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• Same or related diseases in two species– e.g. tuberculosis, influenza
• Rapid efficacy testing in large animal species– allowing biomarker identification
• Large animals better predictors of immunogenicity • Common novel technology platforms• Similar cost constraints for low income markets
But until now largely independent development
Synergies in Human and Livestock Vaccine Development
Malaria Mortality and Morbidity
• Currently about 900,000 deaths each year from Plasmodium falciparum– Mostly in young children– Mostly in Africa
• About 250,000,000 clinical cases a year
• Malaria control now costing $2 billion annually– Tools such as spraying, drugs and impregnated bed nets
have a finite period of utility– Current economic cost of malaria to Africa : ~$12bn
Transmission Blocking Vaccines Parasite Candidate Antigens
a: Expressed in host b: Expressed in vector
Pfs48/45Pfs230
Pfs25PfsHAP2Pfs48/45Pfs230
Transmission Blocking Vaccines Mosquito Vector Candidate Antigens
Alanyl Aminopeptidase N1: a mosquito midgut receptor
• mosquito midgut antigen
• transmission blocking activity against multiple parasite species
• most Anopheles vectors appear susceptible
• Most natural immunity targets blood-stage
• Multiple target antigens are available
• A major target, PfEMP1, shows antigen variation
• Many show substantial polymorphism
Leading Blood-Stage Malaria Antigens
Phase Vaccine name Blood-stage Antigen(s)
Allele(s) Adjuvant Lead Author
Year GIA Efficacy Population
Ia AMA1-C1 AMA1 3D7 + FVO M ISA 720 Pierce 2010 Yes (up to 65%) Not assessed Australian adultsIa AMA1-C1 AMA1 3D7 + FVO Alhydrogel Malkin 2005 Yes (up to 54%) Not assessed US adultsIa AMA1-C1 AMA1 3D7 + FVO Alhydrogel + CpG7909 Ellis 2009 Yes (up to 97%) Not assessed US adultsIa AMA1-C1 AMA1 3D7 + FVO Alhydrogel + CpG7909 Mullen 2008 Y (up to 96%) Not assessed US adultsIa Pf(3D7)AMA1 AMA1 3D7 M ISA 720 Saul 2005 Not assessed Not assessed Australian adultsIa AMA1 FVO AMA1 FVO Alhydrogel/ M ISA720
/AS02Roestenberg 2008 Yes Not assessed Dutch adults
Ia FMP2.1 AMA1 3D7 AS02A Polhemus 2007 Yes (median up to 17%) Not assessed US adultsIa MSP1-C1 MSP1 3D7 + FVO Alhydrogel plus CpG7909 Ellis 2010 Y (up to 32%) Not assessed US adultsIa FMP1 MSP142 3D7/FVO Alhydrogel Malkin 2007 Y (< 20%) Not assessed US adultsIa FMP1 MSP142 3D7 AS02A Ockenhouse 2006 Y (<25%) Not assessed US adultsIa FMP1 MSP142 3D7 AS01B Start 2008Ia Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Saul 1999 Not assessed Not assessed Australian adultsIa P30P2 MSP-119 MSP119 3D7 or FVO Alum Keitel 1999 Not assessed Not assessed US adultsIa MSP3-LSP MSP3 Conserved Alum/ M ISA 720 Audran 2005 Not assessed Not assessed Swiss adultsIa GMZ2 GLURP/MSP3 Conserved Alum Esen 2009 Not assessed Not assessed German adultsIa PfCP2.9 AMA1/MSP119 3D7 + FVO M ISA 720 Hu 2008 No Not assessed Chinese adultsIa PfCP2.9 AMA1/MSP119 3D7 + FVO M ISA 720 Malkin 2008 Yes (up to 13%) Not assessed Chinese adultsIa PfCA AMA1 3D7 AdHu5 NIAID Unpublished Not known Not assessed US adultsIb AMA1-C1 AMA1 3D7 + FVO Alhydrogel + CpG7909 Sagara 2009 FVO only (<10%
