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

Technologies

WHO Geneva, 21 July 2016

Janssen Vaccines: Olga PopovaJerome Custers

Jenner Institute: Prof. Sarah Gilbert

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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

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• 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• Anticipated deployment plans and community engagement

INTERNAL

EXTERNAL

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Jenner ‐ Janssen Partnership: Vaccine Technology Platforms

Janssen Vaccines Jenner InstitutePER.C6® cell line technology for manufacturing

Whole inactivated vaccines

Attenuated vaccines

Recombinant protein or subunit vaccines

Adenoviral vectors

Adenoviral vector technology

Low‐seroprevalent adenovirus‐based

Extensively clinically tested

High capacity/low cost manufacturing using PER.C6® cellline technology

Liquid formulation compatible with current vaccinesupply chains:

o Current liquid formulation; 1 year stability at 2‐8C

o New formulation with at least 2 year real time invitro stability at 2‐8C

Adenoviral vector technology

Chimpanzee‐derived adenovirus‐based

Extensively clinically tested

Thermostabilisation technology for storage attemperatures up to 45C for six months, orambient temperatures for much longer

Modified Vaccinia viral vector technology

Capacity to express multiple antigens

Proprietary strong promoters and insertionsites

Access to manufacturing in immortal avian celllines

Virus Like Particle Technology

HBsAg fusion VLPs produced in yeast

AP205 VLPs produced in E. coli

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The Jenner Institutefounded 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

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Human Vaccines Pipeline a portfolio approach

Disease AreaNumber of GMP Vaccines

Preclinical Phase I Phase IIa Phase Ib Phase IIb Phase III Licensure

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 FacilityUniversity of Oxford

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

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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

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Challenge Trialsor controlled human microbial infections (CHMI)

• Malaria– Sporozoite– Blood-stage

• Influenza• BCG for TB• Typhoid• Paratyphoid• (RSV)

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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

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

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

Adenovirus Prime MVOxford Boost1 - 8 weeks

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Outbreak Pathogen Vaccine Progress Current status

Pathogen Construct Made

Immuno‐genicity

Neutralisation Animal Efficacy

GMP funded

Phase I/II

Pandemic Flu

Rift Valley Fever

MERS

Zika

Chikungunya

CCHF

Lassa

Ebola Zaire

Ebola Sudan

Ebola x2 + Marburg

Marburg

Nipah

SARS

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

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

‐BN

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

Antibody responses after prime and boost

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‐BN

ChAdOx1 RVF can be thermostabilised

For thermostabilisation method see: Alcock R, et al Sci Transl Med 2010 Feb 17;2(19)

-80ºC

25ºC

37ºC

45ºC

55ºC

Unvac

cinate

d

16

32

64

128

256

512

Neu

tral

isin

g an

tibod

y tit

re p=0.2 Vaccine thermostabilised

Stored at various ºC for 6 months

Vaccine reconstituted to same dose

Cattle immunised, single dose

Anti-RVFV antibodies measured

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Jenner ‐ Janssen Partnership: Vaccine Technology Platforms

Janssen Vaccines Jenner InstitutePER.C6® cell line technology for manufacturing

Whole inactivated vaccines

Attenuated vaccines

Recombinant protein or subunit vaccines

Adenoviral vectors

Adenoviral vector technology

Low‐seroprevalent adenovirus‐based

Extensively clinically tested

High capacity/low cost manufacturing using PER.C6® cellline technology

Liquid formulation compatible with current vaccinesupply chains:

o Current liquid formulation; 1 year stability at 2‐8C

o New formulation with at least 2 year real time invitro stability at 2‐8C

Adenoviral vector technology

Chimpanzee‐derived adenovirus‐based

Extensively clinically tested

Thermostabilisation technology for storage attemperatures up to 45C for six months, orambient temperatures for much longer

Modified Vaccinia viral vector technology

Capacity to express multiple antigens

Proprietary strong promoters and insertionsites

Access to manufacturing in immortal avian celllines

Virus Like Particle Technology

HBsAg fusion VLPs produced in yeast

AP205 VLPs produced in E. coli

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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)

