Dengue vaccine โดย ศ. พญ. ก ลก ญญา โชคไพบ ลย ก จ ภาคว ชาก มารเวชศาสตร คณะแพทยศาสตร ศ ร ราชพยาบาล

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1 Dengue vaccine โดย ศ. พญ. ก ลก ญญา โชคไพบ ลย ก จ ภาคว ชาก มารเวชศาสตร คณะแพทยศาสตร ศ ร ราชพยาบาล

2 SANOFI PASTEUR S DENGUE VACCINE*: THE MOST CLINICALLY ADVANCED DENGUE VACCINE CANDIDATE There are 4 genetic constructs, 1 for each serotype. The envelope and precursor membrane genes from each serotype were combined with the genes encoding the capsid and non-structural proteins from the yellow fever (YFV 17D) vaccine strain. The 4 recombinant, live, attenuated dengue viruses are combined into a single vaccine which is freeze-dried and contains no adjuvant or preservatives. DENV-1 (strain PUO-359/TVP-1140, isolated in 1980 in Thailand) DENV-2 (strain PUO-218, isolated in 1980 in Thailand) DENV-3 (strain PaH881/88, isolated in 1988 in Thailand) DENV-4 (strain 1228 (TVP-980), isolated in 1978 in Indonesia) *Vaccine referred to in the literature as Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine (CYD-TDV). Ref: Guirakhoo, 2001, J Virol. / Guirakhoo, 2000, J Virol. / Guy, 2011, Vaccine.

3 Overview: Characterization and GMO aspects Satisfactory genotypic and phenotypic stability impossible to create a wt YFV or virulent vaccine in vaccinees? Chimeric viruses are less hepatotropic and neurotropic than YF17D The vaccine is not transmitted by mosquitoes X Tetravalent vaccination addresses the ADE risk? Natural Recombination is highly unlikely The vaccine neutralizes all circulating strains tested so far Gene transfer is highly unlikely Dengue Vaccinology IP Vaccine 2011;

4 Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial (N=4,002, 4-11 yo) Efficacy % (95% CI) Serotype-specifi c and overall efficacy of CYD tetravalent dengue vaccine against virologically confi rmed dengue disease All D1 D2 D3 D4 Sabchareon A. The lancet 2012.

5 Geometric mean PRNT 50 antibody titre against vaccine parental dengue strains at baseline and after each injection (per-protocol immunogenicity analysis) The recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial m=number of participants per protocol at that point in the study and for whom data are available for that endpoint. PRNT50=plaque-reduction neutralisation test. GMT=geometric mean titre. *Titre 10 or higher. Sabchareon A. The lancet 2012.

6 CYD 14 CYD 15

7 CYD 14 COUNTRIES INCLUDED ARE AMONG THE 10 HIGHEST DENGUE-ENDEMIC COUNTRIES WHO=World Health Organization. WHO, 2012, Global Strategy for Dengue Prevention and Control. Villar L. NEJM 2014 Nov 3.

8 CYD 15 COUNTRIES INCLUDED ARE AMONG THE 10 HIGHEST DENGUE-ENDEMIC COUNTRIES CYD15 Countries and Study Sites WHO=World Health Organization. WHO, 2012, Global Strategy for Dengue Prevention and Control. Capeding MR. Lancet 2014 Jul 10.

9 STUDY DESIGN: RANDOMIZED, OBSERVER-MASKED, PLACEBO- CONTROLLED, MULTICENTER, PHASE III TRIALS 1,2,3 Inclusion criteria Vaccination with CYD-TDV Children 2-14 years CYD years CYD15 Good health No plans to leave study area Exclusion criteria Febrile illness (until resolution) Receiving other vaccines (until 4 weeks after vaccination) Congenital or acquired immunodeficiency R a n d o m i z a t i o n Months 2:1 N=10,275 CYD14 N=20,869 CYD Year 6 Vaccination with placebo* Active phase Active surveillance/detection of dengue cases Symptomatic VCD defined as: Acute febrile illness (temp 38 C on 2 consecutive days) Virologically confirmed PCR and/or dengue NS1 Ag ELISA Hospital phase Additional follow-up for safety of hospitalized dengue cases *Participants who received placebo were designated as the control group. CYD-TDV=Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine VCD: Virologically Confirmed Cases 1 Capeding, 2014, Lancet. ClinicalTrials.gov, 2014, NCT Villar, 2014, N Engl J Med. 3 Villar, 2014, N Engl J Med (Suppl Appendix) 9

