Transcript Phase III HIV Vaccine Trial*Thailand

RV144: Clinical Development Plans
Nelson L. Michael, M.D., Ph.D
Colonel, Medical Corps, U.S. Army
Director
US Military HIV Research Program (MHRP)
Walter Reed Army Institute of Research

IAS 2012, Washington, DC USA
The views expressed are those of the presenter and should not be construed
to represent the positions of the U.S. Army or DoD
1
23 July 2012
Past HIV Vaccine Concepts
Although only three concepts have undergone clinical efficacy testing to date,
each HIV vaccine efficacy trial has yielded unexpected outcomes that have
transformed the HIV landscape.
2003
2003: AIDSVAX
VaxGen Env gp120
Humoral Immunity
• Phase III studies in highrisk subjects in the
US/Thailand
• Elicited type-specific Abs
but not broadly reactive
NAbs
• No efficacy
2005
2007
2007: STEP-PHAMBILI
STUDIES
Merck Ad5-Gag/Pol/Nef
Cellular Immunity
• Phase IIb study in high-risk
subjects in North/South
America
• Elicited cellular immunity by
IFN-γ ELISPOT assays
• No efficacy, possible
increased HIV-1 acquisition
2009
2009: RV144
Sanofi ALVAC prime,
AIDSVAX gp120 boost
Humoral and Cellular
Immunity
• Phase III study in low-risk
subjects in Thailand
• 31% reduction in HIV-1
acquisition with no viral
load effect
Advancing HIV vaccine candidates to efficacy trials will accelerate progress in
the field, bringing us closer to an effective global vaccine.
2
2
23 July 2012
NEJM 361:2209 (03 Dec 09)
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23 July 2012
RV 144 demonstrated efficacy
for HIV acquisition

C. Modified Intention-to-Treat Analysis*
1.0
0.9
Placebo
Probability of HIV Infection (%)
0.8
0.7
0.6
0.5
Vaccine
0.4
0.3
0.2
0.1
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
N=16,395
51 vaccine, 74 placebo HIV infected
Est. VE = 31% 95% CI 1-51% (p=0.04)
4
Rerks-Ngarm et al. (2009, NEJM)
23 July 2012
What we have learned—RV 144

Protection among low incidence heterosexual Thais, VE 31.2% at
42 months

No effect on post-infection viremia or CD4 count

Relatively monophyletic circulating variants CRF01_AE

Efficacy appears to be early and non-durable

Evoked binding Ab but not measurable, primary isolate Nab— BAb
appeared early and decreased by > 10 fold over 6 months

CD4+ Env responses, but not CD8 responses

Correlate/surrogate studies limited by samples and endpoints
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23 July 2012
What we would want next

Extend the observation of early 60% efficacy by increasing the
durability of immune responses




Elucidate correlates of risk of infection.



Adequately powered studies
Adequate sample collections
Public health implementation--establish protection in higher incidence
populations (additional boosts/improved adjuvants)


6
Additional vaccine boosts
Improved adjuvants
Improved vaccines
Heterosexuals in sub-Saharan Africa
MSM in Africa and Asia
23 July 2012
RV 144 correlates of risk—a teaser

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23 July 2012
RV 144 Correlates Discovery Effort
ADVISORY GROUPS
PA H Steering Committee
Clinical Development
Product
Development
Advisory
Group
Humoral &
Innate
Immunity
Cellular
Immunity
Host
Genetics
Animal
Models
8
Scientific
Steering
Committee
MHRP - DAIDS Steering
Committee
RV144 Steering
Committee
Correlates
Scientific
Advisory Groups
23 July 2012
NEJM 366:1275 (05 Apr 2012)
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23 July 2012
Multivariate Logistic Regression: Quantitative
Variables
Variable
Relative risk P-value
Q-value
IgA Binding to Envelope Panel
1.54
0.027
0.08
IgG Avidity A244 gp120
0.81
0.37
0.56
ADCC AE.HIV-1 Infected CD4 Cells
0.92
0.68
0.68
Tier 1 Neutralizing Antibodies
1.37
0.22
0.45
IgG Binding to gp70-V1V2
0.57
0.015
0.08
CD4+ T Cell Intracellular Cytokines
1.09
0.61
0.68
All 6 variables together in multivariate analysis, P=0.08
Only a-Env IgA and IgG gp70:V1V2 binding, p = 0.009 (log reg), 0.012 (Cox)
2 individual variables were significant:
gp70 V1V2 inversely correlates with infection [q = 0.08]
Estimated 43% reduction in infection rate (per SD)
Plasma IgA directly correlates with infection
[q = 0.08]
Estimated 54% increase in infection rate (per SD)
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23 July 2012
Is it V1V2 or both?

