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 Seattle, Washington USA

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 Indiana HIV outbreak: geographic distribution Scott County pop. 24,000; Austin, IN pop. 4,200 Scott County Adams, NEJM 2015;373:1379-1380 Adams, NEJM 2015;373:1379-1380

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 11/14/2018

pandemic lies in a combination of non-vaccine prevention methods and The widespread elimination of HIV will require the development of new, more potent prevention tools. Because HIV acquisition occurs sub-clinically, the elimination of HIV on a population basis will require a highly effective vaccine. “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 702 IAS Durban AMP VaxGen USA (gp120) 1 year 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) Trial start/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 702 IAS Durban AMP VaxGen USA (gp120) 1 year VaxGen IDU Thai Trial (gp120) 1 year Step Trial/Phambili Trial (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) Trial start/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 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*

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-g, TNF-a, IL-17, IL-4 26=64 possible combinations / cell subsets Many empty combinations → 15 considered Important to summarize the response profile as a score. Single number that can be correlated against other assays and outcome variables.

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+ T cell subset 0.59 0.40-0.89 0.011 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 Efficacy Studies 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 (AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085)

2010 Formation of the P5 Partnership Purpose: To build on RV144 data and ultimately license a pox-protein based HIV vaccine with the potential for broad and timely public health impact. Strategy: Developed a partnership to extend the RV144 concept to Clade C regions of the world. Use expert committees to select the strains and then use company expertise 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 Booster at 12 months Construction of ALVAC-HIV-C (vCP2438) Optimize regimen by increasing potency and durability

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 Pivotal Efficacy Trial assessing efficacy and safety Add HVTN in the title? I think this slide would be better if the protocol number was shown horizontally as well.

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

HVTN 702 A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled clinical trial 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

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® 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 Efficacy Studies 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 (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 2 3 Vectors that elicit optimal immune responses Mosaic inserts for global coverage (Gag-Pol-Env) Trimeric env proteins for improved humoral 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 prime prime boost boost months 3 6 12 18 N = 12 per group Per-Exposure Risk Reduction Full Protection after 6 challenges Ad26/Ad26+Env 94% 66% Ad26/MVA+Env 87% 42% Ad26/Env 84% 33%

2016/2017: 3 Novel Strategies Efficacy Studies 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 (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 colleagues Wernicke (left) and Frosch (center) in Robert Koch's laboratory in Berlin. Photo: Courtesy of Aventis Behring WWW.nobelprize.org Pre-Antibiotic Era: Bering and Paul Ehrlich pioneered serum therapy for diseases such as diphtheria, tetanus, streptococcal infections 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 11 10e8 VRC01 PG9 PGT 128 Passive Immunization Systemic IgG Gene-based Ab (AAV) Immune pathways of antibody evolution (B cell biology) Active Vaccination 41

Neutralizing Ab to HIV-1 V1V2-Glycan – bind to trimer cap V3-glycan, N332 supersite gp41 MPER – near membrane gp120/41 interface – bind to parts of both gp120 and gp41 CD4 binding site of gp120 – where the virus attaches to CD4 V3-glycan V1V2-glycan CD4 binding site Only antibodies that have advanced the clinic (VRC01, 3BNC117) gp120/41 interface gp41 MPER Christina Corbaci, Andrew Ward,

VRC01 Blocks Attachment to CD4 gp120 trimer CCR5 gp41 trimer Target Cell CD4 binding site on gp120 is functionally conserved: All viruses must bind CD4 VRC01 neutralizes ~ 90% of diverse viral isolates

How Potent is VRC01 In Vitro Neutralization (IC80) % of viruses resistant to neutralization, IC80 > 50µg/ml 12% 21% 5% 45% 36% 3% Neutralizes 80%-90% of viruses (all major clades) Mean IC80 = 1.0 ug/ml; potential to work at physiologically attainable levels. 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 0/4 protected Figure legend : Plasma concentration of VRC01 IgG1 and infection status after passive transfer of VRC01 IgG1. The plasma concentration of VRC01 IgG1 was measured by a RSC3-based ELISA in animals at different time points after the administration of VRC01 IgG1 to male (A, top panel) or female (B, top panel) rhesus macaques. The percentage of animals remaining uninfected as determined by a real time PCR assay for detecting plasma viremia after either rectal (A, bottom panel) or vaginal (B, bottom panel) challenge with a single high dose of SHIV SF162P3 (300 TCID50) at day 2 post transfer of either a control or VRC01 IgG1 antibody. * denotes a statistical significant difference between the VRC01 and control groups using the log-rank statistical test. 1/4 protected 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? 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 Cohort IV Treatment n= Schedule North + South American MSM (2400) HVTN 704 / HPTN 085 VRC01 10 mg/kg 800 Every 8 wks x 10 doses VRC01 30 mg/kg Placebo Control Sub-Saharan African women (1500) HVTN 703 / HPTN 081 500 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 immunology 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.

66% Overlap in Concentrations 62.5% PYRs

Hypothesis: HIV acquisition will be rare in the first 4 weeks post-infusion at either dose

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: Protect against infection resulting from intrapartum exposure to HIV; i.e., during childbirth Protect the infant during the course of breastfeeding (months)

A Pictorial History of HIV-1 Vaccine Efficacy Trials 1995 2000 2005 2010 2015 2020 702 IAS Durban AMP Janssen Trial VaxGen USA (gp120) 1 year 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 start/end Trial analysis/results Immune correlates First data available

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.

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

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

Collaborators - U.S., South America and Europe Mark Mulligan Paul Goepfert Ray Dolin Lindsey Baden Ken Mayer Richard Novak Benigno Rodriguez Spyros Kalams Scott Hammer Beryl Koblin Ian Frank Michael Keefer Susan Buchbinder Julie McElrath Gepi Pantaleo Jorge Sanchez Martin Casapia Robinson Cabello