Development of high-yield influenza A virus vaccine viruses

Ping, Jihui; Lopes, Tiago J. S.; Nidom, Chairul A.; Ghedin, Elodie; Macken, Catherine A.; Fitch, Adam; Imai, Masaki; Maher, Eileen A.; Kawaoka, Yoshihiro

doi:10.1038/ncomms9148

Cited by 90 publications

(84 citation statements)

References 54 publications

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“…To characterize the receptor-binding properties of the viruses tested here, we used a glycan array in which 129 diverse sialic acid-containing glycans were printed on a microarray (Table S8). Recombinant viruses possessing the HA and NA genes of GD/3, Anhui/1, or A/Kawasaki/173/2001 (H1N1; K173; chosen because of its known human-type receptor-binding specificity; (Imai et al, 2012) and the remaining genes from A/Puerto Rico/8/34 (H1N1; PR8) (Ping et al, 2015) were generated by reverse genetics, and subjected to glycan array analysis. K173 virus bound preferentially to α2,6-linked glycans (Figure 6A), as expected.…”

Section: Resultsmentioning

confidence: 99%

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Imai

Watanabe

Kiso

et al. 2017

Cell Host & Microbe

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129

135

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SUMMARY Low pathogenic H7N9 influenza has recently evolved to become highly pathogenic, raising concerns of a pandemic, particularly if these viruses acquire efficient human-to-human transmissibility. We compared a low pathogenic H7N9 virus with a highly pathogenic isolate, and two of its variants that represent neuraminidase inhibitor-sensitive and -resistant subpopulations detected within the isolate. The highly pathogenic H7N9 viruses replicated efficiently in mice, ferrets, and/or nonhuman primates, and were more pathogenic in mice and ferrets than the low pathogenic H7N9 virus, with the exception of the neuraminidase inhibitor-resistant virus, which showed mild-to-moderate attenuation. All viruses transmitted among ferrets via respiratory droplets, and the neuraminidase-sensitive variant killed several of the infected and exposed animals. Neuraminidase inhibitors showed limited effectiveness against these viruses in vivo, but the viruses were susceptible to a polymerase inhibitor. These results suggest that the highly pathogenic H7N9 virus has pandemic potential and should be closely monitored.

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Section: Resultsmentioning

confidence: 99%

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Imai

Watanabe

Kiso

et al. 2017

Cell Host & Microbe

Self Cite

129

135

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“…Examples of such efforts include the following: Improvement of the global strain‐selection process, coordinated by WHO, to incorporate newer methods for predicting virus evolution and drift and identification of virus vaccine candidates 23, 24 Increasing the availability of more high‐yield candidate vaccine viruses, including candidate vaccines that are optimized for specific production systems (e.g., cell‐based or egg production) 25, 26 Coordinating reagent production among regulatory agencies to address resource issues and developing backup strategies for reagent production to ensure availability in the case of unexpected problemsAccelerating the process of potency reagent calibration and developing improved methods for vaccine testing, such as new methods for testing potency and sterilityDeveloping new types of influenza vaccines with greater cross‐protection and longer duration of protectionIdentifying issues related to development and evaluation of novel influenza vaccines so that appropriate regulatory pathways can be employed to facilitate licensure …”

Section: Resultsmentioning

confidence: 99%

“…Increasing the availability of more high‐yield candidate vaccine viruses, including candidate vaccines that are optimized for specific production systems (e.g., cell‐based or egg production) 25, 26 …”

