johns hopkins university template€¦ · experienced severe (enhanced) disease. two (ages 14 and...
TRANSCRIPT
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RSV Vaccine Development
1 .
Acknowledgements
GSK/Okairos
Ripley Ballou
Jean-Francois Toussaint
Novavax
Greg Glenn
MedImmune
Filip Dubovsky
NIAID/NIH/VRC
Barney Graham
NIAID/NIH/LID
Peter Collins
Ursula Buchholz
.
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Ferolla FM et al. Am J Respir Crit Care Med. 2013 May 1;187(9):983-90.
Burden of RSV Extends Beyond Early Infancy
Obstacles to Successful
RSV Vaccine Development
Peak of severe pediatric disease in early infancy
suppression of the immune response by maternal Ab
Heterogenous at-risk populations require different vaccines:
Newborns
Older infants and young children
Elderly
Imperfect animal models; adult challenge not highly relevant
for pediatric disease
Specter of enhanced disease
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Enhanced RSV Disease following
FI-RSV
• Formalin-inactivated RSV (FI-RSV) developed in the
early 1960s
• Vaccine administered to RSV seropositive toddlers and
RSV naive infants
• The vaccine did not harm the toddlers, but when the
infants later encountered wild-type (live) RSV, they
experienced severe (enhanced) disease. Two (ages 14
and 16 months) died.
Kapikian et al. Am J Epidemiol 1969;89:1699 Kim et al. Am J Epidemiol 1969;89:422-434
0
20
40
60
80
100
vaccinees controls
Potentiation of RSV LRI following formalin inactivated vaccine
% RSV infected% hospitalized
% o
f sub
jects
en
rolled
at
CH
C
Adapted from Kim et al., Am J Epidemiol 89:422-434, 1969
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RSV Vaccines in Development: 2004
RSV F protein
Subunit
Live-
Attenuated
RSV F-based antigenRSV F protein
University of
Saskatchewan
RSV
NanoBio
MERCK
SH protein
Ghent University
MARKET APPROVED
PHASE IIIPHASE IIPHASE IPRECLINICAL
Medi-RSV ΔM2-2
LID/NIAID/NIH
Medi-559, RSV
LID/NIAID/NIH
RSV ΔNS2 Δ1313
LID/NIAID/NIH
Peptide microparticle
Particle-
BasedVLP
Virosome
Virosome
VLPBLP
VLP
University of
Pittsburgh
University of
Pittsburgh
Mucosis
Nucleic
Acid
Whole-
Inactivated
Gene-
Based
Vectors
Alphavirus
Sendai virus
MVA
Adenovirus
BAVARIAN NORDIC
Adenovirus/MVA
Alphavirus
Sendai virus
Medi-534, RSV/PIV3
DNARNA
RSV F protein
Subunit
Wyeth Wyeth Wyeth
(n=3)
VLP
Subunit
Live-
Attenuated
RSV
PHASE 3PHASE 1PRECLINICAL
Medi-RSV ΔM2-2
NIH/NIAID/LID
Medi-559, RSV
Nucleic
Acid
Gene-based
VectorsAlphavirus
Sendai virus
MVA
BAVARIAN NORDIC
Alphavirus
RNA DNA
NanoBio
VLP
Agilvax
VLP
University of
Massachusetts
VLPVirosome
RSV G protein
University
of Georgia
DPX-RSV
Adenovirus
RuenHuei
Biopharma
MARKET APPROVED
Adenovirus/MVA
DNA
Fraunhofer
VLP
VLP
Mucosis
VLP
Combination
Whole-
Inactivated
Updated: July 8, 2014
Particle-
based
RSV F protein
RSV F protein
RSV peptides
PeptiVir
DNA+protein combo
Fudan
University
SH protein
RSV
Codagenix
Peptide
microparticle
RSV cps2
NIH/NIAID/LID
RSV ΔNS2 Δ1313
NIH/NIAID/LID
RSV F protein
University
of Illinois
DNA prime,
Protein boost
RSV F protein
University
of
Saskatchewan
RSV F Nanoparticle
PHASE 2
RSV F protein
Instituto de
Salud Carlos III
VLP
Takeda
Vaccines
RSV
RNA
Adenovirus
SeV/RSVDelta-G RSV
BCG
Pontificia Universidad Católica
de Chile
RSV pre-F protein
NIH/
NIAID/VRC
VLP
RSV peptides
Renaptys
Adenovirus
University of
Pittsburg
Adenovirus
Crucell
RSV F protein
MVA
VLP
Georgia State
University
RSV Vaccine Snapshot
Source http://sites.path.org/vaccinedevelopment/respiratory-syncytial-virus-rsv/
(n=51)
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>1 RSV vaccine type needed; >1 PPC
• Maternal immunization
– Subunit and other nonreplicating vaccines
• Passive prophylaxis
– Next generation RSV F mAbs
VLPs, virosomes (?)
