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![Page 1: Balance of Cellular and Humoral Immunity Determines the Level of Protection by HIV Vaccines in Rhesus Macaque Models of HIV Infection 1.](https://reader036.fdocuments.net/reader036/viewer/2022062909/5a4d1bc37f8b9ab0599d3b33/html5/thumbnails/1.jpg)
Balance of Cellular and Humoral Immunity Determines the Level of
Protection by HIV Vaccines in Rhesus Macaque Models of HIV Infection
1
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777 Old Saw Mill RoadTarrytown, NY
6411 Beckley StreetBaltimore, MD
Profectus BioSciences, Inc.
Profectus is a clinical-stage biotechnology company developing vaccines for Ebola/Marburg, and other
biodefense targets, as well as HIV, HPV, HSV, HCV and Chikungunya.
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Technology to tailor the vaccine response to the target
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The FLSC Subunit Mimics an Early Conformational Change in the HIV-1 Env Trimer Induced During Viral Entry
CD4 binding
gp120 Co-receptor site exposure
Co-receptor binding Bridging pre-
bundle(gp41
exposure)
Fusogenic pre-bundle
(nascent pore)
6-Helix bundle(post
fusion)
CD4
Env
Flexible peptide linkerCCR5 Binding Site
D1D2 Domains of CD4CD4 Binding Site
gp120
Conformational Change in the HIV-1 Env Trimer During Viral Entry
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How the FLSC works?
Chronic viruses hide their vulnerable partsAltering envelope structure (envelope-receptor)
changes how the antigen is presented to the immune systemenhances the immunogenicity of the conserved “vulnerable parts”expands epitope diversity in Ab responses
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Are transition state/CD4i epitopes ever immunoreactive during infection?
– Structural analyses and molecular models of soluble antigens were interpreted to indicate “No”…
– But-• Antibodies to transition state epitopes mediate potent ADCC activity against
cell-bound virions and against chronically infected cellsGuan, Lewis et al., PNAS 2013, Ferrari et al., J. Virol. 2012; Bonsignori et al., J. Virol. 2012; Veillette et al. J. Virol. 2014
• A number of nonhuman primate studies link protection from infection with antibody specificities (including CD4i) and functions that lie outside the sphere of direct virion neutralization.
Fouts et al, PNAS 2015; Barouch, Michael et al Nature 2012; Alpert et al Plos Pathogen 2012; Sun, Letvin et al, J Virol 2011; Xiao, Robert-Guroff et al J Virol 2010; Florese, Robert-Guroff et al, J Immunol 2009; Hidajat, Robert-Guroff et al J Virol 2009; DeVico et al, PNAS 2007, Hessel, Burton et al Nature 2007; Gomez-Roman, Robert-Guroff et al, JAIDS 2006; Banks et al, AIDS Res Hum Retroviruses 2002
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Envelope targets for antiviral Abs
Moore, et al, 2006, JV, 80:2515
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Evidence that FLSC can protect
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0 4 24 115 119 135 171
= i.m. immunization (subunit/adjuvant)
weeks
= single i.r. challenge, 600 TCID50 SHIV162P3
= stop tracking viral load
= sacrifice
Group # Immunogen Dose Adjuvant Dose1 4 Gp120(BaL) 300 ug QS21 100 ug2 4 Chemically crosslinked
gp120(BaL)-shCD4 300 ug QS21 100 ug
3 4 rhFLSC 300 ug QS21 100 ug4 4 Soluble human CD4 (D1-D4) 300 ug QS21 100 ug5 4 Naive
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Vaccine efficacy in high dose challenge model
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Identified relationship between lower viral set point and higher CD4i Ab titers
All other
groups
rhFLSC0
2
4
6
8
10
Set Point Viral Load (Day 56-112)
Log 1
0(Vi
ral L
oad
AU
C)
p = 0.017
All other
groups
rhFLSC
0
100
200
300
N12-i2 Competitive titers
Rec
ipro
cal h
alf-m
axim
alco
mpe
titiv
e tit
er
p = 0.0002
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Survival analysis using the repeat exposure macaque model.
# of i.r. SHIV162P3 exposures
% o
f mac
aque
sre
mai
ning
uni
nfec
ted
0
25
50
75
100
1 3 5 7 9 11 13 15 17 19
control
vaccine
protection
Adapted from Kim et al., J. Med. Primatology 35:210-216 (2006).
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Study 1 Design (powered to detect >82% protection i.e. “slam dunk”)
Iscomatrix: Saponin-ISCOM
RC529: Squalene, glycerol, phosphatidyl choline and synthetic monophosphoryl lipid A emulsion
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One simple formulation, rhFLSC/RC529, trended towards better protection, but not a “slam dunk”
Challenge outcome rhFLSC/RC529 group vs all other groupsChallenge outcome all groups
0 2 4 6 8 10 12 140.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
rhFLSC/RC529All other groups
p = 0.071
0 2 4 6 8 10 120.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
gp120/Iscomatrixgp120/RC529rhFLSC/IscomatrixrhFLSC/RC529Naive
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Immunization with rhFLSC induces antibodies to CD4i epitopes
CD4i MAbs = 17b, A32, 19e, M9 and N12-i2 (next slide)
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Animals with higher anti-CD4i antibody titers resisted infection…..
