Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Biomaterial vaccines capturing pathogen-associated molecular patterns protect against bacterial infections and septic shock

Nature Biomedical Engineering volume 6, pages 8–18 (2022)Cite this article

Subjects

Abstract

Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Production and application of the ciVAX vaccine.
Fig. 2: ciVAX presents a subset of bacterial-cell-wall PAMPs in a biomaterial scaffold that recruits dendritic cells to the injection site and produces robust humoral and cellular immune responses with minimal adverse events.
Fig. 3: ciVAX protects mice from E. coli sepsis in an RS218 challenge model and pigs from E. coli septic shock.
Fig. 4: The PLG ciVAX vaccine is effective compared with individual components, yields a durable protective immune response and demonstrates cross protection to other Enterobacteriaceae.
Fig. 5: ciVAX provides functional immune protection against Gram-positive S. aureus.
Fig. 6: ciVAX produced from an E. coli-infected animal could be used to protect against another E. coli serotype.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The proteomics data are available on the PRIDE repository under the accession code PXD023763 and can also be accessed via the MassIVE data storage at https://doi.org/10.25345/C5XB70.

References

  1. Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 197, 1079–1081 (2008).

    Article  Google Scholar 

  2. Spellberg, B. et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin. Infect. Dis. 46, 155–164 (2008).

    Article  Google Scholar 

  3. Adalja, A. A. Biothreat agents and emerging infectious disease in the emergency department. Emerg. Med. Clin. North Am. 36, 823–834 (2018).

    Article  Google Scholar 

  4. Messner, P., Schaffer, C. & Kosma, P. Bacterial cell-envelope glycoconjugates. Adv. Carbohydr. Chem. Biochem. 69, 209–272 (2013).

    Article  Google Scholar 

  5. Haji-Ghassemi, O., Blackler, R. J., Martin Young, N. & Evans, S. V. Antibody recognition of carbohydrate epitopesdagger. Glycobiology 25, 920–952 (2015).

    Article  CAS  Google Scholar 

  6. Nuttall, J. J. & Eley, B. S. BCG vaccination in HIV-infected children. Tuberc. Res. Treat. 2011, 712736 (2011).

    PubMed  PubMed Central  Google Scholar 

  7. Wilk, M. M. et al. Immunization with whole cell but not acellular pertussis vaccines primes CD4 TRM cells that sustain protective immunity against nasal colonization with Bordetella pertussis. Emerg. Microbes Infect. 8, 169–185 (2019).

    Article  CAS  Google Scholar 

  8. Liang, J. L. et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm. Rep. 67, 1–44 (2018).

    Article  Google Scholar 

  9. Jaffe, J. et al. Effects of conformational changes in peptide-CRM197 conjugate vaccines. Bioconjug. Chem. 30, 47–53 (2019).

    Article  CAS  Google Scholar 

  10. Moginger, U. et al. Cross Reactive Material 197 glycoconjugate vaccines contain privileged conjugation sites. Sci. Rep. 6, 20488 (2016).

    Article  Google Scholar 

  11. Zhang, F., Lu, Y. J. & Malley, R. Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity. Proc. Natl Acad. Sci. USA 110, 13564–13569 (2013).

    Article  CAS  Google Scholar 

  12. Kang, J. H. et al. An extracorporeal blood-cleansing device for sepsis therapy. Nat. Med. 20, 1211–1216 (2014).

    Article  CAS  Google Scholar 

  13. Cartwright, M. et al. A broad-spectrum infection diagnostic that detects pathogen-associated molecular patterns (PAMPs) in whole blood. EBioMedicine 9, 217–227 (2016).

    Article  Google Scholar 

  14. Seiler, B. T. et al. Broad-spectrum capture of clinical pathogens using engineered Fc-mannose-binding lectin enhanced by antibiotic treatment. F1000Res 8, 108 (2019).

    Article  Google Scholar 

  15. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  Google Scholar 

  16. Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 64–72 (2015).

    Article  CAS  Google Scholar 

  17. Ali, O. A., Huebsch, N., Cao, L., Dranoff, G. & Mooney, D. J. Infection-mimicking materials to program dendritic cells in situ. Nat. Mater. 8, 151–158 (2009).

