New Vaccines for Global Health. Adrian Hill The Jenner Institute, Oxford University

Transcription

1 New Vaccines for Global Health Adrian Hill The Jenner Institute, Oxford University

2 1796: Jenner Invents Vaccination Edward Jenner DM (Oxon)

3 Synergies in Human and Livestock Vaccine Development 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

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5 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

6 A Complex Parasite Life-Cycle Many Target Antigens

7 Transmission Blocking Vaccines Parasite Candidate Antigens Pfs48/45 Pfs230 Pfs25 PfsHAP2 Pfs48/45 Pfs230 a: Expressed in host b: Expressed in vector

8 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

9 Blood-Stage Malaria Vaccines

10 Leading Blood-Stage Malaria Antigens Most natural immunity targets blood-stage Multiple target antigens are available A major target, PfEMP1, shows antigen variation Many show substantial polymorphism

11 Blood-Stage Vaccine Trials 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 adults Ia AMA1-C1 AMA1 3D7 + FVO Alhydrogel Malkin 2005 Yes (up to 54%) Not assessed US adults Ia AMA1-C1 AMA1 3D7 + FVO Alhydrogel + CpG7909 Ellis 2009 Yes (up to 97%) Not assessed US adults Ia AMA1-C1 AMA1 3D7 + FVO Alhydrogel + CpG7909 Mullen 2008 Y (up to 96%) Not assessed US adults Ia Pf(3D7)AMA1 AMA1 3D7 M ISA 720 Saul 2005 Not assessed Not assessed Australian adults Ia AMA1 FVO AMA1 FVO Alhydrogel/ M ISA720 /AS02 Roestenberg 2008 Yes Not assessed Dutch adults Ia FMP2.1 AMA1 3D7 AS02A Polhemus 2007 Yes (median up to 17%) Not assessed US adults Ia MSP1-C1 MSP1 3D7 + FVO Alhydrogel plus CpG7909 Ellis 2010 Y (up to 32%) Not assessed US adults Ia FMP1 MSP142 3D7/FVO Alhydrogel Malkin 2007 Y (< 20%) Not assessed US adults Ia FMP1 MSP142 3D7 AS02A Ockenhouse 2006 Y (<25%) Not assessed US adults Ia FMP1 MSP142 3D7 AS01B Start 2008 Ia Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Saul 1999 Not assessed Not assessed Australian adults Ia P30P2 MSP-119 MSP119 3D7 or FVO Alum Keitel 1999 Not assessed Not assessed US adults Ia MSP3-LSP MSP3 Conserved Alum/ M ISA 720 Audran 2005 Not assessed Not assessed Swiss adults Ia GMZ2 GLURP/MSP3 Conserved Alum Esen 2009 Not assessed Not assessed German adults Ia PfCP2.9 AMA1/MSP119 3D7 + FVO M ISA 720 Hu 2008 No Not assessed Chinese adults Ia PfCP2.9 AMA1/MSP119 3D7 + FVO M ISA 720 Malkin 2008 Yes (up to 13%) Not assessed Chinese adults Ia PfCA AMA1 3D7 AdHu5 NIAID Unpublished Not known Not assessed US adults Ib AMA1-C1 AMA1 3D7 + FVO Alhydrogel + CpG7909 Sagara 2009 FVO only (<10% Not assessed Malian adults increase) Ib AMA1-C1 AMA1 3D7 + FVO Alhydrogel Dicko 2008 Not assessed Not assessed Malian children Ib AMA1-C1 AMA1 3D7 + FVO Alhydrogel Dicko 2007 No Not assessed Malian adults Ib FMP2.1 AMA1 3D7 AS02A Thera 2008 Yes (median < 40%) Not assessed Malian adults Ib FMP1 MSP142 3D7 AS02A Thera 2006 Not assessed Not assessed Malian adults Ib FMP1 MSP142 3D7 AS02A Stoute 2007 Not assessed Not assessed Kenyan adults Ib Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Genton 2000 Not assessed Not assessed PNG adults Ib Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Genton 2003 Not assessed None PNG children Ib MSP3-LSP MSP3 Conserved Alum Lusingu 2009 Not assessed Not assessed Tanzanian children Ib MSP3-LSP MSP3 Conserved Alum Sirima 2007 Not assessed Not assessed Burkina Faso adults Ib MSP3-LSP MSP3 Conserved Alum Nebie 2009 Not assessed Not assessed Burkina Faso adults I/IIa FMP2.1 AMA1 3D7 AS02A vs AS01B Spring 2009 Yes (mean 3D7 up to Some US adults 30%) I/IIa PEV3A AMA1 Conserved Virosome Thompson 2008 No Some UK adults I/IIa NYVAC-Pf7 MSP1, AMA1, SERA 3D7 NYVAC Ockenhouse 1998 Not assessed Some US adults IIa Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Lawrence 2000 Not assessed None Australian adults I/IIb SPf66 83, 55, 35 kda Alum Cochrane Not assessed Some (South South America, peptides Review America) Africa, Asia IIb AMA1-C1 AMA1 3D7 + FVO Alhydrogel Sagara 2009 Not assessed None Malian children IIb FMP1 MSP142 3D7 AS02 Ogutu 2009 Not assessed None Kenyan children IIb Combination B MSP1/MSP2/SERA 3D7 M ISA 720 Genton 2002 Not assessed Some PNG children