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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

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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

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

ParamyxoviridaePI 1,2,3NDV 

MeaslesRSV

AdenoviridaeHuman AdVApe AdV

PoxviridaeVaccinia

PicornaviridaePV1, 2, 3

Coxs A9, B2, B4 Echovirus, 7, 11

EV71

TogaviridaeSF

Sindbis

RhabdoviridaeVSV

Rabies

OrthomyxoviridaeInfluenza

FlaviviridaeZIKVWNVJEVYF

HerpesviridaeHSV‐1HSV‐2

ReoviridaeRhesus RVHuman RV

BunyaviridaeHantaan

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

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

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

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

*Dose assumption: Type 1:2:3 = 10:15:70 D antigen units/dose

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

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)

Ad26.HIV manufacturing on PER.C6® cell platform

GP140 subunit vaccine manufacturing on PER.C6® cell platform

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

• The Ad26/Ad26+gp140 HIV vaccine regimen provides substantial protection against repetitive (6) rectal SHIVSF162P3 challenges in NHPs

• Manuscript in preparation

• Study designed to mimic ongoing Phase 1/2a clinical trial (HIV-V-A004; https://clinicaltrials.gov/ct2/show/NCT02315703 )

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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

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AdVac® viral vector technology

“AdVac® constitutes a collection of low-seroprevalent rAdVvectors, 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…

“AdVac® constitutes a collection of low-seroprevalent rAdVvectors, 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 v irus titer (VP /m L)PER.C 6 in iViP proce ss at diffe re nt scale s

2L 10L 50L0

5.010 1 1

1.010 1 2

1.510 1 2

2.010 1 2

2.510 1 2

3.010 1 2

B ioreactor volume

Viru

s tit

er (V

P/m

L)

Conventional process

Intensifiedprocess 10 x increase 

in volumetric virus yield at production scale

AdV vector Titer                                

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

Completed Studies (N=21) Ongoing Studies (N=15)

Total SubjectsAd26: 234 AdultsAd35: 538 Adults, 349 InfantsTotal DosesAd26 342Ad35 1672 (737 pediatric)

PopulationsAdultsTB+adults, HIV+ adultsInfants (4-9 months)

Geographic Regions/countriesUS, UK, India, Kenya, Rwanda, South Africa,Burkina Faso, Mozambique

(HIV, TB, Malaria)

Total Subjects (estimate)Ad26: 1899 AdultsAd35: 117 Adults

PopulationsAdultsHIV+ AdultsChildren 1-17yrs

Geographic Regions/countriesUK, USA, France, Sierra Leone, Burkina Faso, Côte d’Ivoire, Kenya, Rwanda, Tanzania, Uganda, Thailand

(Ebola, HIV, RSV)

Dose levels1x108 to 1x1011 vp

Dose Levels5x1010 to 1x1011 vp

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RSV: NCT02440035,NCT02561871. HIV: NCT02315703, NCT02685020, NCT02788045. Ebola: NCT02313077, NCT02325050, NCT02376426, NCT02376400, NCT02416453, NCT02564523, NCT02598388, NCT02509494, NCT02543567, NCT02543268

HIV: NCT00618605, NCT01103687, NCT01215149. Malaria: NCT01397227, NCT01366534, NCT00371189, NCT01018459. TB: SANCTR (NHREC no. 1381), NCT01378312, NCT02414828, NCT02430506, NCT01017536, SANCTR (DOH‐27‐0209‐2655), NCT02375256, SANCTR (DOH‐27‐0611‐3044)/PACTR201203000306280/NCT01198366, NCT01683773 

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

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Ebola vaccine characteristics

Robust antibody and T cell responses at 8 months post prime

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

In partnership with Bavarian Nordic 

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8 Months Post‐prime Data

0 100 200 3000.01

0.1

1

10

CD8+ T cells (ICS)

Tota

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okin

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spon

se(%

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

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

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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

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Annual program running costs and incremental costs 

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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

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