    Article  CAS  Google Scholar 

  18. Ali, O. A. & Mooney, D. J. Immunologically active biomaterials for cancer therapy. Curr. Top. Microbiol Immunol. 344, 279–297 (2011).

    CAS  PubMed  Google Scholar 

  19. Wibowo, D. et al. Polymeric nanoparticle vaccines to combat emerging and pandemic threats. Biomaterials 268, 120597 (2021).

    Article  CAS  Google Scholar 

  20. Ke, X. et al. Physical and chemical profiles of nanoparticles for lymphatic targeting. Adv. Drug Deliv. Rev. 151–152, 72–93 (2019).

    Article  Google Scholar 

  21. Xu, W., Riikonen, J. & Lehto, V. P. Mesoporous systems for poorly soluble drugs. Int. J. Pharm. 453, 181–197 (2013).

    Article  CAS  Google Scholar 

  22. Ali, O. A. et al. Identification of immune factors regulating antitumor immunity using polymeric vaccines with multiple adjuvants. Cancer Res. 74, 1670–1681 (2014).

    Article  CAS  Google Scholar 

  23. Waterhouse A., et al. Modified clinical monitoring assessment criteria for multi-organ failure during bacteremia and sepsis progression in a pig model. Advan. Crit. Care Med. 1, 002 (2018).

  24. Robbins, J. B., Schneerson, R., Horwith, G., Naso, R. & Fattom, A. Staphylococcus aureus types 5 and 8 capsular polysaccharide-protein conjugate vaccines. Am. Heart J. 147, 593–598 (2004).

    Article  CAS  Google Scholar 

  25. Frenck, R. W. Jr et al. Safety and immunogenicity of a vaccine for extra-intestinal pathogenic Escherichia coli (ESTELLA): a phase 2 randomised controlled trial. Lancet Infect. Dis. 19, 631–640 (2019).

    Article  CAS  Google Scholar 

  26. Shah, N. J. et al. A biomaterial-based vaccine eliciting durable tumour-specific responses against acute myeloid leukaemia. Nat. Biomed. Eng. 4, 40–51 (2020).

    Article  CAS  Google Scholar 

  27. Ali, O. A., Tayalia, P., Shvartsman, D., Lewin, S. & Mooney, D. J. Inflammatory cytokines presented from polymer matrices differentially generate and activate DCs in situ. Adv. Funct. Mater. 23, 4621–4628 (2013).

    Article  CAS  Google Scholar 

  28. Li, A. W. et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat. Mater. 17, 528–534 (2018).

    Article  CAS  Google Scholar 

  29. Dellacherie, M. O., Li, A. W., Lu, B. Y. & Mooney, D. J. Covalent conjugation of peptide antigen to mesoporous silica rods to enhance cellular responses. Bioconjug. Chem. 29, 733–741 (2018).

    Article  CAS  Google Scholar 

  30. Cyster, J. G. & Schwab, S. R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69–94 (2012).

    Article  CAS  Google Scholar 

  31. Lindquist, R. L. et al. Visualizing dendritic cell networks in vivo. Nat. Immunol. 5, 1243–1250 (2004).

    Article  CAS  Google Scholar 

  32. Sun, L., Middleton, D. R., Wantuch, P. L., Ozdilek, A. & Avci, F. Y. Carbohydrates as T-cell antigens with implications in health and disease. Glycobiology 26, 1029–1040 (2016).

    Article  CAS  Google Scholar 

  33. Liebermeister, W. et al. Visual account of protein investment in cellular functions. Proc. Natl Acad. Sci. USA 111, 8488–8493 (2014).

    Article  CAS  Google Scholar 

  34. Sellars, B. B., Sherrod, D. R. & Chappel-Aiken, L. Using word clouds to analyze qualitative data in clinical settings. Nurs. Manag. 49, 51–53 (2018).

    Article  Google Scholar 

  35. Moran, J. L. & Solomon, P. J. Statistics in review Part I: graphics, data summary and linear models. Crit. Care Resusc. 9, 81–90 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

We thank D. Bolgen, A. Nedder, K. Imaizumi and S. Bardales for their assistance with the mouse and pig models. This work was supported by the Wyss Institute for Biologically Inspired Engineering, DARPA (grant no. W911NF-16-C-0050 to D.E.I. and M.S.) and the National Institutes of Health (grant no. 1 R01 CA223255 to D.J.M.).

