CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy.
Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-05-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011357 |
| _version_ | 1797821994035576832 |
|---|---|
| author | Colin P Sharp Beth H Thompson Tessa J Nash Ola Diebold Rute M Pinto Luke Thorley Yao-Tang Lin Samantha Sives Helen Wise Sara Clohisey Hendry Finn Grey Lonneke Vervelde Peter Simmonds Paul Digard Eleanor R Gaunt |
| author_facet | Colin P Sharp Beth H Thompson Tessa J Nash Ola Diebold Rute M Pinto Luke Thorley Yao-Tang Lin Samantha Sives Helen Wise Sara Clohisey Hendry Finn Grey Lonneke Vervelde Peter Simmonds Paul Digard Eleanor R Gaunt |
| author_sort | Colin P Sharp |
| collection | DOAJ |
| description | Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein (ZAP), and so in principle, removing ZAP sensing from a virus propagation system will reverse attenuation of a CpG-enriched virus, enabling high titre yield of a vaccine virus. We tested this using a vaccine strain of influenza A virus (IAV) engineered for increased CpG content in genome segment 1. Virus attenuation was mediated by the short isoform of ZAP, correlated with the number of CpGs added, and was enacted via turnover of viral transcripts. The CpG-enriched virus was strongly attenuated in mice, yet conveyed protection from a potentially lethal challenge dose of wildtype virus. Importantly for vaccine development, CpG-enriched viruses were genetically stable during serial passage. Unexpectedly, in both MDCK cells and embryonated hens' eggs that are used to propagate live attenuated influenza vaccines, the ZAP-sensitive virus was fully replication competent. Thus, ZAP-sensitive CpG enriched viruses that are defective in human systems can yield high titre in vaccine propagation systems, providing a realistic, economically viable platform to augment existing live attenuated vaccines. |
| first_indexed | 2024-03-13T10:01:16Z |
| format | Article |
| id | doaj.art-6c1353e296d148f5a88dfc35be436326 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-13T10:01:16Z |
| publishDate | 2023-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-6c1353e296d148f5a88dfc35be4363262023-05-23T05:31:32ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-05-01195e101135710.1371/journal.ppat.1011357CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy.Colin P SharpBeth H ThompsonTessa J NashOla DieboldRute M PintoLuke ThorleyYao-Tang LinSamantha SivesHelen WiseSara Clohisey HendryFinn GreyLonneke VerveldePeter SimmondsPaul DigardEleanor R GauntSynonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein (ZAP), and so in principle, removing ZAP sensing from a virus propagation system will reverse attenuation of a CpG-enriched virus, enabling high titre yield of a vaccine virus. We tested this using a vaccine strain of influenza A virus (IAV) engineered for increased CpG content in genome segment 1. Virus attenuation was mediated by the short isoform of ZAP, correlated with the number of CpGs added, and was enacted via turnover of viral transcripts. The CpG-enriched virus was strongly attenuated in mice, yet conveyed protection from a potentially lethal challenge dose of wildtype virus. Importantly for vaccine development, CpG-enriched viruses were genetically stable during serial passage. Unexpectedly, in both MDCK cells and embryonated hens' eggs that are used to propagate live attenuated influenza vaccines, the ZAP-sensitive virus was fully replication competent. Thus, ZAP-sensitive CpG enriched viruses that are defective in human systems can yield high titre in vaccine propagation systems, providing a realistic, economically viable platform to augment existing live attenuated vaccines.https://doi.org/10.1371/journal.ppat.1011357 |
| spellingShingle | Colin P Sharp Beth H Thompson Tessa J Nash Ola Diebold Rute M Pinto Luke Thorley Yao-Tang Lin Samantha Sives Helen Wise Sara Clohisey Hendry Finn Grey Lonneke Vervelde Peter Simmonds Paul Digard Eleanor R Gaunt CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy. PLoS Pathogens |
| title | CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy. |
| title_full | CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy. |
| title_fullStr | CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy. |
| title_full_unstemmed | CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy. |
| title_short | CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy. |
| title_sort | cpg dinucleotide enrichment in the influenza a virus genome as a live attenuated vaccine development strategy |
| url | https://doi.org/10.1371/journal.ppat.1011357 |
| work_keys_str_mv | AT colinpsharp cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT bethhthompson cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT tessajnash cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT oladiebold cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT rutempinto cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT lukethorley cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT yaotanglin cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT samanthasives cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT helenwise cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT saraclohiseyhendry cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT finngrey cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT lonnekevervelde cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT petersimmonds cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT pauldigard cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy AT eleanorrgaunt cpgdinucleotideenrichmentintheinfluenzaavirusgenomeasaliveattenuatedvaccinedevelopmentstrategy |