Skip to main content
SpringerLink
Log in

Multiepitope Fusion Antigen: MEFA, an Epitope- and Structure-Based Vaccinology Platform for Multivalent Vaccine Development

  • Protocol
  • First Online:
Bacterial Vaccines

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2414))

Abstract

Vaccines are regarded as the most cost-effective countermeasure against infectious diseases. One challenge often affecting vaccine development is antigenic diversity or pathogen heterogeneity. Different strains produce immunologically heterogeneous virulence factors, therefore an effective vaccine needs to induce broad-spectrum host immunity to provide cross-protection. Recent advances in genomics and proteomics, particularly computational biology and structural biology, establishes structural vaccinology and highlights the feasibility of developing effective and precision vaccines. Here, we introduce the epitope- and structure-based vaccinology platform multiepitope-fusion-antigen (MEFA), and provide instructions to generate polyvalent MEFA immunogens for vaccine development. Conceptually, MEFA combines epitope vaccinology and structural vaccinology to enable a protein immunogen to present heterogeneous antigenic domains (epitopes) and to induce broadly protective immunity against different virulence factors, strains or diseases. Methodologically, the MEFA platform first identifies a safe, structurally stable and strongly immunogenic backbone protein and immunodominant (ideally neutralizing or protective) epitopes from heterogeneous strains or virulence factors of interest. Then, assisted with protein modeling and molecule dynamic simulation, MEFA integrates heterogeneous epitopes into a backbone protein via epitope substitution for a polyvalent MEFA protein and mimics epitope native antigenicity. Finally, the MEFA protein is examined for broad immunogenicity in animal immunization, and assessed for potential application for multivalent vaccine development in preclinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Collaborators GD, Collaborators GH (2017) Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet 390(10100):1260–1344

    Article  Google Scholar 

  2. Global health estimates 2016: Deaths by cause, age, sex, by country and by region, 2000–2016 (2018). https://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html. Accessed 21 Jan 2021

  3. Nabel GJ (2013) Designing tomorrow's vaccines. New Engl J Med 368(6):551–560. https://doi.org/10.1056/NEJMra1204186

    Article  CAS  PubMed  Google Scholar 

  4. Mascola JR, Ahmed R (2015) Vaccines: vaccines for cancer and infectious diseases. Curr Opin Immunol 35:V–Vii. https://doi.org/10.1016/j.coi.2015.07.009

    Article  CAS  PubMed  Google Scholar 

  5. Ruan X, Sack DA, Zhang W (2015) Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity. PLoS One 10(3):e0121623

    Article  PubMed  PubMed Central  Google Scholar 

  6. Duan Q, Lee KH, Nandre RM, Garcia C, Chen J, Zhang W (2017) MEFA (multiepitope fusion antigen)-novel technology for structural vaccinology, proof from computational and empirical immunogenicity characterization of an enterotoxigenic Escherichia coli (ETEC) Adhesin MEFA. J Vaccines Vaccin 8(4):367. https://doi.org/10.4172/2157-7560.1000367

    Article  PubMed  PubMed Central  Google Scholar 

  7. Seo H, Duan Q, Zhang W (2020) Vaccines against gastroenteritis, current progress and challenges. Gut Microbes 11(6):1486–1517. https://doi.org/10.1080/19490976.2020.1770666

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lycke N, Holmgren J (1986) Strong adjuvant properties of cholera toxin on gut mucosal immune responses to orally presented antigens. Immunology 59(2):301–308

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Clements JD, Hartzog NM, Lyon FL (1988) Adjuvant activity of Escherichia coli heat-labile enterotoxin and effect on the induction of oral tolerance in mice to unrelated protein antigens. Vaccine 6(3):269–277

    Article  CAS  PubMed  Google Scholar 

  10. Lycke N (2005) Targeted vaccine adjuvants based on modified cholera toxin. Curr Mol Med 5(6):591–597

    Article  CAS  PubMed  Google Scholar 

  11. Freytag LC, Clements JD (2005) Mucosal adjuvants. Vaccine 23(15):1804–1813. https://doi.org/10.1016/j.vaccine.2004.11.010

    Article  CAS  PubMed  Google Scholar 

  12. Huang JC, Duan QD, Zhang WP (2018) Significance of enterotoxigenic Escherichia coli (ETEC) heat-labile toxin (LT) enzymatic subunit epitopes in LT enterotoxicity and immunogenicity. Appl Environ Microbiol 84(15):e00849-00818. https://doi.org/10.1128/AEM.00849-18

