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Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice

Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where alumi...

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Autores principales: Zhang, Tianyi, Magazine, Nicholas, McGee, Michael C., Carossino, Mariano, Veggiani, Gianluca, Kousoulas, Konstantin G., August, Avery, Huang, Weishan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614945/
https://www.ncbi.nlm.nih.gov/pubmed/37904941
http://dx.doi.org/10.1101/2023.10.18.563016
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author Zhang, Tianyi
Magazine, Nicholas
McGee, Michael C.
Carossino, Mariano
Veggiani, Gianluca
Kousoulas, Konstantin G.
August, Avery
Huang, Weishan
author_facet Zhang, Tianyi
Magazine, Nicholas
McGee, Michael C.
Carossino, Mariano
Veggiani, Gianluca
Kousoulas, Konstantin G.
August, Avery
Huang, Weishan
author_sort Zhang, Tianyi
collection PubMed
description Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4(+) T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety.
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spelling pubmed-106149452023-10-31 Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice Zhang, Tianyi Magazine, Nicholas McGee, Michael C. Carossino, Mariano Veggiani, Gianluca Kousoulas, Konstantin G. August, Avery Huang, Weishan bioRxiv Article Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4(+) T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety. Cold Spring Harbor Laboratory 2023-10-19 /pmc/articles/PMC10614945/ /pubmed/37904941 http://dx.doi.org/10.1101/2023.10.18.563016 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
Zhang, Tianyi
Magazine, Nicholas
McGee, Michael C.
Carossino, Mariano
Veggiani, Gianluca
Kousoulas, Konstantin G.
August, Avery
Huang, Weishan
Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
title Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
title_full Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
title_fullStr Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
title_full_unstemmed Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
title_short Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
title_sort th2 and th17-associated immunopathology following sars-cov-2 breakthrough infection in spike-vaccinated ace2-humanized mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614945/
https://www.ncbi.nlm.nih.gov/pubmed/37904941
http://dx.doi.org/10.1101/2023.10.18.563016
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