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

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

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% VE @ 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

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

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

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*

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

6 assays emerged to be related to Vaccine Efficacy VE 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

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).

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

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.

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.

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.

Peak CD4+ T Cell Response Rates and Magnitudes are Higher in Prevalence in 097 vs. RV144 50.3% 69.2% 2.5% 3.8% 88/175 54/78 1/40 3/78 Response rate: RV144 HVTN 097 RV144 HVTN 097 92TH023-ENV LAI-GAG

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

Comparison of V1V2 IgG responses between 097 and RV144

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

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 1086.Cgp120 Immunogenicity evaluation to be applied to this study to inform advancement into phase 3

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 ≥ 1 . 106 cell culture infectious dose (CCID)50 and < 1 . 108 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

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.

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

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.

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

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

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%

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.

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.

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.

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

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.

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

“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.”

9/17/2018