Section: Resultsmentioning

confidence: 99%

An overview of the regulation of influenza vaccines in the United States

Weir

Gruber

2016

Influenza Resp Viruses

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Influenza virus vaccines are unique among currently licensed viral vaccines. The vaccines designed to protect against seasonal influenza illness must be updated periodically in an effort to match the vaccine strain with currently circulating viruses, and the vaccine manufacturing timeline includes multiple, overlapping processes with a very limited amount of flexibility. In the United States (U.S.), over 150 million doses of seasonal trivalent and quadrivalent vaccine are produced annually, a mammoth effort, particularly in the context of a vaccine with components that usually change on a yearly basis. In addition, emergence of an influenza virus containing an HA subtype that has not recently circulated in humans is an ever present possibility. Recently, pandemic influenza vaccines have been licensed, and the pathways for licensure of pandemic vaccines and subsequent strain updating have been defined. Thus, there are formidable challenges for the regulation of currently licensed influenza vaccines, as well as for the regulation of influenza vaccines under development. This review describes the process of licensing influenza vaccines in the U.S., the process and steps involved in the annual updating of seasonal influenza vaccines, and some recent experiences and regulatory challenges faced in development and evaluation of novel influenza vaccines.

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“…The use of mammalian cells, e.g., Madin-Darby canine kidney (MDCK) cells and African monkey kidney cells (Vero), for the production of influenza viruses has been evaluated. Recently, Ping et al reported that a novel high-yield PR8 vaccine backbone strain isolated from random mutant virus libraries led to improvement in influenza vaccine titers in MDCK and Vero cells (47). Our findings may be additionally applied to mammalian cell-based systems for improving the efficiency of vaccine production.…”

Section: Discussionmentioning

confidence: 96%

Generation of a Genetically Stable High-Fidelity Influenza Vaccine Strain

Naito

Mori

Ushirogawa

et al. 2017

J Virol

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Vaccination is considered the most effective preventive means for influenza control. The development of a master virus with high growth and genetic stability, which may be used for the preparation of vaccine viruses by gene reassortment, is crucial for the enhancement of vaccine performance and efficiency of production. Here, we describe the generation of a high-fidelity and high-growth influenza vaccine master virus strain with a single V43I amino acid change in the PB1 polymerase of the high-growth A/Puerto Rico/8/1934 (PR8) master virus. The PB1-V43I mutation was introduced to increase replication fidelity in order to design an H1N1 vaccine strain with a low error rate. The PR8-PB1-V43I virus exhibited good replication compared with that of the parent PR8 virus. In order to compare the efficiency of egg adaptation and the occurrence of gene mutations leading to antigenic alterations, we constructed 6:2 genetic reassortant viruses between the A(H1N1)pdm09 and the PR8-PB1-V43I viruses; hemagglutinin (HA) and neuraminidase (NA) were from the A(H1N1)pdm09 virus, and the other genes were from the PR8 virus. Mutations responsible for egg adaptation mutations occurred in the HA of the PB1-V43I reassortant virus during serial egg passages; however, in contrast, antigenic mutations were introduced into the HA gene of the 6:2 reassortant virus possessing the wild-type PB1. This study shows that the mutant PR8 virus possessing the PB1 polymerase with the V43I substitution may be utilized as a master virus for the generation of high-growth vaccine viruses with high polymerase fidelity, low error rates of gene replication, and reduced antigenic diversity during virus propagation in eggs for vaccine production.IMPORTANCE Vaccination represents the most effective prophylactic option against influenza. The threat of emergence of influenza pandemics necessitates the ability to generate vaccine viruses rapidly. However, as the influenza virus exhibits a high mutation rate, vaccines must be updated to ensure a good match of the HA and NA antigens between the vaccine and the circulating strain. Here, we generated a genetically stable master virus of the A/Puerto Rico/8/1934 (H1N1) backbone encoding an engineered high-fidelity viral polymerase. Importantly, following the application of the high-fidelity PR8 backbone, no mutation resulting in antigenic change was introduced into the HA gene during propagation of the A(H1N1)pdm09 candidate vaccine virus. The low error rate of the present vaccine virus should decrease the risk of generating mutant viruses with increased virulence. Therefore, our findings are expected to be useful for the development of prepandemic vaccines and live attenuated vaccines with higher safety than that of the present candidate vaccines.

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Development of high-yield influenza A virus vaccine viruses

Cited by 90 publications

References 54 publications

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

An overview of the regulation of influenza vaccines in the United States

Generation of a Genetically Stable High-Fidelity Influenza Vaccine Strain

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