Live Attenuated Influenza Vaccine contains Substantial and Unexpected Amounts of Defective Viral Genomic RNA

Philip S Gould, Andrew J Easton, Nigel J Dimmock

Research output: Contribution to journalArticle

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22 Downloads (Pure)

Abstract

The live attenuated influenza vaccine FluMist® was withdrawn in the USA by the Centers for Disease Control and Prevention after its failure to provide adequate protective immunity during 2013-2016. The vaccine uses attenuated core type A and type B viruses, reconfigured each year to express the two major surface antigens of the currently circulating viruses. Here Fluenz™ Tetra, the European version of this vaccine, was examined directly for defective-interfering (DI) viral RNAs. DI RNAs are deleted versions of the infectious virus genome, and have powerful biological properties including attenuation of infection, reduction of infectious virus yield, and stimulation of some immune responses. Reverse transcription polymerase chain reaction followed by cloning and sequencing showed that Fluenz™ vaccine contains unexpected and substantial amounts of DI RNA arising from both its influenza A and influenza B components, with 87 different DI RNA sequences identified. Flu A DI RNAs from segment 3 replaced the majority of the genomic full-length segment 3, thus compromising its infectivity. DI RNAs arise during vaccine production and non-infectious DI virus replaces infectious virus pro rata so that fewer doses of the vaccine can be made. Instead the vaccine carries a large amount of non-infectious but biologically active DI virus. The presence of DI RNAs could significantly reduce the multiplication in the respiratory tract of the vaccine leading to reduced immunizing efficacy and could also stimulate the host antiviral responses, further depressing vaccine multiplication. The role of DI viruses in the performance of this and other vaccines requires further investigation.

Original languageEnglish
Article number269
JournalViruses
Volume9
Issue number10
DOIs
Publication statusPublished - 21 Sep 2017

Fingerprint

Attenuated Vaccines
Influenza Vaccines
Viral RNA
Vaccines
Defective Viruses
RNA
Viruses
Human Influenza
Cercopithecine Herpesvirus 1
Surface Antigens
Centers for Disease Control and Prevention (U.S.)
Respiratory System
Reverse Transcription
Antiviral Agents
Organism Cloning
Immunity
Genome
Polymerase Chain Reaction
Infection

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Keywords

  • Animals
  • Chick Embryo
  • Defective Viruses
  • Genome, Viral
  • Humans
  • Immunogenicity, Vaccine
  • Influenza A virus
  • Influenza Vaccines
  • Influenza, Human
  • Influenzavirus B
  • RNA, Viral
  • Vaccines, Attenuated
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Live Attenuated Influenza Vaccine contains Substantial and Unexpected Amounts of Defective Viral Genomic RNA. / Gould, Philip S; Easton, Andrew J; Dimmock, Nigel J.

In: Viruses, Vol. 9, No. 10, 269, 21.09.2017.

Research output: Contribution to journalArticle

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abstract = "The live attenuated influenza vaccine FluMist{\circledR} was withdrawn in the USA by the Centers for Disease Control and Prevention after its failure to provide adequate protective immunity during 2013-2016. The vaccine uses attenuated core type A and type B viruses, reconfigured each year to express the two major surface antigens of the currently circulating viruses. Here Fluenz™ Tetra, the European version of this vaccine, was examined directly for defective-interfering (DI) viral RNAs. DI RNAs are deleted versions of the infectious virus genome, and have powerful biological properties including attenuation of infection, reduction of infectious virus yield, and stimulation of some immune responses. Reverse transcription polymerase chain reaction followed by cloning and sequencing showed that Fluenz™ vaccine contains unexpected and substantial amounts of DI RNA arising from both its influenza A and influenza B components, with 87 different DI RNA sequences identified. Flu A DI RNAs from segment 3 replaced the majority of the genomic full-length segment 3, thus compromising its infectivity. DI RNAs arise during vaccine production and non-infectious DI virus replaces infectious virus pro rata so that fewer doses of the vaccine can be made. Instead the vaccine carries a large amount of non-infectious but biologically active DI virus. The presence of DI RNAs could significantly reduce the multiplication in the respiratory tract of the vaccine leading to reduced immunizing efficacy and could also stimulate the host antiviral responses, further depressing vaccine multiplication. The role of DI viruses in the performance of this and other vaccines requires further investigation.",
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