Transcript Malaria Vaccine Development

Malaria Vaccines: Promise
and Challenges
Christian Loucq, MD
Director, PATH Malaria Vaccine Initiative
Vaccines 202X Conference
Philadelphia, PA / May 2-4, 2011
To
accelerate
the development
of
PATH
Malaria Vaccine
Initiative
malaria vaccines and ensure their
availability and accessibility in the
developing world
A world free from
malaria
2
Why a vaccine?
Data as of the end of 2008, WHO
3
Malaria vaccine community goal
• Strategic Goal: To develop an 80%
efficacious malaria vaccine by 2025 that
would provide protection for at least four
years
• Landmark goal: To develop and license a
first-generation malaria vaccine that has
protective efficacy of more than 50%
against severe disease and death and
lasts longer than one year
P. vivax and Pf / Pv transmission-blocking vaccines
Malaria Vaccine Technology Roadmap
http://www.malariavaccineroadmap.net/
4
The major challenges to success
Scientific
Commercial
• No vaccine in human
use against a
parasite
• Limited market in
developed countries
• Malaria parasite has
~6,000 genes, many
more than a virus
• Malaria-endemic
countries mostly poor
• How to predict a
vaccine candidate’s
success?
• Vaccine development
is high-risk, high-cost
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MVI’s portfolio, early 2007
Process
Construct
Selection Development
Final
Formulation
Toxicology
Phase 1a
Phase 1/2a
Phase 1b
Phase 2b
GenVec
Ad5 CSP/
LSA1/Ag2
Monash
MSP4
ISA720
ICGEB/BBI
PvR-II
ASO1/ASO2
WRAIR/GSK
AMA1
ASO1/ASO2
GSK
RTS,S
ASO1/AS02
GenVec
Ad5 MSP1
/AMA1
Monash
MSP5
ISA720
MVDB
AMA-C1
ISA720
MVDB
MSP-C1
AlOH+CpG
WRAIR/GSK
MSP1
ASO2
GSK
Pfs161
AS01/AS02
QIMR
RAP2
ISA720
MVDB
AMA1-C1
AlOH+CpG2
WRAIR
LSA-1
AS02&ASO1
Sanaria
PfSPZ
LaTrobe
MSP2
ISA720
Wanxing
AMA1:MSP1
ISA720
1
Phase 3
In feasibility stage
Clinical development plan under negotiation
X Project failure in 2006
2
MVI portfolio (March 2011)
FEASIBILITY STUDIES *
TRANSLATIONAL PROJECTS
Antigen
Delivery
Preclinical studies
Phase 1/2a
Seattle BioMed
(PE selection)
Aeras
(rBCG)
Crucell
(Ad35.CS/Ad26.CS)
WRAIR/GSK
(PvCSP/AS01)
NMRC
(PE selection)
Inovio/UPenn
(pDNA)
Gennova
(PfCSP)
Profectus
(VSV)
NYU/Merck
(CSP RI conjugates)
Emory
(adjuvanted
nanoparticles)
WEHI/LaTrobe/
WRAIR (AMA1)
Liquidia
(adjuvanted
nanoparticles)
WEHI/Gennova
(EBA/Rh)
VRC/JHU/
Oncovir/IDRI
(adjuvanted CSP)
VACCINE CANDIDATES
Phase 2b
Phase 3
GSK
(RTS,S/AS01)
Tulane/Gennova
(Pfs48)
JHU/Sabin
(AnAPN1)
ICGEB
(PvDBPII)
P. falciparum vaccines:
Pre-erthrocytic
Blood-stage
Transmission-blocking
P. vivax vaccines:
Pre-erthrocytic
Blood-stage
Transmission-blocking
* selected projects
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Current evaluation technologies portfolio
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RTS,S Target Product Profile
A vaccine that will protect infants and children residing in
malaria endemic regions from clinical disease and severe malaria
resulting from Plasmodium falciparum infection
Generally well tolerated with acceptable safety profile
 Compatible with standard EPI vaccines
(DTPw , HBV , Hib, OPV…)
 Implementable through existing
delivery programs such as the EPI
 Complements existing malaria
control measures
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9
MAL 049 – efficacy results
Vaccine Efficacy
%
95% CI
p-value
FU
1st clinical episode
All clinical episodes
53
56
28-69
31-72
< 0.001
< 0.001
8m
8m
1st clinical episode
39
20-54
< 0.001
12 m
All clinical episodes
42
22-57
< 0.001
12 m
in Kenya only
1st clinical episode
All clinical episodes
46
51
24-61
29-66
< 0.001
< 0.001
15 m
15 m
Vaccine Efficacy
RTS,S/AS01
Parasite prevalence
3.5% (1.9-5.9)
8.2% (5.7-12)
< 0.01
12 m
1.8% (0.4-5.2)
7.5% (3.8-13)
< 0.05
15 m
in Kenya only
Bejon et al 2008 NEJM 359; 24: 2521-32
Olotu A. et al. Lancet ID 2011; 11: 102-09
Control
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p-value
FU
MAL 049 / SAEs
RTS,S/AS01E
(N=447)
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Rabies vaccine
(N=447)
(82)
Percent (95% CI)
20
(61)
15
(47)
(40)
(26)
10
(21)
(21)
(18)
5
(10)
(7)
0
All SAEs
Pneumonia
Gastroenteritis P. falciparum
infection
Non malaria
SAE
Indication of non-malaria specific protection
Bejon et al 2008 NEJM 359; 24: 2521-32
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11
RTS,S/AS01 in Infants
Vaccine Efficacy 0,1,2
%
95% CI
p-value
FU
1st clinical episodea
All clinical episodes
62
65
36-77
42-79
< 0.001
< 0.001
12 m
12 m
Vaccine Efficacy 0,1,2
%
95% CI
p-value
FU
1st clinical episodea
All clinical episodes
53
59
26-70
36-74
0.001
< 0.001
17 m
17 m
ATP cohort post dose 3
ATP cohort 17 month as of 2 weeks post dose 3
New
data
VE: Vaccine Efficacy (1-HR); CI: Confidence Interval; p value from Cox PH model; Poisson regression for multiple episodes
a the presence of P. falciparum asexual parasitemia > 500 per µL and the presence of fever  37.5C detected by PCD
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Results unpublished.
