Influenza vaccine: The challenge of antigenic drift

Vaccine 25 (2007) 6852–6862

Review

Influenza vaccine: The challenge of antigenic drift F. Carrat a,b,c,∗ , A. Flahault a,b,c a

Universit´e Pierre et Marie Curie, Paris 6, UMR-S 707, Paris, France b INSERM, UMR-S 707, Paris, France c Assistance Publique, Hˆ opitaux de Paris, Paris F-75012, France

Received 28 March 2007; received in revised form 12 July 2007; accepted 16 July 2007 Available online 3 August 2007

Abstract Influenza continues to have a major worldwide impact, resulting in considerable human suffering and economic burden. The regular recurrence of influenza epidemics is thought to be caused by antigenic drift, and a number of studies have shown that sufficient changes can accumulate in the virus to allow influenza to reinfect the same host. To address this, influenza vaccine content is reviewed annually to ensure protection is maintained, despite the emergence of drift variants; however, it is not always possible to capture every significant drift, partly due to the timing of the recommendations. Vaccine mismatch can impact on vaccine effectiveness, and has significant epidemiological and economical consequences, as was seen most apparently in the 1997–1998 influenza season. To meet the challenge of antigenic drift, vaccines that confer broad protection against heterovariant strains are needed against seasonal, epidemic and pandemic influenza. In addition to the use of vaccine adjuvants, emerging research areas include development of a universal vaccine and the use of vaccines that exploit mechanisms of cross-protective immunity. © 2007 Elsevier Ltd. All rights reserved. Keywords: Antigenic drift; Influenza; Vaccination

Contents 1.

2.

3.

4.

∗

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Influenza and its impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Why is influenza a continuing problem? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Influenza virus mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Antigenic drift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Antigenic shift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of antigenic drift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Natural immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Vaccine-induced immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Requirement for selection of annual vaccine strains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Vaccine effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Seasonal variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Impact in the elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cross-protective vaccines to reduce the impact of antigenic drift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. A universal vaccine—use of alternative antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Cross-protective immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author at: INSERM U707, 27 rue Chaligny, Paris F-75012, France. Tel.: +33 1 44 73 84 58; fax: +33 1 44 73 84 53. E-mail address: [email protected] (F. Carrat).

0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.07.027

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4.3. Adjuvanted vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Other vaccine developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction 1.1. Influenza and its impact 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 [1–4]. 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. 1.2. Why is influenza a continuing problem? 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 [9–11]. 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.

2. Influenza virus mutation 2.1. 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 [14–16]. 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 [8,16–18]. Most of these mutations are ‘neutral’ as they do not affect the conformation of the proteins; however, some mutations cause changes to the viral proteins such that the binding of host antibodies is affected. Consequently, infecting viruses can no longer be inhibited effectively by host antibodies raised to previously circulating strains, allowing the virus to spread more rapidly among the population [19]. Antigenic drift occurs in all strains of A and B viruses, although the observed evolutionary patterns vary dependent on the strain. For influenza A (H1) and B viruses, drift variants often co-circulate with multiple co-existing lineages, allowing the re-emergence of old strains. In contrast, influenza A (H3) subtype viruses undergo antigenic drift much more often and the new variants tend to replace the old ones [16,20,21]. In line with this, fixation rates have been calculated that indicate how often nucleotide and amino acid substitutions occur in the different virus types, with the rates being highest for A (H3) (Table 1) [20,22–24]. Nucleotide substitution rates alone do not tell the whole story, however, as some regions of the surface proteins are more susceptible to change than others. Indeed, as many as 35% of the substitutions have been reported to occur at only 18 of the 329 codons of the A (H3) virus. The fixation rate at these 18 sites is 0.053 substitutions per site per year, revealing the importance of a small group of codons to the evolution of the influenza virus [20]. Five antibody-binding sites (epitopes) have been located in this region [3] thus antigenic drift involving nonneutral point mutations of these epitopes can be expected

