Jenner Institute Complementary Vaccines Platform Technologies

WHO R&D Blueprint: Janssen Vaccines – Jenner Institute complementary Vaccines Platform Technologies

Janssen Vaccines: Jenner Institute: Olga Popova Prof. Sarah Gilbert Jerome Custers

WHO Geneva, 21 July 2016 Background

• Jenner Institute & Janssen Vaccines presented respective proposals to WHO R&D Blueprint Workshop in April 2016, and were invited to join forces for Round 2 submission • Example of alignment, coordination and partnership between public and private sector stakeholders • Understanding nature of vaccine development, established complementary end‐to‐end skills and capabilities • Long‐term, sustainable & consistent approach and funding • High‐level flexible proposal with illustrative examples • «Bona fide»: collaborative framework to be developed

JOINTLY TOWARDS TANGIBLE OUTCOMES x GLOBAL PUBLIC HEALTH

2 Success factors

• Available platforms and previous experience with pathogens • Ability to invest time and resources, leverage expertise, minimise opportunity costs and ensure business continuity • Appropriate and functionable operational model, speed • Lean governance, partner alignment and milestone orientation

INTERNAL • Reliable & qualified partners, durable commitments

• Long‐term reliable funding (min 5‐year horizon) • Resolving vaccination indemnification / liability issue • Consistency in pathogen prioritisation and defined, consistent pre‐ established endpoint commitment • Clear and accelerated / streamlined regulatory pathways, conditions & predictability of licensure

EXTERNAL • Anticipated deployment plans and community engagement

3 Jenner ‐ Janssen Partnership: Vaccine Technology Platforms

Janssen Vaccines Jenner Institute PER.C6® cell line technology for manufacturing Adenoviral vector technology  Whole inactivated vaccines  Chimpanzee‐derived adenovirus‐based  Attenuated vaccines  Extensively clinically tested  Recombinant protein or subunit vaccines  Thermostabilisation technology for storage at  Adenoviral vectors temperatures up to 45C for six months, or ambient temperatures for much longer Modified Vaccinia viral vector technology Adenoviral vector technology  Capacity to express multiple antigens  Low‐seroprevalent adenovirus‐based  Proprietary strong promoters and insertion  Extensively clinically tested sites  High capacity/low cost manufacturing using PER.C6® cell  Access to manufacturing in immortal avian cell line technology lines  Liquid formulation compatible with current vaccine Virus Like Particle Technology supply chains:  HBsAg fusion VLPs produced in yeast o Current liquid formulation; 1 year stability at 2‐8C  AP205 VLPs produced in E. coli o New formulation with at least 2 year real time in vitro stability at 2‐8C

4 The Jenner Institute founded 2005

• Global Health – vaccines that make a difference • HIV, TB, malaria, dengue, pandemic influenza • Emerging pathogens

• Translational Research – rapid early clinical testing • 42 vaccines made for clinical trials

• One Health – vaccines for humans and other animals

5 Human Vaccines Pipeline a portfolio approach

Number Disease Area of GMP Preclinical Phase I Phase IIa Phase Ib Phase IIb Phase III Licensure Vaccines

Oxford Patient Group /Endemic Area Malaria 19

TB 4

HCV 3

HIV 5

Pandemic Flu 2

Meningitis 1

RSV 3

Ebola 4

Prostate cancer 2

Staph aureus

The busiest pipeline of any non-profit vaccine institute 6 Clinical BioManufacturing Facility University of Oxford

This image cannot currently be displayed. This image cannot currently be displayed.