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Meta analysis of all 24 vaccinated animals where 100% of naïve animals became infected within four challenges
0 2 4 6 8 10 12 140.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challengesFr
actio
n un
infe
cted
CD4BD titer MedianCD4BD titer > Median
p = 0.217
0 2 4 6 8 10 12 140.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
N12-i2 titer MedianN12-i2 titer > Median
p = 0.039
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But protection was lost if there were too many T cells…
0 2 4 6 8 10 12 140.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
edIL-2 SFC Mean (n=15)IL-2 SFC > Mean (n=9)
p = 0.028
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Removing animals with high T cell responses reveals that protection tracks with….
ADCCFLSC titer Competitive A32 titer
3.0 3.5 4.0 4.5 5.0 5.50
2
4
6
8
10
Log10(ADCC EC50 titer)
Num
ber
of in
trar
ecta
lch
alle
nges
r = 0.54p = 0.037
3.0 3.5 4.0 4.5 5.0 5.50
2
4
6
8
10
log10(FLSC(162P3) titer)
Num
ber
of in
trar
ecta
lch
alle
nges
r = 0.56p = 0.032
0 100 200 300 400 5000
2
4
6
8
10
Competitive A32 titer
Num
ber
of in
trar
ecta
lch
alle
nges
r = 0.53p = 0.044
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Suggesting a relationship between ADCC, IFN-g Elispots, and protection: A zone of immune balance
IFN-g ELISPOT
250 500 750 1000 1250 1500 1750 2000
Log
10(A
DC
C E
C50
)
3.4
3.6
3.8
4.0
4.2
4.4
4.6
4.8
0 2 4 6 8 10 12 14
# challenges to infection
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Study 2: Different Study, same story
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Key differences from 1st study
• included Tat in one of the immunogen formulations
• used higher rhFLSC vaccine dose (1200 ug) • used a different adjuvant (GPI-0100)• employed multiple dosing throughout the
challenge phase to prolong durability • increased the challenge dose over time
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Addition of Tat toxoid eliminated protection conferred by rhFLSC
Kaplan-Meier Log Rank p = 0.030
0 2 4 6 8 10 12 140.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
edrhFLSCrhFLSC/Tat toxoidAdjuvant
p = 0.030
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ADCC highest in rhFLSC (protected) group
rhFLSC
rhFLSC/T
at tox
oid2.5
3.0
3.5
4.0
4.5
Log
10(A
DC
C E
C50
) p = 0.046
rhFLSC
rhFLSC/T
at tox
oid70
80
90
100
110
Plat
eau
cyto
toxi
city
(%)
p = 0.026
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Tat toxoid enhanced T cell responses
rhFLSC
rhFLSC/T
at tox
oid0
200
400
600
800
1000
IFN
-g E
LSP
OT
s/10
6 PB
Ls p = 0.004
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Immune balance in protected group
rhFLSC
rhFLSC/T
at tox
oid0
100
200
300
400
500
AD
CC
EC
50 ti
ter/
IFN
- g E
LIS
POT
s
p = 0.022
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Grp N SIVsmE543 DNA Vaccine
Genetic Adjuvant Subunit/Al(OH)3
1
8
Empty None None2
rhFLSC + gag/pol
Empty
rhFLSC(CCG7V)3 LTA14 Rhesus IL-125 LTA1 + rhesus IL-12
Study 3: Different model, same story (powered to detect 75% efficacy)
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Key differences from 1st and 2nd study
• uses SIVmac251 challenge (neutralization resistant batch with high quasi-species diversity (2.1%))
• Antigens derived from SIVsmE543 (gag/pol), and SIVsmE660 (env)
• DNA prime/protein boost protocol• Adds IL-12 and heat labile enterotoxin (LTA1) as
genetic adjuvants
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huIL-12• Naturally produced by MΦ and DC• Drives differentiation of Th1 cells that support CD8+ CMI responses• Drives ADCC
GeneVax® IL-12 • Induces CD4+ and CD8+ TCM
Long lived High expansion potential PD-1, CTLA-4, and LAG-3 not up regulated – resistant to anergy CD28 and CD127 up regulated – block tolerance and apoptosis
GeneVax IL-12® clinical status• Safe and well tolerated• Adjuvant active in humans
pPBS-Ckine-005
p35
p40
GENEVAX® IL-12
28
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LTA1/CTA1 Mechanism of Action
ER
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Profectus CTA1 Genetic Adjuvant
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Additive adjuvant effects between IL-12 & LTA1
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0 2 4 6 8 100.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
Controls (n=59)IL-12 (n=8)
p = 0.002
0 2 4 6 8 100.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
DNA aloneIL-12
p = 0.022
Inclusion of IL-12 in the prime yields 76% efficacy
* The addition of 51 historical controls of naïve macaques that received the same SIVmac251 challenge virus stock, at the same dose, administered by the same technical staff in the same animal facility within 1 year of the start of the challenge phase of this study
*
0 2 4 6 8 100.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
All other groupsIL-12
p = 0.024
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LTA1 and IL-12 combination enhances T cell responses
DNA alon
eLTA1
IL-12
IL-12
/LTA1
0
20000
40000
60000
80000
IFN
- g E
LIS
POT
AU
C (w
k 8-
46)
p = 0.013
p = 0.0015
p = 0.0022
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Inclusion of IL-12 during DNA prime enhances ADCC
DNA alon
eLTA1
IL-12
IL-12
/LTA1
0
500
1000
1500
2000
AD
CC
EC
50 ti
ter
p = 0.012
p = 0.008
p = NS
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But…you need immune balance
0 2 4 6 8 100.0
0.2
0.4
0.6
0.8
1.0
Number of intrarectal challenges
Frac
tion
unin
fect
ed
ADCC Neg (9)ADCC Pos, IFN-g<75th percentile (15)ADCC Pos, IFN-g>75th percentile (8) p = 0.043
p = 0.037
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Does the FLSC induce protection?
