Active and Passive Immunization for HIV Prevention

Active and passive immunization Vaccine Strategies for HIV

Hannah Kibuuka Makerere University Walter Reed Project, Uganda INTEREST Conference, 5th May 2016 Younde, Cameroon Outline

• Reason for optimism • Active Immunization- Vaccine strategies with a pathway to efficacy testing • P5 Strategy • Janssen strategy • Passive Immunization- • Studies with VRC 01 Reasons for Optimism Before After vaccines vaccines Vaccines work really well!

Vaccines are among the most successful medical interventions (eradicated or controlled smallpox, polio, measles…) Reasons for Optimism

• Vaccination can alter risk of acquiring HIV infection- RV 144 has shown that an HIV vaccine is possible • Protection correlated with non-neutralizing V1V2 antibodies that are relatively easy to induce • However, better vaccine efficacy will likely require the induction of neutralizing antibodies - Broad and potent neutralizing antibodies have been isolated from HIV-infected individuals Active versus Passive/Vector-based Immunoprophylaxis (VIP)

Vaccination Passive “vaccination” VIP

Stimulating Production of an antibody antibodies by response Infusion vector with protective antibodies

Highly potent bNAbs are being tested as “biological drugs” to prevent HIV infection Active Immunization HIV Vaccine Efficacy Trials To Date

NOTE: Phambili (HVTN 503) began to explore a regimen similar to STEP in South Africa (not included) RV144 – Only link to Clinical Efficacy

1.0 .96 0.9 Placebo .84 0.8

.68 0.7 .64

.58 0.6

0.5 .41 .38 0.4 Vaccine

0.3

0.2 .15

0.1 Placebo Vaccine 0.0

Probability0.0 of H IV-10.5 Infection (%1.0 ) 1.5 2.0 2.5 3.0 3.5

YEARS Waning durability? Follow up Findings Provide Clues

Correlates of Risk (CoR) Provided clues how RV144 protected Plasma Anti-V1V2 (Decreased risk) Plasma Anti-Env IgA (Increased risk )

RV144 Sieve Analysis Reinforces the importance of a region on HIV (Env V2) Pox Protein Public Private Partnership (P5)

• Established to build on the success of RV 144 and provide answers to some unanswered questions and incorporate knowledge into next generation vaccine concepts Timeline for P5 Efficacy Trial

HIV vaccine research program: Janssen and Collaborators

BIDMC Harvard MHRP

IAVI Ragon NIAID/HVTN

13 Confidential – Do not distribute Heterologous prime-boost HIV vaccine aiming at global coverage: currently in Phase 1/2a and tested in non-human primate challenge Prime Boost

Ad26.Mos.HIV Ad26.Mos.HIV gp140 Clade C Ad26 vectors with Mosaic gag-pol-env Soluble trimer gp140 env gag-pol or env inserts protein and/or Ad26.Mos1.Gag-Pol

Ad26.Mos2.Gag-Pol OR MVA-Mosaic gp140 Clade C Ad26.Mos1.Env (clade B-like) MVA vectors with Mosaic Soluble trimer gp140 env gag-pol-env inserts protein +/- MVA-Mosaic 1

MVA-Mosaic 2

months 0 3 6 12 Regimen to be selected after Phase 1/2a

14 Confidential – Do not distribute HIV-V-A004 = APPROACH The path or route to the start of a technical climb. Although this is generally a walk or, at most, a scramble it is occasionally as challenging as the climb itself

15 APPROACH Trial Design: a multicenter, randomized, parallel group, placebo-controlled, double-blind clinical trial in healthy HIV-uninfected adults Primary endpoint

Group N Month 0 Week 12 Week 24 Week 48 Booster (baseline)

Ad26.Mos.HIV Ad26.Mos.HIV Group 1 50 Ad26.Mos.HIV Ad26.Mos.HIV + gp140 (250 µg/adj*) + gp140 (250 µg/adj)