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Table 1 Frequency of nucleotide and amino acid substitutions for the haemaglutinnin gene and protein, respectively, for A (H3), A (H1) and B influenza virus strains [20,22–24] Influenza virus type

Nucleotide substitutions (per site per year)

Amino acid substitutions (per site per year)

A (H3) [22] A (H1) [23] Ba [24]

0.0057 0.0038 0.0014/0.0024

0.0097 0.0058 0.0022/0.0034

a The two different values correspond to results from co-circulating lineage III and lineage II influenza B viruses, respectively.

to have a significant impact on the ability of the protein to bind neutralising antibodies. Mathematical modelling of antigenic drift has also shown that it occurs at a highly non-uniform rate, and that there have been a number of years when antigenic surges and a new strain have substantially increased infective pressure [8,16]. 2.2. Antigenic shift Antigenic shift is only seen in influenza A viruses, and results from the replacement of HA (and less frequently NA) subtypes with novel ones [10]. This results in new viruses that have never been present in human circulation or last circulated decades before. These can have a significant impact on disease burden, causing pandemics or worldwide epidemics and resulting in hundreds of thousands, or possibly millions, of influenza-related deaths [3]. Antigenic shift is estimated to occur approximately three times every 100 years [25], which is in line with the three antigenic shifts (and resulting pandemics) that occurred during the 20th century (1918, 1957 and 1968). An important process that contributes to major shifts in influenza antigenicity is genetic reassortment (mixing of genetic material between different viral strains) which occurs due to co-circulation of different influenza A subtypes, and influenza A and B viruses. Although genetic reassortment can contribute to antigenic drift [26], it is primarily responsible for antigenic shift [27,28]. Genetic reassortment is of particular importance in the evolution of A/H3N2 viruses [29], which emphasises the need for comprehensive analysis of influenza viruses, particularly when considering the annual vaccine composition. Genetic reassortment is also possible between co-infecting influenza A subtypes from different species, a process that has the potential to create new subtypes with substantial antigenic changes that can result in an influenza pandemic. Thus, it is feasible that reassortment between human and avian virus strains will produce a virulent strain. Once a virus has undergone antigenic shift, it remains susceptible to antigenic drift, as occurs with any influenza virus. In fact, all current circulating influenza viruses are drift variants of previously pandemic influenza strains. Currently, a major concern is the possibility that the highly pathogenic A/H5N1 avian influenza strain undergoes antigenic drift in

such a manner that makes human-to-human transmissibility possible, resulting in a major worldwide human pandemic [30]. Although A/H5N1 has undergone considerable drift since it was first isolated in 1996 [31], so far efficient humanto-human transfer has not developed.

3. Impact of antigenic drift 3.1. 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, particularly with antigenically drifted A/H3N2 strains, is more severe than in others [16]. Most recently, the European 2003–2004 influenza season was dominated by the spread of a new drift variant, A/Fujian/411/2002(H3N2)-like virus. Influenza activity associated with this strain began relatively early in the season and spread from Western Europe to the east. Among members of the European Influenza Surveillance Scheme, 13 out of 20 disease surveillance networks reported activity higher than during the previous season and 19 out of 21 countries reported medium or high incidence of influenzalike-illness (ILI). The majority of cases were attributable to the A/Fujian/411/2002(H3N2)-like drifted strain [32]. Similarly, in 1997, the drift variant A/Sydney/5/97-like virus caused severe disease outbreaks in Europe and the US [33,34]. The same drift variant was responsible for a major influenza epidemic in South Africa in 1998 that was characterised by extensive illness and an unusually early season, resulting in increased school-absenteeism and a rise in mortality in the elderly [35]. With no prior exposure to this strain the population was highly susceptible, resulting in early, rapid spread of influenza [35]. 3.2. Vaccine-induced immunity 3.2.1. Requirement for selection of annual vaccine strains In order to tackle the seasonal disease burden caused by influenza, WHO established the Global Influenza Network in 1952. Involving a number of collaborative centres around the world, this network is able to monitor antigenic drift and emerging virus strains and recommend the content of the influenza vaccine for the subsequent season. Recommendations are made to ensure that the vaccine viruses have identical or similar antigenic profiles to the circulating strains and are effective in managing the disease [11,36,37]. Antigenic drift has meant that WHO has altered its recommended

