Upload
jana-carga
View
27
Download
1
Embed Size (px)
Citation preview
T-cell responses induced by immunization with p yAd35-vectored HIV-1 vaccines are broad, durable, polyfunctional and can mediate inhibition of HIV
Josephine H Cox, PhD
AIDS Vaccine 2011Bangkok, Thailand, September 12-15th, 2011
Ad35-GRIN/ENV Phase I OverviewTwo constructs: Ad35-GRIN & Ad35-ENV
Ad35-GRIN/ENV: Groups A-C co-formulated together and Ad35-GRIN: Group Dtogether and Ad35 GRIN: Group D
All administered via intramuscular route at 0 and 6 months.
Subtype A
N = 56, 14/group: 10 vaccine/4 placebo
A (Low) B (Mid) C (High) D (Mid)
Ad35 GRIN/ENVAd35-GRIN/ENVDose escalation
2x109 vp 2x1010vp 2x1011 vp
Ad35-GRIN 1x1010 vp
Clinical Site: University of Rochester Medical Center (USA)Vaccinations completed Sept. 2010Follow up for 18 months post first vaccinationFollow-up for 18 months post first vaccination
Last visit of last volunteer August 20112
Safety Data
• Only Ad35 antibody negative subjects were enrolled. • Ad35 prevalence of 4.9% low in this US populationAd35 prevalence of 4.9% low in this US population
• Ad35-GRIN/ENV is safe and generally well tolerated- No related SAE reported - Reactogenicity and tolerability are dose-dependent- High dose at 2x1011 vp is responsible for severe local and/or
systemic reactions in 50% of vaccinees persisting more than 5systemic reactions in 50% of vaccinees, persisting more than 5 days in one volunteer.
- All reactions resolved spontaneously without complications or sequellaesequellae
• All Ad35 samples (scheduled and symptomatic) tested negative for shedding (urine and saliva).g g ( )
3
Immunogenicity Assessments
3535 Weeks0 24
Ad3
Ad3 Weeks
0, 2 and 4 post 1st 0, 1, 2, 4, 8, 14, 28, 40 and 48 post 2nd
•Immunogenicity: IFN- ELISPOT at all time points
Followed for 72 weeks total (18 months)
g y p•Cut-off 38 SFC/106 PBMC and 4 x background / six peptide pools
•ICS, Viral Inhibition Assay (VIA), epitope mapping, Env Ab, p24 Ab, Ad35 neuts at selected time pointsb, p b, d35 euts at se ected t e po ts
4
High HIV-specific IFN- ELISPOT Response rates maintained over time
60%
80%
100%
A Low
p
Any Antigen
0%
20%
40%
A-LowB-MidC-HighD-GRIN
0%
E A
60%
80%
100% Env Antigen
60%
80%
100%
20%
40%
60%
GRIN Antigen20%
40%
60%
0% 0%
5
HIV-specific IFN- ELISPOT in most individuals maintained up to 10 months post 2nd vaccination p p
3.5Ad35 GRIN-ENV increasing dose Ad35 GRIN
3.0
scal
e)
2.5
BM
C (l
og-s
2.0
FC/1
06PB
1.5
Wk 250%Vac.1
Wk 450%
Wk 286%Vac.2
Wk 475%
Wk 4063%
Wk 250%Vac.1
Wk 456%
Wk 2100%Vac.2
Wk 4100%
Wk 40100%
Wk 278%Vac.1
Wk 470%
Wk 289%Vac.2
Wk 488%
Wk 4075%
Wk 289%Vac.1
Wk 490%
Wk 286%Vac.2
Wk 486%
Wk 4088%
SF
38 SFC
2x109 vp 2x1010 vp 2x1011 vp 1x1010 vp6
IFN- ELISPOT responses of modest magnitude across all vaccine-expressed HIV proteins
35Gag RT Pol/Int Nef Env
3.0
3.5
og-s
cale
)
2.5
PBM
C (l
o
2.0
SFC
/106
1.5
Grp A43%
Grp B88%
Grp C33%
Grp D86%
Grp A57%
Grp B88%
Grp C56%
Grp D71%
Grp A71%
Grp B38%
Grp C33%
Grp D71%
Grp A29%
Grp B38%
Grp C11%
Grp D57%
Grp A86%
Grp B75%
Grp C67%
Median SFC/m 158 79 100 158 126 251 158 200 126 79 251 316 158 50 79 100 63 126 79
7
2 weeks post second vaccination
Multiple HIV proteins targeted by each volunteer
Number of visits (maximum 10) with
Breadth of the response as defined by number of positive
responses to any of the sixpositive responses to
any peptide pool
responses to any of the six (four for Group D) peptide
pools at any time point
Gro p MedianGroup Median
