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VaccineResearchCenterNational Institute of Allergy
and Infectious DiseasesNational Institutes of HealthDepartment of Health and
Human Services
For more information:[email protected]
HVTN 505: Objectives and Timelines
Barney S. Graham, MD, PhDXIX International AIDS Conference
Workshop on Correlates of Immunity in Vaccine Research
July 23, 2012
The Goals of Vaccination
• Individuals– To prevent infection– To prevent disease– To control or reduce disease
• Population– To prevent transmission to susceptible individuals – To control epidemic spread of infection
Measures of Vaccine Efficacy (VE)
VEs
VEp
VEi
2
Transmission
Persistence or clearance
Attachment
Innate response
Adaptive response
Physical barriers orPre-existing antibody
Elements of host immunity
Factors required to maintain an epidemic
Population
Individual Points where vaccination can influence an epidemic
Susceptible host
Invasion or resistance
Exposure
Viral Interaction with Individual Host and Population
Evasion or abortive replication
3
Ro = c DRo = reproductive rate of agent in a population = transmission efficiencyc = rate of partner change or new exposuresD = duration of infectious period
If R0 < 1 epidemic will contract
If R0 >1 epidemic will expand
Reduced exposure
risk
Vaccine-induced T cell response reduces virus
load and shedding
Vaccine-induced antibody reduces transmission efficiency D
c
Ro
How can vaccines impact an epidemic?
4
What is an immunological correlate?
Correlate - An immune response (biomarker) that is statistically correlated with a clinical outcome Correlate of risk (CoR) - Statistically correlated with the rate of HIV
infection in the vaccine group (Qin et al., JID, 2007) Correlate of protection (CoP) - Statistically correlated with vaccine efficacy
in the vaccine and placebo groups (Plotkin and Gilbert, CID, 2012)• nCoP: nonmechanistic CoP is an immune response indirectly associated with protection
mCoP: mechanistic CoP is an immune response causally responsible for protection Surrogate – an immune response that can be used as a substitute
endpoint for clinical efficacy Specific - Predictive of VE for a particular vaccine platform or study
population General - Predictive of VE in different settings (e.g., across vaccine
platforms, study populations, viral populations, or species)
5
Trial Design
New Trial Design
Modifiy: Size
PopulationsPrimary outcome
Randomization or allocation
Outcome
Real-TimeData
Analysis
Trial Design Randomization
Data Analysis
Could start with multiple study groups and continuously roll in
additional groups
Data Analysis
Randomization
Outcome
Adaptive trial design
Conventional trial progression
Randomization
Typically small number of study groups
The key for adaptive vaccine trials to gain efficiency is to analyze study endpoints while accrual is ongoing. This is possible for vaccine studies using a surrogate endpoint based on the identification of an immune correlate, but not if the endpoint is infection since it is likely that sufficient data would not be available until accrual is completed.
Data Analysis
Why is it important to identify immune correlates?
6Koup, Graham, Douek. Nature Reviews Immunology 2011; 11:65-70.
Antibody
T cells +++
+/-+++ -
--
Virus-infected cell
Latency or extracellular sequestration
Isolated virion
How do adaptive immune responses control virus infection?
Brief History of HIV Vaccines
87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13
gp160/gp120 subunits
Poxvirus vector + protein
rAd5-gag/pol/nef
DNA/rAd5-Env/gag/pol/nef
Rela
tive
focu
s on
vac
cine
eff
ecto
r mec
hani
sms
CD8 T cells
Pivotal basic & clinical research discoveries
8
Antibody
HIV Vaccine Efficacy Trial Outcomes
0 1 2 3 6 Vaccine PlaceboRate of Infection (%) Efficacy
1st interim analysis 3Q2013 ?
5.7 5.8 0
0.6 0.9 ↓ 31.2% (p=.04)++RV144
7.3 5.0 ↑ 31.5% (NS)Step
HVTN 505
VaxGen
Schedule (months)
9
HVTN 505
0 1 2 12Months 3 6 9
Env AEnv BEnv C gag Bpol Bnef B
CMV-R promoter
Env AEnv BEnv Cgag/pol B
rAd5
10
Phase 2b, Randomized, Placebo-Controlled Test-of Concept Trial to Evaluate the Safety and Efficacy of a Multiclade HIV-1 DNA Plasmid Vaccine Followed by a
Multiclade Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Adenovirus Type 5 Neutralizing Antibody Negative, Circumcised Men and Male-to-Female
Transgender Persons Who Have Sex with Men
Short Title: VRC DNA/rAd5 Multiclade, Multigene HIV-1 Vaccine Regimen in HIV(-) MSM
Version 3.0
Principal Investigator - Scott M. Hammer, M.D.
HVTN 505
11
HVTN 505: Vaccination Schedule
Prime Boost
HVTN 505 Groups N Day 0 Wk 4 Wk 8 Wk 24
Group 1: Vaccine 1100DNA
(4 mg)DNA
(4 mg)DNA
(4 mg)rAd5
(1010 PU)
Group 2: Placebo 1100 PBS PBS PBS FFB
• 80% power to detect 50% reduction in HIV-1 acquisition• 93% power to detect 1 log10 reduction in setpoint VL if VE=0;
84% power if VE=50%
12
HVTN 505: Primary EndpointsWeek 28 (4 weeks post-boost) through Month 24
Post-infection diagnosis visit schedule
VL setpoint = average of all values between week 10 and 20 after diagnosis study visit and prior to ART initiation
Weeks 0 4 122 24106 8 16 2014
Diagnosis of HIV InfectionAcquisition (VE) endpoint
VL endpoint
13
HVTN 505 Enrollment through July 7, 2012
14Average enrollment over past 40 weeks (since Oct 1,2011) = 14.6 ppts/wk
Non-Efficacy Stopping Boundary: VE(24)
Non-Efficacy Interim
Analysis
No. Week 28+ Infections w/
20 weeks of Post-Dx Follow-up
Expected No. Week
28+ Infections if VE(24)= 0%
Est. VE(24)%Stopping Boundary
No. Vaccine :No. Placebo
Week 28+ Infections
1 30 43 9.1% 21:22
2 48 61 17.4% 28:33
3 66 77 21.8% 34:43
15
Note that a final analysis point estimate of VE(24)=36% (31:46 vaccinee:placebo distribution of infections) would have P<0.05.