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influenza vaccine content four times for influenza A (H3) and B viruses and twice for influenza A (H1) since the 1998–1999 season. However, despite these efforts it is not always possible to tailor the influenza vaccine strains to those in circulation. Vaccines are currently produced using embryonated chicken eggs and can take up to 9 months to produce. If significant antigenic drift occurs during this lengthy production period, a strain may arise for which it is impossible to produce a corresponding vaccine, in sufficient time, with current techniques [38], as occurred in 2003–2004 with the emergence of the A/Fujian strain. This can result in a mismatch between one of the circulating strains and the vaccine strain in the subsequent season, resulting in reduced effectiveness of the vaccine and potential for an epidemic outbreak.

workdays could be demonstrated with vaccination. However, the following influenza season, when the vaccine strain and circulating strain were well matched, vaccine efficacy increased to 86% (P = 0.001) against serologically confirmed influenza illness, and vaccination was able to reduce ILI by 34%, physician visits by 42% and lost workdays by 32%. Data from three other outbreaks of the A/Sydney influenza virus in that year, this time in chronic care facilities, show that between 22 and 49% of those vaccinated with influenza vaccine suffered ILI [42]. The estimated vaccine efficiency was between −34 and 25%, i.e. vaccination seemed to increase the risk of ILI in some cases. The vaccine was also noted to have low efficacy in health care workers in whom vaccine efficacy usually ranges from 70 to 90% [42].

3.2.2. Vaccine effectiveness The impact of antigenic drift on vaccine effectiveness varies between seasons. Although it is apparent that an antigenically drifted strain can result in reduced vaccine effectiveness, not all drifted strains evade vaccine-induced immunity in the population. This is demonstrated through numerous studies documenting vaccine effectiveness against drift variants and well-matched viral strains. For example, in the 1992–1993 season, when two strains co-circulated in Japanese children, the effectiveness of influenza vaccination regarding laboratory-confirmed influenza illness was 68% against an antigenically drifted influenza A virus, and only 44% against the well-matched B strain [39]. Likewise, a recent study demonstrated good vaccine efficacy, with both live attenuated and inactivated influenza vaccines in healthy adults during the 2004–2005 influenza season, when antigenically drifted A/H3N2 and B virus strains were in circulation [40].

3.2.2.2. 2003–2004 influenza season. In 2003–2004 the A/H3N2 strain drifted from A/Panama/2007/99 to an A/Fujian/411/2002-like virus. The available A/Panama influenza vaccine was not optimally effective against the emergent antigenic variant of the virus, the A/Fujian strain. WHO changed the A/H3N2 component for the 2004–2005 influenza vaccine to afford protection but could not avoid a 2003–2004 influenza season dominated by the drifted A/H3N2 strain. In August 2003, in Australia, 98% of the A (H3) subtypes isolated were A/Fujian-like and had shown significant antigenic drift from the A/Panama vaccine strain, which induced a 2–4-fold lower antibody response against the drifted strain [43,44]. In the US, an early rapid assessment of vaccine effectiveness in Colorado during the 2003–2004 season did not find significant reduction in ILI with the vaccine [45]. However, a case-control study in Colorado residents, 50–64 years of age, conducted during the same season showed that vaccine efficacy against laboratory-confirmed influenza illness was 49.1–55.9%, and 53.8–60.0% against hospitalisation, because of laboratory-confirmed influenza [46]. These findings indicate that the influenza vaccine had some effectiveness but remained lower than the expected 70–90% effectiveness seen in years when the vaccine and circulating strains were well matched [45]. Another study from the 2003–2004 season, carried out in California, also indicates that this was a particularly severe season with more than three times as many children reported to be hospitalised in intensive care with influenza, compared with the 2004–2005 season. Furthermore, a non-negligible proportion (16%) of those children in intensive care had received influenza vaccination that season [47].