7 Rapid Clinical Trial Capacity

• Over 150 clinical trials undertaken in the last decade – over 100 of these with vaccines designed / manufactured in Oxford – over 2000 volunteers enrolled in UK trials per annum – Allows rapid down‐selection of the most promising candidates

8 Challenge Trials or controlled human microbial infections (CHMI)

• Malaria – Sporozoite – Blood-stage • Influenza • BCG for TB • Typhoid • Paratyphoid • (RSV)

9 Overseas Trials

• KEMRI‐Wellcome Programme, Kilifi, Kenya • Kenyan AIDS Vaccine Initiative Nairobi, Kenya • South African TB Vaccine Initiative, Western Cape • MRC Laboratories, The Gambia • Cheikh Anta Diop University, Dakar, Senegal • CNRFP, Ouagadougou, Burkina Faso • Uganda Virus Research Institute, Entebbe, Uganda • Patan Hospital, Kathmandu, Nepal

10 Replication‐Deficient Viral Vector Vaccines to Maximise both Humoral and Cellular Immunogenicity Rapid initial response plus extended duration of immunity

1 - 8 weeks Adenovirus Prime MVOxford Boost

Malaria x 6, HCV, HIV, influenza, TB, RSV, Ebola, prostate cancer

11 Outbreak Pathogen Vaccine Progress Current status

Pathogen Construct Immuno‐ Neutralisation Animal GMP Phase Made genicity Efficacy funded I/II

Pandemic Flu    Rift Valley Fever    MERS    Zika   Chikungunya    CCHF  Lassa  Ebola Zaire  Ebola Sudan  Ebola x2 + Marburg  Marburg  Nipah   SARS 

12 Strong T Cell Responses with a One Week Prime‐Boost Interval in Ebola

‐BN

A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA Ewer et al., NEJM 2016. 13 Antibody responses after prime and boost

‐BN

A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA Ewer et al., NEJM 2016.

14 ChAdOx1 RVF can be thermostabilised

512  Vaccine thermostabilised p=0.2

256  Stored at various ºC for 6 months 128  Vaccine reconstituted to same dose 64  Cattle immunised, single dose 32  Anti-RVFV antibodies measured

Neutralising antibody titre 16 d ºC e 5ºC 80 25ºC 37ºC 45ºC 5 at - in cc va Un

For thermostabilisation method see: Alcock R, et al Sci Transl Med 2010 Feb 17;2(19) 15 Jenner ‐ Janssen Partnership: Vaccine Technology Platforms

16 Janssen Vaccines expertise

• Proven technology platforms, expert teams • PER.C6® cell line unique characteristics and ability to apply for multiple pathogens • Process development, manufacturing capabilities and scale up (>1 mio Ebola vaccine regimens in 1 year, potential for >300.000 doses / week). Optimised temperature stability for field use • Clinical development capabilities and know‐how in potentially affected areas and resource‐limited settings • Managing multilateral partnerships (eg. Ebola IMI)

17 Core Technology Platforms Supporting Janssen Vaccine Development

PER.C6® cell line technology

. For the manufacturing of: – Whole inactivated virus vaccines – Attenuated virus vaccines – Viral vectors – Protein vaccines and monoclonal antibodies

. Highly permissive to human and animal viruses

. Culturing at high cell density results in increased volumetric productivities lowering demand of scale and COGs

18 Development of the PER.C6® cell line

History of the PER.C6® cell line

. Primary human retinoblasts were obtained in 1985 from a healthy donor . Immortalized using adenovirus E1A/E1B in 1995 . Human cell substrates have been used for the manufacture of numerous live attenuated vaccines in the past 40 years . To date >60 material and IP licenses granted for applications with gene therapy vectors, vaccines and recombinant proteins . Tested in compliance with applicable regulations and guidances from US FDA, EU, ICH and WHO . Biologics Master File available at FDA

19 PER.C6® cells: for the replication of human viruses for vaccine manufacturing

Picornaviridae Flaviviridae Paramyxoviridae PV1, 2, 3 ZIKV PI 1,2,3 Coxs A9, B2, B4 WNV NDV Echovirus, 7, 11 JEV Measles EV71 YF RSV