RTS,S Phase 3 trial network
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Phase 3 trial of RTS,S
Key safety and
efficacy data to
support file to
regulatory
authorities
Bagamoyo, Tanzania, 26 May 2009
Sites represent different
malaria transmission
settings
Designed in collaboration with
scientific community, with
input and/or feedback of
WHO, FDA, and EMA
Analysis at
each site
for clinical
malaria
disease
Evaluation of public
health endpoints to
inform planning for
implementation 14
Phase 3 update
• 8923 children and 6537 infants
• End of 2011: 12m FU in 5-17m old children
• Efficacy against clinical malaria
• Immunogenicity
• Safety, deaths all causes
• End of 2012: 12m FU in 6-12w old infants
• Efficacy against clinical malaria
• Immunogenicity
• Safety, deaths all causes
• End of 2014: cumulative long term (2.5 years post D3) data
• Long term efficacy against clinical malaria
• Clinical efficacy against severe malaria
• Other secondary endpoints
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Phased availability of Phase 3 efficacy data
2009
Q3
Q4
2010
Q1
Q2
Q3
2011
Q4
Q1
Q2
Q3
2012
Q4
Q1
Q2
Q3
2013
Q4
Q1
Q2
Q3
2014
Q4
Q1
Q2
Q3
2015
Q4
Q1 Q2 Q3
2016
Q4
Q1
Q2
Q3
Phase 3 efficacy study
Children 5-17
months
12 M post dose 3
Infants 6-12 weeks,
EPI
12 M post dose 3
Public health efficacy
endpoints in both
age-groups
32 M- post dose 3
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Overall R&D strategy
• Accelerate development of vaccines
• Clinical disease and death caused by Pf and Pv
• Develop Pf and Pv vaccines to support global
elimination and eradication effort
• Ensure clear development strategies
• Manufacturing
• Preclinical and clinical development
• Regulatory
• Policy
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Multiple target product profiles
• Clinical disease
Next generation P.
falciparum vaccine <5
P. vivax vaccine
<50
• Transmission
SSM-TBV
• PE-TBV
• SSM + PE/BS-TBV
~100,000,000,000
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Pre-erythrocytic vaccine successes
Photograph by Hugh Sturrock
Complexity:
>5,000 genes
<1 gene
Dose:
>1000 bites
3 doses
Protection:
>90%
~50%
Primary mechanism:
CD8
Ab (CD4)
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How can we improve on clinical efficacy
and duration of protection of RTS,S/AS01?
RTS,S
Increase antibody and/or CMI responses to CSP
• Optimize delivery (Translation / Feasibility)
Ab/CMI to additional SPZ/liver stage antigens
• Identify antigens (Feasibility)
• Optimize delivery (Feasibility)
Ab to blood-stage antigens to block merozoite
attachment/invasion
• Develop antigens (Feasibility)
• Optimize delivery (Feasibility)
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P. vivax ≠ P. falciparum
• P. vivax biology consideration
• Relapse due to liver-stage hypnozoites
• Single dominant red cell invasion mechanism
• Disease at lower blood stage parasitemia
• Human challenge models now available
• Universidad del Valle, Cali, Colombia
• WRAIR, Maryland, USA
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Focused P. vivax strategy
• Pre-erythrocytic (translational)
• PvCSP/AS01
• Clinical efficacy data (2011)
Clinical efficacy data from
PvCSP/AS01 will impact
future direction
• Blood-stage (feasibility)
• Duffy binding protein region 2 (DBPII)
• Formulation needs to support combination
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Focused Pf blood-stage strategy
• AMA1 (feasibility)
• Strain-specific efficacy demonstrated in field
• Can allelic variation be overcome?
• Immunization with panel of defined alleles
• Focus immune response to conserved regions
• Go/no-go in 2011
• EBA/Rh (feasibility)
• Redundant invasion network
• Preclinical data supports synergistic effect of
targeting multiple ligands
• Go/no-go in 2013
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Vaccines critical for elimination
• Vector control
– Insecticide treated bednets
– Indoor residual spraying
– Vector management
• Drug therapy
• Vaccines
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Transmission blocking vaccines
Interrupt
lifecycle
Reduce
transmission
Elimination
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SSM-TBVs: Significant progress in 2010
• Target product profile
• SSM-TBV TPP
• Regulatory strategy
• TBV workshop
• Product development partnerships
• JHU – Antigens (AnAPN1, Pfs48/45)
• Gennova & Sabin – Process development
• Development tools
• Membrane feeding assay development (NIH)
• Field site development (TBD)
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SSM-TBVs
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Questions for an EE strategy
• Who is infecting mosquitoes?
• Can we validate a mosquito endpoint?
• Can we define a development model for our
strategy?
• Can we define a policy strategy?
• Can local communities accept the concept?
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Thank you
For more information:
www.malariavaccine.org
www.path.org