increase)Not assessed Malian adults
Ib AMA1-C1 AMA1 3D7 + FVO Alhydrogel Dicko 2008 Not assessed Not assessed Malian childrenIb AMA1-C1 AMA1 3D7 + FVO Alhydrogel Dicko 2007 No Not assessed Malian adultsIb FMP2.1 AMA1 3D7 AS02A Thera 2008 Yes (median < 40%) Not assessed Malian adultsIb FMP1 MSP142 3D7 AS02A Thera 2006 Not assessed Not assessed Malian adultsIb FMP1 MSP142 3D7 AS02A Stoute 2007 Not assessed Not assessed Kenyan adultsIb Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Genton 2000 Not assessed Not assessed PNG adultsIb Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Genton 2003 Not assessed None PNG childrenIb MSP3-LSP MSP3 Conserved Alum Lusingu 2009 Not assessed Not assessed Tanzanian childrenIb MSP3-LSP MSP3 Conserved Alum Sirima 2007 Not assessed Not assessed Burkina Faso
adultsIb MSP3-LSP MSP3 Conserved Alum Nebie 2009 Not assessed Not assessed Burkina Faso
adultsI/IIa FMP2.1 AMA1 3D7 AS02A vs AS01B Spring 2009 Yes (mean 3D7 up to
30%)Some US adults
I/IIa PEV3A AMA1 Conserved Virosome Thompson 2008 No Some UK adultsI/IIa NYVAC-Pf7 MSP1, AMA1, SERA 3D7 NYVAC Ockenhouse 1998 Not assessed Some US adultsIIa Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Lawrence 2000 Not assessed None Australian adultsI/IIb SPf66 83, 55, 35 kDa
peptidesAlum Cochrane
Review1990-1998 Not assessed Some (South
America)South America, Africa, Asia
IIb AMA1-C1 AMA1 3D7 + FVO Alhydrogel Sagara 2009 Not assessed None Malian childrenIIb FMP1 MSP142 3D7 AS02 Ogutu 2009 Not assessed None Kenyan childrenIIb Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Genton 2002 Not assessed Some PNG children
Blood-Stage Vaccine Trials
• Mosquito bites protect!– Irradiated parasites– >1000 bites required
• Effective in mice, fowl, monkeys, humans– Known since 1970s
• Irradiation can now be replaced– by genetic alteration of parasites
Pre-Erythrocytic Malaria VaccinesSporozoite and Liver-stages
Difficulties for the Whole Irradiated Sporozoite Vaccine Approach
• Manufacturing– One batch per day
• Storage– Liquid nitrogen required
• Lack of efficacy– with 137,000 parasites x 6
Parasites
P
Cytoplasm
HLA = HumanLeucocyteAntigen
Receptor
Liver Cell Killer T Cell
Killer T-Cell Attack on an Infected Liver Cell
KILLING
The MeTRAP Vaccine InsertTargets the Liver-Stage of Plasmodium falciparum
ME: Multiple malaria Epitopes
TRAP: Thrombospondin-Related Adhesion Protein
TRAP strain is T9/96in this vaccine
A Polyepitope-Protein Vaccine Construct
Why Use Viral Vectors in Prime-Boost Regimes?
• Best means of safely inducing T cells in humans
• Only 5 vaccines have induced >1000 SFU/ml– in malaria (x 3), tuberculosis and influenza– all used viral vector boosting
• Adenovirus – MVA is the most potent approach– better than DNA – Adenovirus– better than Adenovirus - Heterologous Ad
Adenovirus Prime MVA Boost8 weeks
Viral Vector Vaccines to Maximise Cellular Immunogenicity
Adenovirus Prime MVA Boost
8 weeks
Malaria, HCV, HIV, influenza, TB...
