Progress in the HIV Vaccine Field

Larry Corey, MD Principal Investigator, NIAID supported HIV Vaccine Trials Network (HVTN) Past President and Director, Fred Hutchinson Cancer Research Center Professor, Laboratory Medicine and Medicine, University of Washington , Washington USA Disclosures

• None Acknowledgements • HVTN as an organization, especially my colleagues: Scott Hammer, Glenda Gray, Julie McElrath, Peter Gilbert, Jim Kublin and Susan Buchbinder

• The HVTN’s major pharmaceutical and institutional collaborators: Sanofi, GSK, Janssen, VRC, IAVI and CHAVI programs

• The HVTN’s community members and advisory boards

• Its funders: NIAID and BMGF Special Acknowledgement Tony Fauci, MD HIV: Still the World’s Most Important Global Health Problem

• US still over 45,000 new cases yearly • Globally more than 2 million new infections occur per year • Number of people living with HIV increasing yearly • Long way from an AIDS Free Generation Indiana HIV outbreak: geographic distribution Scott County pop. 24,000; Austin, IN pop. 4,200

Adams, NEJM 2015;373:1379-1380 Scott County

Commentary on HIV Prevention Strategies

• While many prevention strategies have high efficacy in clinical trials, their extended effectiveness requires continuous adherence, which often results in decreased effectiveness over time.

• They also require high saturation in a community and hence their long term effects on population based incidence in country’s with generalized epidemics is uncertain: • Condoms; PrEP; vaginal rings; PEP; circumcision, all deserve support and increased uptake • Test and Treat very effective for the individual; eventual population effect will be achieved The Need for an HIV Vaccine

• With asymptomatic acquisition, prolonged subclinical infection, and sexual transmission, getting to an AIDS Free Generation will require a vaccine.

• Larry’s definition of an AIDS Free Generation; 95% reduction in incident cases annually: • USA < 2,500 incident cases yearly • Globally < 100,000 cases yearly

7/25/16 9 “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.” The Two Major Scientific Questions Facing the HIV Vaccine Field:

• Can non-neutralizing antibodies be potent enough to achieve desirable vaccine efficacy (VE >50%) for at least 2 years? • Can this be achieved by designing better recombinant proteins and adjuvants? • 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? HIV Vaccine Field at the Time of the Durban Conference in July 2000 • HIV vaccines not on the main stage: • No vaccine studies in RSA • HVTN just being organized (1999) • Several phase 1 trials of recombinant proteins were underway, including a phase 1 vaccine study in Uganda • Period of first generation vaccines (1984 – 2004): • Recombinant envelope vaccines all directed at trying to induce neutralizing antibodies • Large number of gp120, gp140, gp145, gp160 manufactured and tested • All immunogenic • Narrow (strain specific) neutralization • Poor durability A Pictorial History of HIV-1 Vaccine Efficacy Trials

1995 2000 2005 2010 2015 IAS Durban 702

VaxGen USA (gp120) 1 year AMP

VaxGen IDU Thai Trial (gp120) 1 year

Step Trial/Phambili Tria ls (Ad 5 g a g / p o l/ nef)

RV144 Thai Trial (ALVAC/gp120)

HVTN 505 (DNA/Ad5 env/gag/pol

AMP Trial (VRC-01)

HVTN 702 (Clade C ALVAC/gp120)

Trial star t/end

Trial analysis/results

Immune correlates Second Generation Vaccines: T Cell Based Vaccines

• Post-VaxGen, HIV vaccine field turned to “T cell based” vaccines • CD8+ T cells were what differentiated elite controllers from progression and it was hoped that vaccines that would induce such responses would be effective in either reducing acquisition or post- acquisition viral load.

