Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination
Background: While mRNA vaccines effectively limit hospitalization and severe COVID-19 disease, the precise early innate immune mechanisms associated with their efficacy and reactogenicity remain underexplored. The identification of innate immune correlates prior to vaccination could provide mechanis...
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MDPI AG
2025-07-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/13/7/718 |
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| author | Amanda E. Zelkoski Emilie Goguet Emily Samuels Darcey Mohamad-Gabriel Alameh Hooda Said Simon Pollett John H. Powers Eric D. Laing Cara Olsen Edward Mitre Allison M. W. Malloy |
| author_facet | Amanda E. Zelkoski Emilie Goguet Emily Samuels Darcey Mohamad-Gabriel Alameh Hooda Said Simon Pollett John H. Powers Eric D. Laing Cara Olsen Edward Mitre Allison M. W. Malloy |
| author_sort | Amanda E. Zelkoski |
| collection | DOAJ |
| description | Background: While mRNA vaccines effectively limit hospitalization and severe COVID-19 disease, the precise early innate immune mechanisms associated with their efficacy and reactogenicity remain underexplored. The identification of innate immune correlates prior to vaccination could provide mechanistic insights and potentially predict responses. Methods: We developed an in vitro model to study the innate immune activation of pre-vaccination peripheral blood mononuclear cells (PBMCs) collected from participants enrolled in a well-characterized COVID-19 BioNTech/Pfizer BNT162b2 vaccine (BNT162b2 vaccine) cohort. Pre-vaccination PBMCs were stimulated with empty lipid nanoparticle (LNP), mRNA-LNP, or Toll-like receptor (TLR) agonists. Using multiparameter spectral flow cytometry, we analyzed the baseline immune state, innate responsiveness to stimuli, and cytokine profiles of study participants. These pre-vaccination in vitro results were analyzed for correlations with post-vaccination symptoms and spike-specific IgG responses. Results: Baseline dendritic cell (DC) states inversely correlated with the magnitude of symptoms following BNT162b2 vaccination. Heightened conventional (cDC) and weaker plasmacytoid DC (pDC) responses to RNA stimuli correlated with the magnitude of an acute IgG response. IgG durability modestly correlated with a lower pDC state but higher cDC2 and monocyte baseline states and inversely correlated with TLR3 agonist responsiveness. Conclusions: The pre-vaccination assessment of innate immune function and resting states can be used to fit models potentially predictive of immunogenicity and reactogenicity to BNT162b2 vaccination. Pre-vaccination DC states may influence reactogenicity, while the response to RNA may impact antibody responses. Our data suggest that pre-vaccination assessment offers insights into the innate mechanisms driving mRNA vaccine responses and has predictive potential. |
| format | Article |
| id | doaj-art-bb1cfb864d1c4c5ea0098c4d94aebc64 |
| institution | DOAJ |
| issn | 2076-393X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj-art-bb1cfb864d1c4c5ea0098c4d94aebc642025-08-20T03:13:58ZengMDPI AGVaccines2076-393X2025-07-0113771810.3390/vaccines13070718Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA VaccinationAmanda E. Zelkoski0Emilie Goguet1Emily Samuels Darcey2Mohamad-Gabriel Alameh3Hooda Said4Simon Pollett5John H. Powers6Eric D. Laing7Cara Olsen8Edward Mitre9Allison M. W. Malloy10Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USAThe Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20814, USAThe Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20814, USADepartment of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAThe Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20814, USAClinical Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USADepartment of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USADepartment of Preventive Medicine & Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USADepartment of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USADepartment of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USABackground: While mRNA vaccines effectively limit hospitalization and severe COVID-19 disease, the precise early innate immune mechanisms associated with their efficacy and reactogenicity remain underexplored. The identification of innate immune correlates prior to vaccination could provide mechanistic insights and potentially predict responses. Methods: We developed an in vitro model to study the innate immune activation of pre-vaccination peripheral blood mononuclear cells (PBMCs) collected from participants enrolled in a well-characterized COVID-19 BioNTech/Pfizer BNT162b2 vaccine (BNT162b2 vaccine) cohort. Pre-vaccination PBMCs were stimulated with empty lipid nanoparticle (LNP), mRNA-LNP, or Toll-like receptor (TLR) agonists. Using multiparameter spectral flow cytometry, we analyzed the baseline immune state, innate responsiveness to stimuli, and cytokine profiles of study participants. These pre-vaccination in vitro results were analyzed for correlations with post-vaccination symptoms and spike-specific IgG responses. Results: Baseline dendritic cell (DC) states inversely correlated with the magnitude of symptoms following BNT162b2 vaccination. Heightened conventional (cDC) and weaker plasmacytoid DC (pDC) responses to RNA stimuli correlated with the magnitude of an acute IgG response. IgG durability modestly correlated with a lower pDC state but higher cDC2 and monocyte baseline states and inversely correlated with TLR3 agonist responsiveness. Conclusions: The pre-vaccination assessment of innate immune function and resting states can be used to fit models potentially predictive of immunogenicity and reactogenicity to BNT162b2 vaccination. Pre-vaccination DC states may influence reactogenicity, while the response to RNA may impact antibody responses. Our data suggest that pre-vaccination assessment offers insights into the innate mechanisms driving mRNA vaccine responses and has predictive potential.https://www.mdpi.com/2076-393X/13/7/718mRNA vaccineBNT162b2antibodydendritic cellsmonocytesreactogenicity |
| spellingShingle | Amanda E. Zelkoski Emilie Goguet Emily Samuels Darcey Mohamad-Gabriel Alameh Hooda Said Simon Pollett John H. Powers Eric D. Laing Cara Olsen Edward Mitre Allison M. W. Malloy Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination Vaccines mRNA vaccine BNT162b2 antibody dendritic cells monocytes reactogenicity |
| title | Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination |
| title_full | Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination |
| title_fullStr | Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination |
| title_full_unstemmed | Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination |
| title_short | Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination |
| title_sort | pre vaccination immune profiles and responsiveness to innate stimuli predict reactogenicity and antibody magnitude following mrna vaccination |
| topic | mRNA vaccine BNT162b2 antibody dendritic cells monocytes reactogenicity |
| url | https://www.mdpi.com/2076-393X/13/7/718 |
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