sp second generation tetravalent dengue vaccine CYD23 Study Efficacy and Safety of Dengue Vaccine in Healthy Children Aged 4 to 1 Years in Thailand Alain Bouckenooghe, MD, MPH, DTM&H Clinical R&D, Head Asia/Pacific region JITMM meeting, Bangkok, Thailand, Oct 28
Dengue Mosquito-borne flaviviral infection Dengue is present in more than 124 countries and territories More than 2.5 billion persons live in endemic regions (intertropical areas) Every year: 7 to 1 million infected persons Estimated over 2 million severe forms (among which 9 % are children) Approximately 21 deaths 2 There is no specific treatment and the care of the disease is based on symptomatic treatment A Dengue vaccine represents a Public Health priority
Impact of vaccination coverage on incidence of DHF/DSS cases 9 8 No vaccination Vaccination coverage 7% Base case 7 Incidence (/1) 6 5 4 3 2 1 5 1 15 2 25 3 35 4 Year Vaccination alters disease dynamics by reducing the frequency and intensity of years with peak dengue incidence 3
Current Dengue Vaccine Developments Butantan NIH licensee Biological E. NIH licensee Panacea NIH licensee Fiocruz Chimeric Hawaii Biotech/NIH/ WRAIR/GSK Subunit Inviragen/CDC/Sha ntha Live attenuated DEN/DEN Chimeric NMRC/WRAIR DNA vaccine (monovalent) Sanofi pasteur Chimeric Live attenuated WRAIR/Crucell Whole virus inactivated NIH/Univ. Of Maryland DEN/DEN Chimeric GSK/WRAIR Live attenuated Preclinical Phase I Phase II Phase III 4
sanofi pasteur second generation Tetravalent dengue vaccine candidate Live attenuated dengue vaccines expressing the pre-membrane (prm) and envelope (E) proteins of each dengue serotype, which genes have been inserted in place of the corresponding genes of the YF 17D vaccine prm E 1 5 C NS1 2A 2B NS3 4A 4B NS5 3 2 3 4 The surface phenotype of these vaccines is thus no longer a YF-17D one, and their tropism is first linked to their dengue envelope Envelope is the immunizing Ag from an heterologous virus RNA replication engine is from YF17D 5
Three phase II observer-blind randomized controlled trials Study: Population FV Immune status at baseline** Protocol Group 1: Group 2: Objective USA 66 Adults 18-4yr 3% 18 Adults 18-45yr 36 Adolescents 12-17yr 72 Children 2-11yr 18 Adults 18-45yr 36 Adolescents 12-17yr 72 Children 2-11yr -------3 injections DV or control: Months, 3-4, 12------ DV*, DV, DV Placebo, DV, DV Philippines 8% DV, DV, DV TyphimVi, DV, DV Mexico 8% DV, DV, DV Stamaril, DV, DV To describe: safety, viremia and humoral immune responses, after each vaccine injection *DV= Dengue Vaccine **based on neut antibodies (dengue and JE for the Philippines) 6
Recent Proof of concept established in flavirivus-naive adult US subjects with this tetravalent vaccine GMT IgM GMT 1 GMT IgG 1 8 1/dil 1 6 4 2 Pre-D1 Post-D1 Pre-D2 Post-D2 Pre-D3 Post-D3 1 1 1 Serotype 1 Serotype 2 Serotype 3 Serotype 4 Dengue Vaccine Tetravalent evaluation in US Flavivirus negative Adults 1 Seroconversion* for 4 types, with robust titers after 3 doses Satisfactory safety profile *Dengue 5% Plaque reduction neutralization titer (seropositivity > 1:1) for each of the four serotypes for two different laboratory strains - data from the WHO Laboratory Reference Center, Mahidol University Thailand % seroconversion (>=1) Safety Dengue vaccine Placebo % 1 8 6 1 8 % 6 4 4 2 Serotype 1 Serotype 2 Serotype 3 Serotype 4 All 4 serotypes 2 Any adverse Injection site Systemic 7
Mexico (Non Endemic Country) - Reactogenicity after each dose of dengue vaccine in grp 1 (DV - 3 doses) (all subjects) No SAE after the 3rd dose 1 8 DV-Dose 1 (n=84) DV-Dose 2 (n=79) % subjects 6 4 2 6 Any AE Any Reaction Inj site Systemic DV-Dose 3 (n=73) Sev inj site Sev syst Trend for a decrease of some systemic s after a 2nd and 3rd dose (headache, malaise, myalgia) Injection site pain tends to be more frequent after a 3rd dose (especially in adults) but s are mild and transient (<=3 days) % subjects 5 4 3 2 DV-Dose 1 (n=84) DV-Dose 2 (n=79) DV-Dose 3 (n=73) 1 Headache M alaise M yalgia Asthenia Pyrexia Inj site pain Inj site erythema Inj site oedema 8
