H5N1 and H7 LAIV-IAV Prime-Boost Studies

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1 NIAID H5N1 and H7 LAIV-IAV Prime-Boost Studies Kanta Subbarao, MD, MPH NIAID, NIH

2 The LID Pandemic Influenza Vaccine Program Program: CRADA with MedImmune Clinical Trials: Center for Immunization Research, JHSPH University of Rochester Approach: Live attenuated cold-adapted vaccines Evaluation: Inpatient setting

3 Replication of H5 and H7 plaiv in healthy adults Vaccine Dose (log 10 TCID 50 ) First dose N % culture + % RT- PCR + H5N1 VN 04 ca H5N1 VN 04 ca H5N1 HK 03 ca * H7N3 BC 04 ca * H7N3 BC 04 ca * H7N7 NL 03 ca >70% were positive on Day 1 only. Karron et al. JID (2009) 199:711; Talaat et al. Vaccine (2009) 27:3744; Treanor et al. Unpublished.

4 Antibody responses to H5 and H7 plaiv Vaccine H5N1 VN 04 ca H5N1 VN 04 ca H5N1 HK 03 ca Dose (log 10 TCID 50 ) # doses % vaccinees with 4-fold rise in serum antibody response indicated by HI NtAb IgG ELISA IgA ELISA Any assay H7N3 BC 04 ca H7N3 BC 04 ca H7N7 NL 03 ca Karron et al. JID (2009) 199:711; Talaat et al. Vaccine (2009) 27:3744; Treanor et al. Unpublished.

5 Rationale for prime-boost studies Recombinant expressed HA, DNA encoding HA and inactivated vaccine prime for a robust HAI and neutralizing response to an inactivated subunit H5N1 vaccine Robust serum H5 antibody responses were observed following the booster vaccination even in individuals who had no detectable antibody response following the initial vaccination. Treanor et al Vaccine 2001; Goji et al JID 2008, Ledgerwood et al Lancet ID 2011, Nicholson et al Lancet 2001; Stephenson et al Vaccine 2003

6 Hypothesis Prior receipt of plaiv will prime for a higher Ab titer and greater frequency of seroconversion to an inactivated pandemic influenza vaccine Primed with matched or unmatched plaiv Boosted with suboptimal dose of inactivated subvirion H5N1 VN04 or H7N7 vaccines (sanofi)

7 plaiv-inactivated vaccine prime-boost studies: General Design Recall subjects who were previously vaccinated with H5 or H7 plaiv. Administer a single dose of inactivated vaccine (IAV): H5N1: Monovalent A/VN/1203/2004 H5N1 (Sanofi), 45 μg. H7N7: Monovalent A/mallard/Netherlands/12/2000 (Sanofi), 45 μg. Assess safety and immunogenicity

8 The inactivated H7N7 vaccine is poorly immunogenic in healthy adults Vaccine dose No. (%) responding* by N HAI MN 7.5 μg X μg X (4) 45 μg X (8) 90 μg X (5) 2 (10) Placebo % subjects with 4-fold rise Couch et al. PLoS One 2012

9 Outcome measures Standard serologic assays: HAI Microneutralization Research assays: IgG, IgA ELISA (serum and nasal secretions) Quality of the Ab response: Mapping of antibody responses using GFPDL Surface plasmon resonance (SPR)-based real time kinetics assays Memory B cell responses Influenza virus-specific CD8+ and CD4+ responses

10 Study 1: H5N1 VN04 Prime Boost Study Group Previous plaiv* Doses of inactivated vaccine Interval between prime and boost N No. of SAEs 1 H5N1 VN μg X 1 56 mo H5N1 HK μg X 1 54 mo H7N3 BC μg X 1 52 mo None 45 μg X 1 NA None 45 μg X 2 1 mo 20 0 Inactivated vaccine: H5N1 VN04 subunit vaccine *plaivs on AA ca backbone

11 Study 2: H7N7 Prime-boost study Group Previous plaiv* Doses of inactivated vaccine Interval between prime and boost N # SAEs 1 H7N3 BC 04** 45 μg X 1 22 mo H7N7 NL μg X 1 19 mo 8 1*** 3 H2N3 MO μg X 1 18 mo None 45 μg X 1 NA 20 0 Inactivated vaccine: Netherlands H7N7 subunit vaccine *plaivs on AA ca backbone ** single dose of plaiv *** unrelated to vaccine

12 Summary Prior receipt of plaiv primes for Higher titer response to a suboptimal dose of inactivated subunit vaccine Increased frequency of response Rapid response (day 7) Greater breadth of reactivity against different clades of H5 viruses

13 Implications Clear evidence of a long lasting B cell memory response to plaiv. Priming with plaiv may allow use of a lower dose of IAV: dose sparing. The rapid response to injected inactivated antigen suggests that plaiv recipients may be protected from severe illness in the event of natural exposure. Explore number of plaiv doses needed, interval, strain specificity.

14 Acknowledgements NIAID, NIH: Catherine Luke Regulatory Compliance and Human Subjects Protection Branch Diane Post Center for Immunization Research, JHU, Baltimore, MD Kawsar Talaat Ruth Karron University of Rochester Medical Center John Treanor Diane O Brien MedImmune Hong Jin George Kemble Kathy Coelingh PATH Vaccine Solutions Kathy Neuzil Kristen Lewis BARDA Bob Huebner Armen Donabedian CBER Hana Golding Surender Khurana Galina Vodeiko Southern Research (SRI) Diana Noah