Ad26.Mos.HIV Ad26.Mos.HIV Group 2 50 Ad26.Mos.HIV Ad26.Mos.HIV + gp140 (50 µg/adj) + gp140 (50 µg/adj)

Group 3 50 Ad26.Mos.HIV Ad26.Mos.HIV Ad26.Mos.HIV Ad26.Mos.HIV 12 month follow-up MVA-Mos MVA-Mos Group 4 50 Ad26.Mos.HIV Ad26.Mos.HIV + gp140 (250 µg/adj) + gp140 (250 µg/adj)

MVA-Mos MVA-Mos Group 5 50 Ad26.Mos.HIV Ad26.Mos.HIV + gp140 (50 µg/adj) + gp140 (50 µg/adj)

Group 6 50 Ad26.Mos.HIV Ad26.Mos.HIV MVA-Mos MVA-Mos

Group 7 50 Ad26.Mos.HIV Ad26.Mos.HIV gp140 (250 µg/adj gp140 (250 µg/adj)

Group 8 50 Placebo Placebo Placebo Placebo

*Adj=AdjuPhos Confidential – Do not distribute 16 Randomizations completed in all 5 countries • On track for all subjects to have week 28 immuno bleed 29 April 2016 (primary endpoint) • 2 independent DMC reviews identified no concerns

Confidential – Do not distribute17 The Ad26/Ad26+Env HIV vaccine regimen provides substantial protection against SHIVSF162P3 challenges in non-human primates [study designed to mimic APPROACH trial (HIV-V-A004), “regimen selection trial”] 6x IR SHIV challenges

months 0 3 6 12 18

N = 12 per group

Per-Exposure Risk Full Protection after Reduction 6 challenges Ad26/Ad26+Env 94% 66% Ad26/MVA+Env 87% 42% Ad26/Env 84% 33%

Confidential – Do not distribute 18 To enter Phase 1/2a evaluation in 2016 Expanding breadth of immune responses/broader clade coverage

Prime Boost

Ad26.Mos4.HIV Ad26.Mos4.HIV gp140 Clade C Ad26 vectors with Mosaic gag-pol-env Soluble trimer gp140 env gag-pol or env inserts + proteins

Ad26.Mos1.Gag-Pol

Ad26.Mos2.Gag-Pol OR gp140 Clade C+Mosaic Ad26.Mos1.Env (clade B-like) Ad26.Mos4.HIV Soluble trimer gp140 env gag-pol-env proteins Ad26.Mos2S.Env (clade C-like) + + Clade C Mosaic (clade B-like)

months 0 3 6 12 Regimen to be selected after Phase 1/2a

19 Confidential – Do not distribute To enter Phase 1/2a evaluation in 2016 Expanding breadth of immune responses/ broader clade coverage

• HPX2004/ TRAVERSE • Phase 1/2a: Ad26.Mos4.HIV (4-valent) vs Ad26.Mos.HIV (3-valent) • N=198 • FSI: 2Q2016

• HPX2003/ ASCENT • Phase 1/2a: Ad26.Mos4.HIV and Mosaic gp140+Clade C gp140 versus Ad26.Mos4.HIV and Clade C gp140 alone • N=150 • FSI: 3Q2016

Confidential – Do not distribute 20 From Phase 1/2a to Phase 2b and Phase 3 Efficacy trials: regimen down-selection . The optimal regimen is hypothesized to elicit a – well balanced immune response with both antibody and T cell immunity – broad coverage of HIV clades A, B and C

. For the choice of regimen, emphasis will be on – immunological correlates that have been identified to correlate with a reduced risk of SIV/SHIV infection in NHP and on – immunological correlates that have been identified to correlate with a reduced risk of HIV infection in RV144 The above is subject to continuous discussions/decisions by all Partners From Phase 1/2a to Phase 2b and Phase 3 Efficacy trials: Go/no Go criteria

. For the ‘Go/No Go’ criteria, emphasis will be on – Antibodies and cellular responses as a measure of vaccine take – Providing an indication that the elicited antibodies are functional