• Hypothesis: the more potent T cell responses, the better the vaccine: • Ad5 vector based vaccine much more effective in inducing CD8+ T cell responses than ALVAC A Pictorial History of HIV-1 Vaccine Efficacy Trials

1995 2000 2005 2010 2015 IAS Durban 702

VaxGen USA (gp120) 1 year AMP

VaxGen IDU Thai Trial (gp120) 1 year

Step Trial/Phambili Tria l (Ad 5 g a g / p o l/ nef)

RV144 Thai Trial (ALVAC/gp120)

HVTN 505 (DNA/Ad5 env/gag/pol

AMP Trial (VRC-01)

HVTN 702 (Clade C ALVAC/gp120)

Trial star t/end

Trial analysis/results

Immune correlates Ad5 HIV Vaccines

• Step and Phambili Trials with the MRK Ad5 gag/pol/nef: • No efficacy in either post infection viremia or reduced acquisition despite a high prevalence and reasonable magnitude of CD8+ T cell responses • Increased rate of acquisition of HIV-1 in both trials among men • Step: MSM Ad5 seropositive, uncircumcised men • Phambili: heterosexual men, also Ad5 seropositive • Mechanism of increased acquisition is unclear, especially as the DNA prime Ad5 boost regimen used in HVTN 505 had no evidence of increased acquisition: • The critical difference is the addition of HIV envelope in the DNA/Ad5 regimen • Envelope antibodies may be a factor in eliminating/negating the effects of increased mucosal T cells after Ad5 vaccination The Good News for HIV Vaccine Development – September 2009 and the RV144 Trial

• Regimen of ALVAC priming followed by gp120 results in efficacy in large trial in Thailand.

• Results met with surprise and skepticism: • ALVAC not as good as Ad vectors for T cell priming • gp120 used had failed in IDU trial

• How could these two together all of a sudden produce efficacy? Thai Trial (RV144) Primary Results

1.0 Modified Intention-to-Treat Analysis*

0.9

0.8 Placebo 0.7

0.6 Vaccine 0.5

0.4

0.3

Probability of HIV Infection (%) 0.2

0.1

0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Post-RV144

• Massive scientific effort to understand how did RV144 work: correlates of risk/correlates of protection.

• Pivot in the field from concentrating on novel vectors to understanding that it is the insert (HIV envelope gene ) and structure of the envelope antigen that one puts in the vector that is critical for vaccine design. Concepts from the RV144 Correlates Program 2010 - 2014

• No direct correlation between neutralizing antibodies and HIV-1 acquisition in RV144: • None of the sera from the RV144 vaccinees neutralized a panel of 20 contemporaneous isolates of HIV-1 circulating in Thailand during the course of the trial

• The antibody related correlations associated with Vaccine Efficacy in RV144 were in the magnitude and the epitope specificity of non-neutralizing antibodies which exhibited virion binding or infected cell associated functions. Correlation Between Antibodies to the V1V2 Loop and Vaccine Efficacy in RV 144

• Antibodies to the conserved region of V2, previously almost completely ignored by the HIV vaccine field, were highly correlated with efficacy. RV144 Correlates Observations

• Sequencing studies of the viral envelope from persons on the trial revealed that distinct immunological pressure was observed in the crown of the V2 loop where vaccine immune responses were directed.

• Distracting/inhibitory antibodies could be produced that reduced vaccine efficacy. CD4+ T cell Responses to HIV envelope in RV144

• Polyfunctional CD4+ T cell responses to HIV-1 envelope also independently contributed to VE.

• The cytokine patterns of these helper T cell responses suggest that T helper responses that influence antibody development are important. COMPASS: Combinatorial Polyfunctionality Analysis of Single-cell Subsets

COMPASS permits the unbiased characterization of polyfunctional subsets

Expression of 6 functional markers: CD154, IL-2, IFN-γ, TNF-α, IL-17, IL-4 § 26=64 possible combinations / cell subsets § Many empty combinations → 15 considered Env-specific CD4+ T cell polyfunctionality score is an independent correlate of Vaccine Efficacy

The five-function CD4+ T subset remains significant (OR=0.59, p=0.010) when the V1V2 and IgA Ab variables are also included in the model. The effects of the V1V2 IgG correlate and the five-function subset are additive (no evidence of interaction).

