Novel Flu Vaccines Lots of choices

Size: px

Start display at page:

Download "Novel Flu Vaccines Lots of choices"

Katherine Mercy Randall
5 years ago
Views:

1 Novel Flu Vaccines Lots of choices Universal M2 ectodomain (A types, only) Universal HA cleavage site (A and B types) HA made by rdna methods (not eggs or mammalian cells) Vectored delivery of HA genes T cell vaccines to conserved internal proteins Engineered influenza viruses (NS1)

2 HA Based Vaccines Protein Sciences: HA in insect cells (baculo) Novavax: HA NA M1 VLPs in insect cells VaxInnate: HA globular head fused to flagellin Vical: Formulated plasmid DNA AlphaVax: HA expressed in alphavirus vector Hawaii Biotech: insect cell VLPs Frauenhofer & Medicago: VLPs in tobacco leaves Monoclonal antibody based vaccines

3 Live virus approaches Green Hills: Live attenuated NS1 mods Vivaldi: Live attenuated NS1 mutants BioDiem: Leningrad 57 Live attenuated Medimmune AZ: Flumist (NIAID) Vaxin: Adenovirus vector, nasal delivery Vaxart: Adenovirus vector capsule delivery of antigen and TLR3 dsrna

4 M2e Vaccines Merck (M2e plus cleavage site) OMPC, alum, Iscomatrix (QS21) Acambis (M2e x3 on HBcAg, alum, QS21) Dynavax (M2e x8 fused to NSP+CpG) VaxInnate (M2e x4 fused to flagellin)

5 M2e The ectodomain of M2 presented as a homotetramer ion channel. Note that no true 3D structure has been determined for M2e

6 Spectrum of M2e Sequences 3 of the recent HIN1 isolates: TEVETPTRSEWECRCSDSSDP TEVETPTRSEWECRCSDSSDP TEVETPTRSEWECRCSDSSDP H1/H2/H3 consensus SLLTEVETPIRNEWGSRSNDSSDP A/New Caledonia/20/99 H1N1 human SLLTEVETPIRNEWGCRCNDSSDP A/Aichi/470/68 H3N1 human SLLTEVETPIRNEWGCRCNDSSDP A/Ann Arbor/6/60 H2N2 human SLLTEVETPIRNEWGCRCNDSSDP A/Berkeley/1/68 H2N2 human SLLTEVETPIRNEWGCRCNDSSDP A/Puerto Rico/8/34 H1N1 human SLLTEVETPIRNEWGCRCNGSSDP A/Wisconsin/3523/88 H1N1 human SLLTEVETPIRNEWGCKCNDSSDP A/Hebei/19/95 H3N2 human SLLTEVETPIRNEWECRCNGSSDP A/Swine/2009 H1N1 human SLLTEVETPTRSEWECRCSDSSDP H5 consensus SLLTEVETPTRNEWESRSSDSSDP A/Viet Nam/1203/2004 H5N1 human SLLTEVETPTRNEWECRCSDSSDP A/Chicken/Nakorn- Patom/Thailand H5N1 avian SLLTEVETPTRNEWECRCSDSSDP A/Thailand/1(KAN-1)/04 H5N1 avian SLLTEVETPTRNEWECRCSDSSDP A/Duck/1525/81 H5N1 avian SLLTEVETPTRNGWECKCSDSSDP A/Hong Kong/156/97 H5N1 human SLLTEVETLTRNGWGCRCSDSSDP A/Chicken/New York/95 H7N2 avian SLLTEVETPTRNGWECKCSDSSDP A/Chicken/Hong Kong/G9/97 H9N2 avian SLLTEVETPTRNGWGCRCSGSSDP A/Hong Kong/1073/99 H9N2 human SLLTEVETLTRNGWECKCRDSSDP

7 Acambis HBcAg Three copies in tandem presented on HepB core antigen

8 TLR2, OMPC, Merck M2e peptides chemically conjugated to outer membrane complex from N. meningitidis

9 TLR5, flagellin, VaxInnate Four copies of the M2e sequence fused to the sequence of flagellin

10 TLR9, CpG Eight copies of the M2e sequence fused to the NP protein and conjugated to CpG containing oligonucleotide

11 Bacteriophage Q, Cytos M2e sequence displayed on the phage Qβ

Innate Immune Responses are Mediated by Toll like Receptors Expressed on the Surface of Immune Cells Toll Like Receptors Recognize Pathogen

