review of published data from dengue phase iib and iii ... 04 longini_paho3.pdfreview of published...
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Review of published data from dengue phase IIb and III
vaccine clinical trials
Ira Longini
Department of Biostatistics
Center for Statistical and Quantitative Infectious Diseases (CSQUID)
Emerging Pathogens Institute
University of Florida Principles for the evaluation of the Effectiveness of Dengue Vaccines
June 11-13, 2014
Pan American Health Organization
http://csquid.org/
Emerging Pathogens Institute University of Florida
Department of Biostatistics
Dauer Hall: UF Campus
Vaccine and Infectious Disease Division Hutchinson Research Center
6
Measures of Vaccine Efficacy
{VE(t)S , VE(t)P , VE(t)I}
• VES Vaccine Effect on Susceptibility
• VEP Vaccine Effect on Clinical Disease
• Classical III vaccine trials
Many times observe
VESP = 1 – (1 – VES) (1 – VEP)
• VEI Vaccine Effect on Infectiousness
Immune correlate is important
• Ideally an immune surrogate for VE would be found
• Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center in Seattle, is working on this with Sanofi data from the vaccine trials.
Infection rates by pre-season HA antibody titer:
influenza A(H3N2) epidemic season 1977-1978
and 1980-1981 combined,
Tecumseh, Michigan *
Pre-season
antibody titer
(1:X)
No.
observed
Fraction Infected
Infection Antibody
Efficacy [95% CI]]
< 8 836 0.23 -
8 267 0.14 0.39 [0.16,0.56]
16 153 0.06 0.74 [0.51,0.86]
32 137 0.09 0.61[0.33,0.77]
64 87 0.05 0.78 [0.45,0.91]
≥ 128 26 0.00 1.00
*Source: Longini, et al. AJE (1988)
Influenza: HI titer as a surrogate for VESP
Source: Coudeville et al. BMC Medical Research Methodology 2010, 10:18
Dengue vaccines • Dengue vaccine development has accelerated
over past decade
• Numerous candidates in clinical trial
• Live attenuated
• Sub-unit protein
• Purified inactivated
• Novel strategies for vaccine development being tested pre-clinically
• Virus-vectored
• DNA
• Virus-like particle (VLP)
Vaccines in clinical trials
Name of
vaccine Manufacturer Type of vaccine Phase
CYD Sanofi Pasteur Live attenuated 3
DENVax Takeda (Inviragen) Live attenuated 2
TV003 US NIH, Instituto
Butantan
Live attenuated 2
TDEN-PIV GSK Purified inactivated 1
V180 Merck Purified subunit 1
DEN1ME100 US NMRC DNA 1
(completed)
Source: Anna Durbin, Johns Hopkins Bloomberg School of Public Health
Sources of VE Heterogeneity
• Mixtures of circulating serotypes
• Baseline immunity before the trial
• Circulating serotypes and genotypes during the trial
• Different reproductive numbers and transmission patterns
• Different genotypes within serotypes circulating
• Other factors: immunologic, epidemiologic, entomologic and demographic, e.g., age structure
• Estimates of VE under heterogeneity
Phase IIb and III vaccine trials of Sanofi Pasteur tetravalent dengue
vaccine • Phase I and II in many countries
• Phase IIb completed in Thailand (CYD23)*
• Phase III will be completed late in 2014
• 5 countries in SE Asia (CYD14)
• 5 countries in Latin America (CYD15)
*Sabchareon, et al. Lancet (2012)
CYD 23 Phase IIb Vaccine Trial
• Rachiburri, Thailand
• 4,002 Thai children aged 4-11
• 2:1 vaccine to placebo randomization
• Immunogenicity subset: 300 children
CYD 23 Phase IIb Vaccine Trial
Sabchareon, Lancet, Sept. 11, 2012
CYD 23 Phase IIb Vaccine Trial
Sabchareon, Lancet, Sept. 11, 2012
Results of Vaccine Trial Intent to Treat Analysis*
• VESP1-4 : 34.9 (6.7 – 54.3)
• VESP1 : 61.2 (17.4 – 82.1)
• VESP2 : 3.5 (-59.8 – 40.5)
• VESP3 : 81.9 (38.3 – 95.8)
• VESP4 : 90.0 (10.6 – 99.8)
• VEP = ? (Symptoms about same in vaccine and placebo arms)
• VEI = ? (NS1-antigen positivity a bit higher in vaccinated)
*Sabchareon, et al. Lancet (2012)
Overall Efficacy Really is a Weighted Average
where the wi are the weights for the frequencies of serotypes in the placebo arm.
, i = 1,2,3,4
W = (0.30, 0.44, 0.18, 0.08), and therefore VESP1-4 = 42, (95% CI:14,61)
Serotypes in Control and Vaccine Arms
• Control arm vs vaccine arm
WC = (0.30, 0.44, 0.18, 0.08) Control
WV = (0.20, 0.73, 0.06, 0.01) Vaccine
Overall Efficacy vs Proportion of Serotype 2 Circulating
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.00.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
VESP1-4
Proportion of total that is serotype 2
Overall Efficacy vs Proportion of Serotype 1 and 2 Circulating
VESP1-4
Vaccination
Dengue Modeling Consortium with Sanofi
• UF/UW/CSQUID, Ira Longini and Betz Halloran
• Imperial College, Neil Ferguson
• John Hopkins, Derek Cummings
• Next meeting in Lyon: July 2-3, 2014
CYD 14 Phase III Vaccine Trial 5 SE Asian Countries
• 10,278 2-14 year olds
• Indonesia, Malaysia, Philippines, Thailand, Vietnam
• Same design as the CYD 23
CYD 15 Phase III Vaccine Trial 5 SE Latin American Countries
• 20,875 9-16 year olds
• Brazil, Colombia, Honduras, Mexico,
Puerto Rico
• Same design as the CYD 23
CYD 14 Phase III Vaccine trial press release
Crude Overall Efficacy
• Annual incidence rate in the placebo arm was 4.7%
• Based on the trials size and the crude VE = 0.56, the 95% CI is about 0.46 – 0.66 .
Efficacy Estimates
• CYD 15 analysis will begin in the 3rd quarter of 2014.
• Results will either be separate for CYD 14 and 15 separately or combined
Funding Sources
• Dengue Vaccine Initiative/Bill and Melinda Gates Foundation
• NIH, NIAID
• R37 AI32042
• NIH, NIGMS
• U01 GM070749 (MIDAS)
Thank you