    Article  Google Scholar 

  13. Lu T, Moxley RA, Zhang W (2019) Mapping the neutralizing epitopes of enterotoxigenic Escherichia coli (ETEC) K88 (F4) fimbrial adhesin and major subunit FaeG. Appl Environ Microbiol 85(11):e00329–e00319. https://doi.org/10.1128/AEM.00329-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lu T, Seo H, Moxley RA, Zhang W (2019) Mapping the neutralizing epitopes of F18 fimbrial adhesin subunit FedF of enterotoxigenic Escherichia coli (ETEC). Vet Microbiol 230:171–177. https://doi.org/10.1016/j.vetmic.2019.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lu T, Moxley RA, Zhang W (2020) Application of a novel epitope and structure vaccinology-assisted fimbria-toxin multiepitope fusion antigen of enterotoxigenic Escherichia coli for multivalent vaccine development against porcine post-weaning diarrhea. Appl Environ Microbiol 86(24):e00274-20. https://doi.org/10.1128/AEM.00274-20

    Article  PubMed  PubMed Central  Google Scholar 

  16. Vita R, Mahajan S, Overton JA, Dhanda SK, Martini S, Cantrell JR et al (2019) The immune epitope database (IEDB): 2018 update. Nucleic Acids Res 47(D1):D339–D343. https://doi.org/10.1093/nar/gky1006

    Article  CAS  PubMed  Google Scholar 

  17. Artimo P, Jonnalagedda M, Arnold K, Baratin D, Csardi G, de Castro E et al (2012) ExPASy: SIB bioinformatics resource portal. Nucleic Acids Res 40(W1):W597–W603. https://doi.org/10.1093/nar/gks400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10(6):845–858. https://doi.org/10.1038/nprot.2015.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chivian D, Baker D (2006) Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection. Nucleic Acids Res 34(17):e112. https://doi.org/10.1093/nar/gkl480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Raman S, Vernon R, Thompson J, Tyka M, Sadreyev R, Pei JM et al (2009) Structure prediction for CASP8 with all-atom refinement using Rosetta. Proteins Struct Funct Genet 77:89–99. https://doi.org/10.1002/prot.22540

    Article  CAS  PubMed  Google Scholar 

  21. Song JS, Liu YQ, Liu CZ, Xie JP, Ma LX, Wang LP et al (2013) Cumulative analgesic effects of EA stimulation of sanyinjiao (SP 6) in primary dysmenorrhea patients: a multicenter randomized controlled clinical trial. Zhen Ci Yan Jiu 38(5):393–398

    PubMed  Google Scholar 

  22. Ausubel FM, Brent R, Kingston RK, Moore DD, Seidman JG, Smith JA, Struhl K (1999) Short protocols in molecular biology, 4th edn. Wiley, New York, NY

    Google Scholar 

  23. Spira WM, Sack RB, Froehlich JL (1981) Simple adult rabbit model for Vibrio cholerae and enterotoxigenic Escherichia coli diarrhea. Infect Immun 32(2):739–747. https://doi.org/10.1128/IAI.32.2.739-747.1981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gerdts V, Wilson HL, Meurens F, van Drunen Littel-van den Hurk S, Wilson D, Walker S et al (2015) Large animal models for vaccine development and testing. ILAR J 56(1):53–62. https://doi.org/10.1093/ilar/ilv009

    Article  CAS  PubMed  Google Scholar 

  25. Swearengen JR (2018) Choosing the right animal model for infectious disease research. Animal Model Exp Med 1:100–108. https://doi.org/10.1002/ame2.12020

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ramin Sedaghat Herati EJW (2018) What is the predictive value of animal models for vaccine efficacy in humans. Cold Spring Harb Perspect Biol 10:a031583. https://doi.org/10.1101/cshperspect.a031583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gordon SB, Rylance J, Luck A, Jambo K, Ferreira DM, Manda-Taylor L et al (2017) A framework for controlled human infection model (CHIM) studies in Malawi: report of a Wellcome Trust workshop on CHIM in low income countries held in Blantyre, Malawi. Wellcome Open Res 2:70. https://doi.org/10.12688/wellcomeopenres.12256.1

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work is supported by NIH R01AI121067-01A1 and University of Illinois at Urbana-Champaign. We also thank Shuangqi Wang, Ti Lu, and Ipshita Upadhyay for technical assistance.

Author information

Authors and Affiliations

  1. Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Siqi Li & Weiping Zhang

  2. Computational Chemistry and Molecular Biophysics Unit, National Institute of Health/National Institute on Drug Abuse, Baltimore, MD, USA

    Kuo Hao Lee

Authors
  1. Siqi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kuo Hao Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weiping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weiping Zhang .

Editor information

Editors and Affiliations

  1. Department of Infectious Disease, Imperial College London, London, UK

    Fadil Bidmos

  2. Department of Infectious Disease, Imperial College London, London, UK

    Janine Bossé

  3. Department of Infectious Disease, Imperial College London, London, UK

    Paul Langford

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Li, S., Lee, K.H., Zhang, W. (2022). Multiepitope Fusion Antigen: MEFA, an Epitope- and Structure-Based Vaccinology Platform for Multivalent Vaccine Development. In: Bidmos, F., Bossé, J., Langford, P. (eds) Bacterial Vaccines. Methods in Molecular Biology, vol 2414. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1900-1_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1900-1_10

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1899-8

  • Online ISBN: 978-1-0716-1900-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation