Elsevier

Vaccine

Volume 27, Issue 52, 9 December 2009, Pages 7428-7435
Vaccine

Immunogenicity and tolerability of an AS03A-adjuvanted prepandemic influenza vaccine: A phase III study in a large population of Asian adults

https://doi.org/10.1016/j.vaccine.2009.07.102Get rights and content

Abstract

The immunogenicity and lot-to-lot consistency of an AS03-adjuvanted H5N1 vaccine were evaluated in 1206 Asian adults, randomised to receive two doses of adjuvanted (3.75 μg haemagglutinin) or diluent-mixed vaccines, 21 days apart. Post-Dose 2, 96.0% of vaccinees in the H5N1-AS03 group demonstrated a four-fold increase in neutralising antibody titres against the vaccine strain A/Vietnam/1194/2004 and 91.4% against strain A/Indonesia/05/2005. Haemagglutination-inhibiting antibodies (titre ≥1:40) against A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains were observed in 94.3% and 50.2% of subjects, respectively. Lot-to-lot consistency of the AS03-adjuvanted vaccine combinations was demonstrated. The AS03-adjuvanted vaccine was well tolerated, induced a high frequency of immune responses to the vaccine strain, allowed antigen sparing and promoted cross-clade immunity. These characteristics make it suitable for presumptive use if an H5N1 pandemic were considered to be imminent.

Introduction

Three influenza pandemics occurred during the twentieth century. The worst, in 1918, resulted in more than 40 million deaths worldwide [1], [2]. Pandemics arise due to antigenic shifts in viral haemagglutinin (HA) and/or neuraminidase proteins [3], which gives rise to a new influenza viral subtype that has three key characteristics: the new subtype is novel in humans and thus little pre-existing immunity is present in the population; infection with the subtype causes clinically significant illness; and the virus is able to spread efficiently from person to person [2], [4]. The world is presently in World Health Organization (WHO) Pandemic Alert Phase 6, in which a new H1N1 influenza virus subtype has given rise to numerous cases in humans. As of 15 June, 2009, 76 countries have reported 35 928 confirmed cases of H1N1 infection, including 163 deaths [5].

Despite the focus now shifting to the H1N1 strain, the previously predominant H5N1 strain continues to be a cause for concern [6]. This highly pathogenic avian influenza H5N1 virus strain was first recognised as a cause of death in poultry in 1996. In Hong Kong in 1997, 18 individuals became severely ill, of which six died, following close contact with infected birds [7]. The virus re-emerged in 2003 and since then, has caused 433 human cases with 262 deaths (valid as of 2 June, 2009 [6]). To date the H5N1 virus has fulfilled two of the three criteria necessary for an influenza pandemic: firstly, the human population is largely immunologically naïve to this subtype. Secondly, the H5N1 virus is capable of causing clinically severe disease in humans. Although the third criterion is not met yet (the virus is not able to spread efficiently from person to person), ongoing genetic diversification of the virus has been demonstrated and the virus may eventually evolve either through direct mutation or genetic re-assortment with human influenza virus to achieve efficient human-to-human transmission. Consequently, the H5N1 virus is still a matter of concern for health authorities, worldwide [6].

The use of a prepandemic influenza vaccine, either before or just after onset of a pandemic, is regarded as the most effective intervention to prevent or attenuate pandemic influenza [3]. The WHO has called for development of prepandemic vaccines that use novel vaccine adjuvants, thus improving immunogenicity and allowing antigen sparing. Prepandemic vaccines should also induce cross-clade immunogenicity, capable of providing protection against variants of the influenza virus [8]. The present paper relates to the development of GlaxoSmithKline's (GSK) prepandemic influenza H5N1 split-virion candidate vaccine adjuvanted with a novel proprietary Adjuvant System (AS03). In a dose-range study previously conducted in adults, a formulation containing only 3.75 μg haemagglutinin (HA) antigen induced high levels of HA-inhibiting and neutralising antibodies directed against the H5N1 A/Vietnam/1194/2004 (clade 1) vaccine strain [9]. The 3.75 μg HA antigen-containing vaccine also showed cross-clade immunogenicity against the heterologous A/Indonesia/5/2005 (subclade 2.1) strain [9], the A/turkey/Turkey/1/2005 (subclade 2.2) and the A/Anhui/1/2005 (subclade 2.3) strains [10]. Here we assessed the immune response against the A/Vietnam/1194/2004 (clade 1) vaccine strain, and the tolerability of the AS03-adjuvanted formulation containing 3.75 μg HA antigen in an 18–60 year-old Asian population. Lot-to-lot consistency of the vaccine antigen and the AS03 Adjuvant System was performed. Cross-clade immune response against the subclade 2.1 strain were also evaluated in these subjects.

Section snippets

Study design

This study (109630/NCT:00449670) was conducted in six centres in Hong Kong, Taiwan, Singapore and Thailand between 24 March and 12 July, 2007. Written informed consent was obtained from subjects before enrolment. The study was conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki and was approved by the Institute Review Board of each participating institution and health authority of each region.

Eligible adults were randomised to receive two doses (21 days

Results

A total of 1206 adults were enrolled and randomised into the study, of which 961 received an H5N1-AS03 formulation. The number of subjects who completed the study and the number of subjects included in the safety and per-protocol immunogenicity cohorts are given in Fig. 1. The mean age of all enrolled subjects was 33.6 years (SD 9.70 years, range 18–59 years). 51.2% of subjects were female. 98.0% of subjects were of South East Asian or East Asian ethnic heritage. The demographic characteristics

Discussion

This large study in which 961 adults received the AS03-adjuvanted H5N1 prepandemic vaccine confirms the findings of Leroux-Roels et al. [9], showing that the inactivated H5N1 influenza A/Vietnam/1194/2004 (clade 1) split-virion AS03-adjuvanted vaccine containing 3.75 μg HA antigen was highly immunogenic and well tolerated. These data build on previous studies of GSK's H5N1-AS03 vaccine [9], [10], [14], [15]: firstly, manufacturing consistency in terms of the immune response to different lots of

Disclosure statement

Hans L. Bock, Mamadou Dramé, Paul Gillard, Yanee Hutagalung, Haiwen Tang, Yee Leong Teoh, Ripley W. Ballou are/were employees of the GlaxoSmithKline Group of Companies at the time of study. Prasert Thongcharoen had received honoria and/or travel support from GlaxoSmithKline for scientific meetings.

Conflicts of interest

All other authors have no conflict of interest.

Role of the funding sources

GlaxoSmithKline Biologicals was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals also took in charge all costs associated with the development and the publishing of the present manuscript. All authors had full access to the data and the corresponding author had final responsibility to submit for publication.

Acknowledgements

The authors would like to thank the individuals who participated in the study, as well as the clinicians, nurses, and laboratory technicians who were involved in the study. The authors are also grateful to GlaxoSmithKline Biologicals’ project staff for their support and contribution and Joanne Wolter, Avishek Pal, Roselynn Tien and Ming-Tung Lim for their assistance in the preparation of the manuscript.

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    1

    All the authors made equal contributions to the study.

    2

    Group member of the H5N1 Flu Study Group for Hong Kong, Singapore, Taiwan and Thailand (listed in Appendix A).

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