeda.
SS Suu umm mmm maa arr ryy y Summary: Severe Dengue
• Small number of events, difficult to stratify by serotype.
• Seropositives:
• Offered protection against dengue hemorrhagic fever and trial-
specific 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
II Imm mmm muu unn noo ogg gee enn nii icc cii itt tyy y 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 recipients.
• GMTs remained stable until 51 months after 1st dose for DENV-1, -3, and -4.
• GMTs for DENV-2 decreased over time but remained higher than other
serotypes at 51 months after 1st dose.
Geometric mean titers (GMTs) calculated using PRNT50
Seropositivity = reciprocal neutralizing titers ≥10
VV Vaa acc ccc cii inn nee ess saa aff fee ett tyy y Vaccine safety
• Solicited AEs were higher among recipients of TAK-003 compared to
placebo.*
• Local: TAK-003 43%; placebo 26%
• General: TAK-003 46%; placebo 40%
• Unsolicited AEs were similar between recipients of TAK-003 and
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.
VV Vaa acc ccc cii inn nee ess saa aff fee ett tyy y:: :ss see err rii ioo ouu uss saa add dvv vee err rss see eee evv vee enn ntt tss s(( (SS SAA AEE E)) ) Vaccine safety: serious adverse events (SAE)
• SAEs were similar among recipients of TAK-003 (8%) and placebo
(10%).
• 1 TAK-003 and 4 placebo recipients had SAEs related to the intervention
• 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 placebo
(n=9) recipients.
• No deaths attributed to TAK-003.
Summary
Findings for TAK-003
•
••
•
• P
rotects seropositive recipients agains t VCD and hospitalization du e t o any serotype.
Protects seronegative r ecipients agains t VCD and hospitalization for DENV-1 or DENV-2.
Does NOT protect seronegative recipients agains t VCD an d hospitalization for DENV-3.
DENV-4 assessmen t among seronegativ e children is limited b y lo w number of events.
• No protection agains t VCD fo r DENV-4.
• Onl y one DENV-4 hospitalization limits efficac y assessment.
Unsolicited , serious advers e events , an d deaths similar in vaccin e an d placeb o arms.
Summary
Pending Questions/Observations
•
•
• No efficacy against hospitalizations for DENV-3 among seronegative vaccin e recipients
compared t o placebo (-87.9%; 95 % CI : -573.4–47.6%).
• Dat a insufficien t t o rul e ou t an increased ris k among vaccin e recipients. Vaccin e efficac y agains t hospitalizations for DENV-4 among seronegative recipients is
unknown.
Unclear significanc e of immunogenicity dat a becaus e no clearl y define d correlat e of
immun e protecti on exists.
AA ACC CII IPP PDD Dee enn ngg guu uee eVV Vaa acc ccc cii inn nee ess sWW Woo orr rkk kgg grr roo ouu upp p ACIP Dengue Vaccines Workgroup
ACIP Members
Wilbu r Che n (Chair)
Kathy Poehling
Beth Bell
Veronic a McNally
CD C Co-Lead
G
abriela Paz-Bailey
Laura Adams
Ex Officio Members
Kaitly n Morabit o (NIH)
Ralp h LeBlan c (FDA)
Ihid Carneir o Lea o (FDA)
Kir k Prutzma n (FDA)
Srihar i Seshadri (DOD) L iaison Representatives
Elizabeth Barnett (AAP)
Rob Schechter (AIM)
Consultants
Edwin Asturias
Robert Atmar
Alan Barrett
Iris Cardona
Ann a Durbin
Tony Marfin
Kristen Pierce
Anit a Shet C DC Contributors
Josh Wong
Mim i Eckert
Rache l Eidex
Alfonso Hernandez
Susan Hills
Terri Hyde
Mike McNeil
Jorge Munoz
Erin Staples
Cindy Weinbaum
Rita Helfand