11
23 July 2012
Case control analysis of microarray shows trend to
inverse correlation at tip of V2 and in CD4 binding site

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23 July 2012
Sieve Analysis of RV144 Breakthrough
Viruses supports importance of V2
loop

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23 July 2012
Sieve Analysis of V2

Comparison of viruses from HIV-1 infected vaccine versus
HIV-1 infected placebo recipients

These are not transmitted/founder viruses—the mean
time to last negative visit was ~ 3 months.

V2 was a major focus of analysis.

Analysis—collaboration between Dr. Morgane Rolland
(MHRP), Dr. Jim Mullins (UW), SCHARP
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Sequence variation in position 169

Edlefsen, SCHARP
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Sequence variation in position 181

Edlefsen, SCHARP
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Results: Sites 169 and 181 Separately

Genotype
No. Infections
Est. VE
95% CI
P-value
169m
87
48%
18% to 66%
0.0036
169mm
23
-45%
-258% to 33%
0.30
181m
88
-20%
-26% to 45%
0.38
181mm
22
78%
35% to 93%
0.0028
Genotypes
No. Infections
Est. HR / HR
95% CI
P-value
169mm/169
m
87/23
2.73
1.08 to 6.92
0.034
181m/181m
22/88
3.77
1.19 to 11.92
0.024
m site, VE significantly differs against match vs. mismatched infection
For each

vaccine reduced infection rate 3.77 times more for 181-mm than 181-m

Positive VE for 169-matched infection and181-mismatched infection

The sieve analysis suggests that the vaccine selectively blocked acquisition
with 169-matched and with 181-mismatched virus; but conferred no
protection against 169-mismatched or 181-matched virus
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23 July 2012
Correlates of Risk of Infection

WARNING—it is textbook (Stan Plotkin’s) knowledge that
different vaccines for the same pathogen can have different
correlates of risk/protection.

Will correlate of risk for ALVAC-AIDSVAX B/E in RV 144
generalize to….




18
These products in Thai MSM?
ALVAC-gp120 engineered for heterosexuals in Africa?
Other HIV vaccines such as DNA/Ad5 (HVTN 505 phase IIb), Ad26MVA, etc?
We want all subsequent efficacy trials to seek correlates—now
more than ever. This impacts clinical design.
23 July 2012
Collaborators
Duke
Bart Haynes
Larry Liao
Georgia Tomaras
Nathan Vandergrift
Garnett Kelsoe
David Montefiori
Thomas Kepler
Marcella Sarzotti-Kelsoe
Munir Alam
Bill and Melinda
Gates Foundation
Nina Russell
Francine McCutchan
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HVTN
Peter Gilbert
Nicole Frahm
Julie McElrath
UMDNJ
Abe Pinter
NYU/VA
Susan Zolla-Pazner
Harvard
Joseph Sodroski
Steve Harrison
Norm Letvin
IHV
George Lewis
Tony DeVico
NIH VRC
Gary Nabel
Peter Kwong
John Mascola
Marie Pancera
Jason McLellan
Thai Ministry of
Public Health
23 July 2012
Towards a Globally Effective HIV Vaccine
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23 July 2012
MHRP’s Product Development Plan
MHRP’s vaccine development strategy emphasizes regional
and global approaches.
1
BUILDING ON RV144
REGIONAL VACCINE STRATEGY
Building on the RV144 outcome and lessons learned,
conduct efficacy trials of the prime-boost concept in:
a) Thai MSM populations
b) High-risk populations in Southern Africa
2
DIVERSIFYING AND REFINING THE PORTFOLIO
GLOBAL VACCINE STRATEGY
Pursuing diverse platforms (e.g. vectors, multivalent constructs or mosaic inserts) that build on
the prime-boost concept and readily translate to
multi-clade testing and a globally effective vaccine.
21 21
23 July 2012
Pox-Protein Public Private Partnership
(NIAID-Gates led)
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23 July 2012
Planned studies are mutually reinforcing and will
amplify public health impact and regional relevance.
Precedent
for vaccine
efficacy
RV144
Focus on
regional
public health
impact
THAILAND
High Risk MSM
Mutually reinforcing
studies strengthen and
support public health
benefit in target
populations and the
translation of the
platform globally.
Future amplification
of global reach
US/EUROPE
SOUTHEAST ASIA
SOUTHERN
AFRICA
Republic of South
Africa (RSA)
High Risk
Heterosexual
Strategy for achieving potential licensure in target markets and having the
broadest public health impact.
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23 July 2012May 2011
Timeline
12
13
14
15
16
17
18
RV305
RV328
RV306
217-Vax (?)
RV348
Bridge Study
RV349
24
Go/No-Go
23 July 2012
Short-term Development Objectives
 Characterize vaccine immune responses using
samples collected



