B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies

Ilana Fox-Fisher; Sheina Piyanzin; Mayan Briller; Esther Oiknine-Djian; Or Alfi; Roni Ben-Ami; Ayelet Peretz; Daniel Neiman; Bracha Lea Ochana; Ori Fridlich; Zeina Drawshy; Agnes Klochendler; Judith Magenheim; Danielle Share; Ran Avrahami; Yaarit Ribak; Aviv Talmon; Limor Rubin; Neta Milman; Meital Segev; Erik Feldman; Yuval Tal; Shai S. Shen-Orr; Benjamin Glaser; Ruth Shemer; Dana Wolf; Yuval Dor

doi:10.1016/j.medj.2022.05.005

B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies

Ilana Fox-Fisher, Sheina Piyanzin, Mayan Briller, Esther Oiknine-Djian, Or Alfi, Roni Ben-Ami, Ayelet Peretz, Daniel Neiman, Bracha Lea Ochana, Ori Fridlich, Zeina Drawshy, Agnes Klochendler, Judith Magenheim, Danielle Share, Ran Avrahami, Yaarit Ribak, Aviv Talmon, Limor Rubin, Neta Milman, Meital SegevErik Feldman, Yuval Tal, Shai S. Shen-Orr, Benjamin Glaser, Ruth Shemer, Dana Wolf, Yuval Dor

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: Much remains unknown regarding the response of the immune system to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. Methods: We employed circulating cell-free DNA (cfDNA) to assess the turnover of specific immune cell types following administration of the Pfizer/BioNTech vaccine. Findings: The levels of B cell cfDNA after the primary dose correlated with development of neutralizing antibodies and memory B cells after the booster, revealing a link between early B cell turnover—potentially reflecting affinity maturation—and later development of effective humoral response. We also observed co-elevation of B cell, T cell, and monocyte cfDNA after the booster, underscoring the involvement of innate immune cell turnover in the development of humoral and cellular adaptive immunity. Actual cell counts remained largely stable following vaccination, other than a previously demonstrated temporary reduction in neutrophil and lymphocyte counts. Conclusions: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine. Funding: This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S. and Y.D.), Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center.

Original language	English
Pages (from-to)	468-480.e5
Journal	Med
Volume	3
Issue number	7
DOIs	https://doi.org/10.1016/j.medj.2022.05.005
State	Published - 8 Jul 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Funding

We thank Idit Shiff and Abed Nasseredin from the Core Research Facility at The Hebrew University Faculty of Medicine for their support in sequencing analysis, and Noa Makhervax and Dr Lilach Gavish for help in coordinating the effort. This work was supported by a generous gift from Shlomo Kramer . Supported by grants from Human Islet Research Network ( HIRN UC4DK116274 and UC4DK104216 to R.S and Y.D.); Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund , The Israel Science Foundation , the Waldholtz/Pakula family , the Robert M. and Marilyn Sternberg Family Charitable Foundation , the Helmsley Charitable Trust , Grail, and the DON Foundation . Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center . We thank Idit Shiff and Abed Nasseredin from the Core Research Facility at The Hebrew University Faculty of Medicine for their support in sequencing analysis, and Noa Makhervax and Dr Lilach Gavish for help in coordinating the effort. This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S and Y.D.); Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation. Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center. Conceptualization, Y.D. and I.F.-F.; investigation, I.F.-F. S.P. M.B. E.O.-D. O.A. N.M. M.S. E.F. R.A. and O.F.; project administration, R.B.-A. A.P. D.N. B.-L.O. O.F. Z.D. A.K. J.M. D.S. Y.R. A.T. and L.R.; supervision, Y.D. R.S. B.G. D.W. Y.T. and S.S.S.-O.; writing – original draft, Y.D. and I.F.-F.; writing – review & editing, R.S. B.G. A.K. D.W. Y.T. and S.S.S.-O. I.F.-F. and R.A. performed statistical analyses. Y.D. I.F.-F. and R.S. had unrestricted access to all data. Y.D. and I.F.-F. prepared the first draft of the manuscript, which was reviewed and edited by all other authors. All authors agreed to submit the manuscript, read and approved the final draft, and take full responsibility for its content, including the accuracy of the data and statistical analysis. I.F.-F. B.G. R.S. and Y.D. have filed patents related to DNA methylation markers.

Funders	Funder number
Alex U Soyka Pancreatic Cancer Fund
Core Research Facility
Glassman Hebrew University Diabetes Center
Robert M. and Marilyn Sternberg Family Charitable Foundation
Waldholtz/Pakula family
National Institute of Diabetes and Digestive and Kidney Diseases	UC4DK104216
Leona M. and Harry B. Helmsley Charitable Trust
Human Islet Research Network	HIRN UC4DK116274
Israel Science Foundation
Stichting Diabetes Onderzoek Nederland

Keywords

BNT162b2
DNA methylation
SARS-CoV-2
Translation to patients
cfDNA
liquid biopsy
mRNA vaccine
memory B-cell
neutralizing antibody
tissue dynamics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.medj.2022.05.005

Cite this

Fox-Fisher, I., Piyanzin, S., Briller, M., Oiknine-Djian, E., Alfi, O., Ben-Ami, R., Peretz, A., Neiman, D., Ochana, B. L., Fridlich, O., Drawshy, Z., Klochendler, A., Magenheim, J., Share, D., Avrahami, R., Ribak, Y., Talmon, A., Rubin, L., Milman, N., ... Dor, Y. (2022). B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies. Med, 3(7), 468-480.e5. https://doi.org/10.1016/j.medj.2022.05.005