Vectored Liver-Stage Vaccines for Malaria
• Efficacy correlated with CD8 T cell numbers in phase II trials– First example for any vaccine
• Excellent safety data for both adenovirus and MVA vectored vaccines
• Phase I trials of AdCh63-MVA completed successfully in Kenya and The Gambia
A Sporozoite and Liver-Stage Vaccinea combination two-hit approach
RBC
schizonts Liver Stage:T Cells clear the
remaining liver cells
Sporozoite Stage: Antibodies clear most sporozoites
RTS,S + Vectored TRAPan infant immunisation regime
A Simple Regime for Deployment in Developing Countries through the Expanded Programme on Immunisation
0 1 2 3 4 5 6 7 8 9 months
R+A R+A R+M
R = RTS,S/AS01 A = AdCh63 MeTRAP M = MVA MeTRAP
Conclusions
• Pre-erythrocytic malaria vaccines have shown most efficacy in humans clinical trials– Blood-stage vaccines have been more difficult– Sexual and mosquito stage vaccines just starting in the clinic
• Both RTS,S and vectored vaccines now show efficacy in most people on sporozoite challenge– Through antibodies and CD8 T cells, respectively
• RTS,S shows efficacy of ~40% in field trials– Now in a large phase III licensure trial– A combination approach with vectors + RTS,S would
probably show much higher efficacy
Centre for Clinical Vaccinology and Tropical Medicine
Churchill Hospital Facilities
Clinical Biomanufacturing Facility
Vaccine Trial Partners in Africa
• Wellcome-KEMRI, Kilifi, Kenya • University of Cape Town, South Africa• MRC Laboratories, The Gambia• University of Nairobi, Kenya• Université Cheikh Anta Diop, Senegal• CNRFP, Ouagadougou, Burkina Faso
Three Priorities for the Jenner Institute
• Global Health– vaccines that make a difference
• HIV, TB, malaria, dengue, pandemic influenza
• Translational Research– rapid early clinical testing
• 28 vaccines made for clinical trials
• One Health– vaccines for humans and other animals
Epidemiology of TB in the21st Century
• 8.8 million new cases per annum• 1.7 million deaths per annum• Resistance
– MDR-TB– XDR-TB
• Overlap with HIV epidemic• Burden of latent infection
Global Plan to Stop TB: 2006 - 2015
• Targets (from Millenium Development Goals)– > 70% with infectious TB will be diagnosed– > 85% of those will be cured– By 2015, global prevalence of TB will be
reduced to 50% of 1990 levels– By 2050, global incidence will be
< 1/ million population
• How?– Use of current tools
• DOTS; DOTS-plus; DOTS expansion– New tools
• New drugs• New diagnostics• New vaccines
Total cost of plan: $56 billion – so a $31 billion funding gap
Bacille Calmette-Guerin
• Live attenuated Mycobacterium bovis
• First used in 1921 (orally)
• 2 big trials in 1950s:– UK (Copenhagen strain, highly effective)– US (Tice strain, no effect)
Efficacy of BCG
• Good– Disseminated TB and TB meningitis – Leprosy
• Bad– Lung disease – at any age – Boosting (Rodrigues et al, Lancet 2005)
New TB Vaccines in the ClinicVaccine Developer What Clinical
StageType
rBCG30 UCLA Recombinant BCG overexpressing Ag85B I - ended Mycobacterial
rBCGΔUreA::Hly VPM Recombinant BCG expressing Lysteriolysin
I Mycobacterial
M72 inAS01
GSKBio Subunit fusion protein of Rv1196 and Rv0125 in ASO1 adjuvant
I Protein inadjuvant
85B-ESAT6in IC31 (Hyb1)
SSI Subunit fusion protein of Ag85B and ESAT6 in IC31 adjuvant
I Protein inadjuvant
85B-TB10.4 in IC31 (HyVAC4)
SSI Subunit fusion protein of Ag85B and TB10.4 in IC31 adjuvant
I Protein inadjuvant
rAd35-Ag85A, 85B,TB10.4
Crucell Recombinant adenovirus35 expressing Ag 85A, 85B, 10.4
Ib Viral vector
MVA85A Oxford University / OETC
Recombinant vaccinia expressing Ag85A IIb Viral vector
MVA85A
• Expresses a major gene from Mycobacterium tuberculosis