Variable OR 95% CI P-value 5-function Env-specific CD4+ 0.59 0.40-0.89 0.011 T cell subset V1V2 IgG Ab primary 0.62 0.42-0.94 0.022 IgA Ab primary 1.76 1.2-2.6 0.003

(Lin L. et al, Nat Biotech. 2015 Jun;33(6):610-6.) 2016/2017: 3 Novel Strategies

P5 “Clade C” approach using ALVAC & gp120/MF59 (HVTN 702)

Multi-clade approach using rAd26/MVA/gp140 trimer (Crucell/Janssen)

Neutralizing antibody approach using VRC01

Efficacy Studies Efficacy (AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085) 2010 Formation of the P5 Partnership

Strategy: Purpose: Developed a partnership to extend the To build on RV144 data and RV144 concept to Clade C regions of the ultimately license a pox-protein world. based HIV vaccine with the Use expert committees to select the potential for broad and timely strains and then use company expertise public health impact. to manufacture these vaccines for immunogenicity, safety and efficacy. The Strategy for the ALVAC/Protein Phase 3 Program

Construction of Bivalent Subtype C gp120/MF59 Construction of Booster at ALVAC-HIV-C 12 months (vCP2438)

Optimize regimen by increasing potency and durability HVTN Strategy for the Phase 3 Program

HVTN 097 HVTN 100 HVTN 702 Designed to A standard A Pivotal evaluate RV144 phase 1 trial of Efficacy Trial vaccine regimen the Clade C assessing in RSA and products to efficacy and compare decide whether safety immunogenicity to proceed to to that in phase 3 Thailand LB xxxx

Meeting the “Go” Criteria: Immunogenicity from HVTN 100, a phase 1/2 randomized, double blind, placebo-controlled trial of clade C ALVAC- ® (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected South African adults.

Bekker LG, Laher F, Moodie Z, Tomaras G, Grunenberg N, Allen M, Daniels B, Innes C, Mngadi K, Malahleha M, Grant S, Gilbert P, Michael N, Phogat S, Diaz Granados C, Kanesa Thasan N, Corey L, Gray G, McElrath J, for the HVTN 100 team. Boxplots of IgG binding antibody titers to the gp120 Vaccine Antigens used in RV144 and HVTN 100

The midline of the box plot indicates the median. The ends of the box indicate the 25th and 75th percentiles. Significantly greater polyfunctionality scores in HVTN 100 (P < 0. 00001) HVTN 702 A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59 in preventing HIV-1 infection in adults in South Africa

§ Scheduled to start Nov. 1, 2016 in RSA § Glenda Gray, Chair § Co-Chairs: Linda Gail Bekker, Fatima Laher, Mookho Malahlela Study Schema: HVTN 702

Primary Vaccine Regimen Booster N (total 5400) Month 0 Month 1 Month 3 Month 6 Month 12

ALVAC-HIV+ Bivalent ALVAC-HIV+ Bivalent ALVAC-HIV+ Bivalent ALVAC-HIV ALVAC-HIV 2700 Subtype C Subtype C Subtype C (vCP2438) (vCP2438) gp120/MF59® gp120/MF59® gp120/MF59®

2700 Placebo Placebo Placebo + Placebo Placebo + Placebo Placebo + Placebo

Estimated Total Study duration 72 months: • Stage 1: 60 months - 18 months for enrollment, 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 2016/2017: 3 Novel Strategies

P5 “Clade C” approach using ALVAC & gp120/MF59 (HVTN 702)

Multi-clade approach using rAd26/MVA/gp140 trimer (Crucell/Janssen)

Neutralizing antibody approach using VRC01

Efficacy Studies Efficacy (AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085) J&J HIV Vaccine Research Program:

• BIDMC/Harvard • HVTN • IAVI • MHRP • NIAID • Ragon Institute Prophylactic Vaccine Aiming at Protection Against all Clades of HIV-1

1 2 3 Vectors that elicit optimal Mosaic inserts for Trimeric env proteins for immune responses global coverage improved humoral (Gag-Pol-Env) immunity The Ad26/Ad26+Env HIV vaccine regimen provides substantial protection against SHIVSF162P3 challenges in non-human primates [study #13-19 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 Reduction after 6 challenges Ad26/Ad26+Env 94% 66% Ad26/MVA+Env 87% 42% Ad26/Env 84% 33% 2016/2017: 3 Novel Strategies

P5 “Clade C” approach using ALVAC & gp120/MF59 (HVTN 702)

Multi-clade approach using rAd26/MVA/gp140 trimer (Crucell/Janssen)

Neutralizing antibody approach using VRC01

Efficacy Studies Efficacy (AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085) Long History of Antibodies to Treat and Prevent Infectious Disease (Serum Therapy)

The Nobel Prize in Physiology or Medicine 1901 to Emil von Behring: “For his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths".