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title = "B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies",

abstract = "Background: Much remains unknown regarding the response of the immune system to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. Methods: We employed circulating cell-free DNA (cfDNA) to assess the turnover of specific immune cell types following administration of the Pfizer/BioNTech vaccine. Findings: The levels of B cell cfDNA after the primary dose correlated with development of neutralizing antibodies and memory B cells after the booster, revealing a link between early B cell turnover—potentially reflecting affinity maturation—and later development of effective humoral response. We also observed co-elevation of B cell, T cell, and monocyte cfDNA after the booster, underscoring the involvement of innate immune cell turnover in the development of humoral and cellular adaptive immunity. Actual cell counts remained largely stable following vaccination, other than a previously demonstrated temporary reduction in neutrophil and lymphocyte counts. Conclusions: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine. Funding: This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S. and Y.D.), Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center.",

keywords = "BNT162b2, DNA methylation, SARS-CoV-2, Translation to patients, cfDNA, liquid biopsy, mRNA vaccine, memory B-cell, neutralizing antibody, tissue dynamics",

author = "Ilana Fox-Fisher and Sheina Piyanzin and Mayan Briller and Esther Oiknine-Djian and Or Alfi and Roni Ben-Ami and Ayelet Peretz and Daniel Neiman and Ochana, {Bracha Lea} and Ori Fridlich and Zeina Drawshy and Agnes Klochendler and Judith Magenheim and Danielle Share and Ran Avrahami and Yaarit Ribak and Aviv Talmon and Limor Rubin and Neta Milman and Meital Segev and Erik Feldman and Yuval Tal and Shen-Orr, {Shai S.} and Benjamin Glaser and Ruth Shemer and Dana Wolf and Yuval Dor",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = jul,

day = "8",

doi = "10.1016/j.medj.2022.05.005",

language = "אנגלית",

volume = "3",

pages = "468--480.e5",

journal = "Med",

issn = "2666-6359",

publisher = "Cell Press",

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Fox-Fisher, I, Piyanzin, S, Briller, M, Oiknine-Djian, E, Alfi, O, Ben-Ami, R, Peretz, A, Neiman, D, Ochana, BL, Fridlich, O, Drawshy, Z, Klochendler, A, Magenheim, J, Share, D, Avrahami, R, Ribak, Y, Talmon, A, Rubin, L, Milman, N, Segev, M, Feldman, E, Tal, Y, Shen-Orr, SS, Glaser, B, Shemer, R, Wolf, D & Dor, Y 2022, 'B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies', Med, vol. 3, no. 7, pp. 468-480.e5. https://doi.org/10.1016/j.medj.2022.05.005

TY - JOUR

T1 - B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies

AU - Fox-Fisher, Ilana

AU - Piyanzin, Sheina

AU - Briller, Mayan

AU - Oiknine-Djian, Esther

AU - Alfi, Or

AU - Ben-Ami, Roni

AU - Peretz, Ayelet

AU - Neiman, Daniel

AU - Ochana, Bracha Lea

AU - Fridlich, Ori

AU - Drawshy, Zeina

AU - Klochendler, Agnes

AU - Magenheim, Judith

AU - Share, Danielle

AU - Avrahami, Ran

AU - Ribak, Yaarit

AU - Talmon, Aviv

AU - Rubin, Limor

AU - Milman, Neta

AU - Segev, Meital

AU - Feldman, Erik

AU - Tal, Yuval

AU - Shen-Orr, Shai S.

AU - Glaser, Benjamin

AU - Shemer, Ruth

AU - Wolf, Dana

AU - Dor, Yuval

PY - 2022/7/8

Y1 - 2022/7/8

N2 - Background: Much remains unknown regarding the response of the immune system to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. Methods: We employed circulating cell-free DNA (cfDNA) to assess the turnover of specific immune cell types following administration of the Pfizer/BioNTech vaccine. Findings: The levels of B cell cfDNA after the primary dose correlated with development of neutralizing antibodies and memory B cells after the booster, revealing a link between early B cell turnover—potentially reflecting affinity maturation—and later development of effective humoral response. We also observed co-elevation of B cell, T cell, and monocyte cfDNA after the booster, underscoring the involvement of innate immune cell turnover in the development of humoral and cellular adaptive immunity. Actual cell counts remained largely stable following vaccination, other than a previously demonstrated temporary reduction in neutrophil and lymphocyte counts. Conclusions: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine. Funding: This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S. and Y.D.), Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center.

AB - Background: Much remains unknown regarding the response of the immune system to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. Methods: We employed circulating cell-free DNA (cfDNA) to assess the turnover of specific immune cell types following administration of the Pfizer/BioNTech vaccine. Findings: The levels of B cell cfDNA after the primary dose correlated with development of neutralizing antibodies and memory B cells after the booster, revealing a link between early B cell turnover—potentially reflecting affinity maturation—and later development of effective humoral response. We also observed co-elevation of B cell, T cell, and monocyte cfDNA after the booster, underscoring the involvement of innate immune cell turnover in the development of humoral and cellular adaptive immunity. Actual cell counts remained largely stable following vaccination, other than a previously demonstrated temporary reduction in neutrophil and lymphocyte counts. Conclusions: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine. Funding: This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S. and Y.D.), Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center.

KW - BNT162b2

KW - DNA methylation

KW - SARS-CoV-2

KW - Translation to patients

KW - cfDNA

KW - liquid biopsy

KW - mRNA vaccine

KW - memory B-cell

KW - neutralizing antibody

KW - tissue dynamics

UR - http://www.scopus.com/inward/record.url?scp=85132886487&partnerID=8YFLogxK

U2 - 10.1016/j.medj.2022.05.005

DO - 10.1016/j.medj.2022.05.005

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35716665

AN - SCOPUS:85132886487

SN - 2666-6359

VL - 3

SP - 468-480.e5

JO - Med

JF - Med

IS - 7

ER -

B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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