In sufficient amounts
At the right times
From systemic as well as mucosal sites
 Improve magnitude and durability of vaccine-
induced responses
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23 July 2012
Research Strategy
Three Exploratory Phase II immunogenicity trials in
Thailand



26
Collections: serum, plasma, cells, genital fluids
Special collections: leukapheresis, gut biopsy, cervical
biopsy, bone marrow aspiration (except RV305)
Broad array of humoral and cellular assays
23 July 2012
RV305 (RV144 extended boost study)
27
135+27=162
23 July 2012
RV306 (Intensive Immunogenicity)
28
404+56=460
23 July 2012
Bridging Study—from AIDSVAX/alum to delta
11/MF59

ALVAC-HIV prime as before

gp120 boost comparison:



One B and one E, both gD negative, C1 delta 11
Novartis process and MF59 adjuvant
Part A Open Label safety assessment in the U.S. for Novartis
product:
Wk
Gp
N
A1
10
29
0
A
2
4
A
8
12
24
A/N
A/N
32
48
A=ALVAC-HIV, N=Novartis rgp120B/E
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Bridging Study Part B Thailand—
compare AIDSVAX/alum vs Novartis gp120/MF59
B
Wk
Gp
N
B1*
90
A
10
B2
B3
0
2
4
8
12
24
32
48
A
A/AVX
A/AVX
A/AVX
P
P
P/P
P/P
P/P
90
A
A
A/N
A/N
A/N
10
P
P
P/P
P/P
P/P
90
A
A
A/N
A/N
A/N
10
P
P
P/P
P/P
P/P
A=ALVAC-HIV, AVX=AIDSVAX B/E, N=Novartis rgp120B/E
*Possibly use RV306 samples
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23 July 2012
Pox-Protein Development Plan
Ongoing RV144 Followup in Thailand
Research
S. Africa ph2b
Population: Heterosexual, high-risk
Products: DNA + NYVAC (sanofi) + gp140 (Polymun)/MF59 (NVD)
vs. NYVAC (sanofi) + gp140 (Polymun)/MF59 (NVD)
Objective: Extend results & accelerate evaluation of other products using
adaptive trial design and first available protein
Partners/Funders: NIH, HVTN, sanofi pasteur, Novartis, BMGF
Studies:
RV144i immune correlates studies
RV305 protein boosting study
RV306 expanded immunogenicity study
Thailand ph2b
Population: MSM, high-risk
Products: ALVAC (sanofi) + gp120/MF59 (NVD)
Partners/Funders:
US Army, Thai Gov’t, NIH, sanofi pasteur, BMGF
Candidate selection
•
•
•
•
•
31
2010
ALVAC is default vector prime
Proteins boosts TBD
RV144 immune correlates
Immune grid
Cost, product availability
2011
2012
Licensure
Objective:
Determine correlate of protection
for use in future trials; optimize the regimen
Objective: Confirm result & demonstrate efficacy in target
population with potential for licensure
Partners/Funders: US Army, Thai Gov’t, NIH, sanofi, BMGF?
Africa ph2b
Population: Heterosexual, high-risk
Products: ALVAC (sanofi) + gp120/MF59 (NVD)
Objective: Extend result & translate vaccine to Africa, other high-risk
groups
Partners/Funders: NIH, HVTN, sanofi, Novartis, BMGF, RSA?
2013
2014
2015
2016
23 July2017
2012
31
Ad26-MVA +/- protein
Barouch et al Nature 482:89-93 02 Feb 2012
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23 July 2012
Nature 482, 89–93 (02 February 2012)
100
% Uninfected
80
DNA/MVA
60
MVA/MVA
Ad26/MVA
40
MVA/Ad26
20
Sham
0
0
2
4
6
8
Number of IR Challenges
33
33
23 July 2012
MVA/Ad26 and Ad26/MVA Regimens Lower Early Setpoint Viral
Loads Following SIVmac251 Infection
9
Sham
8
8
7
7
9
MVA/MVA
418-08
8
419-08
7
420-08
6
6
422-08
5
5
423-08
4
4
5.75
3
3
2
2
0
20
40
60
80
100
424-08
Days Following Infection
446-08
5
447-08
5.47
448-08
449-08
3
2
MEAN
20
40
60
80
100
450-08
MEAN
0
20
Days Following Infection
9
40
60
80
Ad26/MVA
426-08
3x resistance to infection
409-081 log
4/8 : viremia blunted
410-08
3/8 : rapid virologic
control
411-08
1/8 : persistently uninfected
8
8
7
7
6
6
443-08
412-08
5
5
444-08
413-08
434-08
442-08
4.55
4
452-08
4
3.83
453-08
3
3
2
2
20
40
60
80
Days Following Infection
100
454-08
414-08
416-08
417-08
MEAN
0
100
Days Following Infection
9
MVA/Ad26
0
34
441-08
6
4
435-08
0
DNA/MVA
440-08
445-08
6.09
425-08
Log SIV RNA
Log SIV RNA
9
MEAN
20
40
60
80
100
Days Following Infection
23 July 2012
Protection Against Acquisition of IR SIVmac251 by
Ad35/Ad26-SIVsmE543GagPolEnv Vaccine
100
GagPol (N=16)
GagPolEnv (N=16)
% Uninfected
80
Sham (N=8)
60
40
20
0
0
2
4
6
Number of IR Challenges
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Ad26-MVA correlates analysis
•
•
36
Acquisition endpoint.
•
envelope binding antibody r= .79 p<.0001.
•
neutralization antibody r=.50 p=.0034
•
ADCC r=.38 p=.034 (trend)
set point viral load endpoint, Many correlates (N=27);
•
prechallenge gag elispot count and gag elispot breadth
were both correlated (r=-.50 p=.006 and r=-.64 p=.0002,
respectively) with the endpoint.
•
peak envelope binding antibody r=-.70 followed by
prechallenge neutralizing antibody r=.67.
23 July 2012
Summary

RV 144 demonstrated that vaccines can provide HIV acquisition
protection.

Correlates of risk of infection were discovered in RV 144.

Correlates of risk of infection in Ad26-MVA (and other) vaccines
have been discovered in NHP models.

We must educate (and remind) ourselves that correlates of risk
may or may not generalize.

There is great value (but at a cost) to seek correlates of infection
risk in future HIV vaccine trials.

Product development and scientific rationale must
communicate with each other.
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23 July 2012
Acknowledgements
Supported by:
Collaboration for AIDS Vaccine Discovery Grant From the Bill and Melinda Gates
Foundation
HVTN, DAIDS, NIAID
With Collaborations with the MHRP and Thai Ministry of Public Health
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
Division of AIDS (DAIDS)
U.S. Department of Health and Human Services (HHS)
Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-06
HVTN
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23 July 2012