A - Low 7.5 3.5
B - Mid 9 5
C - High 9 5C - High 9 5
D - GRIN 10 4
Data up to 40 weeks post second vaccination8
Median of 4 epitopes recognized per volunteer (n = 25 mapped)volunteer (n = 25 mapped)
Pool ID#
VolunteersUnique
*regionsMedian # *regions RangePool ID Volunteers regions
mappedregions
recognizedRange
Gag 12 >8 1 1-3RT 14 17 2 1 3RT 14 >17 2 1-3Int 12 >8 1 1-4Nef 6 >2 1 1-2Env 12 >14 2 1-4
Median # epitopes recognized / volunteer 4Range of epitopes recognized / volunteer 1-8
9*Unique region = either 2 peptides sharing a sequence or single peptide
Flow Cytometry Panel: IFN-/IL-2/CD107/TNF-, CD4/CD8 memory and homing markersCD4/CD8, memory and homing markers
CD4+: 0.028% IFNg+CD8+: 2.18% IFNg+ NEF ELISPOT: 1060 SFC/m
Example shown is Nef stimulation from sample atExample shown is Nef stimulation from sample at 2 weeks post 2nd vaccination (Group D, GRIN)
10
Predominantly CD8+ T-cell Responses to Gag, RT and Int
>0.5Any Env 1 Env 2 Gag INT NEF RT
CD8 ANY Env 1 Env 2 Gag Int Nef RT
/TN
F
0.2
0.3
0.4
-2/C
D10
7/
Baseline & Placebo
0.13
0.0
0.1
Bl P B C D B C D B C D B C D B C D B C D
Any Env1 Env2 Gag INT NEF RTe IF
N-
/IL-
B - Mid
C - HighCD4 ANY Env 1 Env 2 Gag Int Nef RT
0.3
0.4
>0.5Any Env 1 Env 2 Gag INT NEF RT
e Po
sitiv
e C High
D - GRIN
0.06
0.1
0.2
0.3
% C
ytok
ine
11
0.06
0.0Bl P B C D B C D B C D B C D B C D B C D
%
Responses at 2 weeks post 2nd vaccine
Potent and broad CD8-mediated VIA activity Placebo Low dose Mid dose High dose
CRFAE-01 ELI (AD) IIIB(B) NL4-3(B) U455(A)
inhi
bitio
nLo
g 10
247Fv2(C) 97ZA012(C) CBL4(D) CH077(B) CH106(B)
CD8+ T cell HIV-1 inhibition to several isolates in most vaccinated individuals 12
ENV-A (UG037)- and Gag-p24 (IIIB)-specific ELISA antibodiesspecific ELISA antibodies
10 4Post 1st Vaccination Post 2nd Vaccination
rs
10 4Post 1st Vaccination Post 2nd Vaccination
rs
10 3
A - LowB - MidC - High
an E
nv ti
ter
10 3
A - LowB - MidC - HighD - GRINan
Gag
tite
r
10 2Geo
m M
ea
10 2Geo
m M
ea
0 10 20 30 4010
Weeks post Vaccination0 10 20 30 40
10
Weeks post Vaccination
4 w Post 1st 2 w Post 2ndA - Low 8/10 (80) 9/9 (100)B - Mid 9/10 (90) 8/8 (100)
4 w Post 1st 2 w Post 2ndA - Low 0/10 0/9 (0)B - Mid 0/10 3/8 (38)C High 0/10 8/9 (89)
13
C - High 10/10 (100) 9/9 (100) C - High 0/10 8/9 (89)D - GRIN 0/10 5/7 (71)
T-cell response summary for B001 Ad35 trialHigh response rate by ELISPOT >86% across all groups post 2nd
Magnitude of response is modest but maintained over time
Greater magnitude to GRIN proteins in the absence ofGreater magnitude to GRIN proteins in the absence of ENV but no enhancement of VIA activity
Good breadth; all proteins targeted CD8+ T-cell HIV-1 inhibition in most vaccinated individuals
to several isolatesFl t tFlow cytometryPredominantly CD8+ response Multifunctional (cytokines + degranulation)Multifunctional (cytokines + degranulation)Induction of T cell memory responses (data not
shown) 14
Antibody response summary for B001 Ad35 trialAnti-HIV ENV: 100% responders post second
administration with modest titersNo HIV Nabs to multi-clade panel (Monogram BioSciencesNo HIV Nabs to multi clade panel (Monogram BioSciences,
data not shown)
Anti-HIV Gag p24: no antibody post 1st, modest titer post 2ndpost 2nd
Anti-Ad35 neutralization response rates and titers are modest even after 2 vaccinations and lower than seen with Ad5 (data not shown)
Low-prevalence serotype Ad vectors may exhibit i d f t d i i it dimproved safety and immunogenicity as compared with Ad5 vectors.
