【AI Explained】Systems vaccinology of the BNT162b2 mRNA vaccine in humans.

Literature Information

TL;DR

This study utilizes a systems vaccinology approach to analyze the immune responses of 56 healthy volunteers vaccinated with the Pfizer-BioNTech mRNA vaccine, revealing robust neutralizing antibody production and significant increases in antigen-specific T cells, particularly after the second dose. The findings highlight that booster vaccination enhances the innate immune response and identifies distinct pathways linked to CD8 T cell and antibody responses, providing valuable insights into how mRNA vaccines prime the immune system for stronger protection against SARS-CoV-2 variants.

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mRNA vaccine · immune response · neutralizing antibodies · systems vaccinology · T cells

Abstract

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14+CD16+ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.

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Primary Questions Addressed

1. What are the specific mechanisms by which the BNT162b2 mRNA vaccine enhances the innate immune response upon booster vaccination?
2. How do the immune responses elicited by the BNT162b2 vaccine compare to those induced by other types of vaccines, such as inactivated or protein-based vaccines?
3. What role do specific immune cell types, such as CD4 and CD8 T cells, play in the overall effectiveness of the BNT162b2 mRNA vaccine against emerging variants of SARS-CoV-2?
4. How might individual variability in immune responses to the BNT162b2 vaccine influence recommendations for booster doses in different populations?
5. What are the long-term implications of the immune profiles generated by the BNT162b2 mRNA vaccine on future vaccine development and design?

Key Findings

Research Summary of “Systems Vaccinology of the BNT162b2 mRNA Vaccine in Humans”

Background and Purpose

The emergence of SARS-CoV-2 and the rapid development of mRNA vaccines, such as BNT162b2 by Pfizer-BioNTech, have revolutionized vaccinology. However, the mechanisms by which mRNA vaccines stimulate the immune system remain unclear. This study aimed to utilize a systems vaccinology approach to comprehensively profile both innate and adaptive immune responses in healthy volunteers vaccinated with the BNT162b2 vaccine.

Main Methods/Materials/Experimental Design

• Study Design: This was an observational study involving 56 healthy volunteers who received two doses of the BNT162b2 vaccine.
• Inclusion and Exclusion Criteria: Healthy adults were included; individuals with a history of severe allergic reactions to vaccines or known immunocompromised conditions were excluded.
• Vaccination Protocol: Participants received two doses of the vaccine, with the second dose administered 21 days after the first.
• Immune Response Assessment:
  • Antibody Responses: Measured using enzyme-linked immunosorbent assay (ELISA) and neutralization assays against the wild-type and B.1.351 variants of SARS-CoV-2.
  • T Cell Responses: Evaluated using intracellular cytokine staining for CD4 and CD8 T cells.
  • Innate Immune Profiling: Assessed using CyTOF (cytometry by time of flight) and plasma cytokine profiling via Olink.
  • Transcriptional Analysis: Conducted using bulk RNA sequencing and single-cell transcriptomics (CITE-seq).

Key Results and Findings

• Antibody Responses: The vaccine induced robust binding and neutralizing antibody responses in nearly all participants, significantly boosted after the second dose. Neutralizing antibodies against the B.1.351 variant were produced but at lower levels than against the wild-type strain.
• T Cell Responses: Post-vaccination, there was a marked increase in spike-specific CD4 and CD8 T cell responses, predominantly of the T-helper-1 type.
• Innate Immune Responses: After the second dose, there was a notable increase in inflammatory monocytes and elevated plasma levels of IFNγ and CXCL10, indicating a strong innate immune activation.
• Transcriptional Changes: Bulk RNA sequencing revealed a substantial increase in differentially expressed genes after the second dose, with significant enrichment in pathways related to antiviral responses and innate immunity.

Main Conclusions/Significance/Innovation

This study provides critical insights into the immune mechanisms activated by the BNT162b2 mRNA vaccine. It highlights the vaccine’s ability to prime both innate and adaptive immune responses effectively, especially following booster immunization. The findings suggest that mRNA vaccination can induce a unique transcriptional signature in myeloid cells, which may contribute to enhanced antiviral immunity.

