RV
144
RV
144
Update:
Vaccination
with
ALVAC
and
AIDSVAX
to
Prevent
HIV‐1
Infection
in
Thai
Adults
Nelson
L.
Michael,
MD,
PhD
Colonel,
Medical
Corps,
U.S.
Army
Director,
U.S.
Military
HIV
Research
Program
(MHRP)
CROI
2010,
18
February
2010,
San
Francisco
0
CROI
2010,
San
Francisco
RV
144
1
NEJM
361:2209
(03
Dec
09)
CROI
2010,
San
Francisco
RV
144
Trial
Objectives
Primary
 
To
determine
whether
immunizaUon
with
ALVAC
®‐HIV
(vCP1521)
boosted
by
AIDSVAX®
B/E
gp120
B/E
protects
Thai
volunteers
from
HIV
infecUon.
 
To
determine
effect
of
immunizaUon
on
viral
load
a_er
inter‐
current
infecUon.
Secondary
2
 
To
determine
effect
of
immunizaUon
on
CD4
cell
count
a_er
inter‐current
infecUon.
 
To
confirm
the
safety
of
this
vaccine
combinaUon.
 
To
evaluate
whether
parUcipaUon
is
associated
with
behavior
change
increasing
risk
of
HIV
infecUon.
CROI
2010,
San
Francisco
RV
144
Study
Vaccines
ALVAC®‐HIV
(vCP1521)
 
Recombinant
canarypox
vector
vaccine
geneUcally
engineered
to
express
HIV‐1
gp120
(subtype
E:
92TH023)
linked
to
the
transmembrane
anchoring
porUon
of
gp41
(subtype
B:
LAI),
and
HIV‐1
gag
and
protease
(subtype
B:
LAI). AIDSVAX®
B/E
 
3
Bivalent
HIV
gp120
envelope
glycoprotein
vaccine
containing
a
subtype
E
envelope
from
the
HIV‐1
strain
CM244
and
a
subtype
B
envelope
from
the
HIV‐1
strain
MN. CROI
2010,
San
Francisco
RV
144
Design
4
 
Community‐based,
randomized,
double‐blind,
placebo‐
controlled
trial
(vaccine:
placebo
1:1)
 
Volunteers:
HIV
negaUve,
18‐30
years
of
age
 
Excluded:
chronic
disease,
pregnancy
or
breasceeding
 
6‐month
period
of
study
vaccinaUons
 
HIV
tesUng
every
6
months
for
3
years
post‐vaccinaUon
CROI
2010,
San
Francisco
RV
144
Vaccination
and
Follow‐up
Schedule
HIV
test,
risk
assessment
and
counseling
0.5
6‐month
vaccinaQon
schedule
1
2
3
(Qme
in
years)
3
years
of
follow‐up
(every
6
mo.)
ALVAC®‐HIV
(vCP1521)
priming
at
week
0,
4,
12,
24
AIDSVAX®
B/E
gp120
boosQng
at
week
12,
24
5
CROI
2010,
San
Francisco
RV
144
From
Screening
to
VaccinaUon
26,676
IniQal
Screen
128
Not
Referred
26,548
HIV
Test
418
HIV
seroposiQve
8,780
DisconQnued
17,350
Clinic
Screen
Up
to
45‐days
984
Ineligible
16,402
Randomized
7
Baseline
HIV
PCR
Posi;ve
422
TB/Other
Disease
341
Female
Reproduc;ve
66
Unavailable
for
3.5
years
119
Other
16,395
InfecQon
Free
8,197
Vaccine
6
8,198
Placebo
CROI
2010,
San
Francisco
RV
144
Primary
Populations
(Statistical
Analysis
Plan)
 
All
primary
analyses
were
pre‐specified
prior
to
trial
unblinding
 
Study
design
consideraUons
 
 
 
7
Based
on
ITT
analysis
in
HIV‐uninfected
subjects
Powered
to
reduce
acquisiUon
during
the
vaccinaUon
period
by
25%
Powered
to
reduce
post‐vaccinaUon
acquisiUon
by
50%
CROI
2010,
San
Francisco
RV
144
Intent‐to‐Treat
(ITT)
8
 
Examines
all
subjects,
regardless
of
HIV
infec;on
status,
who
were
randomized
to
either
vaccine
or
placebo
arm
(16,402
subjects
analyzed)
 
