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Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults.

ABSTRACT: Accelerated immunization schedules may help gain early control of influenza pandemics. We investigated different schedules of an AS03(A)-adjuvanted H5N1 vaccine.This phase II, open-label, 6-month study randomized participants (aged 18-64 years) to 2 vaccine doses administered 21 (standard schedule), 14, or 7 days apart, or on the same day. Coprimary end points were that the lower limit of the 98.75% confidence interval 14 days after the last dose must be (1) >40% for seroconversion rate (SCR) (Center for Biologics Evaluation and Research [CBER] criterion) and (2) >50% for seroprotection rate (SPR) (attainment rate for reciprocal hemagglutination inhibition titers ?40, protocol-defined criterion) for the vaccine homologous strain (A/Indonesia/5/2005). European Committee for Human Medicinal Products (CHMP) immunogenicity criteria were also evaluated.Coprimary end points were achieved (lower 98.75% confidence intervals exceeded defined values). Titers were highest with the standard schedule. Nevertheless, CBER SCR, protocol-defined SPR, and CHMP criteria were met with all schedules for the A/Indonesia/5/2005 strain. There were no significant differences between age groups (18-40 vs 41-64 years). Immune response was robust against drift variants A/turkey/Turkey/1/2005 and A/Vietnam/1194/2004.The AS03(A)-adjuvanted H5N1 vaccine in accelerated schedules offers a robust immune response against vaccine homologous and drift variant strains, allowing consideration of compressed vaccination intervals.NCT00695669.

SUBMITTER: Lasko B

PROVIDER: S-EPMC3144173 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults.

Lasko Benjamin B Reich Dennis D Madan Anuradha A Roman François F Li Ping P Vaughn David D

The Journal of infectious diseases 20110801 4

<h4>Background</h4>Accelerated immunization schedules may help gain early control of influenza pandemics. We investigated different schedules of an AS03(A)-adjuvanted H5N1 vaccine.<h4>Methods</h4>This phase II, open-label, 6-month study randomized participants (aged 18-64 years) to 2 vaccine doses administered 21 (standard schedule), 14, or 7 days apart, or on the same day. Coprimary end points were that the lower limit of the 98.75% confidence interval 14 days after the last dose must be (1) >4 ...[more]

PMID: 21791660

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Project description:BackgroundVaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.Objective and methodsWe compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.ResultsBoth vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.ConclusionsUsing this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.Trial registrationClinicalTrials.gov NCT01573312.

Dataset Information

Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults.

Publications

Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults.

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