10 Villar L. NEJM 2014 Nov 3, Capeding MR. Lancet 2014 Jul 10.. Chimerix tetravalent dengue vaccine trials STUDY DESIGN Study Design Age 2-14 y.o y.o. Countries Philippines, Viet Nam, Thailand, Indonesia, Malaysia Incidence rate 1.3% 0.64% Sample Size 10,278 20,875 Lower bound of 95%CI >25% >25% Power 90% 90% Long term follow-up 5 years 5 years Expected number of post dose 3 Dengue cases CYD 14 CYD Definition of fever 38.0 C 38.0 C Brazil, Columbia, Honduras, Mexico, Puerto Rico Laboratory Simplexa TM RT-PCR Simplexa TM RT-PCR

11 Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial (CYD14) Kaplan-Meier curve for symptomatic virologically-confi rmed dengue (VCD) due to any serotypes taking place from 28 days after the third injection (ie, from month 13) in the perprotocol population (A) and at any time during the trial from day 0, irrespective of protocol compliance, in the intention-totreat population (B) Capeding MR. Lancet 2014 Jul 10.

12 Efficacy of a tetravalent dengue vaccine (against any serotype) in children in Latin America (CYD15) Incidence of Virologically Confirmed Dengue occurring more than 28 days after the third dose in the modified per-protocol population (Panel A) and at any time during the active follow-up period in the intentionto-treat population (Panel B). The dashed vertical lines indicate the timing of injections (i.e., at months 0, 6, and 12) Villar L. NEJM 2015;372:

13 OVERVIEW OF EFFICACY RESULTS AGAINST VCD (ANY SEVERITY) PP & mpp POPULATIONS 12 m follow-up from months , 2 STUDY (n episodes) VACCINE EFFICACY and 95% CI Any ST (primary endpoint) DENV-1 DENV-2 DENV-3 DENV-4 CYD14 (n=250) CYD15 (n=397) CYD14 (n=101) CYD15 (n=132) CYD14 (n=67) CYD15 (n=108) CYD14 (n=33) CYD15 (n=125) CYD14 (n=51) CYD15 (n=58) Capeding, 2014, Lancet. 2. Villar, 2014, N Engl J Med. 13 PP = Per protocol; mpp = modified Per Protocol APPROVED FOR EXTERNAL USE BY AUTHORIZED PERSONS SPGLB.DENG

14 OVERVIEW OF EFFICACY RESULTS AGAINST VCD (ANY SEVERITY) ITT POPULATION 25 m follow-up from months , 2 STUDY (n episodes) VACCINE EFFICACY and 95% CI Any ST CYD14 (n=595) CYD15 (n=662) DENV-1 CYD14 (n=242) CYD15 (n=208) DENV-2 CYD14 (n=171) CYD15 (n=168) DENV-3 CYD14 (n=73) CYD15 (n=161) DENV-4 CYD14 (n=112) CYD15 (n=115) Capeding, 2014, Lancet. 2. Villar, 2014, N Engl J Med. 14 ITT: Intent To Treat APPROVED FOR EXTERNAL USE BY AUTHORIZED PERSONS SPGLB.DENG

15 OVERVIEW OF EFFICACY RESULTS AGAINST SEVERE AND HOSPITALIZED VCD Intent-to-treat analysis (follow-up from months 0 25) STUDY (n episodes) EFFICACY and 95% CI 1 VE in severe dengue cases CYD14 (n=32) CYD15 (n=12) VE in DHF dengue cases CYD14 (n=28) CYD15 (n=11) VE* in hospitalized dengue cases CYD14 (n=101) CYD15 (n=60) *The relative risk (RR) of hospital admissions for virologically confirmed dengue was calculated as the ratio of annual incidence in the vaccine group and control groups, and presented here as vaccine efficacy (ie, 1 RR). 15 APPROVED FOR EXTERNAL USE BY AUTHORIZED PERSONS SPGLB.DENG

16 SUMMARY OF CYD14 1,2 (ASIA) COUNTRY-SPECIFIC EFFICACY DURING THE ACTIVE PHASE Vaccine Efficacy, % Dengue Baseline Status % Incidence Density Control Group % ST Distribution Control Group % Indonesia CYD n=40 Control n=43 Total: 1, Malaysia CYD n=9 Control n=21 Total: 1,401 Philippines CYD n=143 Control n=150 Total: 3,501 Thailand CYD n=44 Control n=45 Total: 1,170 Vietnam CYD n=50 Control n=50 Total: 2,333 53,9 51, , Capeding, 2014, Lancet 2. sanofi pasteur, data on file, 2014, CYD14 training deck. N= Seropositive ( 10 1/dil. PRNT50) n=3424 ST1 ST2 ST3 ST4

