1. The role of non-neutraliZing antibodies in preventing HIV infection
EHVA Satellite Symposium, IAS Paris Meeting
Non-ARV Based Interventions to Combat HIV/AIDS: New Insights and Initiatives
July 23, 2017
Susan Barnett, on behalf of the HIV team at BMGF
Senior Program Officer, Product and Clinical Development
HIV Vaccine Program

2. Agenda
Building on the findings from the RV144 trial - the role of non-neutralizing antibody (Ab) responses and contribution to HIV prevention
Findings and contributions from RV144
Antibodies and HIV vaccines
Non-neutralizing Abs as vaccine correlates of protection
The role of non-neutralizing Abs in HIV vaccines
Challenges the field is facing to improve such responses and approaches to overcome such challenges
BMGF- funded HIV vaccine programs
© Bill & Melinda Gates Foundation |

3. Findings and contributions of RV144
Modest protection against HIV acquisition can be achieved by a vaccine
Correlates of risk were identified to guide further vaccine development
“Non-neutralizing” Ab responses shown to play a role in HIV prevention
Motivated new efforts and funding to confirm results (efficacy and correlates)
Energized the HIV vaccine field after years of disappointment
© Bill & Melinda Gates Foundation |

4. Antibodies (Abs) and HIV vaccines
Eliciting broadly reactive neutralizing Ab responses (bNAbs) remains an important goal for the HIV vaccine field
Potential efficacy of bNAbs for HIV prevention and treatment is actively under investigation
bNAbs prevent against SHIV infection in passive transfer studies in non-human primates
Elicitation of bNAbs has not yet been achieved by active vaccination (NHP nor humans)
“Non-neutralizing” antibodies appear to play a role in HIV vaccine efficacy
Non-neutralizing Abs were associated with reduced risk of HIV infection in the RV144 trial
NHP vaccine studies have shown protection associated with various non-neutralizing Fc- mediated effector functions (ADCC, ADCP, ADNP, complement activation, polyfunctionality)
Elicitation of these non-neutralizing Ab responses has been achieved by vaccination
© Bill & Melinda Gates Foundation |

5. Non-neutralizing Functional anti-viral Antibody responses
Abs bind viral epitopes on infected cells.
Effector cells bind Fc exerting anti-viral effects.
Dendritic cell
neutrophil
eosinophil
NK cell
phagocyte
monocyte
complement
cytokines NO
ADCP
ADNP
First studies of ADCC in HIV infection reported in 1987 by K. Weinhold, et al.; role of ADCC in vaccine protection in SIV NHP model reported in 2005 by R. Gomez-Roman, M. Robert- Guroff et, al.
ADCC
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6. correlates of protection
Identifying the immune responses underlying protection against HIV and other infectious diseases is a critical aspect of vaccine development
Correlates of protection (CoP) identified by efficacy trials can be mechanistic or non-mechanistic and can be used as surrogate endpoints to improve vaccines and to optimize vaccine regimens
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7. Correlates identified for existing vaccines are not always neutralizing Abs
S. Plotkin, 2010, Clin. Vacc. Immunol.
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8. Correlates from RV144 Efficacy trial and NHP studies
Correlates of risk (CoR) were identified from the RV144 vaccine trial yet must be confirmed in another trial (HVTN702) before they can be considered CoP
Results from NHP vaccine-challenge studies are emerging that provide insights about protective immune responses and potential CoP
Bridging NHP study results to clinical findings could serve to accelerate vaccine development by providing an animal model to improve HIV vaccines
© Bill & Melinda Gates Foundation |

9. RV144: immune correlates of Risk (CoR) identified
G. Tomaras, S. Plotkin, Immunol. Reviews, 2017.
© Bill & Melinda Gates Foundation |

10. D. Barouch, G. Alter, et al., 2015 Science.
Systems serology approach used to show polyfunctional non-neutralizing Ab responses correlated with vaccine protection (binding Ab, ADCP, polyfunctionality score).
© Bill & Melinda Gates Foundation |

11. Support for The role of Non-neutralizing Abs in Protection against HIV is expanding (NHP)
2007
2011
2013
2014
2015
2016
2017?
2017
Slide content generously provided by G. Alter
© Bill & Melinda Gates Foundation |