3.2.2.1. 1997–1998 influenza season. In 1997–1998 a drift variant, the A/Sydney/05/97(H3N2)-like virus, caused severe disease outbreaks in Europe and the US. A poor match between vaccine antigen (A/Nanchang/933/95 or A/Wuhan/359/95) and the new circulating virus was observed [33,34]. Of the H3N2 influenza A viruses analysed by the WHO collaborating laboratory in the US, only 23% were similar to the vaccine strain and 77% were similar to the A/Sydney/05/97(H3N2)-like virus. As a result, vaccine effectiveness in the elderly was shown to fall from 61% (1996–1997, good virus-vaccine match) to 35% (1997–1998, poor virus-vaccine match) in terms of all-cause deaths prevented [37]. Vaccine effectiveness for preventing hospitalisation for pneumonia and influenza was 20% but did not differ between the two seasons, indicating that the end-point analysed may affect the interpretation of the results. The best level of evidence of reduced vaccine effectiveness because of a drifted virus strain comes from a double-blind, randomised, placebo-controlled trial in healthy adults [41]. The study demonstrated that in 1997–1998, vaccine efficacy was not significantly different from non-vaccination (placebo) and no reduction of ILI, physician visits or lost

3.2.3. Seasonal variability The studies discussed previously indicate that antigenic drift can impact vaccine effectiveness in different seasons; however, the extent varies from season to season. A number of surveys have looked retrospectively at extended periods of time crossing multiple influenza seasons. In a French survey using data from a Sentinel Physicians Network between 1995 and 2005, vaccine effectiveness against ILI was clearly lower in 1997–1998 than in the other nine influenza seasons (Fig. 1)

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Fig. 1. Estimates of the field vaccine effectiveness from the Sentinel Network, France, for the last decade [53].

[48]. Vaccine effectiveness in the elderly was −24% during the 1997–1998 season, and ranged between 26 and 52% during the other seasons. However, despite the circulation of a drifted strain, no decrease in influenza vaccine effectiveness was observed in 2003–2004. Between 1980 and 1992 in Canada, there were a number of years when influenza virus strains did not match those strains in the recommended vaccine formulation; similarity between circulating strains and vaccine antigens was 99% for A/H1N1, 65% for A/H3N2 and 65% for B strains. The study revealed that on a number of occasions there was reduced or no match between the virus strains isolated from infected individuals and those included in the seasonal vaccine (Fig. 2) [49]. Moreover, when the antigenic distance, or sequence difference, between the vaccine and the wild-type strains was calculated as the proportion of different amino acids in the dominant epitope, a strong correlation was obtained between antigenic distance and vaccine effectiveness (Fig. 3) [50]. In the study, the dominant epitope was defined as the antibody recognition site in the HA, which had the largest proportion of changes in amino acid sequence relative to the vaccine strain. Calculating the proportion of change, from vaccine to circulating strain, in this region provided a quantitative definition of the difference between circulating and vaccine strains. When this is plotted against vaccine efficacy, observed and recorded in the literature, there is a clear correlation between that and antigenic distance. Years with increased antigenic distance between the vaccine and wild-type strains generally coincided with years of low vaccine effectiveness. Correspondingly, negative vaccine effectiveness for A/H3N2 occurred 26% of the time in the 33 years analysed in the study