15
Next steps Ad35-GRIN/ENV is immunogenic at the dose with an acceptable safety
profile (2x1010 vp) Evaluate the safety and immunogenicity of Ad35-based HIV vaccine in
heterologous prime-boost regimens, to assess potential enhancement of the breadth and potency of cellular and humoral immune responses as follows:
Ad26 vector (Dan Barouch / Crucell, ongoing)Ad35 ENV d Ad26 ENV P t tAd35-ENV and Ad26-ENV PrototypeMosaic Immunogens to optimize cellular immunologic coverage of global HIV-1 sequence diversity
Adjuvanted Protein (GSK ongoing)Adjuvanted Protein (GSK, ongoing)Ad35-GRIN and Adjuvanted GSK investigational HIV vaccine formulation 1 and 2
Electroporated (EP) DNA and IL-12 (Profectus start late 2011)Electroporated (EP) DNA and IL 12 (Profectus, start late 2011)Ad35-GRIN-Env and multi-antigenic DNA (HIV-MAG), IL-12 and EP
Mucosal delivery – Sendai virus (SeV)Ad35-GRIN and SeV-Gag prototype in pre-clinical developmentAd35 GRIN and SeV Gag prototype in pre clinical development
16
AcknowledgementsUniversity of RochesterUniversity of RochesterMedical CenterMichael KeeferLottie HachaambwaCatherine Bunce
IAVIEddy Sayeed, Angela Lombardo Wendy Komaroff, Sabrina Welsh
Catherine Bunce Mhorag HayEMMESKelley LoughranBurc Barin
James Ackland, Devika ZachariahKamaal Anas, Jean-Louis Excler Patricia Fast
Burc BarinCarol Smith
IAVI Human Immunology Laboratory, Imperial College
Lorna ClarkJustyna Czyzewska
Laura SeamonsAggeliki SpentzouLaboratory, Imperial College
LondonHong WanAmbreen AshrafPhil Bergin
Justyna CzyzewskaChristopher FarranceNatalia FernandezDilbinder GillP t H
Aggeliki SpentzouTony TarragonaParamesh ChettyGwynn StevensJill GilPhil Bergin
Emmanuel CormierJana CargaMichelle Cashin-CoxHannah Cheeseman
Peter HayesVanaja KakarlaJakub KopycinskiFrancesco Lala
Jill Gilmour
Hannah Cheeseman Andrew Raxworthy-Cooper
18
Back- up slide
Range of CD8+ T-cell memory and other phenotypes observedphenotypes observed
No trend towards a particular memory phenotype. Majority of responses lack homing markers
d B7Data is across study arms and visits in samples with >0.2% IFN- production
and are B7-
Ad35-specific neutralization antibody responses
100 500
60
80
resp
onde
rs
300
400
GM
T
0
20
40
% A
d35
0
100
200
0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 20
D - GRINA - Low B - Mid C - High
0 = baseline1 4 k t fi t i1 = 4 weeks post first vaccine2 = 2 weeks post second vaccine