Research Limitations and Future Directions

• Limitations: The study had a relatively small sample size and was conducted in a controlled setting, which may not fully represent broader population responses. Long-term immune response data post-vaccination were also limited.
• Future Directions: Further research is needed to explore the longevity of immune responses and the potential for mRNA vaccines to induce epigenetic changes in immune cells. Additionally, comparative studies with other vaccine platforms could provide further insights into the unique aspects of mRNA vaccine-induced immunity.

This comprehensive profiling of immune responses will aid in understanding how to optimize mRNA vaccines for COVID-19 and future infectious diseases.

References

1. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. - Fernando P Polack;Stephen J Thomas;Nicholas Kitchin;Judith Absalon;Alejandra Gurtman;Stephen Lockhart;John L Perez;Gonzalo Pérez Marc;Edson D Moreira;Cristiano Zerbini;Ruth Bailey;Kena A Swanson;Satrajit Roychoudhury;Kenneth Koury;Ping Li;Warren V Kalina;David Cooper;Robert W Frenck;Laura L Hammitt;Özlem Türeci;Haylene Nell;Axel Schaefer;Serhat Ünal;Dina B Tresnan;Susan Mather;Philip R Dormitzer;Uğur Şahin;Kathrin U Jansen;William C Gruber; - The New England journal of medicine (2020)
2. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. - Mark J Mulligan;Kirsten E Lyke;Nicholas Kitchin;Judith Absalon;Alejandra Gurtman;Stephen Lockhart;Kathleen Neuzil;Vanessa Raabe;Ruth Bailey;Kena A Swanson;Ping Li;Kenneth Koury;Warren Kalina;David Cooper;Camila Fontes-Garfias;Pei-Yong Shi;Özlem Türeci;Kristin R Tompkins;Edward E Walsh;Robert Frenck;Ann R Falsey;Philip R Dormitzer;William C Gruber;Uğur Şahin;Kathrin U Jansen - Nature (2020)
3. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. - Ugur Sahin;Alexander Muik;Evelyna Derhovanessian;Isabel Vogler;Lena M Kranz;Mathias Vormehr;Alina Baum;Kristen Pascal;Jasmin Quandt;Daniel Maurus;Sebastian Brachtendorf;Verena Lörks;Julian Sikorski;Rolf Hilker;Dirk Becker;Ann-Kathrin Eller;Jan Grützner;Carsten Boesler;Corinna Rosenbaum;Marie-Cristine Kühnle;Ulrich Luxemburger;Alexandra Kemmer-Brück;David Langer;Martin Bexon;Stefanie Bolte;Katalin Karikó;Tania Palanche;Boris Fischer;Armin Schultz;Pei-Yong Shi;Camila Fontes-Garfias;John L Perez;Kena A Swanson;Jakob Loschko;Ingrid L Scully;Mark Cutler;Warren Kalina;Christos A Kyratsous;David Cooper;Philip R Dormitzer;Kathrin U Jansen;Özlem Türeci - Nature (2020)
4. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. - Prabhu S Arunachalam;Florian Wimmers;Chris Ka Pun Mok;Ranawaka A P M Perera;Madeleine Scott;Thomas Hagan;Natalia Sigal;Yupeng Feng;Laurel Bristow;Owen Tak-Yin Tsang;Dhananjay Wagh;John Coller;Kathryn L Pellegrini;Dmitri Kazmin;Ghina Alaaeddine;Wai Shing Leung;Jacky Man Chun Chan;Thomas Shiu Hong Chik;Chris Yau Chung Choi;Christopher Huerta;Michele Paine McCullough;Huibin Lv;Evan Anderson;Srilatha Edupuganti;Amit A Upadhyay;Steve E Bosinger;Holden Terry Maecker;Purvesh Khatri;Nadine Rouphael;Malik Peiris;Bali Pulendran - Science (New York, N.Y.) (2020)