during which the A/H3N2 was the most virulent strain. Each of these years, apart from one, was associated with a significantly increased number of amino acid differences in the dominant epitope. Most recently, a Japanese study of vaccine effectiveness over the past five seasons surveyed over 36,000 subjects. The study found that vaccination was significantly effective over all five seasons, but that efficacy for influenza A was reduced in the 2003–2004 and 2004–2005 seasons (30% and 25%, respectively), compared with the other seasons (46–79%) [51]. A separate study from the same group revealed that some of the vaccinated subjects did not show significant elevation of serum titres to circulating A/H3N2 strains. Analysis of the HA gene sequence revealed that antigenic drift of the circulating strains from the virus strains used for vaccination was an important factor affecting the efficacy of the vaccine [52]. Antigenic drift of circulating influenza virus strains occurs on a regular basis and has the potential to impact vaccine effectiveness. It is apparent that not all drifted strains decrease vaccine effectiveness, but if the drift coincides with a particularly pathogenic strain then the new strain can cause significant disease burden. This is most obvious in the 1997–1998 influenza season when there is clear evidence that vaccine effectiveness was significantly reduced (Table 2). 3.2.4. Impact in the elderly Some population groups, such as the elderly, are more susceptible to infection and influenza-related complications than others. Therefore, sub-analysis of the effect of antigenic drift on vaccine effectiveness may be warranted. In 2005–2006

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Fig. 2. Similarity of laboratory-confirmed influenza infections with vaccine antigens, Canada, 13 seasons (1980–1981 to 1992–1993) [49]. The number contained within each bar represents the total number of isolates, detections and seroconversions assessed for the corresponding influenza season and viral type (subtype).

Fig. 3. Vaccine efficacy for years when A/H3N2 was the predominant influenza virus. Years are coloured to represent the degree of vaccine/circulating strain match as determined using P epitope [50]. P epitope defines the degree of antigenic drift.

in a case-control study conducted in a Sentinel Physician Network in Canada, cases were defined as participants with laboratory-confirmed influenza; those who tested negative were included as controls. Vaccine effectiveness against ILI was found to range between 50 and 70% for both influenza A (where 3/4 of isolates were mismatched to the vaccine) and influenza B (where all isolates were mismatched) [53]. In this study, it was concluded that a substantial level of cross-protection between the A (H3) vaccine and the wildtype strains had been achieved. However, more than half of all influenza A detections in vaccinated persons in this study were among the elderly, who comprised only 10% of the cohort. Vaccine effectiveness in this age group was,

therefore, estimated to be negligible. The impact of vaccine mismatch in different age groups is an area requiring further research.

4. 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

Confirmed ILI Confirmed ILI

Confirmed ILI

Influenza-related hospitalisation

Confirmed ILI Confirmed ILI

Confirmed ILI

50 (P = 0.33) 86 (P < 0.001)

Low risk:60 (43–72); high risk: 48 (21–66) Low risk: 90 (68–97); high risk: 36 (0–63)

69 (7–90) 83 (26–97)

Developing a universal influenza vaccine based on a more conserved part of the influenza virus which is not affected by antigenic change or that is consistent across all strains remains the ultimate goal to afford cross-protection [56,57]. While HA and NA are the most highly antigenic proteins of the influenza virus, recent research has investigated the potential of the extracellular domain of the M2 ion channel protein [57–59] and the nucleoprotein (NP) [60] as alternative antigens. In particular, it has been reported that vaccination with M2-containing vaccines may provide broad protection against influenza A [61]. Both the M2 protein and NP have low rates of mutation [60]; in fact, the M2 protein has remained highly conserved since it was first isolated in 1933 [58]. Although the M2 protein is a weak antigen, by linking the protein to an appropriate carrier, such as hepatitis B virus core particles, protection against influenza has been achieved in mice [57,58], particularly when administered with an adjuvant [62]. Similarly, strategies to enhance the immunogenicity of NP are under investigation, including the fusion of NP to the VP22 tegument protein of herpes simplex virus 1 [60]. As such, Saha and colleagues have reported that a VP22/NP plasmid DNA vaccine can confer cross-protective immunity against influenza viral subtypes in mice [60]. These studies show that while an effective universal vaccine is not yet available for use in humans, use of alternative antigens is promising for development of a broad spectrum vaccine.

50–60 Yes

Case-control (all ages) B/Shangai/361/2002

A/Wisconsin/67/2005 A/California/7/2004 B/Hong-Kong/330/01 B/Malaysia/2506/04 VE, vaccine efficacy.