• Infant immunization
– Live vaccines
Maternal RSV Immunization:
RSV F is the primary target
• RSV has 2 major surface glycoproteins:
– RSV F binds to nucleolin on cell surface; mediates virus/cell
membrane fusion and cell/cell fusion
• Most neutralizing antibody is directed against the RSV fusion
(F) surface glycoprotein
• RSV F more highly conserved
between RSV A/ B subgroups than RSV G
• RSV F is therefore the primary antigenic
target for a maternal RSV vaccine
.
F
G
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RSV F Vaccines in Development
Prefusion F
Developer Phase
GSK 1
NIAID/NIH/VRC Preclinical 1
Ins. Salud San Carlos III preclinical
Postfusion F
11 © 2009, Johns Hopkins University. All rights reserved.
Developer Phase
NovaVax 2
MedImmune 1 (elderly)
Novartis/GSK preclinical
U. Illinois preclinical
U. Saskatchewan preclinical
Postfusion F has the palivizumab epitope,
but prefusion F has the majority of neut
epitopes recognized by human sera
12 © 2009, Johns Hopkins University. All rights reserved.
McLellan JS et al. J. Virol. 2011;85:7788-7796
McLellan JS et al. Science 2013;340:1113-1117
Swanson K A et al. PNAS 2011;108:9619-9624
Antigenic site 0
Postfusion Postfusion Prefusion
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Functional form of RSV F in pre-triggered conformation
Candidate RSV vaccine is stabilized native F trimer
Postfusion F in 6-helix bundle conformation
Stabilization Triggering
RSV Prefusion F Structure (Science April 2013)
RSV Vaccine Design (Science November 2013)
RSV Postfusion F Structure (JVI 2011)
Stablization of antigenic site on conformationally
authentic protein results in potent vaccine antigen
Loss or preservation of neutralization sensitive site on
the native F trimer
Prefusion RSV F vaccine (NIH) enhances antibody response in preclinical trials
J S McLellan et al. Science 2013;342:592-598
Published by AAAS
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GSK RSV Maternal vaccine candidate - Ph1 study
• Canada
• Schedule: 1 dose
• N = 128 Men aged 18-44y (16/group)
• 2 step staggered design with safety review by iSRC
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1. Safety/reactogenicity- incl. 12m follow-up 2. Immunogenicity (humoral) – incl. 12m follow-up
Study design/groups:
PreF+Alum
10 µg PreF
30 µg PreF
60 µg PreF
Non-Adj. PreF
10 µg PreF
30 µg PreF
60 µg PreF
Placebo (2 gps)
Saline
GSK Proprietary information
GSK’s proprietary PreF antigen designed to adopt Prefusion conformation
(http://www.clinicaltrials.gov/ct2/show/study/NCT01905215)
• 1- and 2-dose groups are pooled (identical at Day 28)
• 60 and 90µg groups are pooled to show overall impact of alum adjuvant at Day 28
• Peak GMT log2 10.0-10.5
Novavax M201: Safety and immunogenicity of RSV F
nanoparticle vaccine in women of childbearing age
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RSV F-protein Nanoparticle Vaccine
Candidate: Clinical Development Plans
Maternal Immunization (120 mcg F + 0.4 mg Alum; single dose)
• M203 in Pregnant women, 3rd trimester (FSI: Late 2014)
– POC for transfer of maternal antibodies to infants
• M204 in Pregnant women, 3rd trimester (FSI: ~2015)
– Efficacy: Prevention of medically attended RSV+ illness
• M301 in Pregnant women
– Pivotal efficacy study: Prevention of medically attended RSV+ illness
Pediatric Immunization
• P101 in seropositive 2-5 year olds, FSI Q4 2014
Elderly – New Development Plan
• E201 in Elderly, FSI Q4 2014
• Potential next trial, Phase 3/licensure trial
Infant RSV Immunization: Live Vaccines
• Live-attenuated (native RSV)
– cps2 (MedImmune, NIH/NIAID/LID; JHU CIR, IMPAACT)
– ΔNS2Δ1313 (NIH/NIAID/LID; JHU CIR)
– ΔM2-2 (MedImmune, NIH/NIAID/LID; JHU CIR)
– Codon-deoptimized (Codagenix, Emory)
– ΔG + G (Intravac)
• Live-vectored
– Sendai virus (St Jude’s)
– BCG expressing RSV NP or M2 (Pontifica U Catolica de Chile)
• Gene-based vectors
– ChAd3/MVA boost (Okairos)
– Other adenoviruses (Crucell, RuenHuei, Ruhr-Universitat Bochum, U Pittsburgh/Baylor, AmVac)
– Other MVA (Bavarian Nordic, Emergent Biosolutions)
– Alphavirus (Vanderbilt, Alphavax)
.