12 Innate Immune Responses are Mediated by Toll like Receptors Expressed on the Surface of Immune Cells Toll Like Receptors Recognize Pathogen Associated Patterns (PAMPs) 12 VaxInnate s current influenza vaccines incorporate flagellin, a TLR5 ligand, and only well studied protein agonist

13 PAMP TLR Endoplasmic Reticulum IL 12 T H 1 Endocytic PRR CD80/86 CD28 Pathogen Phagosome MHC I or II TCR T Cell Dendritic Cell Nucleus T H 2

Influenza Vaccines Importance of Fusion to Flagellin Conventional Adjuvants Ag specific immune response Excessive inflammatory response Non specific immune response Autoimmune response Ag specific

14 Influenza Vaccines Importance of Fusion to Flagellin Conventional Adjuvants Ag specific immune response Excessive inflammatory response Non specific immune response Autoimmune response Ag specific immune response Minimal inflammatory response VaxInnate s vaccines = antigen 14 Genetic Fusions of the Vaccine Antigen and TLR Ligand Efficiently Stimulate both the Innate and Adaptive Immune Systems and Mimic Natural Infection.

15 VAX102: Low Dose & Alternative Routes Longitudinal anti M2e Responses for Doses Spanning 0.03 to 10 mg ug 0.3 ug Anti-M2e Geometric Mean Titers ug/ml anti-m2e IgG ug 1ug 0.1 ug (IM) 0.1 ug (ID) 0.03 ug (IM) 0.03 ug (ID) 0.50 cutoff 0.00 Dy 0 Dy 7 Dy 14 Dy 28 Dy 35 Dy 42 Dy 60 Dy 120 Dy 180 Low doses of VAX102 delivered on days 0 and 28 elicit robust anti M2e titers that remain above the positive cutoff for 6 months 15 Note good prime and especially the boost after the day 28 dose. Boost is not affected by flagellin antibody raised by the prime

16 Other Conserved Antigens Stalk cleavage site Stalk straight alpha helix Headless stalk Matrix, NP as T cell targets

17 Influenza Vaccine HA Subunit Vaccine Design HA Globular Head Flagellin HA Trimer HA Monomer Fusion of HA globular head (HA1 2) and S. typhimurium flagellin type 2 (STF2) [a TLR5 ligand] to form STF2.HA1 2 VaxInnate's HA subunit vaccines can be produced in E.coli 17

18 HA Cleavage Site, Merck Re drawn from Bianchi, et al., ref 26

19 Peter Palese, Adolfo Garcia Sastre, Mount Sinai

20 Broadly Neutralizing Monoclonals , Crucell and NIH broadly neutralizing antibodies (both the same germline sequence) binding to stalk (fusion intermediate) Bommakanti, et al (Nehru Crucell Merck) antigen designed from MAb binding site 2011, Corti et al., stalk binding monoclonal FI6 Eikert, et al, Group 2 stalk binding monoclonal

21 Corti, et al, Science, 2011

22 How do you turn a MAb into a vaccine? Passive protection, 4 10 mgs/kg reported At catalog price for Synagis (RSV antibody, premature infants) one dose for a 100 kg vaccine developer is $20,000 Use MAb binding site as target antigen Will require full clinical development program since no correlate of protection exists for the target (such as HAI)

23 Bommakanti et al

24 What Matters in a Pandemic? TIME! Time to make seed stock Time to build biomass Time to produce antigen Time to harvest purify (doses per unit time) Time to test for release of bulk Time to package and release Time to ship

25 What Matters? Time to last dose to cover intended population Time to first dose is false comfort Swimming pool analogy (how long to fill?) Garden hose Fire hose It s all about throughput and getting out of eggs, the biological bottleneck!