Togaviridae Herpesviridae Adenoviridae SF HSV‐1 Human AdV Sindbis HSV‐2 Ape AdV

Rhabdoviridae Reoviridae Poxviridae VSV Rhesus RV Vaccinia Rabies Human RV

Orthomyxoviridae Bunyaviridae Influenza Hantaan

20 PER.C6® cells support substantially higher production of poliovirus than VERO cells

Sabin strain yields are greatly enhanced on the PER.C6® cell platform

Sanders et al., 2015. Vaccine 33 (48): 6611–6616

Sabin strain yields on the PER.C6® cell platform are maintained at larger scale and provides a high capacity, low cost option for Sabin‐IPV manufacturing

Strain Scale # of runs Average Productivity at harvest (D antigen/ml) # doses / ml*

Sabin 1 10L 7 2285 > 200 Sabin 2 10L 5 379 > 25 Sabin 3 10L 3 3098 > 40 *Dose assumption: Type 1:2:3 = 10:15:70 D antigen units/dose

21 HIV vaccine development: PER.C6®-derived vaccines provide protection against SHIV challenge

Ad26 prime – Env GP140 boost vaccinations in NHP provide increased protection in stringent SHIV-SF162P3 and SIVmac251 challenge models (Science. July 2015 and unpublished data)

• NHP study #13-19: BIDMC/MHRP/Janssen collaboration

• The Ad26/Ad26+gp140 HIV vaccine regimen provides substantial protection against repetitive (6) rectal SHIV challenges in NHPs Ad26.HIV manufacturing on SF162P3 PER.C6® cell platform • Manuscript in preparation

• Study designed to mimic ongoing Phase 1/2a clinical trial (HIV-V-A004; https://clinicaltrials.gov/ct2/show/N CT02315703 )

GP140 subunit vaccine manufacturing on PER.C6® cell platform

22 Core Technology Platforms Supporting Janssen Vaccine Development

AdVac® viral vector technology

. Flexible and allows vaccine development against various infectious disease targets

. Extensively evaluated in humans, showing good safety profiles and induction of robust humoral and cellular immune responses

. Technology allows a platform approach to facilitate rapid scale up to high capacity and low cost manufacturing

. Compatible with current vaccine supply chain characteristics, in view of its favourable thermostability profile

. The platform technology allows a generic approach for the manufacturing and testing processes and an extrapolation of the release, stability, toxicity and supply chain profiles

23 AdVac® viral vector technology

“AdVac® constitutes a collection of low-seroprevalent rAdV vectors, with specific genetic designs, which grow to high titers on PER.C6® cells, under conditions that allow manufacturing of millions of doses at just 50 liter scale…

Ad35.T B-S virus titer (VP/mL) PER.C6 in iViPAdV process vector at different Titer scales

3.010 12

2.510 12

2.010 12 Intensified 1.5 10 12  process 10 x increase 1.0 10 12  in volumetric virus yield at 11

Virus titer (VP/mL) titer Virus 5.0 10  Conventional production scale 0 process 2L 10L 50L Bioreactor volume

24 Clinical experience with AdVac® -based vaccines (> 3000 subjects)

Completed Studies (N=21) Ongoing Studies (N=15) (HIV, TB, Malaria) (Ebola, HIV, RSV)

Total Subjects Total Subjects (estimate) Ad26: 234 Adults Ad26: 1899 Adults Ad35: 538 Adults, 349 Infants Ad35: 117 Adults Total Doses Dose Levels Ad26 342 5x1010 to 1x1011 vp Ad35 1672 (737 pediatric) Populations Dose levels 8 11 Adults 1x10 to 1x10 vp HIV+ Adults Populations Children 1-17yrs Adults TB+adults, HIV+ adults Geographic Regions/countries Infants (4-9 months) UK, USA, France, Sierra Leone, Burkina Faso, Côte d’Ivoire, Kenya, Rwanda, Tanzania, Uganda, Thailand Geographic Regions/countries US, UK, India, Kenya, Rwanda, South Africa, Burkina Faso, Mozambique