12. Building on these findings from RV144 and other studies and challenges ahead
Building on the findings (BMGF CAVD)
Advanced clinical development programs (P5, Janssen) – with DAIDS-NIAID-NIH
Continued discovery and preclinical research
Central services to provide standardized immunologic readouts and statistical support
Product development and clinical support for translational vaccine research (IAVI)
Challenges ahead and how do we address them
Scientific/technical challenges remain; increased focus on key issues could help the field
Vaccine and product development are costly endeavors and timelines are very long
HIV prevention landscape is dynamic and efficacy trials may become more challenging
Complex partnerships, integrated strategies, sustained funding and resources for translational R&D will be required
© Bill & Melinda Gates Foundation |

13. BMGF CAVD collaborative model (2005-present)
Central Service Facilities (CSF) provide:
Best-in-class services to VDCs
Enable comparative analysis of standardized data
Enable translational efficiency
Vaccine Discovery Consortia (VDC) brought together:
To form communities of interest centered around scientific ideas
To share pre-publication data
To exchange knowledge and ideas
Alliance Management facilitates via:
Scientific & logistical coordination and collaboration
Incentives for sharing: legal agreements, contingent funding
Mechanisms for sharing: web portal, meetings
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14. ADVANCED DEVELOPMENT PROGRAMS PRECLINICAL/EARLY DEVELOPMENT
ALVAC/gp120/MF59
Ad26/gp140
VSVΔG Chimera
hCMV-HIV P5
Janssen
IAVI
Picker/VirBio
RV144 Trial: 31% 3.5 yrs, 60% VE at 12 mos
Multiple immune correlates of risk defined
Need to repeat trial in humans to validate the result with P5 clade C products in RSA
“Go” decision in May 2016 for Phase 2b efficacy trial (HVTN 702) - opened Oct 2016
Phase I safety & immunogenicity studies ongoing
Need human efficacy trial to validate NHP protection correlated to non-nAbs
Q GNG decision for Phase 2b efficacy trial (HVTN 705)
VSV Env protein-expressing vector demonstrates significant protection in NHP model
Elicits specific non-neutralizing antibody responses that appear to correlate with protection
Preparatory work ongoing for potential first-in-human clinical studies
Clinical testing of the prototype HCMV-vector to demonstrate safety and ability of the vector to recapitulate the magnitude and novel immune responses induced in the NHP model
$20M PRI to VirBio. Modifying program to incorporate VirBio capabilities

15. VxPDC services for clinical product development
The VxPDC at IAVI (T. Hassell, PI) delivers value by applying the knowledge and experience of trusted professionals across the unique service areas required for vaccine development to accelerate the path from bench to clinic
Project Management & Leadership
Drive process with efficiency and support development / project planning (e.g., timeline, milestones, budget, deliverables)
Pre-Clinical Development
Process & Product Development
Manufacturing Management
Quality Assurance
Regulatory Management
Clinical Development
Advise on design and outcome of toxicology studies, and facilitate data management, sample testing and tissue binding studies
Identify specialized CROs / other contractors and manage the relationship throughout the development process
Accelerate manufacturing by ensuring all systems and processes comply with required standards, and support assay development
Support quality management by conducting audit of vendors, providing quality standards, and managing release of investigational products
Provide regulatory expertise to support CTA/IND submissions (incl. sponsorship as needed); track health authority correspondences
Build clinical strategy and protocol design incl. identifying sites for clinical testing, TPP development, and data management

16. Thank you
© Bill & Melinda Gates Foundation |

17. acknowledgements BMGF Team members Scientific community
Pervin Anklesaria
Silvija Staprans
Thandi Onami
Peggy Johnston
Amy Weiner
Karen Makar
Steve Hadley
Cara Carrubba
Makenna Klingel
Anna Carter
Nina Russell
Emilio Emini
Scientific community
Georgia Tomaras
Stanley Plotkin
Galit Alter
Margie Ackerman
Dan Barouch
CAVD investigators and many others……..
IAVI
Robert Palermo
© Bill & Melinda Gates Foundation |