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