4.2. Cross-protective immunity

a

2005–2006 Skowronski [53]

A/California/7/2004

Partial

Double-blind RCT (adults) Yes No Yes A/California/07/2004-like B/Shangai/361/2002 B/Hawaii/33/2004 A/Fujian/411/2002-like B/Shangai/361/2002 2004–2005 Ohmit [40]

A/Fujian/411/2002 2003–2004 Herrera [46]

A/Panama/2007/99

Yes

Double-blind RCT (adults) Yes No A/Michigan/8/98 A/Michigan/15/99 A/Nanchang/933/95 A/Sydney/5/97 1997–1998 1998–1999 Bridges [41]

1997–1998

A/Wuhan/359/59 B/Beijing/184/93 A/Sydney/5/97 1996–1997 Nordin [37]

A/Wuhan/359/59 B/Beijing/184/93 A/Wuhan/359/59

Yes

Case-control (50–64 year old)

Hospitalisation for P&I All-causes deaths Hospitalisation for P&I All-causes deaths 19 (2–33) 61 (56–46) 18 (2–32) 35 (25–43) Retrospective cohort (elderly)

4.1. A universal vaccine—use of alternative antigens

Circulating strains

No

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 effect of antigenic drift of this strain. If prevaccination or stockpile strategies are to succeed, a vaccine that offers cross-protection against a broad range of strains is essential as the emergent pandemic strain will undoubtedly have drifted from the strain the vaccine is based on. Thus, there is a pressing need to improve current vaccine effectiveness against heterovariant strains through the development of vaccines that can neutralise a number of viral serotypes, including drifted strains and heterosubtypes within the same genera of influenza virus [54]. There are several novel vaccine developments aimed at achieving this [55].

Vaccine strains Year Reference

Table 2 Impact of antigenic drift on vaccine effectiveness over the last decade

Mismatch

Design population

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VEa (%) (95% CI)

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While the development of a universal vaccine remains at a preclinical stage, in the short-term it may be more achievable to develop conventional vaccines to exploit mechanisms of cross-protective immunity. Recent research in animal models has shown that intranasal administration of live attenuated influenza virus or inactivated intact virus can induce heterosubtypic immunity [63–65]. Live attenuated intranasal vaccines (LAIV) consist of a virus that can still infect cells and thus induce a broader immune response capable of protecting against related

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strains. For example, protection against A/Wuhan(H3N2) has been reported in cotton rats infected with A/PR/8/34(H1N1) [63], and in mice infected with X-31(H3N2), protection against A/PR/8/34(H1N1) was observed [64]. Long-term cross-protective immunity against drifted A/H1N1 strains has also been demonstrated in mice following administration of influenza virus-like particles. Furthermore, cross-protective immunity against an antigenically shifted potentially pandemic strain (A/Vietnam/1203/2004(H5N1)) following administration of a non-pathogenic strain (A/Duck/Pottsdam/1042-6/86(H5N2)) has been reported in mice [66]. Regarding the influenza B virus, co-circulation of different lineages may occur in one season which provides an additional challenge for vaccine formulation; therefore, it would clearly be beneficial if vaccines conferred good immunogenicity against different lineages. In mice, some cross-protective immunity against different lineages of influenza B has been demonstrated following viral infection, mediated by secretory immunoglobulin A (IgA) antibodies [67]. In humans, the ability of an LAIV (FluMist® , MedImmune) to confer cross-protective immunity against drifted influenza strains has been assessed in healthy young adults and children [40,68], compared with a trivalent inactivated influenza vaccine (FluZone® , Sanofi Pasteur). For children (6–59 months of age), higher efficacy was reported against drifted strains using LAIV [68]; however, in adults (18–46 years of age), LAIV was less efficacious than FluZone® [40]. The broad protection that has been observed using LAIV in mice may be explained by antibodies against the M2 protein, although the true mechanism of heterosubtypic immunity is currently unknown [55]. However, it has been suggested that induction of mucosal immune response and cell-mediated immunity may be involved [69]. Thus, protection against influenza viruses of the same type or subtype may occur partly due to selection of cross-reactive cytotoxic T lymphocytes (CTL) targeting epitopes on a wide variety of internal proteins [70–72]. LAIV also enhances human leukocyte antigen-restricted virus-specific CTL activity in healthy [73] and older adults [74]. Furthermore, induction of CTL following immunisation with DNA vaccines (plasmid DNA expression vectors) has also shown promise as a means of inducing a broad immune response [75]. An understanding of this mechanism may help in the development of crossprotective vaccines. Although most research to date has been carried out in animals, methods for predicting vaccineinduced cross-reactive antibody responses in humans have been developed [50,76]. These methods could be applied a priori for improving the selection of vaccine strains, while improved cross-protective vaccines suitable for human use are under development.

