HIV Vaccine Efficacy Studies in

Prof President & CEO SAMRC Research Professor: Paediatrics, University of Witwatersrand Member of the VIDD, FHCRC HVTN-Co-PI

INTEREST 2019, 14-17 May 2019, Ghana Southern & East Africa have been involved in an extraordinary effort and have enrolled 9550/9900 men and women in 3 HIV vaccine efficacy studies These are the trailblazers in this heroic endevour

3 Current Phase 2B/3 HIV Vaccine Efficacy Trials

Uhambo Imbokodo AMP (POC) (Phase 2B/3) (Phase 2B/3) HVTN 703/704 HVTN 702 HVTN 705 3 Different Approaches: 2 active HIV vaccine approaches and one passive immunisation

Clade C approach

Global vaccine approach

Neutralising antibody approach Active Immunization Passive Immunization

Vaccination to stimulate binding Pre-formed broadly neutralizing antibodies previously show to antibody against the CD4 binding correlate with reduced risk of HIV site VRC01 is infused to provide infection in RV144 or in NHP challenge instant protection against HIV models. This is being tested in the infection. This is being tested in the large efficacy trial HVTN 702 & HVTN HVTN 703 (AMP trial) 705 Adapted from a slide from Lynn Morris Why did we advance these into efficacy studies?

HVTN 702 (pox-protein heterologous prime boost) • Evidence of modest efficacy in RV144 • Adapted to Clade C: met the go/no go criteria in HVTN 100 5200 (96%) • Evaluated in RSA only

HVTN 703/704 (monoclonal antibody infusions of VRC 01) • Evidence of protection in NHP challenge model • Being evaluated in MSM and heterosexual women 1900 (100%)

HVTN 705 (Ad26-Ad26/protein, heterologous double prime/double boost) • Evidence of protection in NHP challenge model • Advanced in POC after meeting go/no go criteria in TRAVERSE • heterosexual women in SSA 2450 (94%) We will answer Two Major Scientific Questions

• Can non-neutralizing antibodies be potent enough to achieve desirable vaccine efficacy (VE >50%) for at least 2 years? o Can this be achieved by designing better recombinant proteins and adjuvants? o By eliciting better T helper responses to drive higher and more durable antibody production?

• Is neutralization, as we currently measure it, associated with vaccine protection and will this protection be of a sufficient magnitude to overshadow other vaccine design approaches? RV144: FIRST HINT OF SUCCESS – AND LESSONS

V1V2 loop V3 loop

Correlates associated with ↓HIV acquisition: • Abs (IgG, IgG3) against •magnitude, envelope (vaccine- quality and matched gp120, V1V2) • vaccine • Functionality, durability of polyfunctionality scores efficacy immune responses of env-specific CD4+ T- wanes wanes cell responses

Rerks-Ngarm S. et al. N. Engl. J. Med. 2009; Corey L et al. Science Transl. Med. 2015.9 Haynes BF et al. Immune-Correlates Analysis of an Courtesy: Fatima LaherVaccine Efficacy Trial. 2012;366(14):1275-86. DEVELOPING THE CLADE C STRATEGY

Phase 1-2a Phase 2b-3 Safety & immunogenicity Efficacy n=252 n=5400 , 6 sites South Africa, 14 sites

• ALVAC-HIV (vCP2438) expresses • env gp120 of ZM96 strain (subtype C) + gp41 transmembrane sequence (subtype B LAI strain) • gag + protease (subtype B LAI strain) • Bivalent Subtype C gp120/MF59: • env gp120 of TV1.C strain (subtype C) • env gp120 of 1086.C strain (subtype C) • mixed with MF59 adjuvant

Chairs: Linda Gail Bekker & Fatima Laher 10 HVTN 702

Month 3, Month 6, N= Month 0, Grp Month 12, 14 572 5400 Month 1 trial sites site Month 18 in South research Africa staff ALVAC-HIV (vCP2438) ALVAC- + 2700 HIV 5200 >100 Bivalent Subtype C VACCINE (vCP2438) enrolled 000 gp120 & MF59® by Mar PBMCs 2019 thusfar

2700 Placebo Placebo + Placebo PLACEBO Chairs: Glenda Gray, Linda Gail Bekker, Fatima Laher, & Mookho Malahleha HVTN 705/HPX2008: Vaccine Aiming at Protection Against all Clades of HIV-1

Adolescents (11-17 years) /Adults (18-65 years) in endemic countries and populations at risk in Western world

Different HIV-1 clades dominate in different geographic regions

1 2 3 Potent priming Vectors Mosaic inserts for Trimeric env protein for global coverage improved humoral immunity Low seroprevalentAd26 Ad26.HIV-Gag-Pol Ad26.HIV-Env (MVA.HIV-Gag-Pol-Env)

