Elsevier

Vaccine

Volume 26, Issue 50, 25 November 2008, Pages 6383-6391
Vaccine

Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children

https://doi.org/10.1016/j.vaccine.2008.08.046Get rights and content

Abstract

Objective

Highly pathogenic avian influenza A virus (H5N1) is a leading candidate for the next influenza pandemic, and infants and children may play an important role in transmission in a pandemic. Our objective 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.

Methods

Healthy infants and children (N = 150) received two doses of 30 μg or 45 μg H5 HA with AlPO4 adjuvant 21 days apart. Serum samples were collected for virus microneutralisation (MN) and haemagglutination inhibition (HI) assays on Days 0, 21, and 42. Six-month antibody persistence following second vaccine dose was assessed by MN, and cross-reactive HI antibodies to a clade 2 variant strain (INDO5/RG2) were evaluated at Day 42.

Findings

Both formulations were well-tolerated. Two doses of 30 μg or 45 μg H5 HA formulations elicited strong immune responses by both MN (98–99% ≥1:20) and HI assays (95–100% ≥1:32), with 80–87% of children having MN antibody persistence (≥1:20) up to 6 months post-vaccination. Additionally, robust cross-clade HI antibody responses were elicited following two doses.

Interpretation

Two doses of prototype 30 μg or 45 μg aluminium-adjuvanted, H5N1 vaccines were highly immunogenic and well-tolerated, with considerable antibody persistence 6 months after the primary vaccination course. Additional cross-clade HI antibody responses and an acceptable safety and tolerability profile support the use of the either candidate vaccine formulations in infants and children in the event of a pandemic [ClinicalTrials.gov identifiers: NCT00370864].

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.

Section snippets

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.

References (38)

  • T. Jefferson et al.

    Adverse events after immunisation with aluminium-containing DTP vaccines: systematic review of the evidence

    Lancet Infect Dis

    (2004)
  • I. Leroux-Roels et al.

    Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial

    Lancet

    (2007)
  • World Health Organisation

    Update: WHO-confirmed human cases of avian influenza A (H5N1) infection, 25 November 2003–24 November 2006

    Wkly Epidemiol Rec

    (2007)
  • B. Schwartz et al.

    Vaccination strategies for an influenza pandemic

    J Infect Dis

    (2005)
  • J.S. Horvath et al.

    The Australian response: pandemic influenza preparedness

    Med J Aust

    (2006)
  • H.M.E. Sahly et al.

    Pandemic H5N1 influenza vaccine development: an update

    Expert Rev Vaccines

    (2008)
  • F. Beard et al.

    Influenza related hospitalisations in Sydney, New South Wales, Australia

    Arch Dis Child

    (2006)
  • R.J. Whitley et al.

    Prevention and treatment of influenza in high-risk groups: children, pregnant women, immunocompromised hosts, and nursing home residents

    J Infect Dis

    (2006)
  • N. Smith et al.

    Prevention and control of influenza. Recommendations of the advisory committee on immunization practices (ACIP)

    MMWR

    (2006)
  • Cited by (81)

    View all citing articles on Scopus
    View full text