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
Jan 15, 2016
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