1. HIV preventative vaccines Overview of the P5 program
Glenda Gray
Vaccines & vaccination
June 16-18th 2016
Rome, Italy

2. Innovations in the Prevention of Sexual Acquisition that will be required when secondary transmission is not averted
HIV Cure: the ultimate control of the HIV epidemic will be in the elimination of viremia in those infected
HIV Vaccines & other immune based strategies
Microbicide development & long acting ARVS for PrEP
New classes of Drugs
FDCs, long acting ARVS & child friendly formulations
Point of care viral load & Immunological monitoring
Immunological & Drug Based Strategies aimed at the latent reservoir
Innovations in the management of HIV that will impact on community viral load and infectiousness: prevention of secondary transmission
What we need to end AIDS?
Gray, G et al Plos Biol, in press 2015

3. Clinical HIV-1 Vaccine Efficacy Trials
Study/
location
Vaccine/s
Risk Group/HIV incidence
Result
Vax003
Thailand
AIDSVAX B/E gp120 in alum
IDUs
3.4%
No VE
Vax004
US/Europe
AIDSVAX B/B gp120 in alum
MSM/high risk women
2.6%
HVTN 502
Americas
MRKAd5 HIV-1 gag/pol/nef 3%
Halted for futility; early transient increased infection in vaccinees
HVTN 503
Heterosexual men & women
3.7%
No VE; late increased HIV infection in unblended male vaccinees
RV144
ALVAC-HIV vCP1521, AIDSVAX B/E rgp120 in alum
Heterosexual men and women with variable risk
0.28%
31.2% VE at 42/12;
60% 12/12
HVTN 505
DNA, rAD5 (A,B,C)
Circumcised MSM Ad5 neg
1.8%
Halted at interim analysis for futility
Clinical HIV-1 Vaccine Efficacy Trials

4. Why so little interest?
Scientific: highly variable virus that integrates into host genome, rapidly establishing latency, evading both humoral & cellular responses

5. Why so little interest? Limited pharmaceutical support
Donaldson E, et al, HIVR4P 2014

6. Thai Trial (RV144) Primary Results
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.9
0.8
0.7
0.6
0.4
0.3
0.2
0.1
Years
Probability of HIV Infection (%)
Placebo
Vaccine
Modified Intention-to-Treat Analysis*

7. Defining the correlates of immunity in RV144
Case Control Study
Used specimens 2 weeks after the final vaccination
Case control
41 vaccine recipients who got HIV> 26 weeks
205 controls: vaccine recipients who were negative at the end of the study
40 placebo recipients

8. 6 assays emerged to be related to Vaccine EfficacyVE
The binding of IgG antibodies to the V1V2 region of gp 120
The binding of plasma IgA to env
The avidity of IgG antibodies for env VE
Antibody Dependent Cellular Cytotoxicity (ADCC)
Neutralising Antibodies
The magnitude of CD4 T cells specific for HIV-1 env
In vaccinees with low plasma IgA responses

9. Correlates of Risk of HIV Infection Reported in Haynes et al, NEJM 2012
Changed Title, would add immune response at the top of the column of variables
All results are pulled from the RV144 NEJM Correlates paper.
Primary multivariate results pulled from Table 1.
Primary IgA interactions come from the Table S4.
Secondary results are from Table S1 (confidence intervals were not reported but we of course had them so I pulled the Cis from the source file).

10. lack of a direct correlation between neutralising antibodies and HIV-1 acquisition
Even at peak antibody response, none of the sera from the vaccinees neutralised a panel of 20 contemporaneous isolates of HIV-1 circulating in Thailand during the course of the trial…..
9/17/2018

11. The Pox-Protein Public-Private Partnership (P5)
Testing modified vaccine components from RV144 with the goal of enhancing efficacy and prolonging protection
Early safety and immunogenicity studies in South Africa are currently underway; efficacy studies are planned for Q4 of 2016
This slide is also in the GAC introduction presentation that will be delivered by Shelley. You may wish to skip it or cover it quickly.

12. P5 Vaccine Program: Regimen Optimization
Construct Bivalent
Subtype C gp120/
MF59
Add Booster at
12 months
Construct ALVAC-HIV-C
(vCP2438)
Regional relevance Increased potency Extended durability
The P5 vaccine program is testing a concept that builds on the RV144 regimen by altering vaccine components and dosing to ensure regional relevance, increase vaccine potency and extend the duration of protection.

13. HVTN Strategy for the Phase 3 Program
Designed to evaluate RV144 vaccine regimen in RSA and compare immunogenicity to that in Thailand
HVTN 100
A standard phase 1 trial of the clade C products to decide whether to proceed to phase 3
HVTN 702
A Classic phase 3 RCT assessing efficacy and safety aimed at licensure
Add HVTN in the title?
I think this slide would be better if the protocol number was shown horizontally as well.

