Improvement of H5N1 influenza vaccine viruses: Influence of internal gene segments of avian and human origin on production and hemagglutinin content

Abt, Marion; Jonge, Jørgen de; Laue, Michael; Wolff, Thorsten

doi:10.1016/j.vaccine.2011.05.036

Cited by 30 publications

(31 citation statements)

References 37 publications

(45 reference statements)

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“…Retrospective analysis of seven H3N2 viruses selected as candidate vaccine strains also exhibited similar patterns of protein expression, with those containing the seasonal PB1 gene having higher HA/NP ratios, suggesting that these viruses also had higher HA protein content in virions. In addition, a similar trend of poor growth but increased HA/NP ratio was described when the PB1 of an H5N1 virus was included with its HA and NA in reverse genetics-derived H5N1 vaccine candidates containing all other genes from PR8 virus (31). Supporting our findings, a recent study (32) used cryoelectron microscopy to determine the effect of gene constellation on virion morphology.…”

Section: Discussionsupporting

confidence: 85%

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

Cobbin

Verity

Gilbertson

et al. 2013

J Virol

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The yields of egg-grown influenza vaccines are maximized by the production of a seed strain using a reassortment of the seasonal influenza virus isolate with a highly egg-adapted strain. The seed virus is selected based on high yields of viral hemagglutinin (HA) and expression of the surface antigens from the seasonal isolate. The remaining proteins are usually derived from the highgrowth parent. However, a retrospective analysis of vaccine seeds revealed that the seasonal PB1 gene was selected in more than 50% of reassortment events. Using the model seasonal H3N2 virus A/Udorn/307/72 (Udorn) virus and the high-growth A/Puerto Rico/8/34 (PR8) virus, we assessed the influence of the source of the PB1 gene on virus growth and vaccine yield. Classical reassortment of these two strains led to the selection of viruses that predominantly had the Udorn PB1 gene. The presence of Udorn PB1 in the seed virus, however, did not result in higher yields of virus or HA compared to the yields in the corresponding seed virus with PR8 PB1. The 8-fold-fewer virions produced with the seed virus containing the Udorn PB1 were somewhat compensated for by a 4-fold increase in HA per virion. A higher HA/nucleoprotein (NP) ratio was found in past vaccine preparations when the seasonal PB1 was present, also indicative of a higher HA density in these vaccine viruses. As the HA viral RNA (vRNA) and mRNA levels in infected cells were similar, we propose that PB1 selectively alters the translation of viral mRNA. This study helps to explain the variability of vaccine seeds with respect to HA yield.

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Section: Discussionsupporting

confidence: 85%

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

Cobbin

Verity

Gilbertson

et al. 2013

J Virol

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“…Comparison of reassortant PR8-based IVSs containing PB1 Gi (5 1 2 1 1) or the indigenous PB1 segment (5 1 3) from the donor strain of the HA/NA segments Previous studies suggested that the inclusion of the indigenous PB1 from the IAV donor strain of the HA/NA segments to be transferred into PR8-based IVSs may help to improve replication efficiency (Abt et al, 2011;Wanitchang et al, 2010). Therefore, we compared the impact of the PB1 Gi against the indigenous PB1 of H5N1/KAN and H7N9/ Anhui viruses on the replication efficiency of either the 5+2+1 or 5+3 versions of H5N1 and H7N9 subtype IVSs, respectively.…”

Section: Pb1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Previous studies of HYR-IVSs produced by natural reassortment between circulating strains and PR8 have shown that the PB1 segment of many HYR-IVSs was derived from the circulating strain and, apparently, provided a significant growth advantage over IVSs that contained the PR8 PB1 segment (PB1 PR8 ) (Fulvini et al, 2011;Ramanunninair et al, 2013). This growth advantage was observed for both type A and type B HYR-IVSs (Abt et al, 2011;Compans et al, 1972;Le et al, 2015;Wanitchang et al, 2010). Furthermore, substitution of specific residues within the PB1 PR8 protein (G180E, S216G, S361R, Q621R and N654S), which are known to be involved in enzyme activity or protein interactions with the other polymerase proteins, were found to be beneficial (Plant et al, 2012;Ulmanen et al, 1981).…”

mentioning

confidence: 99%

“…Vero cells) are increasingly being used for the production of IVSs (Hess et al, 2012;Hu et al, 2015;Huang et al, 2015;Naruse et al, 2015). In many cases, however, PR8-based reassortants containing HA and NA segments from circulating strains fail to grow efficiently in embryonated eggs and/ or cell culture, providing a significant obstacle to efficient large-scale vaccine production (Abt et al, 2011;Compans et al, 1972;Wanitchang et al, 2010).Efficient IAV replication is linked to optimal activities and interactions of the viral polymerase complex (and its subunits and co-factors) (Ngai et al, 2013;Wille et al, 2013). Previous studies of HYR-IVSs produced by natural reassortment between circulating strains and PR8 have shown that the PB1 segment of many HYR-IVSs was derived from the circulating strain and, apparently, provided a significant growth advantage over IVSs that contained the PR8 PB1 segment (PB1 PR8 ) (Fulvini et al, 2011;Ramanunninair et al, 2013).…”

mentioning

confidence: 99%

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The PB1 segment of an influenza A virus H1N1 2009pdm isolate enhances the replication efficiency of specific influenza vaccine strains in cell culture and embryonated eggs