Yes, if you induce a CD4i response above a threshold, ADCC, and without an
overabundance of T cells.(immune balance)
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Our goal…..
Improve potency & durability of Fc-mediated protection with the right balance of supportive
CD4+ T cells
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Preclinical Development of IHV01
• HEK-293 Master Cell Bank created and released• FLSC Drug Substance – – cGMP manufactured and released, yield ~ 1g/L – 12 month DS stability at -20oC• Label Drug Product released (Alum formulated FLSC) – AlPO4 formulation with >95% adsorption– 9 month DP stability at 5oC• Standard Rabbit Toxicology – complete• NHP Immunotoxicology Study (FDA requested) – complete– No evidence of deleterious auto-anti-CD4 responses induced by FLSC or rhFLSC
immunization
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Released IHV01
• ~ 3400 vials at 300 µg/mL of formulated drug product
• 800 labeled, 1888 unlabeled in cGMP storage at Sherpa Clinical Packaging
• 700 set aside for release testing, clinical retains, and stability at Catalent RTP
• 125 g of unformulated FLSC [Clinical Grade] is available for future studies
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Planned Phase 1 Clinical Testing of IHV01
Group Admin Route
N**Vaccine / Control
VaccineDose
Vaccination Schedule in Months (Days)
0 1(28) 2(56) 6(168)
1 IM 15 0.25 mL(75 µg)
FLSCAIP04
FLSC AIP04
FLSCAIP04
FLSC AIP04
5 0.25 mL saline saline saline saline
2 IM 15 0.5 ml(150 µg)
FLSC AIP04
FLSC AIPO4
FLSCAIPO4
FLSCAIP04
5 0.5 mL saline saline saline saline
3 IM 15 1.0 mL(300 µg)
FLSCAIP04
FLSCAIP04
FLSCAIP04
FLSCAIP04
5 1.0 mL saline saline saline salineTOTALS 60
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Planned Phase 1 Clinical Testing of IHV01
Primary endpoint: Safety* and TolerabilitySecondary endpoint: Immunogenicity
Immune Response Measure Measures of an immunogenic dose of FLSC(3 or 6 months post vaccination)
Serum antibody titer to FLSC and gp120 (BaL) via ELISA
>80% of vaccinees exhibiting geometric mean titers to FLSC that are 3 SD above background,
and/or
Competitive serum titers to CD4i and other epitopes (A32, 17b, 19e,
N12-i2, and others) via ELISA
>60% of vaccine responders exhibiting competitive binding titers to CD4i epitopes that are 3 SD above
background
*A trial is ongoing to measure fluctuations in CD4+ T cell counts over time in healthy volunteers
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FLSC
+ New Adjuvants
+ DNA prime w/ Genetic Adjuvants
(IL-12 or IL-15)
+ rVSV (or other virus) prime
Exploratory clinical trials to learn how to reach this goal
Subunit
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Acknowledgements
John EldridgeTerry HigginsMarc TremblayKenneth BagleyJennifer SchwartzIlia PradoKate BobbWenlei Zhang
Anthony DevicoGeorge LewisRobert RedfieldBruce GilliamRobert Gallo
Funding:
Darrick CarterErik IversonSteve Reed
Ron SalernoKerin AblashiPeter PatriarcaKelly ReichMelanie Hartsough
Michael JenkinsRob GustinesIan CollinsAmy AustinGreg BleckJie DiLani KroopnickBrian WoodrowPamela Keith
Ranajit PalAnthony CristilloJessica LivesayLindsey Galmin
Deborah WeissJim Treece