System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans

doi:10.1038/s41590-024-02036-z

. 2025 Jan;26(1):116-130.

doi: 10.1038/s41590-024-02036-z. Epub 2025 Jan 2.

System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans

Mario Cortese^#¹, Thomas Hagan^#^{2

3}, Nadine Rouphael⁴, Sheng-Yang Wu¹, Xia Xie¹, Dmitri Kazmin¹, Florian Wimmers¹, Shakti Gupta⁵, Robbert van der Most⁶, Margherita Coccia⁶, Prabhu S Aranuchalam¹, Helder I Nakaya⁷, Yating Wang⁸, Elizabeth Coyle⁹, Shu Horiuchi¹⁰, Hanchih Wu¹⁰, Mary Bower⁴, Aneesh Mehta⁴, Clifford Gunthel⁴, Steve E Bosinger^{11

12

13}, Yuri Kotliarov¹⁴, Foo Cheung¹⁴, Pamela L Schwartzberg^{14

15}, Ronald N Germain^{14

15}, John Tsang^{14

15}, Shuzhao Li⁸, Randy Albrecht¹⁰, Hideki Ueno^{10

16}, Shankar Subramaniam⁵, Mark J Mulligan¹⁷, Surender Khurana⁹, Hana Golding⁹, Bali Pulendran^{18

19

20}

Affiliations

¹ Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, USA.
² Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁴ Hope Clinic of the Emory Vaccine Center, Decatur, GA, USA.
⁵ Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
⁶ GSK, Rixensart, Belgium.
⁷ Hospital Israelita Albert Einstein, São Paulo, Brazil.
⁸ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁹ Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
¹⁰ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA, USA.
¹² Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Atlanta, GA, USA.
¹³ Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD, USA.
¹⁵ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
¹⁶ Department of Immunology, Kyoto University, Kyoto, Japan.
¹⁷ Division of Infectious Diseases and Immunology, Department of Medicine and NYU Langone Vaccine Center, NYU Grossman School of Medicine, New York, NY, USA.
¹⁸ Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, USA. bpulend@stanford.edu.
¹⁹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. bpulend@stanford.edu.
²⁰ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA. bpulend@stanford.edu.

^# Contributed equally.

PMID: 39747435
PMCID: PMC12158788 (available on 2026-01-02)
DOI: 10.1038/s41590-024-02036-z

System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans

Mario Cortese et al. Nat Immunol. 2025 Jan.

. 2025 Jan;26(1):116-130.

doi: 10.1038/s41590-024-02036-z. Epub 2025 Jan 2.

Authors

Affiliations

¹ Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, USA.
² Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁴ Hope Clinic of the Emory Vaccine Center, Decatur, GA, USA.
⁵ Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
⁶ GSK, Rixensart, Belgium.
⁷ Hospital Israelita Albert Einstein, São Paulo, Brazil.
⁸ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁹ Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
¹⁰ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA, USA.
¹² Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Atlanta, GA, USA.
¹³ Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD, USA.
¹⁵ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
¹⁶ Department of Immunology, Kyoto University, Kyoto, Japan.
¹⁷ Division of Infectious Diseases and Immunology, Department of Medicine and NYU Langone Vaccine Center, NYU Grossman School of Medicine, New York, NY, USA.
¹⁸ Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, USA. bpulend@stanford.edu.
¹⁹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. bpulend@stanford.edu.
²⁰ Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA. bpulend@stanford.edu.

^# Contributed equally.

PMID: 39747435
PMCID: PMC12158788 (available on 2026-01-02)
DOI: 10.1038/s41590-024-02036-z

Abstract

We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity. We found that TPO administration enhanced the durability of vaccine-induced antibody responses. TPO-activated megakaryocytes also promoted survival of human bone-marrow plasma cells through integrin β1/β2-mediated cell-cell interactions, along with survival factors APRIL and the MIF-CD74 axis. Using machine learning, we developed a classifier based on this platelet-associated signature, which predicted antibody response longevity across six vaccines from seven independent trials, highlighting a conserved mechanism for vaccine durability.

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Conflict of interest statement

Competing interests: R.v.d.M., M. Cortese and M. Coccia are or were employees of GSK. B.P. serves or has served on the External Immunology Board of GSK and on the Scientific Advisory Board of Sanofi, Medicago, Boehringer Ingelheim, Pharmajet, Icosavax, Imu Biosciences and Ed-Jen, and holds shares at CircBio and Orbital Therapeutics. R.v.d.M. and T.H. hold shares in the GSK group of companies. The other authors declare no competing interests.

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References

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[1] Goldblatt D, Alter G, Crotty S & Plotkin SA Correlates of protection against SARS-CoV-2 infection and COVID-19 disease. Immunol Rev 310, 6–26 (2022). - PMC - PubMed

[2] Goldblatt D, Alter G, Crotty S & Plotkin SA Correlates of protection against SARS-CoV-2 infection and COVID-19 disease. Immunol Rev 310, 6–26 (2022). - PMC - PubMed

[3] Rappuoli R, Alter G & Pulendran B Transforming vaccinology. Cell 187, 5171–5194 (2024). - PMC - PubMed

[4] Rappuoli R, Alter G & Pulendran B Transforming vaccinology. Cell 187, 5171–5194 (2024). - PMC - PubMed

[5] Bhattacharya D Instructing durable humoral immunity for COVID-19 and other vaccinable diseases. Immunity 55, 945–964 (2022). - PMC - PubMed

[6] Bhattacharya D Instructing durable humoral immunity for COVID-19 and other vaccinable diseases. Immunity 55, 945–964 (2022). - PMC - PubMed

[7] Amanna IJ, Carlson NE & Slifka MK Duration of humoral immunity to common viral and vaccine antigens. N Engl J Med 357, 1903–1915 (2007). - PubMed

[8] Amanna IJ, Carlson NE & Slifka MK Duration of humoral immunity to common viral and vaccine antigens. N Engl J Med 357, 1903–1915 (2007). - PubMed

[9] Gu XX et al. Waning Immunity and Microbial Vaccines-Workshop of the National Institute of Allergy and Infectious Diseases. Clin Vaccine Immunol 24 (2017). - PMC - PubMed

[10] Gu XX et al. Waning Immunity and Microbial Vaccines-Workshop of the National Institute of Allergy and Infectious Diseases. Clin Vaccine Immunol 24 (2017). - PMC - PubMed

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System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans

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System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans

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