Elsevier

Vaccine

Volume 24, Issues 44–46, 10 November 2006, Pages 6683-6690
Vaccine

Reassortment between human A(H3N2) viruses is an important evolutionary mechanism

https://doi.org/10.1016/j.vaccine.2006.05.105Get rights and content

Abstract

Phylogenetic relationships of whole genomes of H3N2 viruses circulating in Germany during a 6-year period from 1998 to 2005 revealed the co-circulation of different lineages of viruses. Multiple reassortment events occurred during this time between viruses belonging to different lineages or different subgroups. Strains isolated during 1998–1999 were characterised by a surprisingly high heterogeneity and multiple reassortment events. Seventy percent of the examined 1998–1999 viruses had completely different genome compositions. To our knowledge, such an exceptional high proportion of different reassortant strains, encompassing all eight genome segments, have not been described before. In contrast, only one reassortant virus was prevalent during 1999–2000 even though two of the three 1998–1999 lineages were co-circulating. Reassortant viruses were isolated also in each of the other seasons. However, the proportion of H3N2 viruses with different genome compositions varied from season to season. Strains with a reassortant NA played an important role and were also detected during 2003–2004 and 2004–2005 accounting for 45% and 70% of the circulating H3N2 viruses, respectively. Moreover, different reassortment events occurring during these seasons included also the PB1, PB2 and NP genes. The results presented here emphasize that genetic reassortment is an important factor in the evolution of H3N2 viruses and highlight the need for a comprehensive analysis of influenza viruses, especially with regard to the annual vaccine composition.

Introduction

One of the characteristic features of influenza viruses is their segmented genome, which allows for the exchange of the eight gene segments between virus strains. Genetic reassortment between different co-infecting influenza A virus subtypes from various species may create new human subtypes with drastic antigenic changes referred to as antigenic shift. Reassortment between human and avian subtypes of influenza A viruses was the reason for the occurrence and spread of the H2N2 virus causing the “Asian flu” pandemic in 1957 and the H3N2 strain causing the “Hong Kong Flu” pandemic in 1968, respectively [1], [2]. Multiple reassortment events have been described among late H2N2 and H3N2 viruses suggesting that H2N2 viruses continued to circulate after 1968 and that establishment of H3N2 viruses in humans was associated with multiple reassortment events [3]. A reassortant H1N1 virus with the polymerase and NP genes derived from a H3N2 virus circulated in several countries from 1978 to 1980 [4], [5]. H1N2 viruses which contained seven genes of an H3N2 precursor were isolated sporadically in China between December 1988 and March 1989 but did not persist or appear to spread beyond China [6]. An H1N2 virus appeared 13 years later and was associated with outbreaks in Egypt, Israel and the UK. Subtype H1N2 viruses circulated also in other parts of the world causing sporadic infections [7] but did not become established in the human population. These H1N2 viruses arose by genetic reassortment between recently cocirculating human H1N1 and H3N2 viruses, between 1999 and 2001 [8].

Even if pandemic influenza occurs occasionally, inter-pandemic influenza remains the major cause of morbidity and mortality. It is estimated that during the last century annual epidemics have had an even greater cumulative impact than the three pandemics [9]. The two surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) comprise the principal immunizing antigens of the influenza virus. The HA and NA genes mutate with high frequency [10], [11] resulting in the accumulation of point mutations that may lead to gradual antigenic change of the surface glycoproteins known as antigenic drift. The severity of influenza seasons differs from year to year and is mainly associated with the emergence of immunologically distinct strains known as drift variants. Every few years influenza epidemics boost the mortality rate causing thousands of additional deaths in countries such as the United States or Germany [12], [13], [14].

The analyses of the HA and NA of seasonal circulating strains demonstrate the ongoing antigenic and genetic drift of influenza viruses. The timely detection of new drift variants is a prerequisite for an optimal vaccine composition. Understanding the evolution of influenza viruses and prediction of new emerging strains is very important for the selection of vaccine strains. There are some reports indicating that not only antigenic drift but also genetic reassortment may contribute to the variability and evolution of A(H3N2) viruses. Reassortment of NA genes was demonstrated between two lineages of A(H3N2) viruses, A/Beijing/353/89 and A/Beijing/32/92, during their circulation [15]. Limited gene reassortment for some of the internal genes was shown for the first time by a Japanese group [16]. Reassortment events detected for the external and internal genes of H3N2 virus isolated in Germany during 1998–1999 prompted us to examine the origin of all eight genes of H3N2 viruses circulating during distinct seasons to get more information about the appearance of intra-subtype reassortment and its contribution to the evolution of influenza A(H3N2) viruses.

Section snippets

Material and methods

Influenza A(H3N2) viruses isolated in Germany from October 1998 to April 2005 were obtained from the strain collection of the National Influenza Centre. Between 10 and 15 strains of each season were selected to represent different regions of the country. Influenza viruses isolated in Germany are named according to the county where the sample was taken. The abbreviations used for different counties are as follows: Bayern (BAY), Baden-Württemberg (BWB), Berlin (BLN), Brandenburg (BBG), Bremen

Season 1998–1999

Phylogenetic analysis of the external genes of viruses from the season 1998–1999 revealed a high degree of variability. The HA genes of eight isolates were closely related to that of the reference strain Moscow/99 (clade B) whereas five strains had HA genes which were closer to that of the reference strain Panama/99 (Fig. 1 clade C). The NA genes of 1998–1999 viruses fell broadly into three groups. Two viruses grouped with the reference strain Moscow/99 (clade B) whereas one of them was closer

Discussion

Recurrent epidemics of influenza are caused by the frequent emergence of new antigenic variants. With co-circulation of two influenza A virus subtypes and two antigenically distinct lineages of B viruses, genetic reassortment has an important role in antigenic drift [19], [20]. Genetic reassortment of the NA gene between two variants of H3N2 viruses was first described in 1996 [15]. Evolutionary analysis of the NS gene led to the conclusion that reassortment between co-circulating viruses is a

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