12 Pre-Erythrocytic Malaria Vaccines Sporozoite and Liver-stages 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

13 SANARIA The quest for a whole sporozoite vaccine

14 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

15 Killer T-Cell Attack on an Infected Liver Cell Parasites Liver Cell HLA = Killer T Cell Human Leucocyte Antigen P Receptor Cytoplasm KILLING

16 The MeTRAP Vaccine Insert Targets the Liver-Stage of Plasmodium falciparum A Polyepitope-Protein Vaccine Construct ME: Multiple malaria Epitopes TRAP: Thrombospondin- Related Adhesion Protein TRAP strain is T9/96 in this vaccine

17 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 8 weeks MVA Boost

18 Viral Vector Vaccines to Maximise Cellular Immunogenicity 8 weeks Adenovirus Prime MVA Boost Malaria, HCV, HIV, influenza, TB...

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20 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

21 The RTS,S Malaria Vaccine Candidate

22 RTS,S Sporozoite Challenge Typically Shows 60% Sterile or Partial Protection RT

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24 A Sporozoite and Liver-Stage Vaccine a combination two-hit approach Sporozoite Stage: Antibodies clear most sporozoites schizonts Liver Stage: T Cells clear the remaining liver cells RBC

25 RTS,S + Vectored TRAP an infant immunisation regime A Simple Regime for Deployment in Developing Countries through the Expanded Programme on Immunisation months R+A R+A R+M R = RTS,S/AS01 A = AdCh63 MeTRAP M = MVA MeTRAP

26 Sukuta Vaccine Clinic The Gambia

27 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

28 Jenner Institute Laboratories OLD ROAD CAMPUS RESEARCH BUILDING

29 Churchill Hospital Facilities Centre for Clinical Vaccinology and Tropical Medicine Clinical Biomanufacturing Facility

30 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

31 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

32 Estimated tuberculosis incidence rates 2008

33 Epidemiology of TB in the 21 st 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

34 Global Plan to Stop TB: 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

35 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)

36 Efficacy of BCG Good Disseminated TB and TB meningitis Leprosy Bad Lung disease at any age Boosting (Rodrigues et al, Lancet 2005)

37 New TB Vaccines in the Clinic Vaccine Developer What Clinical Stage Type rbcg30 UCLA Recombinant BCG overexpressing Ag85B I - ended Mycobacterial rbcgδurea::hly VPM Recombinant BCG expressing Lysteriolysin I Mycobacterial M72 in AS01 GSKBio Subunit fusion protein of Rv1196 and Rv0125 in ASO1 adjuvant I Protein in adjuvant 85B-ESAT6 in IC31 (Hyb1) SSI Subunit fusion protein of Ag85B and ESAT6 in IC31 adjuvant I Protein in adjuvant 85B-TB10.4 in IC31 (HyVAC4) SSI Subunit fusion protein of Ag85B and TB10.4 in IC31 adjuvant I Protein in adjuvant 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

38 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

39 BCG / MVA85A: Enhanced Protection In The Lungs of M. Bovis Infected Calves Dunn s: *, p < 0.05; **, p < 0.01 Vordermeier et al. 2009

40 Summary of Clinical Trials with MVA85A since 2002

41 BCG MVA85A induces High and Sustained Antigen 85A-Specific Immune Responses in UK Vaccinees * * p<0.05 ** p<0.01 SFC / 10^6 PBMC ** ** * BCG MVA85A BCG- MVA85A Time (weeks) McShane et al, Nature Medicine 2004

42 MVA85A Induced Antigen Specific CD4+ T Cells Are Highly Polyfunctional Pre-MVA85A Wk 1 Wk 2 Wk 8 Wk 24 Pre-MVA85A Wk 1 Wk 2 Wk 8 Wk 24 Number of functions: Beveridge N et al, EJI 2007

43 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

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45 Infant Phase IIb Efficacy Trial Objectives: Safety Immunogenicity Efficacy (against disease & infection) Immune correlates Design: BCG vaccinated infants in Worcester, South Africa Randomised at weeks to receive either: MVA85A (1 x 10 8 pfu) 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

46 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

47 Global Distribution of HIV Strains B B B A C E C C 32 million people are living with HIV infection, mainly in Africa

48 Synthetic HIV CONSV Vaccine C D A B C D A B C D A B C D Gag Pol Vif Env Mamu-A*01 epitope H-2D d & L d epitope mab epitope Pk Humanized codons AdCh63 attenuated adenoviruses MVA attenuated poxvirus Tom Hanke, Lucy Dorrell, Andrew McMichael

49 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

50 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.

51 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

52 Enhancing the Immunogenicity and Efficacy of Vectored Vaccines Grand Challenge 5: Solve how to design antigens for effective, protective immunity

53 The HydRIS System Glass stabilisation of vaccines on a membrane

54 Bioengineering Technologies for Vaccine Delivery Microneedle array Stratum corneum (10-20µm) Epidermis Dermis Nerve Sweat gland Hair follicle Subcutaneous layer

55 Funders JENNER VACCINE FOUNDATION

56 Key Contributors Helen McShane Sarah Gilbert Simon Draper Andrew McMichael Tuberculosis Influenza Malaria HIV Babatunde Imoukhuede, Souleyman Mboup, Greg Hussey, Kevin Marsh, Tumani Corrah