Behring together with his Pre-Antibiotic Era: Bering and Paul Ehrlich pioneered serum therapy for colleagues Wernicke (left) and Frosch (center) in Robert Koch's diseases such as diphtheria, tetanus, streptococcal infections laboratory in Berlin. Photo: Courtesy of Aventis Behring WWW.nobelprize.org Nobel Prizes awarded for discoveries related to antibodies in infectious diseases: - 1901: Serum therapy for diphtheria (Behring), - 1908: Describing humoral immunity (Mechnikov, Ehrlich), - 1972: Defining the chemical structure of antibodies (Edelman, Porter) - 1984: Production of monoclonal antibodies (mAbs) (Jerne, Köhler, Milstein) - 1987: Explaining the mechanism for antibody diversity (Tonegawa) Antibodies Teach Us About HIV Vaccine Development

MPER CD4bs V1V2 glycan V3 glycan Trimer 1 1

10e8 VRC01 PG9 PGT 128

Passive Active Vaccination Immune pathways of - Systemic IgG antibody evolution - Gene-based Ab (AAV) (B cell biology) 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 • gp120/41 interface – bind to parts of interface both gp120 and gp41 gp41 MPER • CD4 binding site of gp120 – where the virus attaches to CD4

Only antibodies that have advanced 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 21% 45% 1 0 0 12% 5% 36% 3%

1 0

•) Neutralizes 80%-90% of viruses (all major clades) l 1 m /

•g Mean IC80 = 1.0 ug/ml; potential to work at m ( r physiologically attainable levels. e 0 .1 t i T

0 8 0 .0 1 C I

0 .0 0 1

0 .0 0 0 1

1 7 S 1 4 8 0 1 L 2 7 E C 1 - 1 0 0 C 3 T 1 1 R 2 - V N 5 G 0 B - P 1 3 7 0 C R V

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 Mucosal Pharmacokinetics in Rhesus Macaques 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 VRC01 Control Control 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 Protection • NHP studies tell us that physiologically achievable levels of Ab could prevent HIV-1 infection • But no direct proof in humans • Learn from Proof of Concept Trial in Humans: • What level of neutralizing Ab is needed to prevent infection? o Pertains to passive bNAb infusion or vectored delivery • Convert the mAb levels to serum level of neutralization needed to protect (e.g., neut titer 1:50, 1:500) • Provides a benchmark for vaccine development; i.e. what antibody level does a vaccine need to achieve 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 & Hetersosexual Women in sub-Saharan Africa

Chairs: Lawrence Corey, HVTN Mike Cohen, HPTN Co-chairs: Srilatha Edupuganti Nyaradzo Mgodi The AMP Studies: Highlights

• Placebo controlled trial of VRC01 mAb (IV), given on q2 month schedule • Two cohorts: • 2,400 MSM + TG in North & South America • 1,500 Women in sub-Saharan Africa • Powered to detect 60% efficacy; and to associate VRC01 plasma level with protection • Both trials opened in April/May 2016 The AMP Studies: Highlights

Cohort IV Treatment n= Schedule

North + South VRC01 10 mg/kg 800 American MSM (2400) Every 8 wks VRC01 30 mg/kg 800 x 10 doses HVTN 704 / HPTN 085 Placebo Control 800

Sub-Saharan VRC01 10 mg/kg 500 African women (1500) Every 8 wks VRC01 30 mg/kg 500 x 10 doses HVTN 703 / HPTN 081 Placebo Control 500

• Two different infusion doses: Important to know if lower dose of 10 mg/kg can protect • Powered to associate mAb serum level with protection Rationale for the 2 Cohorts and 2 Dosing Regimens

• Route of acquisition and genital tract and anatomy may influence the distribution of VRC01 and potential efficacy.

