Improving Influenza vaccines: Looking ahead

Transcription

1 Improving Influenza vaccines: Looking ahead Gerd Sutter ESWI Flu Summit - Brussels

2 First 20th century pandemic - The Spanish Flu Courtesy: A. Garcia-Sastre Influenza A/CDC/1918 virus

3 History of influenza vaccines Experimental vaccinations with active influenza virus (Stokes et al J Clin Invest) Whole-virus inactivated influenza vaccine in clinical trials (Francis 1945 Am J Hyg, Salk et al Am J Hyg) Adjuvanted influenza vaccines to enhance antibody responses (Salk et al Am J Hyg, Salk et al JAMA) Subvirion (split) inactivated influenza vaccines (Cate et al J Infect Dis, Wright et al J Infect Dis) Live attenuated influenza virus vaccines: Clinical trials with safety, immunogenicity and efficacy data in children (Alexandrova et al Vaccine, Belshe et al J Infect Dis)

4 Seasonal vaccines against human influenza DE ~20 Mio doses/year egg-(cell) produced mostly inactivated (split subunit), intramuscular trivalent (H1, H3, B) or quadrivalent (H1, H3, B yam, B vic ) mostly without adjuvant annual strain selection: Courtesy: Solvay

5 Shortcomings of seasonal influenza vaccines immunogenicity limited to virus-specific antibodies low level memory responses vulnerable to immune escape by virus drift variants suboptimal efficacy in high risk populations no efficacy against new viruses (avian, pandemic) Strategies: - need for antigen update every season - need for repeated immunizations over years

6 Experten schlagen Grippe-Alarm Schon 1,5 Mio. Infizierte +++ Virus besonders aggressiv

7 Need to improve influenza vaccines Objective is to induce broadly protective immunity: - against virus drift variants within subtypes - against viruses across all subtypes Strategies: - optimizing antigens for immunization - testing additional antigens for immunization - strengthen and broaden immunogenicity to elicit virus-specific antibodies and T cells

8 Induction of antibodies and T cells against conserved influenza virus proteins HA antibodies NA antibodies M2 antibodies Cell mediated immunity (NP, M1) Adapted from K. Subbarao et al., Immunity 2006

9 Optimize delivery of influenza antigens Infection with MVA vector virus cytotoxic T-cell CD8+ Strategies: - antigen targeting - antigen presentation Proteasome Production of endogenous antigen Trans-Golgi - antigen modification Peptides TAP Golgi to elicit virus-specific antibodies and T cells MHC class I Endoplasmatic Reticulum Cytoplasm of antigen-presenting cell

10 Triggering the immune system! Adapted from Pichlmair and Reis e Sousa; Immunity 2007

11 New vaccine technologies under development Proteins with adjuvants Nucleic acids Virus-like particles Recombinant viruses

12 Desirable properties of new (vector) vaccines against influenza suitable for use under biosafety level 1 conditions acceptable safety profile in clinical testing capacity to deliver multiple foreign antigens immunostimulatory capacity (no need for adjuvants) induction of balanced immune responses (cellular & humoral) suitability for long term storage

13 Concept A universal influenza vaccine based on Modified Vaccinia virus Ankara (MVA), inducing broad protective and long lasting immunity: Doing better than Nature

14 Modified Vaccinia virus Ankara (MVA) electron micrograph - D. Spehner/ G. Sutter

15 Modified Vaccinia virus Ankara (MVA) excellent characterization in many preclinical models various candidate vector vaccines in clinical testing large scale production compliant with GMP regulations entry uncoating early genes DNA replication intermediate genes structural proteins late genes Cytoplasm viral and recombinant gene expression assembly Nucleus block in morphogenesis Sutter & Moss PNAS 1992 Sutter Vaccine 1994 egress actin tails Golgi wrapping

16 Regulatory guidance on Quality, Safety and Efficacy of recombinant MVA vaccines 24 June 2010 EMA/CHMP/VWP/141697/2009 Committee for Medicinal Product for Human Use (CHMP) Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines

17 MVA vaccines targeting new influenza viruses Kreijtz et al. JID 2007, JID 2009, JID 2015, Vaccine 2009, PLoS ONE 2009, JGV 2010

18 MVA-H5 vaccine Double blind randomized study 80 subjects male/female yrs healthy Kreijtz Lancet Infect Dis 2014 MVA-H5-sfMR MVA-F6-sfMR 1shot * 10 7 pfu 1shot * 10 8 pfu 2shot * 10 7 pfu 2shot * 10 8 pfu 1shot * 10 7 pfu 1shot * 10 8 pfu 2shot * 10 7 pfu 2shot * 10 8 pfu 1) Safety 2) Immunogenicity 27 volunteers received additional booster, 1 year post primary vaccination

19 GMT HI A/Vietnam/1194/04 MVA-H5 vaccine induces immunity to influenza H5N group 1: MVA-H5-sfMR 10 8 group 2: MVA-H5-sfMR 10 7 group 5: 2x MVA-H5-sfMR 10 8 group 6: 2x MVA-H5-sfMR 10 7 * * * * * * 10 0 weeks 4 weeks 8 weeks 20 weeks 1 year 4 weeks st Time post 1 immunization Kreijtz Lancet Infect Dis 2014 Time post boost

20 Avian Influenza H5N8 in Asia and Europe in 2014

21 Induction of influenza H5N8 antibodies by MVA-H5 vaccine H5N8 antigenically distinct from H5N1 Cross-clade antibodies in 82% participants receiving 10E8 pfu MVA-H5 De Vries Emerg Infect Dis 2015

22 Progress in Vaccine Development: Better Vaccines on the Horizon! Adaptive humoral response B cells Virus Neutralization by antibody Adaptive cellular response DC function CD8+ Innate response Cytokine secretion T cells CD4+ Killing by CD8+ CTL

23 Acknowledgements Christine Brandmüller Sylvia Jany Astrid Freudenstein Robert Fux Martina Kaserer Michael Lehmann Marcus Müller Phil Price Fei Song Lino Torres Asisa Volz Joost Kreijtz Byron Martina Bart Haagmans Guus Rimmelzwaan A.D.M.E. Osterhaus Alexandra Kupke Markus Eickmann Stephan Becker

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26 Die Vogelgrippe erreicht Peking: Ärzte kämpfen um 7-jähriges Mädchen Ärzte kämpfen um 7-jähriges Mädchen Die Vogelgrippe erreicht Peking 20-Mio-Stadt in Angst vor der Epidemie