Dan H Barouch et al., 2010

19 Chairs: Glenda Gray, Kathy Mngadi, Susan Buchbinder, Frank Tomaka Mixture of 4 mosaic Ad26 constructs + gp140 Clade C boost 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

Ad26.Mos1.Env (clade B-like) Ad26.Mos4.HIV gag-pol-env Ad26.Mos2S.Env (clade C-like)

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

13 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)]

6x IR SHIV challenges

months 0 3 6 12 18

N = 12 per group

Per-Exposure Risk Full Protection Reduction after 6 challenges

Ad26/Ad26+Env 94% 66% Ad26/MVA+Env 87% 42% Ad26/Env 84% 33% 14 HVTN 705 Study Design and Stages

29/05/2019 15 Another Pause to Reflect

• Two non-neutralizing strategies are being undertaken: o 1 based upon RV144 correlates data and the other based upon correlates in NHP challenge experiments. o Both approaches suggest correlates relate to both binding/functional antibodies (ADCP and ADCC), as well as some T cell response (CD4 envelope and the other ELISPOT data). o We shall see whether these presumed correlates are shown to be consistent in human efficacy trials. o We shall see if any NHP challenge studies are predictive of vaccine efficacy.

29/05/2019 16 Neutralizing Ab to HIV-1

• V1V2-Glycan – bind to trimer cap V3-glycan V1V2-glycan • V3-glycan, N332 supersite CD4 binding site • gp41 MPER – near membrane • gp120/41 interface – bind to parts of gp120/41 both gp120 and gp41 interface gp41 • CD4 binding site of gp120 – where the MPER virus attaches to CD4

antibodies that have advanced farthest in the clinic (VRC01, 3BNC117) Christina Corbaci, Andrew Ward, VRC01 Blocks Attachment to CD4

gp41 trimer

gp120 trimer CD4 binding site on gp120 is functionally conserved: all viruses must bind CD4

VRC01 neutralizes ~ 90% of CD4 CCR5 diverse viral isolates

Target Cell How Potent is VRC01 In Vitro

Neutralization (IC80)

% of viruses resistant to neutralization, IC80 > 50µg/ml 12% 21% 5% 45% 36% 3% 1 0 0

1 0

• Neutralizes 80%-90% of viruses (all major clades) )

l 1

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•g Mean IC80 = 1.0 ug/ml; potential to work at

 ( physiologically attainable levels.

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Panel of 170 genetically diverse Env-pseudoviruses, representing all major clades Line shows median IC value - based on results from all viruses, including those not neutralized. VRC01 Protects Against Mucosal SHIV-Challenge in Non-Human Primates 20 mg/kg infusion of VRC01: Challenge with SHIV SF162P3

RECTAL CHALLENGE VAGINAL CHALLENGE

4/4 protected 4/4 protected 100 100

80 VRC01 80 VR C 01 Control C ontrol 60 60

40 40

20 0/4 protected uninfected Percent Percent uninfected Percent 20 1/4 protected 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Days post challenge Days post challenge

• Pegu et al. Science Transl Med (2014) • Ko et al. Nature (2014) • Rudicell et al. J Virol (2014) Passive Antibody Prevention Phase IIB Efficacy Studies

AMP = Antibody Mediated Prevention

Can a passively infused monoclonal antibody prevent HIV-1 infection in high risk adults: MSM in Americas & heterosexual women in sub-Saharan Africa

Chairs: Lawrence Corey, HVTN Mike Cohen, HPTN Co-chairs: Srilatha Edupuganti Nyaradzo Mgodi Cohorts for the AMP Studies

Cohorts Antibody Antibody Placebo Total (VRC01) (VRC01) Saline Population 10mg/kg 30mg/kg

HVTN704/HPTN085: 900 900 900 2,700 MSM & TG persons (Clade B) United States, Peru, Brazil & Switzerland

HVTN703/HPTN081: 634* 634* 634* 1,900 Heterosexual women (Clade C) Sub-Saharan Africa – 7 countries

Total 1,534 1,534 1,534 4,600

* Due to the randomization scheme, the numbers of vaccine and control recipients may differ slightly. AMP Study Research Sites

HVTN 704/HPTN 085, MSM + TG

HVTN 703/HPTN 081, Women 24 HVTN 703/HPTN 081: Summary*

Enrollment: 1924 (complete)

Retention: 96% of 30,976 visits

Adherence: 98% of 14,490 infusions

*As of 2 March 2019 A SOUTH AFRICAN BNAB! CAP256.25 neutralizes 72% of subtype C viruses often with exceptional potency making subcutaneous administration possible

