Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge.
Zika virus (ZIKV) is a mosquito-borne flavivirus with maternal infection associated with preterm birth, congenital malformations, and fetal death, and adult infection associated with Guillain-Barré syndrome. Recent widespread endemic transmission of ZIKV and the potential for future outbreaks necess...
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ftdoajarticles:oai:doaj.org/article:f3fe48d30d62421cb530592af7854bb0 2023-05-15T15:15:05+02:00 Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. Danielle Thompson Ben Guenther Darly Manayani Jason Mendy Jonathan Smith Diego A Espinosa Eva Harris Jeff Alexander Lo Vang Christopher S Morello 2022-07-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010588 https://doaj.org/article/f3fe48d30d62421cb530592af7854bb0 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010588 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010588 https://doaj.org/article/f3fe48d30d62421cb530592af7854bb0 PLoS Neglected Tropical Diseases, Vol 16, Iss 7, p e0010588 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010588 2022-12-31T01:05:24Z Zika virus (ZIKV) is a mosquito-borne flavivirus with maternal infection associated with preterm birth, congenital malformations, and fetal death, and adult infection associated with Guillain-Barré syndrome. Recent widespread endemic transmission of ZIKV and the potential for future outbreaks necessitate the development of an effective vaccine. We developed a ZIKV vaccine candidate based on virus-like-particles (VLPs) generated following transfection of mammalian HEK293T cells using a plasmid encoding the pre-membrane/membrane (prM/M) and envelope (E) structural protein genes. VLPs were collected from cell culture supernatant and purified by column chromatography with yields of approximately 1-2mg/L. To promote increased particle yields, a single amino acid change of phenylalanine to alanine was made in the E fusion loop at position 108 (F108A) of the lead VLP vaccine candidate. This mutation resulted in a modest 2-fold increase in F108A VLP production with no detectable prM processing by furin to a mature particle, in contrast to the lead candidate (parent). To evaluate immunogenicity and efficacy, AG129 mice were immunized with a dose titration of either the immature F108A or lead VLP (each alum adjuvanted). The resulting VLP-specific binding antibody (Ab) levels were comparable. However, geometric mean neutralizing Ab (nAb) titers using a recombinant ZIKV reporter were significantly lower with F108A immunization compared to lead. After virus challenge, all lead VLP-immunized groups showed a significant 3- to 4-Log10 reduction in mean ZIKV RNAemia levels compared with control mice immunized only with alum, but the RNAemia reduction of 0.5 Log10 for F108A groups was statistically similar to the control. Successful viral control by the lead VLP candidate following challenge supports further vaccine development for this candidate. Notably, nAb titer levels in the lead, but not F108A, VLP-immunized mice inversely correlated with RNAemia. Further evaluation of sera by an in vitro Ab-dependent enhancement assay ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Barré ENVELOPE(-68.550,-68.550,-67.500,-67.500) PLOS Neglected Tropical Diseases 16 7 e0010588 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Danielle Thompson Ben Guenther Darly Manayani Jason Mendy Jonathan Smith Diego A Espinosa Eva Harris Jeff Alexander Lo Vang Christopher S Morello Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Zika virus (ZIKV) is a mosquito-borne flavivirus with maternal infection associated with preterm birth, congenital malformations, and fetal death, and adult infection associated with Guillain-Barré syndrome. Recent widespread endemic transmission of ZIKV and the potential for future outbreaks necessitate the development of an effective vaccine. We developed a ZIKV vaccine candidate based on virus-like-particles (VLPs) generated following transfection of mammalian HEK293T cells using a plasmid encoding the pre-membrane/membrane (prM/M) and envelope (E) structural protein genes. VLPs were collected from cell culture supernatant and purified by column chromatography with yields of approximately 1-2mg/L. To promote increased particle yields, a single amino acid change of phenylalanine to alanine was made in the E fusion loop at position 108 (F108A) of the lead VLP vaccine candidate. This mutation resulted in a modest 2-fold increase in F108A VLP production with no detectable prM processing by furin to a mature particle, in contrast to the lead candidate (parent). To evaluate immunogenicity and efficacy, AG129 mice were immunized with a dose titration of either the immature F108A or lead VLP (each alum adjuvanted). The resulting VLP-specific binding antibody (Ab) levels were comparable. However, geometric mean neutralizing Ab (nAb) titers using a recombinant ZIKV reporter were significantly lower with F108A immunization compared to lead. After virus challenge, all lead VLP-immunized groups showed a significant 3- to 4-Log10 reduction in mean ZIKV RNAemia levels compared with control mice immunized only with alum, but the RNAemia reduction of 0.5 Log10 for F108A groups was statistically similar to the control. Successful viral control by the lead VLP candidate following challenge supports further vaccine development for this candidate. Notably, nAb titer levels in the lead, but not F108A, VLP-immunized mice inversely correlated with RNAemia. Further evaluation of sera by an in vitro Ab-dependent enhancement assay ... |
format |
Article in Journal/Newspaper |
author |
Danielle Thompson Ben Guenther Darly Manayani Jason Mendy Jonathan Smith Diego A Espinosa Eva Harris Jeff Alexander Lo Vang Christopher S Morello |
author_facet |
Danielle Thompson Ben Guenther Darly Manayani Jason Mendy Jonathan Smith Diego A Espinosa Eva Harris Jeff Alexander Lo Vang Christopher S Morello |
author_sort |
Danielle Thompson |
title |
Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. |
title_short |
Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. |
title_full |
Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. |
title_fullStr |
Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. |
title_full_unstemmed |
Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge. |
title_sort |
zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect ag129 mice against zika virus challenge. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0010588 https://doaj.org/article/f3fe48d30d62421cb530592af7854bb0 |
long_lat |
ENVELOPE(-68.550,-68.550,-67.500,-67.500) |
geographic |
Arctic Barré |
geographic_facet |
Arctic Barré |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 7, p e0010588 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010588 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010588 https://doaj.org/article/f3fe48d30d62421cb530592af7854bb0 |
op_doi |
https://doi.org/10.1371/journal.pntd.0010588 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
16 |
container_issue |
7 |
container_start_page |
e0010588 |
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