. Go/no Go decision to start PoC/Ph2b expected in Q4 2016

. Aim: start a Proof of Concept (PoC) trial in SSA in 2017

The above is subject to continuous discussions/decisions by all Partners Confidential – Do not distribute Passive Immunization Long History of Antibodies to Prevent Viral Infections

Pathogen Product Description Indication Concentrated human gamma Measles Prevention globulin Concentrated human gamma Polio Prevention globulin Cytomegalovirus Immune CMV Prevention Globulin Prevention Hepatitis A Immune serum globulin (ISG) (travel) Hepatitis B Hepatitis B Immune Globulin Post Exposure

Rabies Rabies Immune Globulin Post Exposure mAb (palivizumab) for Prevention in RSV prophylaxis of high high risk infants risk Infants Varicella Zoster Immune VZIG Post Exposure Globulin

mAbs in development: Rabies, Ebola, HCV The Promise of Passive Immunization

• Provide proof-of-principle that bNAbs can prevent HIV infection in humans • Determine the minimal dose of antibody (including levels at mucosal surfaces) • Identify the best viral epitopes to target • Assess the importance of antibody isotypes • Provide additional correlates of protection Desirable properties of monoclonal antibodies for HIV prevention

• Safe and effective at low doses (1-5 mg/kg) • Broad coverage (>95%) of global HIV isolates. May require combination of 2-3 mAbs or bispecifics • Long half-life (up to 4-6 months) • Subcutaneous injection • Cost comparable to ARV for PreP Antibody Epitopes on Env Trimer

PGT128

PG9 V2 apex (glycan)

VRC01 High-mannose Patch (V3-glycan) CD4- binding site

gp120-gp41 interface 8ANC195

gp41 MPER

Peter Kwong, Jonathan Stuckey Combined Antibodies: Improved Potency and Breadth

1.0

r 0.8 t VRC07

d PG9

i 0.6

l V PGT128

r H 10E8

u o 0.4 2 mAb Combinations

3 mAb Combinations

i t 4 mAb Combination c 0.2

F 0.0 0.001 0.01 0.1 1 10 100

IC50 cut-off (mg/ml) Kong, Montefiori, Nussenzweig, Korber, Mascola et al. J. Virol (2015)

Protective Efficacy of VRC01 in SHIV challenge model

- Infuse VRC01 (SC or IV) and wait 2-5 days - Rectal challenge with virus: SHIV-BaLP4

VRC01 Dose: 20 mg/kg 5 mg/kg 0.3 mg/kg

6/6 6/6 2/6

viremia

(copies/ml) Plasma Plasma

What is the serum level of VRC01 at time of SHIV challenge?

Pegu et al. Science Tranl Med (2014) Phase I Study of VRC01 (Safety and PK)

• 28 healthy adults • Dose escalation (5, 20, 40 mg/kg) • 2 infusions (iv and sc-5mg/kg only) • Safe and well tolerated • No ADA (anti-VRC01 or anti-allotype antibodies) • Anti-viral activity of VRC01 in serum matched experimental values • Potentially protective VRC01 levels for up to 8 weeks after infusion Time-concentration curves (median + inter-quartiles): IV infusion q8 weeks

Kenneth Mayer CROI Feb 2016 HVTN704/HPTN085 &HVTN 703/HPTN 081; The AMP study

AMP=Antibody Mediated Prevention

A phase 2b study to evaluate the efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection

Summary

• Animal studies provide proof-of-concept for mAbs but we need efficacy data in humans • Currently only 2 mAbs tested in humans (VRC01 and 3BNC117) with many others in the pipeline (VRC07, PGT121/10-1074, CAP256- VRC26.25 and PGDM1400). PG9 also in Phase I trial as VIP • Broader and more potent antibodies are being engineered • Possibilities to extend half-life of mAb • Antibodies may be more useful for prevention than treatment and will provide a benchmark for vaccines