Philippines (Endemic Country) - Reactogenicity after each dose of dengue vaccine in grp 1 (DV 3 doses) (all subjects) 1 No SAE after the 3rd dose % subjects 8 6 4 2 DV-Dose 1 (n=84) DV-Dose 2 (n=82) DV-Dose 3 (n=8) 6 Any AE Any Reaction Inj site Systemic Sev inj site Sev syst Trend for a decrease of s (both injection site & systemic s) after a 2 nd and 3 rd dose % subjects 5 4 3 2 DV-Dose 1 (n=84) DV-Dose 2 (n=82) DV-Dose 3 (n=8) 1 Headache M alaise M yalgia Asthenia Pyrexia Inj site pain Inj site erythema 9 Inj site oedema
CYD5(Philippines)/CYD6 Mexico)Trials % of seropositive subjects against at least 3 serotypes after each injection all subjects CYD5 - % Seropositivity (95% CI) - >= 3 serotypes 1 8 Grp 1 - DV 3 doses #REF! % Subjects 6 4 2 93.8 8.5 65.5 5 1 Pre-Vacc 1 Post-Vacc 1 Post-Vacc 2 Post-Vacc 3 Three doses of DV with the schedule, 3, 12 months induce a good immune response in a naïve and nonnaïve population CYD6 - % Seropositivity (95% CI) - >= 3 Serotypes 1 8 Grp 1 - DV 3 doses % Subjects 6 4 2 82.2 57 14.5 Post-Vacc 1 Post-Vacc 2 Post-Vacc 3 1
From phase II trials to phase III trials Phase II trials Safety and Immunogenicity (S&I) CYD22 S&I Adults-ado Children JE+/-, Den+/- Vietnam CYD28 S&I Child-Ado-Adults Den+/- Singapore CYD12 S&I Adults FV naive US CYD13 S&I Adolescents Den+/- Latin Am CYD24 S&I Children YF+, Den+/- Peru CYD23 POC -Efficacy Children JE+/-, Den+/- Thailand Phase III trials Large Scale S&I Co-administration study Efficacy trial Lot to lot consistency 11
3 POC efficacy trial (CYD23, Thailand) Trial Design Choice of Ratchaburi province: PDVI cohort High dengue incidence average: 1.4 % in children Long-lasting collaboration with a team at Mahidol University* Observer-blind study Principal Investigator : Pr Arunee Sabchareon 42 children from 4 to 11 years old at time of inclusion:1/3 control vaccine (rabbies vaccine Verorab); 2/3 dengue vaccine Vaccination period : 3 sub-cutaneous injections at D, D + 6 months, D + 12 months, with a two-step approach for the first vaccination: * Faculty of Tropical Medecine and Center for Vaccine Development (Mahidol University) 12
Trial Design Population Group 1 (Dengue Vaccine Group) Group 2 (Control Group Verorab) TOTAL Children: 4-1 years 2668 1334 42 13
Objectives: Primary To assess the efficacy of dengue vaccine after three injections in preventing symptomatic virologically* confirmed dengue cases, regardless of the severity, due to any of the four serotypes in children aged 4 to 1 years at the time of inclusion * According to WHO Guidelines for the evaluation of dengue vaccines in populations exposed to natural infection. TDR/IVR/DEN/1 14
Objectives: Secondary (All subjects) Efficacy To assess the efficacy of dengue vaccine in children aged 4 to 1 years at the time of inclusion in: Preventing severe virologically-confirmed dengue cases due to any of the four serotypes Preventing symptomatic dengue cases, either virologically-confirmed or probable based on serological criteria, due to any of the four serotypes These evaluations will be performed in subjects having received at least two injections having received three injections of dengue vaccine Safety To evaluate the occurrence of SAEs in all subjects throughout the trial period 15
Flow Chart (All subjects) Efficacy Evaluation D 6M 12M 12M +3d 24M 48M ICF Inclusion/Exclusion Criteria 3 Minute observation period Blood sample / Efficacy Evaluation 16
Flow Chart (Subgroup) Reactogenicity, Immunogenicity, Viremia D D8 D15 D28 6M 6M+ 6M+ 6M+ 12M 12M+ 8D 15D 28D 3d 12M+ +12M 12M+ +24M 12M+ +36M ICF Inclusion/Exclusion Criteria Reactogenicity: 15 subjects Immunogenicity: 3 subjects Viremia / Biological safety: 1 subjects 17
Trial Design Follow-up of dengue cases Months 6 12 18 24 36 48 Detection of Dengue cases: 12 months after the third injection 27 cases Additional follow-up: hospitalized cases Active detection -school absenteism during school terms -weekly phone call/home visits during holiday periods Passive detection -parents/guardians asked to spontaneously bring their child to the RRH in case of febrile illness 18
Dengue Asia IDMC members Pr. Kim Mulholland (Chairman) Pr. Siripen Kalayanarooj Dr.Tran Tinh Hien Pr. Quak Seng Hock Pr. Peter Smith Mr Jukka Jokinen, PhD (Expert statistician) 19