Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children
Introduction
The present epizootic of highly pathogenic H5N1 avian influenza, accompanied by rare but severe infections of humans [1], has raised concerns regarding emergence of a pandemic influenza strain. Vaccination is a critical public health strategy for definitive containment of such a virus [2]. Development and evaluation of candidate pandemic vaccines based on presently circulating H5 strains are, therefore, essential to preparedness [3].
We have previously described the dose–response profile of a candidate H5N1 vaccine in a phase I trial in healthy adults, with or without AlPO4 adjuvant [4], which demonstrated that AlPO4 adjuvanted vaccine augmented the seroresponse. This effect was also apparent with another split virion candidate vaccine using Al(OH)3 as adjuvant [5], although preliminary reports from more recent studies also evaluating Al(OH)3 as adjuvant in younger adults and in the elderly have not replicated this benefit [6]. Higher H5N1 antigen dose AlPO4 adjuvanted vaccines have been evaluated in adults [4], and concurrent immunogenicity and safety evaluation in paediatric subjects of these vaccines is a priority on a number of grounds.
Increased recognition of the high burden of disease borne by children during seasonal influenza outbreaks [7], [8] has led to broadening of recommendations for annual influenza vaccination in North America [9], [10]. In addition, the highest mortality rates observed during the 1918 influenza pandemic were in children less than 2 years of age [11], making protection of this highly susceptible population through immunisation a clear priority. The potential for additional indirect benefits of paediatric-targeted immunisation strategies is further recognised [12]. Vaccination of pre-school aged children in day-care protects other family members against influenza [13], with greater efficacy than immunisation of school children [14]. Models of seasonal and pandemic influenza have explored the impact of targeting interventions, such as vaccination, to children of pre-school and school age to limit transmission of infection [15], [16] and observed disease reductions in the wider community.
The purpose of this study was to evaluate the safety and immunogenicity of a prototype inactivated, aluminium adjuvanted, split-virus, clade 1 H5N1 vaccine (A/Vietnam/1194/2004/NIBRG-14) in infants and children aged ≥6 months to <9 years.
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Study design
The safety, tolerability and immunogenicity of a 30 μg or 45 μg formulation of a H5N1 vaccine with aluminium phosphate (AlPO4) adjuvant (Phase II trial, ClinicalTrials.gov identifier: NCT00370864) was assessed in a prospective, randomised double-blind, multicentre trial. The trial was conducted from September 2006 to July 2007 at: (i) the Murdoch Children’s Research Institute, and the Melbourne School of Population Health, at the University of Melbourne (MCRI; Victoria); and (ii) the Princess
Participant distribution and demographic data
A total of 150 children were enrolled and randomised to each treatment group (Fig. 1, Table 1). All enrolled children were included in the safety population, with the exception of one participant who received only the first dose, but was then lost to follow-up with no post-vaccination safety or immunogenicity data available. Over 93% (140/150) of children completed the primary vaccination course, and all but one of these children completed the Day 42 follow-up visit. Of the 11 children enrolled
Discussion
The results from this study demonstrate a vigorous immune response by HI and MN assays to two doses of a candidate H5N1 split virion aluminium phosphate adjuvanted vaccine in infants and children under the age of 9 years. Persistent neutralising antibody 6 months after the second dose of vaccine was also demonstrated at levels higher than observed following 2 doses of the same vaccine in adults, and substantially higher than seen in adults at the 6-month time point [4]. The immune responses
Acknowledgments
The authors would like to extend their thanks to the parents/guardians and children, investigators and personnel at each study site. Specifically, the authors would like to thank staff from the Vaccine and Immunisation Research Group in Melbourne (Dr. L. Thorn, Dr. K. Alexander, Dr. J. Davey, Dr. W.L. Fah, Dr. L. Horng, Dr. J. Luong, Dr. N. Rose, M. Kefford, J. Ryrie, J. Sonego, L. Baker, M. Boglis, P. Fennessy, E. Hill, S. Macnee, E. Nolan, K. O’Grady, C. Sandhu, D. Saunders, S. Simms, J.
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