5. Systems biology of vaccination for seasonal influenza in humans. - Helder I Nakaya;Jens Wrammert;Eva K Lee;Luigi Racioppi;Stephanie Marie-Kunze;W Nicholas Haining;Anthony R Means;Sudhir P Kasturi;Nooruddin Khan;Gui-Mei Li;Megan McCausland;Vibhu Kanchan;Kenneth E Kokko;Shuzhao Li;Rivka Elbein;Aneesh K Mehta;Alan Aderem;Kanta Subbarao;Rafi Ahmed;Bali Pulendran - Nature immunology (2011)
6. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. - Troy D Querec;Rama S Akondy;Eva K Lee;Weiping Cao;Helder I Nakaya;Dirk Teuwen;Ali Pirani;Kim Gernert;Jiusheng Deng;Bruz Marzolf;Kathleen Kennedy;Haiyan Wu;Soumaya Bennouna;Herold Oluoch;Joseph Miller;Ricardo Z Vencio;Mark Mulligan;Alan Aderem;Rafi Ahmed;Bali Pulendran - Nature immunology (2009)
7. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. - Denis Gaucher;René Therrien;Nadia Kettaf;Bastian R Angermann;Geneviève Boucher;Abdelali Filali-Mouhim;Janice M Moser;Riyaz S Mehta;Donald R Drake;Erika Castro;Rama Akondy;Aline Rinfret;Bader Yassine-Diab;Elias A Said;Younes Chouikh;Mark J Cameron;Robert Clum;David Kelvin;Roland Somogyi;Larry D Greller;Robert S Balderas;Peter Wilkinson;Giuseppe Pantaleo;Jim Tartaglia;Elias K Haddad;Rafick-Pierre Sékaly - The Journal of experimental medicine (2008)
8. Global analyses of human immune variation reveal baseline predictors of postvaccination responses. - John S Tsang;Pamela L Schwartzberg;Yuri Kotliarov;Angelique Biancotto;Zhi Xie;Ronald N Germain;Ena Wang;Matthew J Olnes;Manikandan Narayanan;Hana Golding;Susan Moir;Howard B Dickler;Shira Perl;Foo Cheung; ; - Cell (2014)
9. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19. - Nicole Doria-Rose;Mehul S Suthar;Mat Makowski;Sarah O’Connell;Adrian B McDermott;Britta Flach;Julie E Ledgerwood;John R Mascola;Barney S Graham;Bob C Lin;Sijy O’Dell;Stephen D Schmidt;Alicia T Widge;Venkata-Viswanadh Edara;Evan J Anderson;Lilin Lai;Katharine Floyd;Nadine G Rouphael;Veronika Zarnitsyna;Paul C Roberts;Mamodikoe Makhene;Wendy Buchanan;Catherine J Luke;John H Beigel;Lisa A Jackson;Kathleen M Neuzil;Hamilton Bennett;Brett Leav;Jim Albert;Pratap Kunwar; - The New England journal of medicine (2021)
10. Neutralizing Activity of BNT162b2-Elicited Serum. - Yang Liu;Jianying Liu;Hongjie Xia;Xianwen Zhang;Camila R Fontes-Garfias;Kena A Swanson;Hui Cai;Ritu Sarkar;Wei Chen;Mark Cutler;David Cooper;Scott C Weaver;Alexander Muik;Ugur Sahin;Kathrin U Jansen;Xuping Xie;Philip R Dormitzer;Pei-Yong Shi - The New England journal of medicine (2021)