Includes
7
HIV
infected
subjects
(5
vaccine,
2
placebo)
discovered
to
be
HIV
infected
at
baseline
by
look‐back
analysis
CROI
2010,
San
Francisco
RV
144
Per
Protocol
(PP)
 
12,542
subjects
analyzed
 
Excludes
3,853
subjects
who
were
included
in
the
mITT
 
 
 
9
2,422
who
did
not
receive
all
six
study
injecUons
1,412
who
received
any
injecUon
“out
of
window”
19
for
other
protocol
violaUons
 
Excludes
first
6
months
(14%)
of
the
42‐month
trial
period
 
Excludes
39
HIV‐infected
subjects
(15
vaccine,
24
placebo),
reducing
the
number
of
endpoints
by
31%
CROI
2010,
San
Francisco
RV
144
Modified
Intent‐to‐Treat
(mITT)
 
Examines
all
HIV‐uninfected
subjects
who
were
randomized
 
This
was
a
pre‐specified
analysis
in
the
StaUsUcal
Analysis
Plan
 
 
10
Primary
analysis
for
DSMB
examinaUons
throughout
the
trial
Any
other
outcome
scenario
(VE
>
50%;
VL
effect
only;
no
VE
or
VL
effect)
would
have
been
based
on
the
mITT
as
the
primary
analysis
CROI
2010,
San
Francisco
RV
144
RV
144
Primary
Population
Efficacy
11

CROI
2010,
San
Francisco
RV
144
Summary
of
Analyses
ITT
N
(#
subjects)
16,402
Person
years
52,985
Vaccine/Placebo
(event
#)
56
/
76
Vaccine
efficacy
26.4%
2‐sided
p
value
0.08
95%
confidence
interval
‐4.0,
47.9
Includes
5
vaccine
and
2
placebo
recipients
who
were
HIV
posi;ve
at
baseline
12
mITT
16,395
52,985
51
/
74
31.2%
0.04
1.1,
51.2
PP
12,542
36,720
36
/
50
26.2%
0.16
‐13.3,
51.9
Decreased
event
numbers,
lower
precision
CROI
2010,
San
Francisco
RV
144
mITT
 
The
mITT
analysis
is
the
most
clinically
relevant
analysis
as
it:
 
 
 
 
13
Excludes
volunteers
with
prior
infecUon
and
reflects
the
study
design
and
protocol
Does
not
assume
that
all
four
vaccinaUons
are
important
Does
not
assume
that
Uming
of
all
4
vaccinaUons
is
criUcal
Limits
bias
compared
to
PP
CROI
2010,
San
Francisco
RV
144
Does
Vaccine
Efficacy
Appear
Transient?
(Kaplan‐Meier‐based
esEmates)
mITT
PP
month
Events
Efficacy
Events
Efficacy
6
16
54%
n/a
n/a
12
42
60%
21
68%
18
67
44%
41
41%
24
82
36%
53
27%
30
95
36%
62
31%
Efficacy
did
not
decrease
with
Eme
in
a
staEsEcally
meaningful
way
14
CROI
2010,
San
Francisco
RV
144
Early
Viremia
Endpoint
Vaccine
Placebo
Mean
Viral
Load
Vaccine
recipients:
4.3
log10
Placebo
recipients:
4.2
log10
p
=
NS
15
CROI
2010,
San
Francisco
RV
144
Post‐infection
CD4+
T
cell
count
Mean
CD4
T
cell
count
@
noUficaUon
and
verificaUon
visits
Vaccine:
554.7/ul
(SE
=
38.0)
Placebo:
567.5/ul
(SE
=
27.2)
p
=
NS
16
CROI
2010,
San
Francisco
RV
144
Risk
and
incidence
17
CROI
2010,
San
Francisco
RV
144
Traditional
High
Risk
Group
Analysis
  14
of
125
(11.2%)
infecUons
were
in
high‐risk
groups
(mITT)
 
 
 
Same‐gender
sex
risk (12)
CSW (2)
IDU (0)
  Equivalent
distribuUon
across
study
arms
18
CROI
2010,
San
Francisco
RV
144
Baseline
Risk‐stratified
Treatment
Effects
(mITT)
Vaccine
N
Endpoints
PY
Rate
%
N
Placebo
Treatment
Effect
Endpoints
PY
Rate
%
Efficacy
95%
CI
Low
3,865
17
0.135
3,924
29
0.227
40.4%
‐8.5,
67.2
Medium
2,369
12
0.157
2,292
22
0.299
47.6%
‐6.0,
74.0
High
1,963
22
0.349
1,982
23
0.364
3.7%
‐72.7,
46.3
VE
for
each
risk
category
was
staEsEcally
similar
19
CROI
2010,
San
Francisco
RV
144
Baseline
versus
cumulative
risk
Risk
Assessment
risk:treatment
interacQon
Baseline
risk
(pre‐hoc
analysis)
p
=
0.36
Ever
vs
never
high
risk
(post‐hoc)
p
=
0.008
This
may
reflect
the
transient
protecUve
effect
of
the
vaccine
regimen
rather
than
imply
protecUon
only
in
“lower
risk”
individuals
20
CROI
2010,
San
Francisco
RV
144
Immunogenicity
data
21
CROI
2010,
San
Francisco
RV
144
IFN‐γ/IL‐2
ICS
6
months
post‐final
vaccination
Frequency (%)
CD4
CD8
Antigen
V
P
V
P
Env Only
45/142 (32) *
1/54 (2)
5/133 (4)
4/52 (8)
Gag Only
0/144
0/56
3/136 (2)
1/53 (2)
Env + Gag
2/142 (1)
0/54
0/131
0/51
Any HIV
47/142 (33)*
1/54 (2)
8/131 (6)
5/51 (10)
*P
<0.0001
compared
to
placebo
22
CROI
2010,
San
Francisco
RV
144
Ag‐Specific
Lymphoproliferation
2
weeks
post‐final
vaccination‐
FINAL
DATA
Frequency (%)
Antigen
Vaccinee
Placebo
gp120 E (A244)
115/130 (88)
4/50 (8)
gp 120 B (MN)
96/116 (83)
4/44 (9)
p24
59/114 (52)
9/48 (19)
P<0.001
compared
to
placebo
group
‐
all
AnQgens
23
CROI
2010,
San
Francisco
RV
144
Frequency
of
Binding
Antibody
Responses
2
and
24
weeks
post‐final
vaccination
Antigen
Frequency (%)
2 weeks
24 weeks
B gp120
140/142 (99)
140/142 (99)
74/142 (52)
26/142 (18)
E gp120
B p24
24
P<0.0001
compared
to
placebo
group
‐
all
AnQgens
CROI
2010,
San
Francisco
RV
144
Magnitude
of
Binding
Antibody
Responses
2
and
24
weeks
post‐final
vaccination
Antigen
25
Reciprocal GMT (Range)
2 weeks
24 weeks
B gp120
31207 (800-204800)
1758 (200-25600)*
E gp120
14558 (200-204800)
1000 (100-12800)*
B p24
205 (100-1600)
149 (100-200)*
P<0.0001
compared
to
placebo
group
‐
all
AnQgens
*:
P<0.001
compared
to
2
week
Qme‐point
CROI
2010,
San
Francisco
RV
144
Initial
SGA
of
Acute
Viruses
(Env
only)
B
CRF01_AE
Vaccine
strains
Acute
cases
26
S.
Tovanabutra,
E.
Sanders‐Buell
CROI
2010,
San
Francisco
RV
144
Correlate
discovery
27
CROI
2010,
San
Francisco
RV
144
Sample
Request
Vetting
&
Funding
Approves
MRMC
funding
requests
PA
H
Steering
Commibee
(MRMC)
Humoral
&
Innate
Immunity
Cellular
Immunity
Host
GeneEcs
Animal
Models
28
NHP
studies
do
not
require
samples
DAIDS‐MHRP
Steering
Commibee
Approves
IAA
funding
requests
RV144
Steering
Commibee
Vets
sample
requests
ScienQfic
Steering
Commibee
Product
Development
Advisory
Group
‐Vets
WG
and
non‐WG
proposals
‐Might
be
asked
to
vet
intramural
proposals
by
the
PA
H
or
DAIDS‐
MHRP
SCs
‐IniUal
and
non‐
exclusive
advice
to
RV
144
collaborators
on
follow‐on
clinical
studies
CROI
2010,
San
Francisco
RV
144
Timeline
 
Pilot
studies/Assay
development‐6
months
 
 
 
Design
of
case
controlled
study‐2
months
 
 
September
2010‐January
2011
Begin
data
analysis
of
case‐controlled
study
in
one
year.
 
29
Concurrent
with
pilot
study
experiments
ImplementaUon
of
case‐controlled
study‐4
months
 
 
Planning
iniUated
Nov
2009
Bench
work
likely
to
start
March
2010
January‐March
2011
CROI
2010,
San
Francisco
RV
144
Proposal
Submission
www.hivresearch.org
30
CROI
2010,
San
Francisco
RV
144
What
we
have
learned—RV
144
31
 
ProtecUon
in
low
incident
heterosexuals,
VE
31.2%
 
CRF01_AE
variants,
Thailand
 
Subtype
matched,
sieve
analysis
pending
 
Effect
appears
to
be
early
and
transient
 
No
obvious
effect
on
post‐infecUon
viremia
or
CD4
count
 
Binding
Ab
but
not
Nab
 
CD4,
but
not
CD8
responses
 
All
hands
on
deck—find
the
correlate
CROI
2010,
San
Francisco
RV
144
Possible
steps
for
ALVAC
+
AIDSVAX
 
RV
144
extended
boost
study
(RV
305)
 
 
 
Intensive
immunogenicity
study
(RV
306)
 
 
 
 
ALVAC
+
AIDSVAX
Right
samples,
right
Ume,
right
amounts
Prime‐boost
deconvoluUon,
extended
boosts
AddiQonal
phase
IIB
studies
?
 
 
 
32
ExisUng
RV
144
uninfected
vaccine
recipients
Value
of
boosts?
SE
Asia,
low
vs
higher
incidence
heterosexual
populaUons
Africa,
subtype
C
with
subtype
matched
products
Other
risk
groups,
subtypes,
and
geography?
CROI
2010,
San
Francisco
RV
144
Three
layers
of
defense
(Picker)
 
AnUbody
at
the
mucosal
surface
(interdict)
 
 
 
Effector
memory
CD8
cells
in
the
mucosal
Ussue
(contain)
 
 
33
ADCC/ADCVI
Nab
Epitope
breadth
and
depth
Central
memory
CD8
cells
systemically
(control)
CROI
2010,
San
Francisco
RV
144
Expanded
Cellular
Immune
Breadth
by
Mosaic
AnQgens
The
mosaic
vaccine
yielded
many
more
Gag,
Pol,
and
Env
(A)
epitope‐specific
T
lymphocyte
responses
as
well
as
conservaQvely
(B)
the
number
of
epitope
response
regions
to
PTE
pepQdes
than
did
an
M
consensus
vaccine,
a
2‐
valent
clade
B
+
clade
C
vaccine,
or
an
opQmal
natural
C
clade
vaccine
P
=
1
x
10‐11,
Poisson
regression
P
=
2
x
10‐7,
Poisson
regression
Barouch
Nat
Med
2010
in
press
34
CROI
2010,
San
Francisco
RV
144
Ad26/MVA Regimen Optimal for Induction of Week 26 Gag/
Pol/Env-Specific IFN-γ ICS Responses
35
CROI
2010,
San
Francisco
RV
144
Proposed
HIV
Vaccine
Clinical
Trials
36
ConfidenUal
CROI
2010,
San
Francisco
RV
144
Conclusions
37
 
Auempt
to
find
a
correlate
of
protecUon
in
RV
144
 
Confirm,
extend,
and
exploit
the
lessons
of
RV
144
 
Co‐develop
heterologous
vector
prime‐boost
with
mosaic
inserts
to
improve
the
quality
of
CD8
T‐cell
responses
 
Employ
improved
Tem
+
Tcm
evoking
vaccine
combinaUons
with
protein
subunit
boosUng
for
future
efficacy
studies
 
We
are
a
long
way
off
to
a
globally
effecUve
vaccine—non‐
vaccine
prevenUon
measures
remain
central
to
HIV
disease
control
CROI
2010,
San
Francisco
RV
144
Acknowledgements
38
 
RV144
volunteers
and
community
members
 
AFRIMS
–
US
and
Thai
Component
 
Division
of
AIDS,
NaUonal
InsUtute
of
Allergy
and
InfecUous
Diseases,
NIH
 
Faculty
of
Tropical
Medicine,
Mahidol
University
 
Global
SoluUons
for
InfecUous
Diseases
 
Henry
M.
Jackson
FoundaUon
for
the
Advancement
of
Military
Medicine
 
Ministry
of
Public
Health,
Thailand
 
sanofi
pasteur
 
U.S.
Military
HIV
Research
Program,
Walter
Reed
Army
InsUtute
of
Research;
U.S.
Army
Medical
Research
and
Materiel
Command
CROI
2010,
San
Francisco