V2g V3g CD4bs MPER

50 50 10 25 25 20 10 20 20 25 25 20 50 25 25 Max. Conc. 70 75 71 67 72 68 54 67 64 89 96 79 84 71 98 % Neutralized 10 2

10 1

10 0

10 -1

10 -2

IC50 Titer (ug/ml) Titer IC50 10 -3

10 -4

PG9 10E8 VRC07 VRC01 VRC13 PGT145 PGT121PGT128 10-1074 10-1074V 3BNC117 PGDM1400 VRC07-523.LS CAP256-VRC26.08CAP256-VRC26.25

Wagh et al., PLoS Path, 2016 Exceptional potency of CAP256.25 translates into protection at very low doses in monkeys

Julg et al, Science Translational , 2017 CAP256.25 in combination with a CD4bs or V3-glycan antibody shows high breadth and potency against subtype C viruses

Wagh et al. PLoS Pathogens, 2016 From Bench to Bedside: the CAP256 Story

Clinical trial of CAP256.25-LS at CAPRISA cohort CAPRISA (SAMRC, established (NIH, NDoH, VRC, IAVI, DST) BIDMC, others tbd) 2019 2004

Identified CAP256 as GMP production 2017- 2008- donor with exceptional (VRC-NIH) 2018 2011 neutralization breadth (SHARP, TIA, SAMRC, NIH) 2017 2014- 2016

Isolation of CAP256-VRC26.25 CAP256.25 shown to be mAb in collaboration with VRC efficacious in monkeys (VRC-NIH, SAMRC, DST, (Ragon, VRC-NIH) Wellcome Trust) An exciting time to be in the HIV vaccine finding business! • Three pivotal HIV vaccine related efficacy trials are underway (AMP/702/705).

• These pivotal efficacy studies will define if either or both neutralizing and/or non-neutralizing antibodies can be tweaked to provide reasonable vaccine efficacy in high risk Clade C regions of the world.

• These studies will set the stage for the entire design and development of HIV vaccines for the next decade. The Day after Success…should begin before

Vaccinate the Placebo recipients and set into motion the correlates programme +/- additional phase 3 studies

Scale-up product for bridging studies and other phase 3B studies to prepare for registration in consultation with regulators

Advance clinical development into Adolescents and younger children as well as infants LETS ALL MAKE HIV HISTORY Collaborators - Africa

• Fatima Laher • Jani Ilesh • Erica Lazarus • Stewart Reid • Linda Gail-Bekker • Leonard Maboko • Gita Ramjee • Maphoshane Nchabeleng • Cheryl Louw • Lungiswa Mtingi • Kathy Mngadi • Dumezweni Ntshangase • Graeme Meintjes • William Brumskine • Craig Innes • Zvavahera Chirenje • Phillip Kotze • Mookho Malahlela • Francis Martinson • Modulakgotla Sebe

All the study staff, the community engagement teams, and most of all, the participants who join the journey Acknowledgments HVTN Lab Program HVTN Core, SDMC, EMT Julie McElrath, Georgia Tomaras, Nicole Frahm, Jim Kublin, Peter Gilbert, Larry Corey, John Hural, Susan Buchbinder, Scott Hammer, Gepi David Montefiori, Steve DeRosa, Pantaleo, Shelly Karuna, Erica Andersen-Nissen, Lynn Morris Nicole Grunenberg, Carter Bentley Guido Ferrari Site Investigators USMHRP Study Volunteers Nelson Michael, Robert O’Connell CHAVI ID Bill and Melinda Gates Foundation Bart Haynes, Larry Liao and colleagues Emilio Emini, Nina Russell and team DAIDS Vaccine Research Program Sanofi Pasteur Carl Dieffenbach, Mary Marovich, Jim Tartaglia, Sanjay Gurunathan, Dale Hu, Phil Renzullo, Pat D’Souza, Paul Sanjay Phogat Kitsutani, Mary Allen, Jim Lane, Mike Janssen Pensiero Frank Tomaka, Maria Pau, CAPRISA Hanneke Schuitemaker, Paul Stoffels Collaborators and Funders

NICD HVTN/HPTN Penny Moore Larry Corey Nono Mkhize Glenda Gray Cathrine Scheepers Julie McElrath Simone Richardson John Hural Zanele Ditse Peter Gilbert Nigel Makoah Bronwen Lambson VRC Charissa Mynhardt John Mascola Tandile Hermanus Peter Kwong Valerie Bekker Nicole Doria-Rose Sharon Madzorera Duke and CAVD Rutendo Ziki David Montefiori Jinal Bhiman Barton Haynes Kurt Wibmer Georgia Tomaras Carol Crowther Mike Seaman Bette Korber CAPRISA Salim Abdool Karim Ragon Dan Barouch Nigel Garrett Boris Julg Carolyn Williamson Galit Alter