1 / 29

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.

fritzi
Download Presentation

Malaria Vaccines: Promise and Challenges

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related