review of published data from dengue phase iib and iii ... 04 longini_paho3.pdfreview of published...

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