27 Virus Like Particles, Tobacco Landry et al. Medicago

29 Virus Like Particles made in insect cells

31 Vectored Gene Delivery Vaxin, replication deficient adenovirus vectors expressing HA, delivered intranasally Vaxart, replication deficient adenovirus vectors expressing HA plus dsrna (TLR3), delivered via oral capsule MVA expressing conserved conserved antigens Inovio, electroporation of plasmid DNA Vical, injection of formulated DNA

32 Engineered Influenza Viruses (Palese Lab, Mt Sinai) Nine segment virus (two different HA genes) Reassortment incompetent viruses NS1 modifications (Palese, AVIR Green Hills) NS1 encodes an inhibitor of poly adenylated RNA Also encodes a viral rnp export protein Interferes with interferon response of infected cell

Influenza Vaccine HA Subunit Vaccine Design

typhimurium flagellin type 2 (STF2) [a TLR5

33 Influenza Vaccine HA Subunit Vaccine Design HA Globular Head Flagellin HA Trimer HA Monomer Fusion of HA globular head (HA1 2) and S. typhimurium flagellin type 2 (STF2) [a TLR5 ligand] to form STF2.HA1 2 VaxInnate's HA subunit vaccines can be produced in E.coli 33

34 Seasonal Vaccines VAX125 Immunogenicity in Man Phase I Clinical Evaluation Prototype (one component) seasonal influenza vaccine, VAX125: Dose response of antibody formulation in adults years of age Antibody Titer Day Placebo Dose (ug) 34 Immunogenicity for doses of 1 µg or above is excellent in healthy adults (18 45 years old)

35 Whole Virion and Adjuvanted Split Virus Immune Response Immune response to single dose whole virion (WV, Baxter, 7.5 ug) and ASO3 adjuvanted split virus (ASO3, GSK, 3.75 ug) H1N1 CA7/2009 vaccine in different age groups Whole virion ASO3 adjuvanted n=70 n=68 n=34 n=70 n=68 n=37 GMT day GMT day MFR SP % SC % from Nicholson et al. Lancet Infectious Diseases 2010 Adjuvanted vaccine is more immunogenic, but performance in the elderly is modest 35

36 VAX 125 HAI Response in the Elderly Peak GM HAI response 14 days after VAX125 among subjects 65 years old (left panel). GM HAI titers measured from day 0 to 28 after a single dose of VAX125 ranging from 0.5 to 8 µg among subjects 65 years old (right panel) HAI Titers (GMT+95%CI) Dose (ug) HAI titer (SI) Day Elderly adults respond to higher vaccine doses 36

2x = C (2 Antigens Fused to Flagellin) Alternative vaccine formats, which differ in the point of

37 HA Subunit Vaccines Development of Alternative Vaccine Formats D0 D0 D0 D1 D3 D2 D1 D2 D2 D1 C Term = A (Antigen Attached to C terminus) R3 = B (Antigen Replaces D3 Domain) R3.2x = C (2 Antigens Fused to Flagellin) Alternative vaccine formats, which differ in the point of antigen attachment to flagellin were developed, initially, to improve the potency of poorly immunogenic H5 HA vaccines 37

38 VAX HAI Response Serum HAI response for VAX128C in VAX VAX128C dose (µg) 1.25 (n=47) 2.5 (n=50) Total (n=97) GMT 95% C.I. GMT 95% C.I. GMT 95% C.I. GMT Day GMT Day Mean fold resp % % % Seroconversion Seroprotection

39 VAX 128C GMT HAI, SC & SP HAI titers, Seroconversion (SC) and Seroprotection (SP) rates after a single IM dose of VAX128C (CA07) Age group Total Dose (µg) n= GMT HAI day GMT HAI day Mean fold response Seroconversion % Seroprotection %

40 VaxInnate s E. Coli Based Manufacturing High Efficiency & Large Capacity Manufacturing Influenza Vaccine for the US Substrate Cost of Recently Built Facilities (without validation) Time to build and Validate New Facility Annual Capacity (TIV) Eggs $150 million > 3 years 100 million Cell Culture $680 million > 3 years 50 Million Baculovirus $40 million > 2 years 100 Million E. coli/vaxinnate $0 (CMO) 0 years million* *VaxInnate's capacity is based on performing a single 1,000 liter run for each antigen included in the vaccine. Yields differ by antigen and construct. 40

41 What s Next? New vaccines will face long and expensive development programs (efficacy based) HA based vaccines have advantage of correlate of protection (HAI) Current low incidence of flu (infant vax?) makes trial size much larger US universal recommendation makes placebo trial impossible, go somewhere else? Major focus on better vaccine for elderly

Clinical Trials of Pandemic Vaccines: Key Issues. John Treanor University of Rochester Rochester, NY

Clinical Trials of Pandemic Vaccines: Key Issues John Treanor University of Rochester Rochester, NY Inactivated vaccine approach Proven technology Used successfully in 1957 and 1968 Abundant efficacy data