who r&d blueprint: janssen vaccines –jenner institute … · “advac® constitutes a...
Post on 24-Jul-2020
1 Views
Preview:
TRANSCRIPT
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
2
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
3
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
4
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
5
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.
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 Trialsor 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 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
11
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
12
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
13
A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVAEwer et al., NEJM 2016.
Antibody responses after prime and boost
14
‐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
15
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
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
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
20
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
21
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 )
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 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
24
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
25
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
26
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
27
8 Months Post‐prime Data
0 100 200 3000.01
0.1
1
10
CD8+ T cells (ICS)
Tota
l cyt
okin
e re
spon
se(%
of s
ubse
t)
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
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
31
top related