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Vaccines for influenza pandemic preparedness - current developments and future opportunities - Beijing, 28-30 Jan. 2007 Chinese CDC; NBAR; Bill &Melinda.

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Presentation on theme: "Vaccines for influenza pandemic preparedness - current developments and future opportunities - Beijing, 28-30 Jan. 2007 Chinese CDC; NBAR; Bill &Melinda."— Presentation transcript:

1 Vaccines for influenza pandemic preparedness - current developments and future opportunities - Beijing, Jan Chinese CDC; NBAR; Bill &Melinda Gates Foundation; The Wellcome Trust Albert Osterhaus

2 The Ideal vaccine should: induce strong antibody responses high titers long-lasting virus neutralizing induce T cell mediated immunity strong T helper responses induction of cytotoxic T cell responses induce mucosal immunity induce of robust broad protection be needle free administered be safe upon administration and challenge

3 1 dose (trivalent): 1 chicken egg! Current vaccines

4 Pandemic influenza vaccines - Key issues -  Response time (currently >6 months)  Production capacity (currently 350 million doses worldwide)  Efficacy/Safety (human trials with prototype vaccines)

5 Strain selection Production systems Seed-strain preparation Improve efficacy; novel adjuvants & delivery systems New targets; identify correlates of protection Pandemic influenza vaccines - Room for improvement - “small” changes; easy to incorporate larger changes; long path before implementation?

6 Pandemic influenza vaccines - Improvements in production systems - Cell culture: MDCK, Vero, PERC-6, others: - Continuous availability of production substrate - Flexibility in optimizing production (GMO cell lines, substrate, carriers, continuous flow systems, etc) Strain selection Production systems Seed-strain preparation

7 Dose-Related Safety and Immunogenicity of a Trivalent Baculovirus-Expressed Influenza-Virus Hemagglutinin Vaccine in Elderly Adults JJ Treanor et al., JID 2006

8 Pandemic influenza vaccines - Improvements in seed strain preparation Reverse genetics Rapid generation of reassortants (Wood et al., Webby et al.) Adjustment of high-throughput virus backbone for increased yields (E. de Wit et al., Virus Research 103:155-61, 2004) Modification of basic cleavage site (HPAI H5, H7) Genetic modification for increased virus (or HA) yields? Strain selection Production systems Seed-strain preparation

9 Pandemic influenza vaccines - Improvements in vaccine strain selection - -Antigenic mapping to determine best HA/NA vaccine candidates (D.J. Smith, A.S. Lapedes et al., Science 305: , 2004) -Influenza A virus surveillance in wild birds; database of LPAI viruses. Bypass the necessity of reverse genetics (e.g. LPAI H7N7 from ducks) (V.J. Munster et al., EID., 2006) Strain selection Production systems Seed-strain preparation

10 Avian influenza A virus surveillance - HA and NA subtypes - Subtypes detected in wild birds globally Subtypes detected in wild birds in our own studies (Northern Europe) Fouchier et al., J Virol., 2005 Munster et al., Emerg Inf Dis., 2005 Olsen et al., Science., 2006

11 Pandemic influenza vaccines - Improvements in vaccine strain selection - Surveillance in wild birds & poultry; strain collection Europe/Africa/Asia North & South America Oceania Analysis of antigenic properties (HI assay) Selection of prototype strains with desired properties Antigenic map American lineage Eurasian lineage Pre-selected vaccine prototype D.J. Smith et al., Science 305:371-6 (2004)

12 Antigenic cartography - H5N1 strains - D.J. Smith et al. submitted

13 Strain selection Production systems Seed-strain preparation Improve efficacy; adjuvants & delivery systems New targets; identify correlates of protection Pandemic influenza vaccines - Room for improvement - “small” changes; easy to incorporate larger changes; long path before implementation?

14 Neuraminidase (9 subtypes) Haemagglutinin (16 subtypes) Viral RNA M2 protein M1 protein Orthomyxovirus Structure of Influenza A Virus

15 Pandemic influenza vaccines - Identification of new targets,correlates of protection - -Role of antibodies to NA in protection upon vaccination? Only 9 NA subtypes, versus 16 HA subtypes Less drift in NA as compared to HA? -Role of cellular immunity in protection? Identify targets (conserved internal proteins, epitopes!) Identify modes of antigen delivery (vectors, LAV, DNA vac) -Targeting M2; a “universal” influenza vaccine ? Clinical protection rather than sterile immunity? - Cross-protective immunity between virus subtypes?

