Replication of live attenuated influenza vaccine viruses in human nasal epithelial cells is associated with H1N1 vaccine effectiveness

Hawksworth, Amy; Lockhart, R.; Crowe, Jonathan; Maeso, Rubén; Ritter, Lydia; Dibben, Oliver; Bright, Helen

doi:10.1016/j.vaccine.2020.04.004

Cited by 19 publications

(31 citation statements)

References 35 publications

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“…2b), with A/NC99 reaching peak shedding levels 100-fold higher than those of A/BOL13 (P = 0.0078). This confirmed the A/BOL13 replicative fitness deficiency previously observed in hNEC 16 . Interestingly, while MLAIV A/NC99 shed significantly more infectious virus than MLAIV A/BOL13, viral RNA (vRNA) shedding for A/BOL13 was higher than that of A/NC99 ( Supplementary Fig.…”

Section: Introductionsupporting

confidence: 89%

“…However, to obtain sufficient egg yield, the A/BOL13 HA protein incorporated the residues N119 and D186, previously identified in an A/CA09 high growth reassortant 17 . However, both A/CA09 and A/BOL13 suffered from reduced replication in human nasal epithelial cells 16 . It is possible that these residues, while increasing egg yield, could have had a deleterious effect on virus replication in human cells and ferrets, although this has yet to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…1). Earlier studies had demonstrated that multi-cycle infectivity (TCID 50 ) for A/BOL13 in tissue culture was significantly lower than single-cycle (FFU) infectivity 16 . These observations suggested that the reduced fitness of A/BOL13 was at least partly due to a deficiency in fully infectious virus production.…”

Section: Discussionmentioning

confidence: 99%

“…Hawksworth et al previously showed that A/H1N1pdm09 LAIV strains suffered from reduced replicative fitness in hNEC, with A/ H1N1pdm09 strain A/BOL13 producing peak viral titers approximately 100-fold lower than those of clinically effective, pre-2009 strain A/NC99 16 . Here, we further demonstrated that the reduced fitness of A/BOL13 was replicated in vivo, with similarly decreased levels of MLAIV shedding in ferrets relative to A/NC99.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro investigations then found that post-pandemic A/ H1N1pdm09 replicative fitness in fully differentiated primary human nasal epithelial cells (hNEC) was significantly reduced relative to pre-2009 LAIV strains 16 . This provided a plausible root cause for a generalized reduction in A/H1N1pdm09 VE.…”

Section: Introductionmentioning

confidence: 99%

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Defining the root cause of reduced H1N1 live attenuated influenza vaccine effectiveness: low viral fitness leads to inter-strain competition

et al. 2021

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In the 2013–14 and 2015–16 influenza seasons, reduced vaccine effectiveness (VE) was observed for the H1N1 component of the FluMist quadrivalent live attenuated influenza vaccine (QLAIV) in the USA, leading to loss of Advisory Committee on Immunization Practices recommendation. Here we demonstrate in ferrets that 2015–16A/H1N1pdm09 vaccine strain A/Bolivia/559/2013 (A/BOL13) is outcompeted in trivalent (TLAIV) and QLAIV formulations, leading to reduced protection from wild-type challenge. While monovalent (MLAIV) A/BOL13 provided significant protection from wild-type virus shedding and fever at doses as low as 3.0 log10 fluorescent focus units (FFU), it failed to provide a similar level of protection in TLAIV or QLAIV formulation, even at a 6.0 log10 FFU dose. Conversely, clinically effective H1N1 strain A/New Caledonia/20/1999 provided significant protection in MLAIV, TLAIV, and QLAIV formulations. In conclusion, reduced A/BOL13 replicative fitness rendered it susceptible to inter-strain competition in QLAIV, contributing to its reduced VE in the 2015–16 season.

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Section: Introductionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Defining the root cause of reduced H1N1 live attenuated influenza vaccine effectiveness: low viral fitness leads to inter-strain competition

et al. 2021

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Assessment of trivalent live influenza vaccines in MDCK cell line

2021

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We applied a one-step reverse transcriptase real-time PCR (rRT-PCR) analysis using TaqMan technique to evaluate the infectious titers of vaccine strains containing in trivalent live influenza vaccines (LAIVs). The cold-adapted reassortant influenza viruses A/H1N1 pdm09, A/H3N2, B/Yamagata and B/Victoria, included in the composition of the LAIV in 2015-2016, 2017-2018 and 2018-2019 flu season were studied for reproductive activity in MDCK cells as part of a mono-vaccine and tri-vaccine. For this we have developed a set of specific primers and probes. Method validation was performed using ELISA-test after mouse monoclonal antibodies to hemagglutinin (HA) staining of MDCK monolayer. Influenza B viruses B/Yamagata and B/Victoria were studied in MDCK cells in mono-infection and coinfection with different multiplicity of infection (MOI) using quantitative rRT-PCR. RT-PCR analysis was adjusted to assess the growth characteristics of cold-adapted reassortant influenza viruses in MDCK cell line. The greatest suppression in the composition of the tri-vaccine was exposed to the H1N1 pdm09 LAIV component. Influenza B viruses are least suppressed in trivalent LAIV. Influenza viruses B/Yamagata and B/Victoria reproduced as part of a mixed preparation not lower, if not better than as a mono-preparation at an MOI of 0.1. At an MOI of 0.01, the reproduction of both B/Yamagata and B/Victoria in the mixture was reduced compared to mono-vaccine. The interference of trivalent LAIV vaccine viruses in MDCK cells was minimal at low dilutions. This indicates that it is undesirable to reduce the titers of vaccine viruses, including at the stages of transportation and storage of LAIV

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Changes in sialic acid binding associated with egg adaptation decrease live attenuated influenza virus replication in human nasal epithelial cell cultures

Powell

Liu

Pekosz

2021

Vaccine

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Replication of live attenuated influenza vaccine viruses in human nasal epithelial cells is associated with H1N1 vaccine effectiveness

Cited by 19 publications

References 35 publications

Defining the root cause of reduced H1N1 live attenuated influenza vaccine effectiveness: low viral fitness leads to inter-strain competition

Defining the root cause of reduced H1N1 live attenuated influenza vaccine effectiveness: low viral fitness leads to inter-strain competition

Assessment of trivalent live influenza vaccines in MDCK cell line

Changes in sialic acid binding associated with egg adaptation decrease live attenuated influenza virus replication in human nasal epithelial cell cultures

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