14. Peak CD4+ T Cell Response Rates and Magnitudes are Higher in Prevalence in 097 vs. RV144
50.3% % % %
88/ / / /78
Response rate:
RV144
HVTN 097
RV144
HVTN 097
92TH023-ENV
LAI-GAG

15. Strong IgG Responses to V1V2, gp120 and gp140 Antigens
Number of antigens
in compiled analysis:
V1V2 15
Gp120 8
Gp140
98.6%
68/69
100%
69/69

16. Comparison of V1V2 IgG responses between 097 and RV144

17. P5 Vaccine Program: HVTN 100 & HVTN 702Dosing Schedule
Dose 1 ALVAC
Dose 3
ALVAC, gp120/MF59
Dose 2
ALVAC
Dose 4
Booster 1 6 12 3
HVTN 100
HVTN 702
MONTH
RV144
Dose 1 ALVAC
Dose 3
ALVAC,
AIDSVAX gp120
Dose 2
ALVAC
Dose 4
ALVAC, AIDSVAX gp120 1 6 3
MONTH

18. Primary Vaccine Regimen
Study Schema: HVTN 100 N
(total 252)
Primary Vaccine Regimen
Booster
Month 0
Month 1
Month 3
Month 6
Month 12
210
ALVAC-HIV
(vCP2438)
ALVAC-HIV (vCP2438)
ALVAC-HIV+ Bivalent Subtype C gp120/MF59®
ALVAC-HIV+ Bivalent Subtype C gp120/MF59® 42
Placebo
Placebo + Placebo
Products:
ALVAC-HIV (vCP2438) expressing HIV-1 env (clade C gp120), clade B (gp41), gag (clade B) & protease (clade B) (Dose: >1 X 106 CCID50)
Bivalent subtype C gp120/MF59 containing 100mcg TV1.Cgp120 & 100mcg Cgp120
Immunogenicity evaluation to be applied to this study to inform advancement into phase 3

19. ALVAC-HIV® vCP2438
ALVAC-HIV® (vCP2438) was designed to preserve the link to the RV144 demonstration of clinical efficacy using ALVAC-HIV® (vCP1521)
Sequence differences in vector inserts rationalized based on geographical relevance of circulating clades
ALVAC-HIV (vCP2438) expresses the gene products ZM96 gp120 (clade C strain) linked to the sequences encoding the HIV-1 transmembrane anchor (TM) sequence of gp41 (28 amino acids clade B LAI strain) and gag and pro (clade B LAI strain). It is formulated as a lyophilized vaccine for injection at a viral titer ≥ cell culture infectious dose (CCID)50 and < CCID50 (nominal dose of 107 CCID50) and is reconstituted with 1mL of sterile sodium chloride solution (NaCl 0.4%) for intramuscular (IM) injection as a single dose
vCP2438
vCP1521
gp120 TH023

20. Subunit Proteins in HVTN 100
Bivalent Subtype C gp120/MF59® consists of 2 subtype C recombinant monomeric proteins, TV1.C gp120 Env and 1086.C gp120 Env, each at a dose of 100 mcg, mixed with MF59® adjuvant (an oil-in-water emulsion) delivered as a 0.5 mL IM injection.

21. Go/No-Go Criteria: HVTN 100 Met all of the Following Conditions to advance to HVTN 702
Variable Measured
at Month 6.5
Rationale
Env Ab Response Rate
(≥ 2 of 3)
Adequate Ab take to vaccine Env
Env Ab Magnitude*
Non-inferior Ab magnitude vs. RV144
Env CD4 Response Rate*
(1 of 1)
Non-inferior CD4 T cell take vs. RV144
Env V1V2 Response Rate
(≥ 1 of 3)
Adequate to predict achieving VE=50% for 2 years if V1V2 Ab is an immune correlate
* Based on simultaneous assessment of clade C vaccinee samples vs. RV144 vaccinee samples by the same lab

23. HVTN 100: Conclusions of go/no-go criteria evaluation
There are no safety concerns with the HVTN 100 vaccine regimen (5th vaccinations still ongoing; study remains blinded).
Cellular and humoral immune responses in HVTN 100 met all four predetermined go/no-go criteria to support the evaluation of this regimen in HVTN 702.
Data indicate that the level of immune responses to the key immunogenicity markers will allow assessment of correlates of protection in the HVTN 702 study design.
The immune correlates measured in HVTN 100 achieved sufficient prevalence and magnitude to recommend moving forward with HVTN 702.

