Presentation by adrian hill [university of oxford]


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Presentation by adrian hill [university of oxford]

  1. 1. Malaria Vaccines Adrian HillThe Jenner Institute, Oxford University
  2. 2. How to Make a Vaccine1790s pub, pustule, publish1890s isolate, inactivate, inject21st Century sequence, select, synthesize
  3. 3. Malaria Mortality and Morbidity• Currently about 700,000 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 $1.5 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
  4. 4. A Complex Parasite Life-Cycle Many Target Antigens
  5. 5. Some Difficulties in Malaria Vaccine Development• Stage-specificity of antigen expression• Antigenic variation• Extensive genetic diversity• Exceptional immunogenicity required
  6. 6. Main Approaches to Malaria Vaccine Development1. Protein-adjuvant vaccines • RTS,S/AS01 antibodies • AMA1/AS02 • MSP3/alum2. Vectored vaccines • Adenovirus-MVA cellular immunity • DNA-Adenovirus3. Whole parasite vaccines • Irradiated sporozoites • Genetically attenuated parasites both to multiple antigens • Low dose blood-stage parasites
  7. 7. SANARIAThe quest for a whole sporozoite vaccine
  8. 8. Efficacy of Sporozoites Administeredby the Bites of Irradiated Mosquitoes Courtesy S Hoffman
  9. 9. Difficulties for the Whole Irradiated Sporozoite Vaccine Approach• Manufacturing – One batch per day• Storage – Liquid nitrogen required• Lack of efficacy – Only 2 / 44 vaccinees protected – 137,000 parasites x 6 in high dose group – Implications for genetically-attenuated parasites
  10. 10. Viral Vector Vaccines to Maximise Cellular Immunogenicity 8 weeksAdenovirus Prime MVA Boost Malaria, HCV, HIV, influenza, TB...
  11. 11. Vaccine Efficacy in Murine Malaria Photon ImagingChAd63-MVAChAd63 alone controls
  12. 12. A PolyEpitope-Protein Construct pSG.ME.TRAP ME: Malaria Epitopes TRAP: Thrombospondin- Related Adhesion Protein TRAP strain is T9/96 in this vaccine
  13. 13. Clinical BioManufacturing Facility University of Oxford
  14. 14. ME-TRAP T Cell Immunogenicity in the ClinicVACCINE T CELL RESPONSE ANTIGEN mean cells/ million PBMCsDNA x 3 48 ME-TRAPFowlpox x 2 50 ME-TRAPMVA x 3 41 ME-TRAPChAd63 x 1 850 ME-TRAPDNA x 2 - MVA boost 430 ME-TRAPFowlpox x 2 - MVA boost 475 ME-TRAPChAd63 x 1 - MVA boost 2800 ME-TRAP
  15. 15. Induced CD8 and CD4 Cells Show Substantial Polyfunctionality
  16. 16. Responses are Durable and Can BeRe-Boosted at 6-30 Months Post-MVA
  17. 17. Vectored Liver-Stage Vaccines for Malaria• Efficacy correlates with induced CD8+ T cell numbers in phase II trials – First example for any vaccine – Correlate is with mono-functional effectors secreting g-interferon• Excellent safety data for both ChAd63 and MVA vectored vaccines – About 500 and 3000 vaccinees, respectively, in malaria, TB, HIV – Re-boosting with each vector demonstrated• Phase I trials of ChAd63-MVA completed successfully in African adults, children and infants
  18. 18. Sukuta Vaccine Clinic The Gambia
  19. 19. The Malaria Vectored Vaccine Consortium African Prime-Boost Trials • EDCTP funded: ChAd63-MVA MeTRAP – Kenya, Gambia, Burkina Faso, Senegal • Phase I trials in adults, children and infants – 164 adults in The Gambia, Kenya, Senegal – 24 children and 48 infants in The Gambia – Excellent safety and immunogenicity • Phase IIb efficacy trials underway – 2012: Adults in Kenya and Senegal (Q2 and Q3) – 2013: 5-17 month olds in Burkina Faso MVVC