16 Heterosubtypic cross-protection against lethal influenza in C57BL/6 mice Sub-lethal X-31 (H3N2) infection Lethal challenge PR8 (H1N1): only H and N different from X-31 Kreijtz et al., Vaccine 2007

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18 Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine JJ Treanor et al., NEJM 2006

19 MF59 adjuvant, H5N3 adults - K.G. Nicholson et al., Lancet 357: (2001), I. Stephenson et al., Vaccine 21: (2003) - From: I. Stephenson et al., Lancet Inf. Dis. 4: (2004) Hemagglutination inhibition H5N3 Single radial haemolysis H5N3 Single radial haemolysis H5N1 Microneutralisation H5N3

20 Adjuvants and antigen presentation systems for viral vaccines tested in humans (1/2) Adjuvant Viral antigen Mineral salts Aluminium saltsFlu, numerous Alum + MPLHBsAg, HSV (gD) Emulsions MF 59Flu (split) HBV (rPreS2-S) HSV2 (rgB + rgD) HIV1 (gp 120) CMV (rgB) MF59 + MTP-PEFlu (split) HIV1

21 Adjuvants and antigen presentation systems for viral vaccines tested in humans (2/2) Emulsions (cont.) QS21HIV1 (gp120) Incomplete Freund (IFA)HIV1 (gp120 depleted) Montamide ISA51HIV1 (Tat toxoid) Bacterial products MPL (like)numerous Holotoxins (CT, PT, LT)Flu Immunoadjuvants Cytokinesnumerous Particulate formulations LiposomesFlu VirosomesFlu, HAV ISCOMSFlu, numerous

22 Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. JL Bresson et al., the Lancet 2006

23 Protective immunity Nature 308: , 1984

24 - Clinical response upon lethal challenge in mice - H7N7 vaccine E.De Wit et al., J.Virol. 2005

25 Influenza virus A/HK/156/97 (H5N1) in chickens

26 Monkey #1 Day 4 p.i. Monkey #2 Day 4 p.i. Monkey #3 Day 7 p.i. Monkey #4 Day 7 p.i. Trachea Lung TBLN Spleen Heart Liver Kidney Cerebrum Cerebellum Plasma Neg. control Pos. control Detection of influenza virus RNA by RT-PCR in organs of macaques infected with A/HK/156/97 (H5N1) Rimmelzwaan et al., J.Virol Kuiken et al., J.Vet Pathol 2003

27 Influenza A virus (H5N1) pathogenic for cats (Kuiken et al., Science,2004)

28 Results: histo and IHC Rimmelzwaan et al., Am.J.Pathol. 2006

29 Vectors For Viral Antigen Delivery Retroviruses Poxviruses Adenoviruses Adeno-associated viruses Herpesviruses Alphaviruses VLP’s (HPV, rotavirus, parvovirus, HBV….) Bacterial vectors Plasmid DNA DC’s and exosomes

30 Vectors For Viral Antigen Delivery Retroviruses Poxviruses Adenoviruses Adeno-associated viruses Herpesviruses Alphaviruses VLP’s (HPV, rotavirus, parvovirus, HBV….) Bacterial vectors Plasmid DNA DC’s and exosomes NB: LAIV !!

31 Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice MA Hoelscher et al., the Lancet 2006

32 HK/97 VN/04 IND/05 MVA-HA vaccines in a H5N1 mouse model Kreijtz et al., JID in press

33 Conclusions: Improvements in pandemic flu vaccine development Short-term improvements: - Strain selection - Seed strain production - Manufacturing (cell substrates) - Approved adjuvants: safety and efficacy in humans!!! Longer term: - “New” targets; NA, M2, internal proteins - Cross-protection between subtypes (cellular immunity?) - New vaccine candidates (DNA, vectors, VLPs, etc.) - New adjuvants - Genetic manipulation of virus (increase yields) - Genetic manipulation of cell substrate

34 Conclusions: Improvements in pandemic flu vaccine development Short-term improvements: - Strain selection - Seed strain production - Manufacturing (cell substrates) - Approved adjuvants: safety and efficacy in humans!!! Longer term: - “New” targets; NA, M2, internal proteins - Cross-protection between subtypes (cellular immunity?) - New vaccine candidates (DNA, vectors, VLPs, etc.) - New adjuvants - Genetic manipulation of virus (increase yields) - Genetic manipulation of cell substrate

35 Dept. Virology National Influenza Centre Erasmus MC Rotterdam Ron Fouchier Theo Bestebroer Vincent Munster Ruud van Beek Chantal Baas Judith Guldemeester Martin Schutten Bert Niesters Hester van Bolhuis Thijs Kuiken Guus Rimmelzwaan Jan de Jong Ab Osterhaus Lab. Inf. Dis. Screening National Influenza Centre Inst. Public Health and Environment, Bilthoven Marion Koopmans Berry Wilbrink Adam Meijer Hans van der Nat Marina Conyn Arnold Bosman Paul Ehrlich Institute Langen, BRD Gerd Sutter Dept. Avian Virology ID-DLO, Lelystad Guus Koch Arie Kant Acknowledgements Jeroen Bosch Hospital, Den Bosch Peter Schneeberger Frans Rozendaal Jan Boekman Stiena Kemink

36 Emerging virus infections Department of Virology Acknowledgements: Vincent Munster Emmie de Wit Debby van Riel Theo Bestebroer Ger van der Water Brigitte van Uden Geert van Amerongen Robert Dias d’Ullois Martin Schutten Jan de Jong Guus Rimmelzwaan Thijs Kuiken Ron Fouchier


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