1. VAC-3S : a gp 41 therapeutical vaccine increasing CD4 cells in patients under HART
Patrice Debré

2. Conflict of Interest
Founder : Innavirvax
Consultant : Innavirvax

3. 3S motif of GP40 Viral membrane
“SWSNKS”
HR1
HR2
NH2
Fusion Peptide TM
3S : highly conserved and exposed motif
Pancera et al., Nature, 2014
613
618
505gp120
31gp120
664gp41
Viral membrane
Residues Form a Membrane-Proximal Epitope on the Pre-fusion Closed Structure of the HIV-Env Spike

4. 3S Vaccine Concept Hypothesis  Generation of anti-3S motif Antibodies
NKP44
NK cells
HIV-Infected cells
VIH-1
Env
gp120
gp41 3S
NKP44Ligand
NK mediated
cytotoxicity
3S motif
Anti-3S motif
antibody responses
gC1qR
CD4 cells
Hypothesis
 Generation of anti-3S motif Antibodies
would induce the Inhibition of pathogenesis (loss of CD4 cells)
Petitdemange et al. Clin Infect disease 2013
Vieillard et al. Oncotarget. 2016

5. IPROTECT1 Clinical study
Vac3S 3S-CRM197
with Alum
4 arms: 16, 32, 64µg, & placebo
FOLLOW-UP 4w
Screen
* 64µg arm not boosted 4w
12w
12w
12w
Multi-center: 13
France: 10 – Spain: 2 – Germany: 1
Clinical trial.gouv: NCT

6. IPROTECT1 Clinical study flow chart
Assessed for eligibility (n=112)
Allocated to Arm A :
VAC-3S = 16 mg
Received intervention
Week 0, 4, 8, 20, 32, 44
n=24
Allocated to Arm B :
VAC-3S = 32 mg
n=25
Allocated to Arm C :
VAC-3S = 64 mg
Week 0, 4, 8
n=23
Allocated to Arm D :
Placebo
n=14
Randomized : n=86
Excluded (n=26)
- Not meeting inclusion criteria (n=16)
- Declined to participate (n=10)
Lost follow up
n=1
Safety (n=24)
Week 8, 24, 36, 48
Immunomonitoring (n=24)
Week -4, 0, 12, 48
Safety (n=25)
Safety (n=23)
Immunomonitoring (n=23)
Safety (n=14)
Immunomonitoring (n=14)
Completed : n=85

7. Objectives Primary objectives:
to evaluate the overall immunogenicity of VAC-3S at doses of 16 μg and 32 μg after 3maintenance vaccinations at the end of the full immunization scheme
Secondary objectives:
to assess safety
to assess the impact of VAC-3S immunotherapy on CD4 cell counts and percentages in acohort of virologically controlled HIV-1 infected patients with stable CD4 cell counts

8. Inclusion Criteria Documented HIV-1 infection
Adults > 18 and < 60 years of age,
Able and willing to comply with the protocol, including availability for all scheduled study visits,
Provided a signed written informed consent,
Meets study screening physical, medical history and laboratory assessments (defined below),
On stable antiretroviral therapy that is consistent with the current standard of care for at least 12 months prior to study screening,
Plasma HIV RNA < 50 cps/mL during the previous 12 months,
CD4+ T cell count at screening > 200 and < 500 cells/mm3,
Adequate hematology, biochemistry, and metabolic blood tests defined as being less than grade 2 according to the Division of AIDS Adverse Events (See Appendix 23.1), except for the numeration of CD4 and for the numeration of lymphocytes,

9. IPROTECT1 demographic A: 16 mg B: 32mg C: 64 mg D: Placebo ALL
Sex, n (%)
male
Female 24
19 (79.2%)
5 (20.8%) 25
19 ( 76.0%)
6 (24.0%) 23
21 (91.3%)
2 (8.7%) 14
9 (64.3%)
5 (35.7%) 86
68 (79.1%)
18 (20.9%)
Age, years
mean (SD)
median (IQR)
44.6 (6.1)
46.0 (39-51)
46.9 (8.6)
48.0 (42-51)
47.4 (6.9)
48.0 (42-54)
50.6 (8.6)
50.5 (44-55)
47.0 (7.9)
Ethinc origin (%)
White
Black
Asian
other
14 (58.3%)
10 (41.7%)
0 (0.0%)
13 (52.0%)
10 (40.0%)
2 (8.0%)
17 (73.9%)
6 (26.1%)
8 (58.3%)
4 (28.6%)
1 (7.1%)
52 (60.5%)
30 (34.9%)
3 (3.5%)
1 (1.2%)
Body mass index, kg/m2
23.71 (3.08)
23.46 ( )
25.19 (3.78)
25.76 ( )
23.64 (4.22)
22.02 ( )
24.80 (3.33)
24.73 ( )
24.30 (3.66)
24.00 ( )
CD4 cell counts
(93.02)
( )
(94.61)
( )
(80.95)
364.0 ( )
(75.61)
( )
( )
CD4/CD8 ratio
0.707 (0.377)
0.618 ( )
0.719 (0.331)
0.640 ( )
0.700 (0.543)
0.555 ( )
0.662 (0.273)
0.670 ( )
CD4 Nadir
(94.97)
( )
(80.89)
( )
(74.34)
( )
(108.27)
( )
(74.34)
HIV duration
12.90 (8.86)
10.80 ( )
12.85 (8.17)
10.46 ( )
14.07 (8.15)
14.05 ( )
15.67 (10.11)
15.88 ( )
13.65 (8.60)
11.94 ( )

