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Dengue and Dengue Vaccines

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Dengue and Dengue Vaccines Dengue and Dengue Vaccines Anna P Durbin Johns Hopkins Bloomberg School of Public Health Pathogen, disease and unmet medical need • Dengue is a member of the Flavivirus family – Dengue, Yellow fever virus, Japanese encephalitis virus • Four dengue serotypes • Endemic in all tropical and subtropical regions of the world • Mosquito-borne disease – Dengue is the most important arboviral infection world-wide – Aedes species are the primary vector Pathogen, disease and unmet medical need • Nearly 4 billion people at risk – 400 million infections annually • ~ 100 million are symptomatic • ~ 500,000 severe cases • Mortality rate ranges <1% - >10% Messina et al, Nature Reviews, Vol 13 2015 Pathogen, disease and unmet medical need • Treatment for dengue is supportive only – No antiviral agents • Currently there is no licensed vaccine – The first dengue vaccine will likely be registered very soon • Prevention of dengue is primarily vector control centered around outbreaks Pathogen, disease and unmet medical need • Although dengue cases can occur year- round in endemic areas, outbreaks are seasonal • Large outbreaks occur every few years in endemic areas • Dengue outbreaks overwhelm health care systems • Great pressure in endemic areas for a dengue vaccine Pathogen, disease and unmet medical need • Target population for a dengue vaccine may differ by region • In areas that have had multiple serotypes circulating for generations (Asia), the target group is children ~ 1 year of age • In areas that have more recently become hyper- endemic (Latin America), adults bear a significant amount of disease burden • The burden of disease may vary by region within a country (Brazil) • Most countries will want to target children for vaccination Vaccine development: background • Four DENV serotypes all capable of causing the full spectrum of disease (need for a tetravalent vaccine) • Life-long homotypic protection afforded after infection but only short term (months) heterotypic protection is afforded • Secondary infection with a different serotype is strongly associated with severe disease – Antibody-mediated enhancement of infection Vaccine development: background • Humans, some NHP, and mosquitoes are the only natural hosts – DENV replicates in NHP but does not cause disease • Immunodeficient mouse models exist but do not fully replicate human disease – AG129 (IFN훼/훽 and IFN훾 receptor deficient) – Humanized NOD/SCID mouse • DENV generally need to be adapted to replicate in mice Vaccine development: background • The plaque reduction neutralization titer (PRNT) assay has been the gold standard for measuring the immune response to dengue/dengue vaccines • Primary human monocytes or immortalized cell lines (K562, U936) have been used to detect enhancing antibody • Currently no single assay that measures both neutralizing and enhancing antibody • The role of cellular immunity in protection against severity of illness is being studied Vaccine development: background • Correlates of protection currently do not exist – Neutralizing antibody thought to be a correlate but a Phase 2b efficacy trial of a dengue candidate vaccine demonstrated no efficacy against DENV-2 despite the presence of neutralizing antibody – The PRNT assay is currently performed in cells that do not express the Fc훾R and therefore do not measure enhancing antibody Vaccine development: background • Endpoint for licensure is demonstrated efficacy against symptomatic dengue of any severity – Efficacy against each of the four serotypes is not required – All four serotypes do not circulate in the same place at the same time with high enough frequency to power a study for this outcome Vaccine development: background • Risk of enhanced disease as vaccine induced immunity wanes is a great safety concern for dengue vaccines – Antibody-dependent enhancement • Longer-term safety follow-up of subjects enrolled in dengue vaccine trials is required (3 – 5 years at least, the longer the better) Vaccine development: pipeline • Live attenuated tetravalent vaccines – CYD-TDV (Sanofi-Pasteur) – TV003/TV005 (U.S. NIH) – TDV (Takeda) • Purified inactivated tetravalent vaccine – WRAIR, GSK • Sub-unit protein vaccine (V180) CYD-TDV • Live attenuated tetravalent chimeric vaccine • Administered as 3 doses on a 0/6/12 month schedule DENV-1 DENV-2 DENV-3 DENV-4 YFV NS proteins are from YFV 17D CYD-TDV • Completed a Phase 2b trial – Thailand (CYD23) • Enrolled 4002 children between 4-11 • Completed two pivotal Phase 3 trials – Asia (CYD14) • Enrolled 10,275 children between 2 – 14 • Thailand, Indonesia, Malaysia, Philippines, and Viet Nam – Latin America (CYD15) • Enrolled 20,869 children between 9 – 16 • Colombia, Brazil, Mexico, Puerto Rico, and Honduras CYD-TDV efficacy trials • All studies randomized 2:1 vaccine:placebo • Primary efficacy endpoint was prevention of symptomatic dengue of any severity • Efficacy was determined from 28 days following the third dose of vaccine to month 25 (12 month period) Efficacy and long-term follow-up periods Hadinegoro et al, NEJM, 2015 Efficacy1 of CYD-TDV Vaccine Overall Efficacy in Efficacy in recipients Efficacy (95% seropositive seronegative Trial Region enrolled Age CI) at baseline at baseline 30.2 Not Not CYD232 Thailand 2,669 4-11 (-13.4-56.6) reported reported 56.5 74.3 35.5 CYD143 SE Asia 6,851 2-14 (43.8-66.4) (53.2-86.3) (-26.8-66.7) 60.8 83.7 43.2 CYD154 Latin America 13,920 9-16 (52.0-68.0) (62.2-93.7) (-61.5-80) 1. Per protocol analysis. Period of primary efficacy evaluation was > 28 days after the third dose to month 25 (12 month period) 2. Sabchareon, The Lancet, 2012 3. Capeding et al, The Lancet, 2014 4. Villar et al, NEJM, 2014 Efficacy1 of CYD-TDV by serotype Overall Study Efficacy DENV-1 DENV-2 DENV-3 DENV-4 30.2 55.6% 9.2% 75.3% 100% CYD23 (-13.4-56.6) (-21.6 - 84) (-75 – 51.3) (-37.5 – 99.6) (24.8 – 100) 56.5 50.0% 35.0% 78.4% 75.3% CYD14 (43.8-66.4) (24.6 – 61.0) (-9.2 – 61.0) (52.9 – 90.8) (54.5 – 87.0) 60.8 50.3% 42.3% 74.0% 77.7% CYD15 (52.0-68.0) (29.1 – 65.2) (14.0 – 61.1) (61.9 – 82.4) (60.2 – 88.0) 1. Per Protocol analysis 2. Sabchareon, The Lancet, 2012 3. Capeding et al, The Lancet, 2014 4. Villar et al, NEJM, 2014 Efficacy of CYD-TDV by age (CYD14) Age / Serostatus Vaccine efficacy % (95% CI) 2 – 5 years 33.7 (11.7; 50.0) 6 - 11 years 59.5 (48.9; 68.0) 12 -14 years 74.4 (59.2; 84.3) Seropositive 74.3 (53.2; 86.3) Seronegative 35.5 (-26.8; 66.7) Efficacy CYD-TDV summary • Efficacy varied by: – Region – Serotype – Serostatus at baseline – Age • Post-hoc analysis demonstrated efficacy against hospitalized dengue (67.2% CYD14, 80.3% CYD15) CYD long-term safety follow-up • Re-enrolled participants from CYD23 for longer-term safety follow-up (CYD57) – Data available for 3203/4002 (80%) • Follow-up data available for 99% of CYD14 and 95% CYD15 participants • Long-term safety analyses based on data collected during year 3 of CYD14 & CYD15 and years 3 and 4 of CYD23/57 Incidence of hospitalization in first year of long-term follow-up Vaccine Group Control Group Cases Total Cases of Total Relative risk Trial dengue subjects dengue subjects (95% CI) CYD14 All subjects 27 6,778 13 3,387 1.01 (0.52-2.19) 2-5 yr 15 1,636 1 813 7.45 (1.15-313.8) 6-11 yr 10 3,598 8 1,806 0.63 (0.22-1.83) 12-14 yr 2 1,544 4 768 0.25 (0.02-1.74) < 9 yr 19 3,493 6 1,741 1.58 (0.61-4.83) ≥ 9yr 8 3,285 7 1,646 0.57 (0.18-1.86) CYD15 All subjects 16 13,268 15 6,630 0.53 (0.25-1.16) 9 - 11 10 6,029 9 3,005 0.55 (0.2-1.54) 12 - 16 6 7,239 6 3,625 0.50 (0.13-1.87) Efficacy against hospitalization over time Trial Cases M Cases M RR (95% CI) CYD14-All participants Year 1 (Day 0 – Dose 3) 20 6,848 26 3,424 0.38 (0.20; 0.72) Year 2 (Dose 3 – month 25) 20 6,812 35 3,407 0.29 (0.16; 0.51) Year 3 27 6,778 13 3,387 1.04 (0.52; 2.19) Day 0 – Year 3 67 6,813 73 3,406 0.46 (0.32; 0.65) CYD15-All participants Year 1 (Day 0 – Dose 3) 5 13,915 15 6,939 0.17 (0.05; 0.48) Year 2 (Dose 3 – month 25 12 13,522 28 6,749 0.21 (0.10; 0.43) Year 3 16 13,268 15 6,630 0.53 (0.25; 1.16) Day 0 – Year 3 33 13, 568 58 6,773 0.25 (0.18; 0.44) Summary of long-term follow-up data • In the CYD14 trial, the pre-specified age- specific analysis showed a clear trend toward a high RR for hospitalization for virologically confirmed dengue among young children – RR if age <9 = 1.58 (0.61; 4.83) – RR if age ≥ 9 = 0.57 (0.18; 1.86) • This trend was not apparent in CYD15 (all participants were ≥ 9) – RR = 0.53 (0.25; 1.16) Summary of CYD-TDV • 3 Doses of vaccine given over 12 months (0/6/12) • Variable efficacy based on region, serotype, age at vaccination, serostatus at vaccination • RR of hospitalization increased over time for vaccine recipients who were < 9 at time of vaccination • Licensure being sought for those ≥ 9 years of age NIH dengue vaccine TV003/TV005 • Live attenuated tetravalent vaccine given as a single dose • Primary attenuation mutation is 30 nt deletion in 3´ UTR • One component is a chimeric virus TV003/TV005 Dose of each component (log10PFU) DENV-1 DEN-2 DEN-3 DENV-4 TV003 3,3,3,3 rDEN1Δ30 rDEN2/4Δ30 rDEN3Δ30/31 rDEN4Δ30 TV005 3,4,3,3 rDEN1Δ30 rDEN2/4Δ30 rDEN3Δ30/31 rDEN4Δ30 rDEN1Δ30 DENV-1 rDEN2/4Δ30 DENV-2 rDEN3∆30/31 DENV-3 rDEN4Δ30 DENV-4 TV003/TV005 • Evaluated in numerous Phase I trials in the U.S.
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