Literatures Citing This Work

1. The self-assembled nanoparticle-based trimeric RBD mRNA vaccine elicits robust and durable protective immunity against SARS-CoV-2 in mice. - Wenqiang Sun;Lihong He;He Zhang;Xiaodong Tian;Zhihua Bai;Lei Sun;Limin Yang;Xiaojuan Jia;Yuhai Bi;Tingrong Luo;Gong Cheng;Wenhui Fan;Wenjun Liu;Jing Li - Signal transduction and targeted therapy (2021)
2. Robust immune response to the BNT162b mRNA vaccine in an elderly population vaccinated 15 months after recovery from COVID-19. - Hye Kyung Lee;Ludwig Knabl;Ludwig Knabl;Sebastian Kapferer;Birgit Pateter;Mary Walter;Priscilla A Furth;Lothar Hennighausen - medRxiv : the preprint server for health sciences (2021)
3. Hidden in plain sight: uncovering the role of CREB1 in HIV-1 vaccine-induced immunity. - Helder I Nakaya - Nature immunology (2021)
4. Comparison of antibody and T cell responses elicited by BBIBP-CorV (Sinopharm) and BNT162b2 (Pfizer-BioNTech) vaccines against SARS-CoV-2 in healthy adult humans. - István Vályi-Nagy;Zsolt Matula;Márton Gönczi;Szabolcs Tasnády;Gabriella Bekő;Marienn Réti;Éva Ajzner;Ferenc Uher - GeroScience (2021)
5. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. - Rishi R Goel;Mark M Painter;Sokratis A Apostolidis;Divij Mathew;Wenzhao Meng;Aaron M Rosenfeld;Kendall A Lundgreen;Arnold Reynaldi;David S Khoury;Ajinkya Pattekar;Sigrid Gouma;Leticia Kuri-Cervantes;Philip Hicks;Sarah Dysinger;Amanda Hicks;Harsh Sharma;Sarah Herring;Scott Korte;Amy E Baxter;Derek A Oldridge;Josephine R Giles;Madison E Weirick;Christopher M McAllister;Moses Awofolaju;Nicole Tanenbaum;Elizabeth M Drapeau;Jeanette Dougherty;Sherea Long;Kurt D’Andrea;Jacob T Hamilton;Maura McLaughlin;Justine C Williams;Sharon Adamski;Oliva Kuthuru; ;Ian Frank;Michael R Betts;Laura A Vella;Alba Grifoni;Daniela Weiskopf;Alessandro Sette;Scott E Hensley;Miles P Davenport;Paul Bates;Eline T Luning Prak;Allison R Greenplate;E John Wherry - Science (New York, N.Y.) (2021)
6. Case Report: ANCA-Associated Vasculitis Presenting With Rhabdomyolysis and Pauci-Immune Crescentic Glomerulonephritis After Pfizer-BioNTech COVID-19 mRNA Vaccination. - Samy Hakroush;Björn Tampe - Frontiers in immunology (2021)
7. Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients. - Rima Hajjo;Dima A Sabbah;Sanaa K Bardaweel;Alexander Tropsha - Vaccines (2021)
8. Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022. - Kevin J Downes;Victoria A Statler;Rachel C Orscheln;Melissa K Cousino;Michael Green;Marian G Michaels;William J Muller;Tanvi S Sharma;Lara A Danziger-Isakov;Monica I Ardura - Journal of the Pediatric Infectious Diseases Society (2022)
9. Age-Dependent Reduction in Neutralization against Alpha and Beta Variants of BNT162b2 SARS-CoV-2 Vaccine-Induced Immunity. - Hitoshi Kawasuji;Yoshitomo Morinaga;Hideki Tani;Yumiko Saga;Makito Kaneda;Yushi Murai;Akitoshi Ueno;Yuki Miyajima;Yasutaka Fukui;Kentaro Nagaoka;Chikako Ono;Yoshiharu Matsuura;Hideki Niimi;Yoshihiro Yamamoto - Microbiology spectrum (2021)
10. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. - Mohamad-Gabriel Alameh;István Tombácz;Emily Bettini;Katlyn Lederer;Chutamath Sittplangkoon;Joel R Wilmore;Brian T Gaudette;Ousamah Y Soliman;Matthew Pine;Philip Hicks;Tomaz B Manzoni;James J Knox;John L Johnson;Dorottya Laczkó;Hiromi Muramatsu;Benjamin Davis;Wenzhao Meng;Aaron M Rosenfeld;Shirin Strohmeier;Paulo J C Lin;Barbara L Mui;Ying K Tam;Katalin Karikó;Alain Jacquet;Florian Krammer;Paul Bates;Michael P Cancro;Drew Weissman;Eline T Luning Prak;David Allman;Michela Locci;Norbert Pardi - Immunity (2021)

… (290 more literatures)

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