1. FDA/CBER Vaccines and Related biological Products Advisory Committee Meeting Discussion of Clinical Trials to Support use of Vaccines against the 2009 H1N1 Influenza Virus Overview of Clinical Studies by NIAID/NIH July 23, 2009 Linda C. Lambert, Ph.D. Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Discussion of Clinical Trials to Support use of Vaccines against the 2009 H1N1 Influenza Virus Overview of Clinical Studies by NIAID/NIH July 23, 2009 Linda C. Lambert, Ph.D. Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health

2. Outline NIAID H1N1 vaccine trials Initial 5 protocols Clinical infrastructure TIV study in pregnant women NIAID H1N1 vaccine trials Initial 5 protocols Clinical infrastructure TIV study in pregnant women

3. H1N1 Outbreak: Initial Response FDA, NIAID, BARDA initiated regular discussions on vaccine-related issues FDA - licensure discussions with companies BARDA - US H1N1 vaccine supply US stockpile clinical trial material NIAID - identify options for USG clinical trial support; assess trial capacity FDA, NIAID, BARDA initiated regular discussions on vaccine-related issues FDA - licensure discussions with companies BARDA - US H1N1 vaccine supply US stockpile clinical trial material NIAID - identify options for USG clinical trial support; assess trial capacity

4. Areas identified for possible NIAID trial support Licensure or EUA Special populations young infants, pregnant women, immunocompromised Help inform policy, “gap” areas accelerate availability of 1 vs. 2 dose data in different populations administration with seasonal influenza vaccine different dosing intervals use of different adjuvanted products mixing stockpiled vaccines and adjuvant Licensure or EUA Special populations young infants, pregnant women, immunocompromised Help inform policy, “gap” areas accelerate availability of 1 vs. 2 dose data in different populations administration with seasonal influenza vaccine different dosing intervals use of different adjuvanted products mixing stockpiled vaccines and adjuvant

5. NIAID H1N1 Vaccine Trials: Initial Studies 5 separate protocols Data not intended to support licensure Complimentary to company planned trials 1 vs. 2 doses of unadjuvanted CSL vaccine in healthy adults 1 vs. 2 doses of unadjuvaned SP vaccine in healthy adults 1 vs. 2 doses of unaduvanted SP vaccine in healthy children co- vs. sequential administration of TIV and H1N1 vaccine in adults co- vs. sequential administration of TIV and H1N1 vaccine in children 5 separate protocols Data not intended to support licensure Complimentary to company planned trials 1 vs. 2 doses of unadjuvanted CSL vaccine in healthy adults 1 vs. 2 doses of unadjuvaned SP vaccine in healthy adults 1 vs. 2 doses of unaduvanted SP vaccine in healthy children co- vs. sequential administration of TIV and H1N1 vaccine in adults co- vs. sequential administration of TIV and H1N1 vaccine in children v

6. NIAID H1N1 Response: Clinical Trial Infrastructure Vaccine and Treatment Evaluation Units (VTEUs) 1962 - consortium of individual contracts ready resource for the conduct of clinical research 2008 - 8 contracts academic centers and other organizations subcontracts Broad range of capabilities phase I, II, III, and IV trials bacterial, viral, parasitic vaccines novel delivery systems, compare formulations/dosing schedules therapeutics, immunotherapeutics targeted surveillance, burden of disease studies Access to different populations healthy adults and elderly, pediatric populations special populations (e.g. immunocompromised, pregnant women) Vaccine and Treatment Evaluation Units (VTEUs) 1962 - consortium of individual contracts ready resource for the conduct of clinical research 2008 - 8 contracts academic centers and other organizations subcontracts Broad range of capabilities phase I, II, III, and IV trials bacterial, viral, parasitic vaccines novel delivery systems, compare formulations/dosing schedules therapeutics, immunotherapeutics targeted surveillance, burden of disease studies Access to different populations healthy adults and elderly, pediatric populations special populations (e.g. immunocompromised, pregnant women)

7. Credit: AS Fauci

8. 1 vs. 2 Doses of H1N1 Vaccine in Healthy Populations 3 protocols Goal: rapid availability of immunogenicity data 2 doses,15µg or 30µg, 21 days apart SP and CSL vaccine adult trials (n = 400 each protocol) 100 adults (18-64y), 100 elderly (65y+); per dose group SP vaccine pediatric trial (N = 600) children (6mo to < 36mo, 3y to 9y, 10y to 17y) 100 per dose group in each age stratum endpoints: safety and immunogenicity SAEs, AEs - 6 months post dose 2 4-fold rises, proportion with titer ≥ 1:40 by HAI at day 21, 42 early immunogenicity data points - post each dose additional blood draws: 8 to 10 days subset of vaccinated subjects Lead PIs: Pat Winokur, UIowa; Karen Kotloff, UMD 3 protocols Goal: rapid availability of immunogenicity data 2 doses,15µg or 30µg, 21 days apart SP and CSL vaccine adult trials (n = 400 each protocol) 100 adults (18-64y), 100 elderly (65y+); per dose group SP vaccine pediatric trial (N = 600) children (6mo to < 36mo, 3y to 9y, 10y to 17y) 100 per dose group in each age stratum endpoints: safety and immunogenicity SAEs, AEs - 6 months post dose 2 4-fold rises, proportion with titer ≥ 1:40 by HAI at day 21, 42 early immunogenicity data points - post each dose additional blood draws: 8 to 10 days subset of vaccinated subjects Lead PIs: Pat Winokur, UIowa; Karen Kotloff, UMD v