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Gene-based vector vaccines
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Open label dose escalation study in healthy adults (NCT01805921)
Experimental groups
1. PanAd3-RSV IM / MVA-RSV IM
2. PanAd3-RSV IM / PanAd3-RSV IM
3. PanAd3-RSV IN / MVA-RSV IM
4. PanAd3-RSV IN / PanAd3-RSV IM
Doses
PanAd3-RSV: Low 5 x 109 and High 5 x 1010 vp
MVA-RSV: Low 1 x 107 and High 1 x 108 pfu
GSK/Okairos RSV Paediatric vaccine candidate
20 GSK Proprietary information
GSK/Okairos ChAd & MVA encoding RSV F, N & M2-1 proteins
10 volunteers/group (2 & 8 volunteers at low & high dose)
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Live-attenuated vaccines
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RSV cps2 and ΔNS2Δ1313
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• Codon-stabilized version of the previously evaluated RSV 248/404/1030/ΔSH
• Phase I evaluation being completed in 51 RSV-seronegative infants and
children (NCT1852266, NCT 1968083)
cps2
• Deletion of the NS2 gene (IFN antagonist) and 1313 codon in L gene
• Phase I evaluation: completely restricted in replication in RSV-seropositive
children (n=15); currently being evaluated in RSV-seronegative children (n=60)
NCT1893554
ΔNS2Δ1313
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3' 5' M2 NS 1 NS 2 N P M S H G F L
l
RSV MEDI ΔM2-2: a novel rRSV
deletion mutant
(MedImmune/ LID, NIAID) • M2-2 is an RNA regulatory factor
• Deletion of M2-2 results in:
• decreased RNA replication
• increased transcription and antigen
expression1 (more Ag/ virion)
1. Bermingham A Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11259-64.
RSV MEDI ΔM2-2
• Phase I trial completed in 15 adults (open label), 15 RSV-
seropositive and 30 RSV-seronegative infants and children
(placebo controlled)
• Non-infectious in adults and RSV seropositive children
• Highly restricted in replication in RSV seronegative children
(mean peak titer 1.5 log10 pfu/mL), yet substantial increases in
RSV PRNT in 95% (19/20) vaccinees
• Further development of Δ M2-2 mutant viruses ongoing
.
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Some clinical trial considerations
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Clinical endpoints:
Define appropriate parameters for a
variety of clinical settings
• Hospitalization and medically-attended lower respiratory tract illness
(MA-LRI) have been used as endpoints for trials of palivizumab and
motavizumab in high-resource countries
• These outcomes may not be sufficiently sensitive or appropriate for
low-resource settings
• Definitions used in global studies of the
pediatric impact of influenza vaccines may be
useful, but will need to be modified
.
www.savethechildren.org.uk
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Clinical endpoints: some examples
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Study Primary Outcomes in Infants
Maternal Influenza Immunization1 Respiratory Illness with Fever (RIF)2
Maternal RSV immunization Tachypnea ? Difficulty breathing? Hypoxia?
1. Zaman K et al. N Engl J Med 2008; 359:1555-1564
2. RIF= T>38.0 and runny nose, congestion, cough, difficulty breathing or swallowing (maternal report)
Consider potential efficacy determinants in
low-resource settings
• In resource limited settings, RSV exposure, disease, and
vaccine efficacy may be influenced by
– Crowding
– Limited access to water
– Indoor air pollution
• Maternal illnesses that may affect transplacental transmission
of antibody
– HIV
– Hypergammaglobulinemia
– Placental malaria
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