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Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants

Serum titers of SARS-CoV-2 neutralizing antibodies (nAb) correlate well with protection from symptomatic COVID-19, but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are life-long after measles vaccination, possibly due to persistence of th...

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Autores principales: Muñoz-Alía, Miguel Á., Nace, Rebecca A., Balakrishnan, Baskar, Zhang, Lianwen, Packiriswamy, Nandakumar, Singh, Gagandeep, Warang, Prajakta, Mena, Ignacio, Narjari, Riya, Vandergaast, Rianna, García-Sastre, Adolfo, Schotsaert, Michael, Russell, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774211/
https://www.ncbi.nlm.nih.gov/pubmed/36561187
http://dx.doi.org/10.1101/2022.12.16.520799
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author Muñoz-Alía, Miguel Á.
Nace, Rebecca A.
Balakrishnan, Baskar
Zhang, Lianwen
Packiriswamy, Nandakumar
Singh, Gagandeep
Warang, Prajakta
Mena, Ignacio
Narjari, Riya
Vandergaast, Rianna
García-Sastre, Adolfo
Schotsaert, Michael
Russell, Stephen J.
author_facet Muñoz-Alía, Miguel Á.
Nace, Rebecca A.
Balakrishnan, Baskar
Zhang, Lianwen
Packiriswamy, Nandakumar
Singh, Gagandeep
Warang, Prajakta
Mena, Ignacio
Narjari, Riya
Vandergaast, Rianna
García-Sastre, Adolfo
Schotsaert, Michael
Russell, Stephen J.
author_sort Muñoz-Alía, Miguel Á.
collection PubMed
description Serum titers of SARS-CoV-2 neutralizing antibodies (nAb) correlate well with protection from symptomatic COVID-19, but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are life-long after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We therefore sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated potent induction of high titer nAb in measles-immune mice and confirmed the significant incremental contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin-display of the SARS-CoV-2 spike glycoprotein, and vaccine resurfacing. In animals primed and boosted with a MeV vaccine encoding the ancestral SARS-CoV-2 spike, high titer nAb responses against ancestral virus strains were only weakly cross-reactive with the omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the omicron BA.1 spike, antibody titers to both ancestral and omicron strains were robustly elevated and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that antigen engineering can enable the development of potent measles-based SARS-CoV-2 vaccine candidates.
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spelling pubmed-97742112022-12-23 Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants Muñoz-Alía, Miguel Á. Nace, Rebecca A. Balakrishnan, Baskar Zhang, Lianwen Packiriswamy, Nandakumar Singh, Gagandeep Warang, Prajakta Mena, Ignacio Narjari, Riya Vandergaast, Rianna García-Sastre, Adolfo Schotsaert, Michael Russell, Stephen J. bioRxiv Article Serum titers of SARS-CoV-2 neutralizing antibodies (nAb) correlate well with protection from symptomatic COVID-19, but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are life-long after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We therefore sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated potent induction of high titer nAb in measles-immune mice and confirmed the significant incremental contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin-display of the SARS-CoV-2 spike glycoprotein, and vaccine resurfacing. In animals primed and boosted with a MeV vaccine encoding the ancestral SARS-CoV-2 spike, high titer nAb responses against ancestral virus strains were only weakly cross-reactive with the omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the omicron BA.1 spike, antibody titers to both ancestral and omicron strains were robustly elevated and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that antigen engineering can enable the development of potent measles-based SARS-CoV-2 vaccine candidates. Cold Spring Harbor Laboratory 2022-12-16 /pmc/articles/PMC9774211/ /pubmed/36561187 http://dx.doi.org/10.1101/2022.12.16.520799 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Muñoz-Alía, Miguel Á.
Nace, Rebecca A.
Balakrishnan, Baskar
Zhang, Lianwen
Packiriswamy, Nandakumar
Singh, Gagandeep
Warang, Prajakta
Mena, Ignacio
Narjari, Riya
Vandergaast, Rianna
García-Sastre, Adolfo
Schotsaert, Michael
Russell, Stephen J.
Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
title Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
title_full Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
title_fullStr Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
title_full_unstemmed Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
title_short Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
title_sort surface-modified measles vaccines encoding oligomeric, fusion-stabilized sars-cov-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774211/
https://www.ncbi.nlm.nih.gov/pubmed/36561187
http://dx.doi.org/10.1101/2022.12.16.520799
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