• Made in Oxford in 1999– Replication-impaired
• First clinical trial in Oxford in 2002• Now 14 completed clinical trials
• In the UK, The Gambia, Senegal, South Africa• Remarkable CD4 T cell potency
• The most advanced new TB vaccine in clinical development
Helen McShane
Dunn’s: *, p < 0.05; **, p < 0.01
BCG / MVA85A:Enhanced Protection In The Lungs
of M. Bovis Infected Calves
Vordermeier et al. 2009
BCG – MVA85A induces High and Sustained Antigen 85A-Specific Immune Responses in UK
Vaccinees
0
500
1000
1500
2000
2500
3000
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time (weeks)
SFC
/ 10
^6 P
BM
C BCG
MVA85A
BCG-MVA85A
McShane et al, Nature Medicine 2004
* p<0.05** p<0.01*
**
** *
MVA85A Induced Antigen Specific CD4+ T Cells Are Highly Polyfunctional
2+
1+
4+
3+
Number of functions:Pre-MVA85A Wk 1 Wk 2 Wk 8 Wk 24
Pre-MVA85A Wk 1 Wk 2 Wk 8 Wk 24
Beveridge N et al, EJI 2007
MVA85A Target Indications
• Booster vaccine administered in infancy (4-6 months)• Booster vaccine administered to HIV+ at diagnosis• Booster vaccine administered in adolescence
– i.e. 3 possible efficacy trials
• If effective, MVA85A would be indicated anywhere in the world where BCG is used
– But you need a high incidence area to test efficacy
Infant Phase IIb Efficacy Trial• Objectives:
– Safety– Immunogenicity– Efficacy (against disease & infection)– Immune correlates
• Design: – BCG vaccinated infants in Worcester, South Africa– Randomised at 18-22 weeks to receive either:
• MVA85A (1 x 108pfu)• placebo (Candin)
– Sample size = 2784 (1392/arm)• Cumulative TB incidence of 3%• 90% power to detect 60% improvement over BCG alone
Oxford + Emergent BioSolutions: Oxford Emergent Tuberculosis Consortium- with Wellcome Trust and Aeras Global TB Vaccine Foundation funding - collaboration with University of Cape Town
Phase IIb Efficacy Trial of MVA85A in HIV-Infected Adults
• Proof of concept study in HIV+ adults– protection against TB disease– protection against M. tb infection– safety & immunogenicity
• Two sites– South Africa: Cape Town with R Wilkinson– Senegal: Dakar with S Mboup
• Sponsored by Aeras Global TB Vaccine Foundation
• Funded by EDCTP, MRC and Aeras
• Due to start in May 2011
AE
C
C
C
B
BB
32 million people are living with HIV infection, mainly in Africa
Global Distribution of HIV Strains
Gag Pol Vif Env
mAb epitope PkMamu-A*01 epitope H-2Dd & Ld epitope
C C C CD D D DA A AB B B
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Humanized codons
AdCh63attenuated
adenoviruses
MVAattenuated poxvirus
Synthetic HIVCONSV Vaccine
Tom Hanke, Lucy Dorrell, Andrew McMichael
A New Cross-Strain Influenza Vaccine
• targets the internal antigens of flu• these are conserved between human and avian viruses• excellent phase I safety and immunogenicity
The Influenza A Virus Virion
Two surface glycoproteins
- haemagglutinin (HA)
- neuraminidase (NA)
Embedded M2 protein
The ribonucleoprotein complex
- nucleoprotein (NP)
- three polymerase proteins
- matrix (M1) protein .
FLU002- a Phase IIa Efficacy Trial
• Collaboration with Retroscreen Virology Ltd.
• Screen healthy volunteers for low anti-flu antibodies
• Challenge all intranasally 4 weeks after vaccination date, in a contained facility– Monitor viral shedding and symptoms for 10 days– All given oseltamivir prior to leaving containment
51
Enhancing the Immunogenicity and Efficacy of Vectored Vaccines
Grand Challenge 5: Solve how to design antigens for effective, protective immunity
Bioengineering Technologiesfor Vaccine Delivery
Stratum corneum (10-20µm)
Epidermis
Nerve
Sweat gland
Dermis
Hair follicle
Subcutaneous layer
Microneedle array