HIV: NCT00618605, NCT01103687, NCT01215149. Malaria: NCT01397227, NCT01366534, NCT00371189, NCT01018459. TB: SANCTR (NHREC no. 1381), RSV: NCT02440035,NCT02561871. HIV: NCT02315703, NCT02685020, NCT01378312, NCT02414828, NCT02430506, NCT01017536, SANCTR (DOH‐27‐ NCT02788045. Ebola: NCT02313077, NCT02325050, NCT02376426, 0209‐2655), NCT02375256, SANCTR (DOH‐27‐0611‐ NCT02376400, NCT02416453, NCT02564523, NCT02598388, NCT02509494, 3044)/PACTR201203000306280/NCT01198366, NCT01683773 NCT02543567, NCT02543268

25 Proof of concept rapid scale-up of AdVac®– based vaccine: The Ebola vaccine example

. August 8th 2014, Ebola outbreak in West Africa declared a Public Health Emergency of International Concern (PHEIC)

. Sept 4th 2014, JnJ announced fast-tracking of Ebola vaccine program in conjunction with Bavarian Nordic and the NIAID, NIH

. Oct 22nd 2014, JnJ announces to invest up to $200 million in the Ebola vaccine program and targets 1M doses by the end of 2015

. Process development and manufacturing rapidly geared up – 18 runs at 20L scale at 2 different manufacturing sites between October 2014 and July 2015 with an average yield of 150.000 doses per run  2.7 mio doses DS manufactured – Real time stability 2-8°C > 1year

. First Phase I study initiated and first subject dosed on 30 December 2014

. Program is supported by multiple external sources, including the NIH, BARDA, and IMI

26 In partnership with Ebola vaccine characteristics Bavarian Nordic

Safety and Immunogenicity of Ad26/MVA EBL1001

• Over 1500 adults vaccinated in EBOVAC/non-EBOVAC studies to date • Post vaccination AEs as expected mild to moderate in severity overall and short in duration • No SAEs related to study vaccines reported • No differences in AE patterns based on sequence or schedule observed

8 Months Post‐prime Data

CD8+ T cells (ICS) 10

0.1 (% of subset)

Total cytokine response cytokine Total 0.01 0 100 200 300

JAMA. 2016 Apr 19;315(15):1610‐23. doi: 10.1001/jama.2016.4218

Robust antibody and T cell responses at 8 months post prime

27 Core Technology Platforms Supporting Global Vaccine Development

. PER.C6® cell line technology allows platform approach to vaccine development, enables high capacity and low cost manufacturing for whole virus vaccines, protein vaccines and viral vector-based vaccines

. AdVac® viral vector vaccines can be manufactured at high capacity, low cost and product storage and stability are compatible with existing vaccine supply chains

. AdVac® viral vector technology has been evaluated in several vaccine clinical trials for diseases like Ebola, HIV, Malaria, TB, Flu, RSV etc and have shown a good safety profile and potent immunogenicity in several target populations

28 Clinical development of a novel vaccine; Chikungunya example I • Chikungunya is caused by a mosquito‐borne alphavirus – outbreaks in Asia, Central and South America and Africa. • Hundreds of thousands of people may be infected during an outbreak – acute phase symptoms are generally short‐lived, but followed by severe, often immobilising joint pains which can persist for many years, preventing the sufferer from working and thereby contributing to marginalization and poverty. • Two candidate vaccines have progressed to phase I clinical trials – live measles‐virus vectored vaccine produced by Themis Bioscience (2 doses) – virus‐like particle produced by NIAID (3 doses). • The Jenner Institute has produced ChAdOx1 Chik – induces excellent neutralising antibody titres in small animals after a single dose. • The Jenner Institute will undertake GMP manufacture and phase Ia testing – funding secured for manufacture and UK phase I

29 Annual program running costs and incremental costs

30 Collaboration and access • Complement and leverage available development & manufacturing platforms between Jenner & Janssen • Master Development Plan and Committee, oversight coordination, governance to be established • Driven by chosen project(s) and sharing of organisational capabilities • Previous experiences: managing multilateral partnerships, access agreements and technology transfers • Pre‐existing LMIC clinical trials networks and relationships with regulators (eg. AVAREF) • Engaging additional partners, eg. Hilleman Institute • Envisaging (LMIC) access provisions based on existing policies