Host Adaptation and the Alteration of Viral Properties of the First Influenza A/H1N1pdm09 Virus Isolated in Japan

Ainai, Akira; Hasegawa, Hideki; Obuchi, Masatsugu; Odagiri, Takato; Ujike, Makoto; Saijo, Masayuki; Nobusawa, Eri; Tashiro, Masato; Asanuma, Hideki

doi:10.1371/journal.pone.0130208

Cited by 14 publications

(19 citation statements)

References 24 publications

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“…Substitution at residue 223 (Q223R) of HA has been observed to occur during the propagation of viruses in eggs (28,30); in the present study, this mutation also appeared in both PB1-wild type-6:2 and PB1-V43I-6:2 viruses during egg adaptation. L40P, V83A, and N146K substitutions in the NA were observed only with the PB1-wild type-6:2 virus following prolonged passaging.…”

Section: Resultssupporting

confidence: 61%

“…wt, wild type. the A(H1N1)pdm09 virus and HG-PR8 with wild-type PB1, the virus is required to undergo egg adaptation via serial passages in eggs (2,28). HA titers of both of the egg-passaged 6:2 reassortant viruses increased gradually with the number of passages (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Tables 3 and 4 show that the K154N mutation in group 3 and the G155E mutation in groups 1 and 2 were accompanied by low HAI titers. Several studies have attributed the low HAI titer to the amino acid substitutions at positions 154 and 155 of the HA protein (28,30). On the other hand, the amino acid changes K153E and N156D, which occurred in both 6:2 viruses, were located at the antigenic epitope Sa site (23,24).…”

Section: Resultsmentioning

confidence: 99%

“…An egg adaptation mutation leading to a Q223R substitution in HA was found to have occurred in the passaged viruses encoding both wild-type PB1 and PB1-V43I. The Q223R mutation in the receptor binding site improves infectivity in egg and in human cells without changing HA antigenicity (28,35). Interestingly, the K154N and G155E antigenic mutations were introduced into the HA of the PB1 wild-type vaccine virus following passages; however, these mutations were not found in the PB1-V43I vaccine strain (Tables 3 and 4).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Generation of a Genetically Stable High-Fidelity Influenza Vaccine Strain

Naito

Mori

Ushirogawa

et al. 2017

J Virol

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“…Mouse-adapted influenza virus A/ Narita/1/2009, which was obtained after 15 passages in mice, was used to represent the A(H1N1)pdm09 virus (pH1N1) in this study [26]. The virus was grown in the allantoic cavities of 10-to-11-day-old fertile chicken eggs.…”

Section: Virusmentioning

confidence: 99%

Impacts of allergic airway inflammation on lung pathology in a mouse model of influenza A virus infection

et al. 2017

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Influenza A virus is the respiratory pathogen responsible for influenza. Infection by the 2009 pandemic influenza A (H1N1) virus caused severe lower airway inflammation and pneumonia. Asthma is a chronic inflammatory disorder of the airways that affects the entire brachial tree, and was one of the commonest underlying medical conditions among patients hospitalized with the 2009 pandemic influenza virus infection. Although respiratory virus infections are the major causes of asthma exacerbation, the mechanism by which influenza exacerbates asthma is poorly understood. Animal models of disease comorbidity are crucial to understanding host-pathogen interactions and elucidating complex pathologies. Existing murine models of influenza virus infection in asthmatics show that asthmatic mice are highly resistant to influenza virus infection, which contradicts clinical observations in humans. Here, we developed a murine model of influenza virus/asthma comorbidity using NC/Nga mice, which are highly sensitive to allergic reactions such as atopic dermatitis and allergic airway inflammation. This model was then used to examine the impact of allergic airway inflammation on lung pathology in the 2009 pandemic influenza virus infected mice. The results showed that induction of acute allergic airway inflammation in pre-existing influenza virus infection had additive effects on exacerbation of lung pathology, which mirrors findings in human epidemiological studies. In contrast, pre-existing allergic airway inflammation protected from subsequent influenza virus infection, which was compatible with those of previous murine models of influenza virus infection in asthmatic mice. These variable outcomes of this murine model indicate that the temporal relation between allergic airway inflammation and influenza virus infection might play a critical role in asthma and influenza comorbidity. Thus, this murine model will further our understanding of how influenza virus infection affects an asthmatic host and may aid the development of strategies to improve treatments and outcomes for asthmatics harboring influenza virus infection.

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Efficient protection of mice from influenza A/H1N1pdm09 virus challenge infection via high avidity serum antibodies induced by booster immunizations with inactivated whole virus vaccine

Sato

Takahashi

Adachi

et al. 2019

Heliyon

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The immunogenicities of inactivated whole and split virus vaccines derived from influenza A/H1N1pdm09 virus were compared in a mouse model. We demonstrated the unique properties of whole virus vaccine boosters on the serum memory antibody response in mice. Consistent with previous studies, booster immunization with either whole or split virus vaccines of A/H1N1pdm09 virus produced comparable titers of serum antibodies with hemagglutination inhibition and virus-neutralizing activities. However, superior protection against the challenge infection was unexpectedly observed in mice primed and boosted with whole virus vaccines compared with those treated with split virus vaccines, despite similar levels of antibody titers in each group. Immune serum antibodies were shown to be primarily responsible for this protection via passive transfer experiments of immune serum antibodies to naive recipient mice. Moreover, this protection correlated with elevated affinity maturation of the antibodies. Thus, booster immunization with whole virus vaccines elicited a robust serum antibody response with high avidity to the virus, which was not measurable via conventional serological assays.

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Host Adaptation and the Alteration of Viral Properties of the First Influenza A/H1N1pdm09 Virus Isolated in Japan

Cited by 14 publications

References 24 publications

Generation of a Genetically Stable High-Fidelity Influenza Vaccine Strain

Generation of a Genetically Stable High-Fidelity Influenza Vaccine Strain

Impacts of allergic airway inflammation on lung pathology in a mouse model of influenza A virus infection

Efficient protection of mice from influenza A/H1N1pdm09 virus challenge infection via high avidity serum antibodies induced by booster immunizations with inactivated whole virus vaccine

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