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Malaria Vaccines: Promise and Challenges

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 malaria vaccines and ensure their availability and accessibility in the developing world.

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Malaria Vaccines: Promise and Challenges

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  1. Malaria Vaccines: Promise and Challenges • Christian Loucq, MD • Director, PATH Malaria Vaccine Initiative • Vaccines 202X Conference • Philadelphia, PA / May 2-4, 2011

  2. To accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world PATH Malaria Vaccine Initiative A world free from malaria

  3. Why a vaccine? Data as of the end of 2008, WHO

  4. 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 Malaria Vaccine Technology Roadmap http://www.malariavaccineroadmap.net/ P. vivax and Pf / Pv transmission-blocking vaccines

  5. Commercial Limited market in developed countries Malaria-endemic countries mostly poor Vaccine development is high-risk, high-cost Scientific No vaccine in human use against a parasite Malaria parasite has ~6,000 genes, many more than a virus How to predict a vaccine candidate’s success? • The major challenges to success

  6. MVI’s portfolio, early 2007 Phase 2b Phase 1b Phase 3 Phase 1a Phase 1/2a Final Formulation Toxicology Process Development Construct Selection GenVec Ad5 CSP/ LSA1/Ag2 Monash MSP4 ISA720 ICGEB/BBI PvR-II ASO1/ASO2 WRAIR/GSK AMA1 ASO1/ASO2 GSK RTS,S ASO1/AS02 WRAIR/GSK MSP1 ASO2 GenVec Ad5 MSP1 /AMA1 MVDB MSP-C1 AlOH+CpG MVDB AMA-C1 ISA720 Monash MSP5 ISA720 WRAIR LSA-1 AS02&ASO1 GSK Pfs161 AS01/AS02 MVDB AMA1-C1 AlOH+CpG2 QIMR RAP2 ISA720 Sanaria PfSPZ Wanxing AMA1:MSP1 ISA720 LaTrobe MSP2 ISA720 1 In feasibility stage 2 Clinical development plan under negotiation X Project failure in 2006

  7. P. falciparum vaccines: Pre-erthrocytic Blood-stage Transmission-blocking P. vivax vaccines: Pre-erthrocytic Blood-stage Transmission-blocking MVI portfolio (March 2011) feasibility studies* translational projects vaccine candidates Antigen Delivery Preclinical studies Phase 1/2a Phase 2b Phase 3 Seattle BioMed (PE selection) Aeras (rBCG) Crucell (Ad35.CS/Ad26.CS) WRAIR/GSK (PvCSP/AS01) GSK (RTS,S/AS01) NMRC (PE selection) Inovio/UPenn (pDNA) Gennova (PfCSP) Profectus (VSV) Emory (adjuvanted nanoparticles) NYU/Merck (CSP RI conjugates) WEHI/LaTrobe/ WRAIR (AMA1) Liquidia(adjuvanted nanoparticles) VRC/JHU/Oncovir/IDRI (adjuvanted CSP) WEHI/Gennova (EBA/Rh) Tulane/Gennova (Pfs48) JHU/Sabin (AnAPN1) ICGEB (PvDBPII) * selected projects

  8. Current evaluation technologies portfolio

  9. RTS,S Target Product Profile • A vaccine that will protect infants and children residing inmalaria 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

  10. MAL 049 – efficacy results Vaccine Efficacy % 95% CI p-value FU 1st clinical episode5328-69 < 0.001 8 m All clinical episodes 56 31-72 < 0.001 8 m 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 46 24-61 < 0.001 15 m All clinical episodes 51 29-66 < 0.001 15 m Vaccine Efficacy RTS,S/AS01 Control p-value FU Parasite prevalence3.5% (1.9-5.9)8.2%(5.7-12) < 0.01 12 m in Kenya only1.8% (0.4-5.2) 7.5% (3.8-13) < 0.05 15 m Bejon et al 2008 NEJM 359; 24: 2521-32 Olotu A. et al. Lancet ID 2011; 11: 102-09

  11. MAL 049 / SAEs (N=447) (N=447) (82) (61) (47) (40) (26) (21) (21) (18) (7) (10) Indication of non-malaria specific protection Bejon et al 2008 NEJM 359; 24: 2521-32 11

  12. Vaccine Efficacy 0,1,2 % 95% CI p-value FU 1st clinical episodea5326-70 0.001 17 m All clinical episodes 59 36-74 < 0.001 17 m ATP cohort 17 month as of 2 weeks post dose 3 Vaccine Efficacy 0,1,2 % 95% CI p-value FU 1st clinical episodea6236-77 < 0.001 12 m All clinical episodes 65 42-79 < 0.001 12 m ATP cohort post dose 3 New data RTS,S/AS01 in Infants 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 Results unpublished.

  13. RTS,S Phase 3 trial network

  14. Phase 3 trial of RTS,S • Key safety and efficacy data to support file to regulatory authorities Bagamoyo, Tanzania, 26 May 2009 • Analysis at each site for clinical malaria disease • Sites represent different malaria transmission settings • Designed in collaboration with scientific community, with input and/or feedback of WHO, FDA, and EMA • Evaluation of public health endpoints to inform planning for implementation

  15. 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 15,460

  16. Phased availability of Phase 3 efficacy data Phase 3 efficacy study Children 5-17 months 12 M post dose 3 Infants 6-12 weeks, EPI12 M post dose 3 Public health efficacy endpoints in both age-groups32 M- post dose 3

  17. 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

  18. Multiple target product profiles • Clinical disease • Next generation P. falciparum vaccine • P. vivaxvaccine • Transmission • SSM-TBV • PE-TBV • SSM + PE/BS-TBV <50 <5 ~100,000,000,000

  19. 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)

  20. How can we improve on clinical efficacy and duration of protection of RTS,S/AS01? 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) RTS,S

  21. 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

  22. Focused P. vivax strategy • Pre-erythrocytic (translational) • PvCSP/AS01 • Clinical efficacy data (2011) • Blood-stage (feasibility) • Duffy binding protein region 2 (DBPII) • Formulation needs to support combination • Clinical efficacy data from PvCSP/AS01 will impact future direction

  23. 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

  24. Vaccines critical for elimination • Vector control • Insecticide treated bednets • Indoor residual spraying • Vector management • Drug therapy • Vaccines

  25. Transmission blocking vaccines Interrupt Reduce lifecycle transmission Elimination

  26. 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)

  27. SSM-TBVs FDA:TBV licensure possible

  28. 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?

  29. Thank you For more information:www.malariavaccine.orgwww.path.org

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