1. National Vaccine Advisory Committee November 29, 2005 Update on NIH H5N1 Vaccine Trials Linda C. Lambert Chief, Respiratory Diseases Branch Division of Microbiology and Infectious Diseases NIAID/NIH/DHHS

2. H5 inactivated vaccine candidate rg A/Vietnam/1203/04 (H5N1) –Basic amino acid sequence at cleavage site replaced by sequence of apathogenic avian virus (St. Jude’s CRH) Egg-grown subunit vaccines without adjuvant, using current production Formulated at 90 mcg and 30 mcg per mL,

3. Evaluation of H5 vaccines: Objectives Determine dose-related safety and immunogenicity Gain experience with the logistical issues involved in producing a pandemic vaccine

4. Initial evaluation of H5: DMID 04-063 Product produced by Sanofi Pasteur for NIH Subjects: Healthy adults ages 18 to 64 Design: Prospective, randomized, double blind Interventions: Two IM doses H5 vaccine separated by 28 days –Placebo, 7.5 mcg, 15 mcg, 45 mcg, 90 mcg –1:2:2:2:2 randomization Endpoints –Safety: solicited and unsolicited AEs –Immunogenicity: neutralizing titer of 1:40

5. 04-063 Demographics (N=451) CharacteristicN% White35779.2 Black378.2 Pacific Islander10.2 Asian4810.6 Am Ind/Alaskan10.2 Multi71.6 Female24253.6 Age (mean)40.0

6. 04-063 Assessment of immune response Sera collected on day 0 (pre dose 1), 28 (pre dose 2), 56 (28 days post dose 2), 180. Microneutralization (MN) against vaccine seed virus in MDCK cells Hemagglutination-inhibition (HAI) against vaccine seed virus using horse erythrocytes Also tested for H3-specific antibody Results available for stage I only

7. DMID 04-063: Summary Vaccine was well tolerated at all doses Dose related local pain and tenderness Some neutralizing responses seen at all doses Best responses seen at two highest doses HAI test using horse erythrocytes correlates well with neutralizing response

8. H5N1 Vaccine Trials Dosage Sparing Approaches 1. Type of Vaccine - Whole virus vs. subunit >Baxter - Live vs. inactivated >LID/NIAID: Kanta Subbarao 2. Intradermal route 3. Inclusion of an adjuvant

9. Design: Phase I, randomized trial; subjects & investigators blinded to dosage level but not to route Population: Healthy 18-49 years old Vaccine: Inactivated rg A/Vietnam (H5N1) Two formulations: 30µg and 90µg/mL Study Groups (N=25/group): Intradermal - 3µg or 9µg in 0.1mL Intramuscular - 15µg or 45µg in 0.5mL DOSAGE SPARING Intradermal Immunization Patel S, et. al., study in progress at BCM.

10. STUDY PROCEDURES Vaccination on Day 0 and Day 28 Reactogenicity Assessments –Clinic visits Days 1, 2, and 7 after each vaccine dose; symptoms/signs recorded daily for 7 days; 6-month SAE follow-up Immunogenicity Assessments –Serum HAI and neutralizing antibody levels to be assayed on samples collected before dose 1, 1 month after each dose, and 6 months after dose 2.

11. PRIMARY ENDPOINTS Adverse events (AE) or serious adverse events (SAE) solicited in-clinic and via memory aids and periodic targeted physical assessments Proportion of subjects in each vaccine group achieving a serum neutralizing antibody titer of 1:40 against the influenza A/H5N1 virus on Day 56

12. REACTOGENICITY IM Groups – Occasional erythema observed; usually resolved in 1-2 days ID Groups – Erythema and induration lasting 3-5 days; occasional faint pigmentation at injection site No severe vaccine- associated adverse events

13. PROGRESS TO DATE All 100 subjects completed the 56 day follow up HAI and Neut immunoassays; results in December Follow-up visit scheduled for day 206

14. Dose Sparing Inclusion of Adjuvants HHS and NIH are supporting several manufacturers to produce adjuvanted H5N1 vaccines for clinical testing by the NIH Trials will assess safety and whether adjuvants improve the immunogenicity of influenza vaccines Aluminum hydroxide adjuvanted H5N1 vaccines: Sanofi Pasteur (under HHS contract); Q12006 Chiron (also MF59); Q12006 Baxter (cell based/whole virus); Q22006 IDBiomedical (GSK) NIH grant (cell based); 1 year +

15. NIH Vaccine Evaluation Units Baylor College of Medicine Cincinnati Children’s Hospital St. Louis University UCLA Harborview Medical Center University of Maryland University of Rochester Vanderbilt University