ReviewInfluenza vaccine: The challenge of antigenic drift
Introduction
Influenza is a highly contagious, acute, febrile, respiratory disease, which has been in circulation for centuries. The disease is caused by the influenza virus, which is a segmented, enveloped RNA virus. Within the influenza virus family, there are three genera: A, B and C; although only A and B cause significant disease in humans. Influenza A viruses are further subtyped according to their surface antigens, haemagglutinin (HA) and neuraminidase (NA), of which 16 HA subtypes and 9 NA subtypes have been identified to date [1], [2], [3], [4]. Influenza has a high incidence in human populations and causes regular, large-scale morbidity and mortality. During seasonal epidemics, 5–15% of the worldwide population is typically infected, resulting in 3–5 million cases of severe illness and up to 500,000 deaths per year [5]. While all age groups are affected by the disease, most influenza-related hospitalisations in industrialised countries occur in young children (<5 years of age) and in the elderly (≥65 years of age) [6] and most deaths occur among the elderly (≥65 years of age) [7]. Taking into account work absenteeism as well as direct medical costs, the annual economic impact of influenza in the US has been estimated to be as high as US $12–14 billion [2]. Thus, influenza continues to have a major worldwide impact, resulting in significant human suffering and economic burden.
The influenza virus is able to evade the host immune system as it continuously undergoes antigenic evolution through the genetic processes of antigenic drift and shift [1], [2], which may occur much more frequently than currently believed in some quarters. A single influenza infection is enough to provide lifelong immunity to the invading strain [8]; however, intense selection to evade the host immune system results in genetic variation producing antigenically novel strains. Emergence of these novel strains mean that most people who have had influenza are susceptible to a new circulating strain within a few years of infection [9], [10], [11]. To address this, the influenza vaccine content is reviewed every influenza season, by a panel of World Heath Organization (WHO) experts, in the Northern and Southern hemispheres. This process aims to ensure that the vaccine strains match the circulating strains and provide reliable immunogenic protection [12]. Currently, three strains are selected for inclusion in the vaccine, based on the WHO recommendation made 9–12 months prior to the targeted season. Thus for the Northern hemisphere, the WHO meeting takes place in February to recommend vaccine strains for the following winter. However, as antigenic changes continue to occur during the months between the recommendations and the influenza season vaccine, mismatch can occur, rendering the vaccine less effective.
Section snippets
Antigenic drift
Antigenic drift is the gradual evolution of viral strains, due to frequent mutations [13]. It occurs on average every 2–8 years in response to selection pressure to evade human immunity [14], [15], [16]. The process of antigenic drift is subtle, involving point mutations within antibody-binding sites in the HA protein, the NA protein, or both, which potentially occur each time the virus replicates [8], [16], [17], [18]. Most of these mutations are ‘neutral’ as they do not affect the
Natural immunity
It has been suggested that epidemiologically significant antigenic drift is associated with a more severe, early-onset influenza epidemic, resulting in increased mortality [3]. This seems logical since the population will lack immunity to the newly drifted virus, allowing it to spread more efficiently. Although evidence for an increase in disease burden during seasons with an antigenically drifted circulating strain is mixed, it is apparent that disease burden in some influenza seasons,
Cross-protective vaccines to reduce the impact of antigenic drift
In light of the significant impact that antigenic drift has on vaccine effectiveness, it is evident that new vaccines are needed to ensure optimal protection against seasonal and epidemic influenza. The problem of antigenic drift in the pandemic setting is also a major concern with the emergence of the lethal avian-flu A/H5N1 virus [30]. This virus has the potential to cause a worldwide influenza pandemic, and vaccination plans aimed at tackling this situation must also take in to account the
Summary and conclusions
Influenza infection remains a global concern, with continued high seasonal infection causing considerable morbidity and mortality. The regular recurrence of influenza epidemics is thought to be caused by antigenic drift, as a number of studies show that over some years, sufficient changes accumulate in the virus to allow influenza to reinfect the same host [10], [11]. Influenza virus strains that are not matched with the seasonal vaccine circulate on a regular basis, which can have a
Acknowledgements
The authors would like to thank Professor Plotkin for valuable discussions during preparation of this manuscript. The authors would also like to thank Dr. Jonathan Brennan and Dr. Rebecca Bradley (AlphaRmaxim Healthcare Communications) for their help in manuscript preparation.
References (85)
Selection of influenza vaccine strains and developing pandemic vaccines
Vaccine
(2002)- et al.
Influenza drift and epidemic size: the race between generating and escaping immunity
Theor Popul Biol
(2004) - et al.
Recent changes among human influenza viruses
Virus Res
(2004) - et al.
Reassortment between human A (H3N2) viruses is an important evolutionary mechanism
Vaccine
(2006) - et al.
Surveillance and impact of influenza in Europe. Groupe Regional d’Observation de la Grippe and European Influenza Surveillance Scheme
Vaccine
(1999) - et al.
Surveillance and impact of influenza in the United States
Vaccine
(1999) - et al.
Influenza virus: a master of metamorphosis
J Infect
(2000) - et al.
Influenza vaccine effectiveness among 50–64-year-old persons during a season of poor antigenic match between vaccine and circulating influenza virus strains: Colorado, United States, 2003–2004
Vaccine
(2007) - et al.
Real-time monitoring of the influenza vaccine field effectiveness
Vaccine
(2006) - et al.
Quantifying influenza vaccine efficacy and antigenic distance
Vaccine
(2006)