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

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,

Evaluation of H5 vaccines: Objectives

• Determine dose-related safety and immunogenicity

• Gain experience with the logistical issues involved in producing a pandemic vaccine

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

04-063 Demographics (N=451)

Characteristic N %

White 357 79.2

Black 37 8.2

Pacific Islander 1 0.2

Asian 48 10.6

Am Ind/Alaskan 1 0.2

Multi 7 1.6

Female 242 53.6

Age (mean) 40.0

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

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

H5N1 Vaccine TrialsDosage 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

• 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 0.1mLIntramuscular - 15µg or 45µg in 0.5mL

DOSAGE SPARINGIntradermal Immunization

Patel S, et. al., study in progress at BCM.

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.

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

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

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

Dose SparingInclusion 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 +

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