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added adjuvants, such as MF59TM . MF59TM -adjuvanted influenza vaccine is currently the only truly adjuvanted influenza vaccine available for use in humans. Adjuvants can boost vaccine efficacy to address or overcome the decrease in effectiveness when a heterovariant strain is in circulation [77,78]. Elderly people (≥65 years of age) who received MF59TM -adjuvanted influenza vaccine produced significantly (P = 0.011) more antibodies, by 36%, against a drifted influenza strain (A/Shangdon/9/93) than those given a conventional non-adjuvanted vaccine [77]. Furthermore, seroprotection (haemagglutinin inhibition titres ≥40) against A/Wyoming/3/2002(H3N2) was observed in 98% of elderly people following vaccination with MF59TM -adjuvanted influenza vaccine containing A/Panama/2007/1999, compared with 80% and 76% of elderly people vaccinated with a non-adjuvanted split or subunit vaccine, respectively [61]. The MF59TM -adjuvanted influenza vaccine has also shown potential to confer protection against pandemic strains [79,80] following vaccination with non-pathogenic strains, including cross-reactivity with heterovariant A/H5N1 strains including A/Hong Kong/156/97, A/Hong Kong/213/03, A/Thailand/16/04 and A/Vietnam/1203/04 [80]. In addition, another candidate pre-pandemic vaccine containing a novel proprietary adjuvant system has been reported to confer cross-protection against an A/H5N1 drifted strain, further supporting the use of adjuvanted vaccines to address antigenic drift in the pandemic situation [81]. 4.4. Other vaccine developments Another type of vaccine aimed at enhancing the immune response is that of virosomal vaccines which utilise virosomes to present antigens to the immune system. Virosomes are virus-like particles that lack the viral genetic material [82]. Virosomal vaccines have been shown to activate both the cellular and humoral immune responses; a similar level of immunogenicity has been observed with virosomal vaccines compared with adjuvanted vaccines against homologous vaccine strains [83]. However, at this time, broader cross-protective protection has not been demonstrated. Recently, a novel trivalent influenza virus haemaglutinnin vaccine currently under development as cell culture-derived vaccine, has been developed in insect cells using recombinant baculovirus [84]. Preliminary results with this vaccine have shown that some protection was afforded against drifted strains, suggesting that vaccine prepared using recombinant DNA techniques may be promising in the development of cross-protective vaccines.

5. Summary and conclusions 4.3. Adjuvanted vaccines Another potential solution to the challenge presented by antigenic drift may be the development of vaccines with

Influenza infection remains a global concern, with continued high seasonal infection causing considerable morbidity and mortality. The regular recurrence of influenza epidemics

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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 significant impact on vaccine effectiveness. Indeed it has been suggested that approximately once every decade the mismatch between virus and vaccine is enough to reduce vaccine effectiveness by 70% [85]. Vaccination remains a priority but a number of issues need to be addressed. Improved vaccines are needed, especially for vulnerable patients who are at increased risk of hospitalisation such as infants, the immunosuppressed and the elderly. This is not only the case for seasonal influenza but also for epidemic influenza and for a potential influenza pandemic. Under these circumstances an influenza vaccine that offered protection against drift variants would be in high demand. In addition to the use of adjuvants to induce a broader immune response, emerging research areas include development of a universal vaccine and exploitation of the mechanisms of cross-protective immunity.

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.

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