Mostafa

Kanrai

Ziebuhr

et al. 2016

Journal of General Virology

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Influenza vaccine strains (IVSs) contain the haemagglutinin (HA) and neuraminidase (NA) genome segments of relevant circulating strains in the genetic background of influenza A/ PR/8/1934 virus (PR8). Previous work has shown that the nature of the PB1 segment may be a limiting factor for the efficient production of IVSs. Here, we showed that the PB1 segment (PB1 Gi ) from the 2009 pandemic influenza A virus (IAV) A/Giessen/06/2009 (Gi wt, H1N1pdm) may help to resolve (some of) these limitations. We produced a set of recombinant PR8-derived viruses that contained (i) the HA and NA segments from representative IAV strains (H3N2, H5N1, H7N9, H9N2); (ii) the PB1 segment from PR8 or Gi wt, respectively; and (iii) the remaining five genome segments from PR8. Viruses containing the PB1 Gi segment, together with the heterologous HA/NA segments and five PR8 segments (5+2+1), replicated to higher titres compared with their 6+2 counterparts containing six PR8 segments and the equivalent heterologous HA/NA segments. Compared with PB1 PR8 -containing IVSs, viruses with the PB1 Gi segment replicated to higher or similar titres in both cell culture and embryonated eggs, most profoundly IVSs of the H5N1 and H7N9 subtype, which are known to grow poorly in these systems. IVSs containing either the PB1 Gi or the cognate PB1 segment of the respective specific HA/NA donor strain showed enhanced or similar virus replication levels. This study suggests that substitution of PB1 PR8 with the PB1 Gi segment may greatly improve the large-scale production of PR8-derived IVSs, especially of those known to replicate poorly in vitro. INTRODUCTIONInfluenza viruses belong to the family Orthomyxoviridae and are classified into three genera termed Influenza virus A, B and C. Among these, influenza A viruses (IAVs) pose the greatest threat to human and animal health. They contain eight segments of negative-sense ssRNA (Ritchey et al., 1976;Shaw & Palese, 2013). The eight genomic segments encode at least 10 viral proteins, comprising the three subunits of the viral RNA polymerase complex [polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1) and polymerase acidic protein (PA)], the surface glycoproteins [haemagglutinin (HA) and neuraminidase (NA)], the nucleoprotein (NP), the matrix protein (M1), the ion channel protein (M2), the non-structural protein 1 (NS1) and the nuclear export protein (NEP). IAVs are genetically diverse, with new strains rapidly emerging by point mutations introduced by the low-fidelity viral RNA replicase (potentially resulting in antigenic drift if changes occur in the HA and/or NA coding sequences and affect important antigenic epitopes) or by genetic reassortment of genomic segments (potentially leading to antigenic shift if antigenically distant HA and NA segments are incorporated). Minor and major antigenic changes in the HA and NA proteins of circulating IAV are important driving forces for the emergence of new strains causing epidemics or even major pandemics (Neumann et al., 2009;Peng et al., 2014;Smith...

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Molecular pathogenesis of H5 highly pathogenic avian influenza: the role of the haemagglutinin cleavage site motif

Luczo

Stambas

Durr

et al. 2015

Reviews in Medical Virology

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SummaryThe emergence of H5N1 highly pathogenic avian influenza has caused a heavy socio‐economic burden through culling of poultry to minimise human and livestock infection. Although human infections with H5N1 have to date been limited, concerns for the pandemic potential of this zoonotic virus have been greatly intensified following experimental evidence of aerosol transmission of H5N1 viruses in a mammalian infection model. In this review, we discuss the dominance of the haemagglutinin cleavage site motif as a pathogenicity determinant, the host‐pathogen molecular interactions driving cleavage activation, reverse genetics manipulations and identification of residues key to haemagglutinin cleavage site functionality and the mechanisms of cell and tissue damage during H5N1 infection. We specifically focus on the disease in chickens, as it is in this species that high pathogenicity frequently evolves and from which transmission to the human population occurs. With >75% of emerging infectious diseases being of zoonotic origin, it is necessary to understand pathogenesis in the primary host to explain spillover events into the human population. © 2015 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.

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Improvement of H5N1 influenza vaccine viruses: Influence of internal gene segments of avian and human origin on production and hemagglutinin content

Abstract: The H5N1-clade 1 influenza vaccine strain

Cited by 30 publications

References 37 publications

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

The PB1 segment of an influenza A virus H1N1 2009pdm isolate enhances the replication efficiency of specific influenza vaccine strains in cell culture and embryonated eggs

Molecular pathogenesis of H5 highly pathogenic avian influenza: the role of the haemagglutinin cleavage site motif

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