17 HIGHER EFFICACY OBSERVED IN CHILDREN WHO WERE DENGUE SEROPOSITIVE AT BASELINE 1,2 Intent-to-treat analysis (follow-up from months 0 25) แสดงว า ว คซ น prime ไม ด แต boost ได ด 1 Dengue status + at baseline CYD 14 1 CYD , , Dengue Status** - at baseline CYD 14 1 CYD ,5 43, Comparison made on ITT. RR=relative risk: incidence of VC dengue cases in CYD group vs control group. ** Dengue +: baseline titer for at least 1 DENV serotype is 10 1/dil. 1. Capeding, 2014, Lancet. 2. Villar, 2014, N Engl J Med 17 APPROVED FOR EXTERNAL USE BY AUTHORIZED PERSONS SPGLB.DENG

18 The finding that the vaccines confer higher efficacy in those with baseline antibody rejected the theory of antibody-dependence enhancement (ADE)

19 Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease: Efficacy wane over the time esp. in youngers Hadinegoro SR. N Engl J Med Jul 27.

20 Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease (CYD 14, CYD 15: up to 3 years; CYD 23 (57): year 3-4) Hadinegoro SR. N Engl J Med Jul 27.

21 Against virologic confirm diseases Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease: by serotype Hadinegoro SR. N Engl J Med Jul 27.

22 Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease: By disease severity Hadinegoro SR. N Engl J Med Jul 27. [Epub ahead of print]

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26 ว คซ นด จะม ประส ทธ ภาพป องก นโรคได 30-66% ป องก นการนอน รพ.ได 67-80% ป องก นโรคได ด ในเด กท ม ภ ม อย ก อน แต เม อเวลาผ านไป ประส ทธ ภาพด จะลดลงไปเร อยๆ จนหมดประสทธ ภาพในป ท 3 ในเด กอาย <9 ป เด กอาย 2-5 ป อาจเส ยงต อโรคมากข นในป ท 3 ผ ผล ตจ งขอข นทะเบ ยนใช ก บอาย 9-45 ป

27 CONSISTENT EFFICACY PROFILE IN SUBJECTS 9 16 YEARS OF AGE DURING THE EFFICACY PHASE SPGLB.DENG Key Efficacy Results 25-month active phase* Pooled efficacy analyses 1 Reduction in symptomatic dengue 65.6% (95% CI: ) Reduction in hospitalized dengue 80.8% (95% CI: ) Reduction in severe dengue 93.2% (95% CI: ) *Data come from the 2 pivotal, phase III, large-scale efficacy trials CYD14 and CYD15, which were designed to fully assess efficacy; postdose 1; 1 Full Analysis Set for Efficacy (FASE): all subjects who received at least one injection. dengue hemorrhagic fever, World Health Organization 1997 criteria. CI=confidence interval; DENV=dengue virus.

28 SAFETY OVERVIEW AFTER ANY DENGUE VACCINE OR PLACEBO DOSE SUBJECTS AGED 9 60 YEARS: SAFETY POOLED ANALYSIS* Unsolicited non-serious AE Placebo (n=1780) CYD vaccine (n=4615) Solicited systemic reaction Solicited injection site reaction Solicited AR Immediate unsolicited AR Percentage of subjects presenting with at least 1 reaction or event *Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51). AE=adverse event; AR=adverse reaction.

29 OVERVIEW OF SAFETY : SOLICITED INJECTION SITE REACTIONS 1 (AGE 9 60 YEARS) - SAFETY POOLED ANALYSIS* %, 95% CI Solicited injection site reaction Adults aged years Subjects aged 9 17 years Grade 3 solicited injection site reaction Adults aged years Subjects aged 9 17 years Pain Adults aged years Subjects aged 9 17 years Erythema Swelling Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years *Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51). AE=adverse event; AR=adverse reaction.

30 OVERVIEW OF SAFETY : SOLICITED SYSTEMIC REACTIONS 1 (AGE 9 60 YEARS) - SAFETY POOLED ANALYSIS* %, 95% CI Solicited systemic reaction Grade 3 Fever Headache Malaise Myalgia Asthenia Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years Adults aged years Subjects aged 9 17 years *Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51). AE=adverse event; AR=adverse reaction.

31 It is still debating whether the vaccine with 30-66% efficacy (prevent 67-80% hospitalization); may not prevent Dengue2 would be good enough. BUT -It would be a good booster for those who already are immune -It will create herd immunity -It will decrease burden of disease

32 When the President visited Paris for the COP21 [21st Conference of Parties], he had a meeting with the executive of this company and we were given an additional 34 percent discount According to the Health secretary, the Philippines has been spending P16 billion a year to combat dengue. Garin added that the government has already set P3 billion in the 2016 budget for the dengue vaccine

33 Thank you