• Variation in the doses allows us to more precisely define what are the optimal concentrations of neutralizing activity associated with protection from acquisition. Concentrations of Antibody in Serum in HVTN 104 Per protocol Per protocol

(VRC01 30 mg/Kg) (VRC01 10 mg/Kg) 66% Overlap in Concentrations

62.5% PYRs Hypothesis: HIV acquisition will be rare in the first 4 weeks post-infusion at either dose AMP Research Sites

HVTN 704/HPTN 085, MSM + TG

HVTN 703/HPTN 081, Women AMP sub-Saharan Africa Sites

• Gaborone, Botswana • Cape Town, RSA • Kisumu, Kenya • Durban, RSA (2 clinics) • Blantyre, Malawi • Johannesburg, RSA • Lilongwe, Malawi • Soweto, RSA • Maputo, Mozambique • Vulindlela, RSA • Harare, Zimbabwe (3 clinics) • Mbeya, Tanzania MSM+TG AMP Sites

• , GA (2 clinics) • , PA • Birmingham, AL • Rochester, NY • , MA (2 clinics) • San Francisco, CA • Chapel Hill, NC • Seattle, WA • , OH • Washington, DC • , CA • Lima, Peru (3 clinics) • Nashville, TN • Iquitos, Peru • Newark, NJ • Rio de Janeiro, Brazil • New York, NY (4 clinics) Concepts from the AMP Studies

· Can lower levels of neutralization activity afford protection or does in vivo protection require only high concentrations of CD4 binding site antibodies?

· Are non-neutralizing effector functions as predictive of efficacy as neutralizing activity?

• Defining the optimal concentration defining efficacy allows one to engineer a second generation product and delivery system that will provide protective levels in a way that can be delivered efficiently on a population basis.

• Higher potency; longer half-life; cheaper delivery. Potential Role in Interruption of Maternal to Child Transmission

Could HIV mAbs: q Protect against infection resulting from intrapartum exposure to HIV; i.e., during childbirth q Protect the infant during the course of breastfeeding (months) A Pictorial History of HIV-1 Vaccine Efficacy Trials

1995 2000 2005 2010 2015 2020 IAS Durban 702

Janssen Trial VaxGen USA (gp120) 1 year AMP

VaxGen IDU Thai Trial (gp120) 1 year

Step Trial/Phambili Trials (Ad5 gag/pol/nef)

RV144 Thai Trial (ALVAC/gp120)

HVTN 505 (DNA/Ad5 env/gag/pol

AMP Trial (VRC-01)

HVTN 702 (Clade C ALVAC/gp120)

Janssen Test of Concept

Trial star t/end Trial analysis/results Immune correlates First data available 61 62 The HIV Vaccine Field is Open for Business

• Three pivotal HIV vaccine related efficacy trials are either in progress (AMP) or soon to be initiated: HVTN 702 and Janssen POC trial in 2016 - 2017.

• 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 HIV Vaccine Field is in a Novel Space

• Using human clinical trials with intense evaluation of the Correlates of Protection is in the end - true “rational vaccine design”.

• For the first time, the basic science agenda in HIV vaccine development will be based on human clinical trials. Acknowledgments HVTN Lab Program HVTN Core, SDMC, EMT Julie McElrath, Georgia Tomaras, Jim Kublin, Peter Gilbert, Glenda Gray, Nicole Frahm, John Hural, Susan Buchbinder, Scott Hammer, David Montefiori, Steve DeRosa, Gepi Pantaleo, Shelly Karuna, Erica Andersen-Nissen, Lynn Morris Nicole Grunenberg, Carter Bentley 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, Sanjay Phogat Paul Kitsutani, Mary Allen, Jim Lane, Janssen Mike Pensiero Frank Tomaka, Maria Pau, Hanneke Schuitemaker, Paul Stoffels Collaborators - Africa

• Glenda Gray • Jani Ilesh • Linda Gail-Bekker • Stewart Reid • Gita Ramjee • Leonard Maboko • Cheryl Louw • Maphoshane Nchabeleng • Kathy Mngadi • Lungiswa Mtingi • Graeme Meintjes • Dumezweni Ntshangase • Craig Innes • William Brumskine • Nicole Hunt • Zvavahera Chirenje • Phillip Kotze • Mookho Malahlela • Francis Martinson • Modulakgotla Sebe Collaborators - U.S., South America and Europe

• Mark Mulligan • Beryl Koblin • Paul Goepfert • Ian Frank • Ray Dolin • Michael Keefer • Lindsey Baden • Susan Buchbinder • Ken Mayer • Julie McElrath • Richard Novak • Gepi Pantaleo • Benigno Rodriguez • Jorge Sanchez • Spyros Kalams • Martin Casapia • Scott Hammer • Robinson Cabello