24. HVTN 702 is planned to commence in Q4 of 2016
HVTN 702 primary objectives
To evaluate the preventive vaccine efficacy of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 for the prevention of HIV infection in HIV-seronegative South African adults over 24 months from enrollment
To evaluate the safety and tolerability of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 in adults in South Africa

25. Primary Vaccine Regimen
Study Schema: HVTN 702 N
(total 5400)
Primary Vaccine Regimen
Booster
Month 0
Month 1
Month 3
Month 6
Month 12
2700
ALVAC-HIV
(vCP2438)
ALVAC-HIV (vCP2438)
ALVAC-HIV+ Bivalent Subtype C gp120/MF59®
ALVAC-HIV+ Bivalent Subtype C gp120/MF59®
Placebo
Placebo + Placebo
Estimated Total Study duration 72 months:
Stage 1: 60 months-18 months for enrolment, 24 months of follow-up for HIV-1 uninfected individuals, 18 months follow up for HIV-1 infected individuals)
Stage 2: an additional 12 months of follow up for uninfected individuals

26. Power to reject null: VE (0-24) ≤ 25%
Study Design Features
HVTN 702
Evaluates Stage 1 vaccine efficacy (VE) to 24 months after 1st vaccination
If evidence of positive VE, evaluates VE durability to 36 months after 1st vaccination
Continuous monitoring for harm
Sequential monitoring for non-efficacy non-efficacy/efficacy futility
Monitoring for high efficacy
90% power to detect VE of 50% (enrollment through 24 months)
= 90% power to reject null hypothesis (VE ≤ 25%)
True Average VE (0-24)
Power to reject null: VE (0-24) ≤ 25%
30% 7
40% 45
50% 90
60%
100
70%
80%

27. Prevalence of Response
Vaccine immune responses observed in RV144 decay at differing rates and loosely correlate with VE
Ramp-up
Peak VE
Waning VE
Prevalence of Response
Time (months)
There are multiple immune responses that correlate with vaccine efficacy.
These and other responses will be assessed during the HVTN 100/702 trials and can be used to update/refine VE assumptions of the model.
Corey et al., (2015) Science Translational Medicine
The relationship between VE and immune responses can be used to inform assumptions in the P5 modelling exercise.

28. HYPOTHETICAL HVTN 702 kinetics of vaccine-induced immune response and vaccine protection based on RV144
Ramp-up
Peak VE
Poor Ab Response,
T-cells
T-cells
Pox + Env
protein
Levels Ab 1 3 6 9 12 18
Months
These are hypothetical curves with a predicted increase due to the addition of the 12-month booster.
Pox
Pox
Pox + Env
protein
Pox + Env
protein
RV144 results have been used to predict immunogenicity kinetics for the HVTN 702 regimen—including the response to the month 12 booster; a similar approach can be used for VE scenarios of interest to be modelled.

29. Efficacy results observed in RV144
Prospective improvements in VE with the HVTN 702 vaccine regimen
HVTN 702
Hypothesized HVTN 702 results with efficacy extended by month 12 booster
Efficacy results observed in RV144
Ramp-up
Waning VE
Peak VE
Ramp-up
Waning VE
Peak VE
Booster
Potential Additional Booster
It can be emphasized that the “Potential Additional Booster” at month 36 is not part of the HVTN 702 protocol and that the modellers are modelling a scenario in which additional boosters are given at month 36 and then every 2 years afterwards.
You may wish to consult with Peter Gilbert or Carlos DiazGranados on the assumptions that went into developing the hypothesized HVTN 702 curve.
Addition of a booster at month 12 in HVTN 702 is hypothesized to extend the period of peak VE and the duration of protection.

30. Cape Town—Emavundleni Cape Town—Khayelitsha
Clinical Trial Sites
HVTN 702
Brits
Shoshanguve
Medunsa
Rustenberg
Soweto—Baragwanath
Soweto—Kliptown
Tembisa
Ladysmith
Klerksdorp
eThekwini
Isipingo
Verulam
Mthatha
Cape Town—Emavundleni
Cape Town—Khayelitsha

31. Duration of Protection
P5 Vaccine Program: Target Product Profile
Base Case TPP
Indication
Prevention of HIV Infection
Target Population
Seronegative adults at high risk for acquiring HIV infection
Vaccine Efficacy
≥ 50% reduction in HIV infection at 24 months after first administration
Safety
Well tolerated, AE profile comparable to standard adult vaccines
Duration of Protection
24 months from first administration (may require periodic boosting)
Doses
5 doses administered over 12 months
While the TPP presented here represents the base case for the HVTN 702 study, the modellers will also include other populations (e.g. adolescents) as well as a range of vaccine efficacy levels in the model.
The complexity of the pox-protein regimen has important implications for potential public health impact, feasibility and cost-effectiveness.

32. P5 Vaccine Program: Current Draft Clinical Development Plan
HVTN 100
Regulatory Review
Enrollment
Follow-up
Final Statistical Report
Final Stage 1 Efficacy Analysis
Phase 2b/3
Go/No Go Decision
1st – 6th Efficacy/ Futility Analyses
HVTN 702
For the purposes of modelling, 2027 represents the date at which the model will assume unconstrained vaccine supply in order to determine the maximum public health impact achievable for the P5 HIV vaccine.
Additional studies*
MAA preparation and review
2026
2025
2024
2023
2022
2021
2020
2019
2018
2017
2016
2015
2027
2014
*May include multilot consistency, adolescent and other bridging studies, dose reduction, PMTCT studies

33. “Ultimately, we believe, the only guarantee of a sustained end of the AIDS
pandemic lies in a combination of non-vaccine prevention methods and
the development and deployment of a safe and effective HIV vaccine.”

34. 9/17/2018