Peter Gilbert
What will we learn from HVTN 505?
• Is the rate of HIV acquisition reduced by >50%?• Is mean VL reduced by >1 log10 genome copy/ml?
• Is there a sieve effect or selective escape from vaccine-induced antibody or T cell responses in breakthrough viruses?
• Is there an immune correlate of protection?
16
HVTN 505 Timeline
1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4
RV 144
Enrollment Follow-up
HVTN 505
Safety & Futility
20172013 2014 2015 2016
Next potential efficacy trial
♦
2009 2010 2011 2012
V(E), VL, & correlates
Final analysis
Interim analysis
17
CDC 4370 TDF/FTC PrEP in IVDU – Thailand
iPrEx TDF/FTC PrEP – Americas – 44% efficacy MSM
CAPRISA 004TDF microbicide gel
39% efficacy
Partners PrEP TDF/FTC – East Africa - 62-73% efficacy
HPTN 052 – Treatment of discordant couples – global - 96% efficacy
CDC 4940 TDF/FTC PrEP in heterosexuals – Botswana - 63% efficacy
VOICE – TDF oral &TDF gel microbicide – South & East Africa – stopped early
FEM-PrEP TDF/FTC – Africa – stopped early – no efficacy
Future trials will compete with other preventive approaches
Considerations in Choosing Endpoints for the Correlates Analysis
• Strength of association between the immune response and the rate of HIV infection in vaccinees
• Dynamic range of the immune response in vaccinees• Precision of assay for measuring functionally relevant
response • Number of Week 28+ infected vaccinees
– The correlates analysis is based on comparing infected vaccinees with control vaccinees who are not infected
18
HVTN 505: Scientific Planning
• Preparation for correlates analysis• Marker Working Group established to direct and prioritize activities
(Scott Hammer and Peter Gilbert co-Chairs)• Pilot studies to down-select assays for immune correlates not used in
RV144• Confirm specificity and sensitivity, background levels, controls of
assays to be used• Real-time analysis
• Sequencing of breakthrough viral isolates• Selected humoral and cellular immune studies• TDF/FTC levels
• Mucosal studies have been added to last 1/3 of subjects• Optional rectal secretion and semen sampling for antibody and
cytokine analysis
19
V1V2
gp70
His6
Pinter A, et al.Vaccine 16:1903, 1998
Scaffold:Murine leukemia Virus gp70
HIV-1 V1V2
Scaffolded gp70-V1V2 Protein
V1V2 alpha4,beta7
interaction motif
20
membrane proximal domain + lipid
V3/glycan (aa332N)
CD4 binding site (aa368D)
V1V2/glycan (aa160N-165I)
gp120inner domain
gp120 outer domain
bridging sheet
McLellan, Ofek, Zhou, Zhu, Kwong
Prototypic Antibodies for Broad Neutralization of HIV-1
21
Transmission bottleneck is point of greatest vulnerability
Blood or mucosal exposure
Regional spread18-72 hours
Systemic Disseminationbetween 4 and 12 days
Latency
Infection of immunoprivileged
sites & sequestration
22
Study population is important
Weak physical barrier, many target cells
Strong physical barrier, sparse target cells
No physical barrier, abundant target cells
Rectal mucosa
Cervical/vaginal mucosa
Blood
Thai general population
IVDU
MSM
23
HVTN 505 Protocol Team
Chair: Scott HammerCo-Chairs: Magdalena Sobieszczyk & Michael Yin
Protocol Team Leader: Shelly Karuna
Biostatisticians: Peter Gilbert, Holly Janes, Doug Grove & Amy Krambrink
DAIDS Medical Officers: Chuka Anude & Elizabeth Adams
VRC Developer Representatives: Barney Graham & Mary Enama
VRC Immunologist: Richard Koup
Core Medical Monitor: Shelly Karuna
HVTN Laboratory Program: John Hural & Julie McElrath
Clinical Trials Manager: Shelly Mahilum
Protocol Development Coordinator: Carter Bentley
SDMC Senior Project Manager: Drienna Holman
SDMC Project Manager: Diana Lynn
SDMC Clinical Affairs: Pat Farrell
DAIDS Pharmacist: Ana Martinez
DAIDS Regulatory Affairs: Michelle Conan-Cibotti
HVTN Regulatory Affairs : Renee Holt
HVTN Pharmacist: Jan Johannessen
Community Ed Unit Representative: Gail Broder
Communications: Jim Maynard
Community Engagement: Steve Wakefield
Community Educators/Recruiters: Coco Alinsug & Jason Roberts
CAB Members: Rick Church & Rich Trevino
Clinic Coordinator: Steven Chang Clinical Trials Manager
HVTN Investigators: Susan Buchbinder, Mike Keefer, Beryl Koblin, & Mark Mulligan
Technical Editor: Adi Ferrara 24
VaccineResearchCenter
National Institute of Allergy and Infectious Diseases
National Institutes of Health
1-866-833-LIFEwww.vrc.nih.gov
