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Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-vaccinated ACE2-humanized Mice (preprint)
biorxiv; 2023.
Preprint
em Inglês
| bioRxiv | ID: ppzbmed-10.1101.2023.10.18.563016
ABSTRACT
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.
Texto completo:
Disponível
Coleções:
Preprints
Base de dados:
bioRxiv
Assunto principal:
Pneumonia
/
Embolia Pulmonar
/
Doenças Respiratórias
/
Síndrome Respiratória Aguda Grave
/
Dor Irruptiva
/
COVID-19
Idioma:
Inglês
Ano de publicação:
2023
Tipo de documento:
Preprint
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