Elsevier

Vaccine

Volume 28, Issue 38, 31 August 2010, Pages 6221-6227
Vaccine

Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: A phase I–II randomized trial

https://doi.org/10.1016/j.vaccine.2010.07.008Get rights and content

Abstract

Objective

Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children.

Methods

An open-labelled phase I trial was conducted in children aged 3–11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5–30 μg) and in children aged 12–17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5–15 μg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3–11 years received the split-virion vaccine (10 or 15 μg) and 280 children aged 12–17 years received the split-virion vaccine (10–30 μg) or the whole-virion vaccine (5 μg). Serum samples were collected for hemagglutination-inhibition (HI) assays.

Findings

5–15 μg adjuvated split-virion vaccines were well tolerated in children aged 3–11 years and 5–30 μg adjuvated split-virion vaccines and 5 μg adjuvated whole-virion vaccine were well tolerated in children aged 12–17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naïve to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3–11 years children, the 10 and 15 μg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer ≥1:40) rates. In 12–17 years children, the 30 μg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 μg whole-virion vaccine induced higher response than the 10 μg split-virion vaccine did.

Interpretation

The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in children and 30 μg dose induced immune response complying with European Union licensure criteria. [ClinicalTrials.gov identifiers: NCT00900588 and NCT00900991].

Introduction

In the last century, three human influenza pandemic outbreaks had caused tens of millions of deaths. A novel swine-origin influenza A/H1N1 virus emerged in North America had caused a pandemic influenza as declared by the World Health Organization on June 11, 2009 [1]. The concerns on the potential human influenza pandemic had been growing since 1997 when the highly pathogenic avian influenza A/H5N1 virus firstly showed its ability to infect human and cause high mortality in Hongkong, China [2]. As of March 16, 2010, there were 489 human cases of H5N1 infection, 289 of which were fatal, according to WHO release [3]. The high mortality caused by H5N1 infection makes the virus an awful potential murderer in case of the evolution of the virus into a strain capable of efficient person-to-person transmission.

Although the current influenza pandemic is unexpectedly caused by influenza A/H1N1 virus instead of H5N1 virus which had been regarding as the most potential virus to cause an influenza pandemic, the world is better prepared for the pandemic than ever. Over the last decade, much attention and investment had been drawn to the preparedness against potential influenza pandemic caused by H5N1 virus. The world are now benefiting from the investment to H5N1 virus as indicated by WHO. The effective vaccines against H5N1 virus were considered as the crucial preference to combat the potential influenza pandemic. In recent years, many prototype pandemic influenza A (H5N1) vaccines had been developed and clinically evaluated in adults [4], [5], [6], [7], [8], [9]. These trials showed that H5N1 vaccines tested so far were all tolerated in adults and that a 2-dose vaccination schedule was needed to elicit satisfactory immune response complying with licensure criteria. However, clinical evaluations of H5N1 vaccines in children are limited [10], [11], [12]. Children are expected to be one of the most vulnerable populations during an influenza pandemic. It was reported that the mortality rate in children in Thailand after infection with H5N1 virus was close to 90% [13]. Development of pediatric H5N1 vaccines would be critical. In addition, the clinical evaluations of whether spilt-virion or whole-virion vaccines should be used in children, as well as comparison of these two types of vaccines in children still remains unsettled.

In our previous studies [7], [14], [15], adjuvanted whole-virion vaccine has been well evaluated in adults; in this study, adjuvanted spilt-virion and adjuvanted whole-virion vaccine were both evaluated in children aged 12–17 years, respectively. Moreover, as influenza whole-virion vaccine was not permitted to be used in children under 12 years old according to the Chinese regulation, only adjuvanted spilt-virion vaccine was evaluated in children aged 3–11 years (Table 1).

Section snippets

Participants

From August to October 2007, 228 participants selected from clinically healthy adults (18–60 years), elders (≥61 years) and children (3–17 years) were enrolled in the phase I + Ib trial; from July to October 2008, 420 clinically healthy children (3–17 years) were enrolled in the phase II + IIb trial. The main exclusion criteria were current febrile illness; any acute diseases; allergic history to vaccines and eggs; history of hematologic, hepatic, renal, cardiac or respiratory diseases;

Study subjects

As shown in Fig. 1, in phase I + Ib trial, 160 eligible subjects were randomly assigned to receive 2 doses of split-virion vaccine 14 days apart, and 68 eligible subjects were randomly assigned to receive 2 doses of whole-virion vaccine 14 days apart. No subjects lost to follow-up and all subjects were assessed for safety and tolerance.

In phase II + IIb trial, 421 participants, including 141 3–11 years children and 280 12–17 years children, were randomly assigned to receive 2 doses of the vaccines

Discussion

Due to the high mortality after infection with H5N1 virus, the potential influenza pandemic caused by the virus had been drawing much attention in the last decade. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults, making the world better prepared for pandemic than ever. However, clinical evaluation of H5N1 vaccines in children is worthy of more work since children are likely to be one of the most vulnerable population during a pandemic and an

Acknowledgments

We appreciate the UK National Institute for Biological Standards and Control for kindly providing the virus strains and reference standards.

Contributors: All authors participated in the interpretation of results, writing of the manuscript and approval of the final version. Conceived and designed the experiments: J Wu, ZJ Feng, WD Yin, JT Chen, XP Dong, YZ Qiu and SS Dong. Performed the experiments: J Wu, M Lu, WL Zhang, JC Zhou and LY Liu. Assayed antibody titer: SZ Liu, CG Li, HF Fang and Q

References (21)

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Both authors contributed equally to this work.

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