Barney S. Graham, MD, PhD
XIX International AIDS Conference
Workshop on Correlates of Immunity in Vaccine Research
July 23, 2012
V accine
R esearch
C enter
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Department of Health and
Human Services
For more information:
1-866-833-LIFE vrc.nih.gov
VRCforLIFE@mail.nih.gov

Measures of Vaccine Efficacy (VE)
– To prevent infection
– To prevent disease
– To control or reduce disease
– To prevent transmission to susceptible individuals
– To control epidemic spread of infection
VEs
VEp
VEi
2

Factors required to maintain an epidemic
Susceptible host
Transmission
Exposure
Attachment
Physical barriers or
Pre-existing antibody
Invasion or resistance
Innate response
Evasion or abortive replication
Adaptive response
Persistence or clearance
Elements of host immunity
Individual
Population
Points where vaccination can influence an epidemic
3

R o
=
  c

D
R o
= reproductive rate of agent in a population

= transmission efficiency c = rate of partner change or new exposures
D = duration of infectious period
If R
0
If R
0
< 1 epidemic will contract
>1 epidemic will expand
R o
Vaccine-induced antibody reduces transmission efficiency
 c
Reduced exposure risk
D
Vaccine-induced
T cell response reduces virus load and shedding
4



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

Conventional trial progression
Trial
Design
Randomization
Data
Analysis
Typically small number of study groups
Adaptive trial design
Trial
Design
Randomization
Could start with multiple study groups and continuously roll in additional groups
Real-
Time
Data
Analysis
New Trial
Design
Randomization
Modifiy:
Size
Populations
Primary outcome
Randomization or allocation
Data
Analysis
Data
Analysis
Outcome
Outcome
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.
Koup, Graham, Douek. Nature Reviews Immunology 2011; 11:65-70.
6

Isolated virion
Virus-infected cell
Latency or extracellular sequestration
Antibody
T cells
+++
-
+/-
+++ -
-

gp160/gp120 subunits
Poxvirus vector + protein
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 rAd5-gag/pol/nef
DNA/rAd5-Env/gag/pol/nef
Pivotal basic & clinical research discoveries
Antibody
CD8 T cells
8

VaxGen
Step
RV144
HVTN 505
Schedule (months)
0 1 2 3 6
+ +
Rate of Infection (%) Efficacy
Vaccine Placebo
5.7 5.8 0
7.3 5.0 ↑ 31.5% (NS)
0.6 0.9 ↓ 31.2% (p=.04)
1st interim analysis 3Q2013 ?
9

Months 0 1 2 3 6 9 12
CMV-R promoter
Env A
Env B
Env C gag B pol B nef B rAd5
Env A
Env B
Env C gag/pol B
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.
11

HVTN 505 Groups
Group 1: Vaccine
Group 2: Placebo
N
1100
1100
Day 0
DNA
(4 mg)
PBS
Prime
Wk 4
DNA
(4 mg)
PBS
Wk 8
DNA
(4 mg)
PBS
Boost
Wk 24 rAd5
(10 10 PU)
FFB
• 80% power to detect 50% reduction in HIV-1 acquisition
• 93% power to detect 1 log
10
84% power if VE=50% reduction in setpoint VL if VE=0;
12

HVTN 505: Primary Endpoints
Week 28 (4 weeks post-boost) through Month 24
Post-infection diagnosis visit schedule
Weeks 0 2 4 6 8 10 12 14 16 20 24
Diagnosis of HIV Infection
Acquisition (VE) endpoint
VL endpoint
VL setpoint = average of all values between week 10 and 20 after diagnosis study visit and prior to ART initiation
13

HVTN 505 Enrollment through July 7, 2012
Average enrollment over past 40 weeks (since Oct 1,2011) = 14.6 ppts/wk
14

Non-Efficacy Stopping Boundary: VE(24)
Non-
Efficacy
Interim
Analysis
1
2
3
No. Week 28+
Infections w/
20 weeks of Post-Dx
Follow-up
30
48
66
Expected
No. Week
28+
Infections if
VE(24)= 0%
43
61
77
Est.
VE(24)%
Stopping
Boundary
9.1%
17.4%
21.8%
No. Vaccine :
No. Placebo
Week 28+
Infections
21:22
28:33
34:43
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 15

• Is the rate of HIV acquisition reduced by >50%?
• Is mean VL reduced by >1 log
10 genome copy/ml?
• Is there a sieve effect or selective escape from vaccineinduced antibody or T cell responses in breakthrough viruses?
• Is there an immune correlate of protection?
16

Future trials will compete with other preventive approaches
2009 2010 2011 2012 2013 2014 2015 2016 2017
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
Safety & Futility V(E), VL, & correlates RV 144
HVTN 505 ♦
Next potential efficacy trial
CAPRISA 004
TDF microbicide gel
39% efficacy
Enrollment Follow-up
Final analysis
Interim analysis
CDC 4370 TDF/FTC PrEP in IVDU – Thailand
VOICE – TDF oral &TDF gel microbicide – South & East Africa – stopped early
HPTN 052 – Treatment of discordant couples – global - 96% efficacy
Partners PrEP TDF/FTC
– East Africa - 62-73% efficacy
FEM-PrEP TDF/FTC
– Africa – stopped early – no efficacy
CDC 4940 TDF/FTC PrEP in heterosexuals – Botswana - 63% efficacy iPrEx TDF/FTC PrEP
– Americas – 44% efficacy MSM
17

• 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

• Preparation for correlates analysi s
• 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

V1
V2 alpha4,beta7 interaction motif
His
6
Pinter A, et al.
Vaccine 16:1903, 1998
Murine leukemia
Virus gp70
20

V1V2/glycan (aa160N-165I) V3/glycan (aa332N) membrane proximal domain
+ lipid
CD4 binding site
(aa368D) gp120 inner domain gp120 outer domain bridging sheet
McLellan, Ofek, Zhou, Zhu, Kwong 21

Blood or mucosal exposure
Regional spread
18-72 hours
Systemic Dissemination between 4 and
12 days
Latency
Infection of immunoprivileged sites & sequestration
22

Blood
IVDU
No physical barrier, abundant target cells
Rectal mucosa
MSM
Weak physical barrier, many target cells
Cervical/vaginal mucosa
Thai general population
Strong physical barrier, sparse target cells
23

Chair: Scott Hammer
Co-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

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