  20. 20. Pre-Erythrocytic Vaccine Efficacy Sporozoite Challenge Trials Vectors encode ME-TRAP; RTS,S encodes CSP80%70%60%50%40%30%20%10% 0% Controls Other DNA-MVA* FP9-MVA* Ad-MVA* RTS,S* n = 68 candidates n = 22 n =16 n = 14 n >100 n = 104 + Sterile Protection Partial Protection*Vaccine groups differing significantly from controls+Delay to day 14 or beyond = > 95% reduction in liver parasite burden
  21. 21. Options for Better Pre-Erythrocytic Efficacy1. Assess alternative antigens – ChAd-MVA encoding AMA1, MSP1, CSP assessed so far – None better than TRAP2. Add an encoded adjuvant to vectors3. Add an RTS,S biosimilar = R21
  22. 22. 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 RBC cells CONFIDENTIAL
  23. 23. RTS,S Immunogenicity and Efficacy• Exceptional antibody titres to the central repeat of the circumsporozoite protein – 70-600 mg per ml – No CD8+ T cell response induced• 45% sterile efficacy on sporozoite challenge• 35% reduction in malaria clinical episodes – over 12 months follow-up – in older infants
  24. 24. Multi-Component Malaria Vaccine Strategy• A Four-Stage High Efficacy Modular Vaccine against P. falciparum malaria – Sporozoite Stage: R21 – Liver Stage: TRAP – Blood Stage: PfRH5 – Mosquito Stage: Pfs25
  25. 25. Screening for Better P. falciparum Blood-Stage Antigens 8wkAdHu5 Prime MVA Boost Douglas AD (2011) Nat Commun 2, 601
  26. 26. PfRH5: a promising novel blood-stage vaccine antigen• PfRH5 is essential for invasion of human and Aotus RBCs – Interacts with the basigin receptor on RBCs Hayton et al, CHM 2008; Baum et al, IJP 2008; Crosnier et al, Nature 2011• Vaccination of rabbits with PfRH5 elicits antibodies which neutralise all tested strains of P falciparum. Douglas et al, Nature Comms 2011• RH5 sequence is highly conserved – among circulating parasites in the field: <1% amino acid variation Williams & Douglas et al, submitted• Not very immunogenic during natural infection – a target for non-natural vaccine-induced immunity Douglas et al, Nature Comms 2011
  27. 27. Transmission-Blocking Vaccines: Leading Target Antigens – Parasitic and MosquitoPfs48/45 and Pfs 230 PfsHAP2 Pfs25 HUMAN HOST VECTOR HOST Alanyl Aminopeptidase N1 (AgAPN1)
  28. 28. Standard Membrane Feeding Assay Cardiac bled two weeks after immunization for serumPlasmodium oocysts in mosquitomidgut are counted 12 days later Serum (at different dilutions) mixed with P. falciparum gametocyte culture and put in membrane feeders A pot of 50 mosquitoes (starved 5-6 hrs prior to the feed) via mini-feeders
  29. 29. Summary• There is considerable progress in vaccine development for malaria – RTS,S could be licensed by 2015 – Further components should increase efficacy• Partial efficacy has required unprecedented immunogenicity• Access to challenge models and functional assays has been crucial
  30. 30. Pre-Erythrocytic Acknowledgements Malaria Pre-Clinical BioManufacturing Clinical Trials Arturo Reyes-Sandoval Sarah Moyle Geraldine O’Hara Katharine Collins Eleanor Berrie Susanne Sheehy Alex Spencer Chris Duncan Migena Bregu Nick Anagnostou Anita Milicic Carly Bliss Sarah Gilbert Alfredo Nicosia Katie Ewer Matt Cottingham Stefano Colloca Ian Poulton Riccardo Cortese Nick Edwards The Gambia Alison Lawrie Kalifa Bojang Kilifi, Kenya Bob Sinden Muhammed Afolabi Roma Chilengi Jenny Mueller Caroline Ogwang Britta Urban Rino RappuoliEuropean Vaccine Initiative Kevin Marsh Giuseppe del Giudice Egeruan Imoukhuede
  31. 31. Blood-Stage and Mosquito-Stage Vaccine Acknowledgements Oxford Oxford NIHSimon Draper Sumi Biswas Carole LongSandy Douglas Melissa Kapulu Sam MoretzAndrew Williams Bob Sinden Kazutoyo MiuraJoe Illingworth Lynn LambertPrateek Choudhary NAMRU, Lima Sanger CentreLinda MurungiSara Zakutansky Gavin WrightAli Turner Willy Lescano Cecile CrosnierVector Core Luis LugoJulie Furze Jeremy MoorheadDrew Worth