10. Safety conclusion There are no related serious adverse events (SAEs)
There are no SAEs leading to death
Drug related AEs are mostly local: injection site pain, hypersensitivity, erythema, oedema, pruritus, swelling
Other drug related AEs: asthenia, pyrexia, myalgia, and headache

11. Primary endpoint (week 12)
Anti-3S antibodies (units)
Mean (SD)
Median (IQR)
A: 16 ug
B: 32 ug
C: 64 ug
D: Placebo
p-values
Baseline
21.89 (45.76)
11.50 ( )
11.64 (0.70)
11.50 (11.5–11.5)
11.81 (1.48)
17.36 (18.12)
Week 12
71.97 (84.47)
35.45 (11.5–104.1)
62.43 (67.49)
48.42 ( )
62.59 (116.01)
32.35 ( )
16.63 (15.30)
0.0003
0.0026
0.0002
0.0020 -

12. Anti-3S antibody responses** **

13. High/low antibody responses post-hoc analysis
High Responders (HR): ≥ 10 fold increase in anti-3S Ab at 2 consecutive time points
Low responders (LR): ≥ 4 fold increase in anti-3S Ab at 2 consecutive time points
Non responders (NR): < 4 fold increase in anti-3S 14 10 9 8 1 4 18
Level of anti-3S Abs at W48
High versus low versus Non-responders

14. Biological markers at Baseline in HR / LR / NR

15. Biological effect of Vac-3S vaccine in responders at week 12
High Responders
p value =
***
Low Responders
Non significant
Non Responders
Non significant
Placebo
Non significant
High responders significantly increased their CD4 counts of about 59 CD4/mm3 at week 48 compared to Baseline

16. Biological effect of Vac-3S vaccine in responders at week 48
High Responders
p value = **
Low Responders
Non significant
Non Responders
Non significant
Placebo
Non significant
High responders significantly increased their CD4 counts of about 60 CD4/mm3 at week 48 compared to Baseline

17. Correlation between anti-3S Ab titers and delta CD4 cell counts
Fold change from baseline
Spearman r 0.38
P value 0.002 **
Delta W48- W0
cell/mm3

18. Conclusion
Vac-3S is immunogenic with approximatively % responders after 6 injections of 16 ug or 32 ug of vaccine
High anti-3S Ab responders = ≥10 fold change at two consecutive time points >100 Ab units and Low anti-3S Ab responders = ≥ 4-10 fold change at two consecutive time points ( Abs units)
Immunocompetent HIV patients with High CD4/CD8 ratio respond better to Vac-3S
High responders significantly increased their CD4 counts of about 59 CD4/mm3 after vaccination (W12 and W48) compared to Baseline
Significant correlation between delta CD4 counts from baseline and fold change of anti-3S Ab in all vaccinees

19. Acknowledgments Medical Monitor Robert L. Murphy, MD
Study Medical Monitor
Innavirvax
Alain Maiore CEO
Delphine Lucas COO
Shahin Gharakhanian
Coordinating Investigator [France]
Pr Christine Katlama, MD, PhD
Infectious and Tropical Diseases Unit
Statistics and analysis of biomedical data
Effistat
Jean-Christophe Lemarié
Coordinating Investigator [Germany]
Pr Jürgen Rockstroh
Department of General Internal Medicine
Medical Faculty, University of Bonn
Coordinating Investigator [Spain]
Pr José Gatell
Infectious Diseases & AIDS Units
Hospital Clinic
CIMI-Paris Inserm
Behazine Combadiere, DR inserm
Vincent Vieillard, DR CNRS