9. Co- or Sequential Administration of H1N1 and ‘09-’10 TIV 2 protocols: safety and immunogenicity of co- and sequential administration of inactivated H1N1 vaccine and TIV H1N1 vaccine before, after, or at the same time as TIV 2 doses,15 µg sanofi pasteur H1N1 vaccine, 21 days apart 1 dose TIV 400 adults (18-64y), 400 elderly (65y+) 600 primed children (50 per group) 6mo to < 36mo, 3y to 9y, 10y to 18y unprimed children - finalizing protocol endpoints: safety and immunogenicity SAEs, AEs - 6 months post dose 2 4-fold rises, proportion with titer ≥ 1:40 by HAI Lead PI: Sharon Frey, St. Louis VTEU 2 protocols: safety and immunogenicity of co- and sequential administration of inactivated H1N1 vaccine and TIV H1N1 vaccine before, after, or at the same time as TIV 2 doses,15 µg sanofi pasteur H1N1 vaccine, 21 days apart 1 dose TIV 400 adults (18-64y), 400 elderly (65y+) 600 primed children (50 per group) 6mo to < 36mo, 3y to 9y, 10y to 18y unprimed children - finalizing protocol endpoints: safety and immunogenicity SAEs, AEs - 6 months post dose 2 4-fold rises, proportion with titer ≥ 1:40 by HAI Lead PI: Sharon Frey, St. Louis VTEU

10. Mixing and Matching Vaccines, Adjuvants HHS 2009 H1N1 vaccine strategy Assess safety and immunogenicity mixing stockpiled vaccine antigen and adjuvants from different manufacturers vaccines: CSL and sanofi pasteur H1N1 vaccine adjuvant: GSK’s AS03 mixed prior to administration protocol: 3.75µg +AS03, 7.5ug and 15µg +/- AS03 2 doses, 21 days apart status: submit IND for sanofi pasteur/AS03 study within a week; CSL/AS03 study to follow Lead PIs: Lisa Jackson (Seattle Group Health) and Kathryn Edwards (Vanderbilt) HHS 2009 H1N1 vaccine strategy Assess safety and immunogenicity mixing stockpiled vaccine antigen and adjuvants from different manufacturers vaccines: CSL and sanofi pasteur H1N1 vaccine adjuvant: GSK’s AS03 mixed prior to administration protocol: 3.75µg +AS03, 7.5ug and 15µg +/- AS03 2 doses, 21 days apart status: submit IND for sanofi pasteur/AS03 study within a week; CSL/AS03 study to follow Lead PIs: Lisa Jackson (Seattle Group Health) and Kathryn Edwards (Vanderbilt)

11. Other studies Additional H1N1 vaccine studies Protocols in development pregnant women Safety and immunogenicity of TIV in pregnant women trial initiated June 11, 2009 in VTEUs and subcontract sites 2 nd and 3 rd trimester women single dose 2008-2009 TIV ( Fluzone, Fluarix) antibody responses: HAI 41 women enrolled as of July 22 nd, 2009 PI: Shitel Patel, Baylor Fall 2009 planned follow on study with 2009-2010 TIV 4 licensed US manufacturers of inactivated vaccine Additional H1N1 vaccine studies Protocols in development pregnant women Safety and immunogenicity of TIV in pregnant women trial initiated June 11, 2009 in VTEUs and subcontract sites 2 nd and 3 rd trimester women single dose 2008-2009 TIV ( Fluzone, Fluarix) antibody responses: HAI 41 women enrolled as of July 22 nd, 2009 PI: Shitel Patel, Baylor Fall 2009 planned follow on study with 2009-2010 TIV 4 licensed US manufacturers of inactivated vaccine

12. ACKNOWLEDGEMENTS DHHS H1N1 vaccines for NIH trials under BARDA contract FDA CDC Manufacturers VTEU investigators EMMES Corporation SRI Birmingham Fisher Bioservices PPD Independent Safety Committee members NIAID and DMID colleagues DHHS H1N1 vaccines for NIH trials under BARDA contract FDA CDC Manufacturers VTEU investigators EMMES Corporation SRI Birmingham Fisher Bioservices PPD Independent Safety Committee members NIAID and DMID colleagues