Author information

Author notes

  1. These authors contributed equally: Michael Super, Edward J. Doherty.

Authors and Affiliations

  1. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Michael Super, Edward J. Doherty, Mark J. Cartwright, Benjamin T. Seiler, Fernanda Langellotto, Nikolaos Dimitrakakis, Des A. White, Alexander G. Stafford, Mohan Karkada, Amanda R. Graveline, Caitlin L. Horgan, Kayla R. Lightbown, Frank R. Urena, Chyenne D. Yeager, Sami A. Rifai, Collin Leese-Thompson, Hamza Ijaz, Vasanth Chandrasekhar, Justin M. Scott, Shanda L. Lightbown, Donald E. Ingber & David J. Mooney

  2. Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Michael Super, Amanda R. Jiang & Donald E. Ingber

  3. Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Maxence O. Dellacherie, Aileen W. Li, Donald E. Ingber & David J. Mooney

Authors
  1. Michael Super
    View author publications

    Search author on:PubMed Google Scholar

  2. Edward J. Doherty
    View author publications

    Search author on:PubMed Google Scholar

  3. Mark J. Cartwright
    View author publications

    Search author on:PubMed Google Scholar

  4. Benjamin T. Seiler
    View author publications

    Search author on:PubMed Google Scholar

  5. Fernanda Langellotto
    View author publications

    Search author on:PubMed Google Scholar

  6. Nikolaos Dimitrakakis
    View author publications

    Search author on:PubMed Google Scholar

  7. Des A. White
    View author publications

    Search author on:PubMed Google Scholar

  8. Alexander G. Stafford
    View author publications

    Search author on:PubMed Google Scholar

  9. Mohan Karkada
    View author publications

    Search author on:PubMed Google Scholar

  10. Amanda R. Graveline
    View author publications

    Search author on:PubMed Google Scholar

  11. Caitlin L. Horgan
    View author publications

    Search author on:PubMed Google Scholar

  12. Kayla R. Lightbown
    View author publications

    Search author on:PubMed Google Scholar

  13. Frank R. Urena
    View author publications

    Search author on:PubMed Google Scholar

  14. Chyenne D. Yeager
    View author publications

    Search author on:PubMed Google Scholar

  15. Sami A. Rifai
    View author publications

    Search author on:PubMed Google Scholar

  16. Maxence O. Dellacherie
    View author publications

    Search author on:PubMed Google Scholar

  17. Aileen W. Li
    View author publications

    Search author on:PubMed Google Scholar

  18. Collin Leese-Thompson
    View author publications

    Search author on:PubMed Google Scholar

  19. Hamza Ijaz
    View author publications

    Search author on:PubMed Google Scholar

  20. Amanda R. Jiang
    View author publications

    Search author on:PubMed Google Scholar

  21. Vasanth Chandrasekhar
    View author publications

    Search author on:PubMed Google Scholar

  22. Justin M. Scott
    View author publications

    Search author on:PubMed Google Scholar

  23. Shanda L. Lightbown
    View author publications

    Search author on:PubMed Google Scholar

  24. Donald E. Ingber
    View author publications

    Search author on:PubMed Google Scholar

  25. David J. Mooney
    View author publications

    Search author on:PubMed Google Scholar

Contributions

M.S., E.J.D. and M.J.C. conceived the project, which was directed by D.E.I. and D.J.M. Vaccines were prepared and analysed by B.T.S., D.A.W., A.G.S., N.D., M.K., C.L.H., S.A.R., M.O.D., A.W.L. and J.M.S. Experiments in the mouse and pig models were conducted by F.L., A.R.G., K.R.L., F.R.U., C.D.Y., A.R.J. and S.L.L. The data were analysed by M.S., F.L., M.J.C., N.D. and V.C. The manuscript was written by M.S., E.J.D., D.E.I. and D.J.M. All authors critically reviewed the manuscript.

Corresponding author

Correspondence to David J. Mooney.

Ethics declarations

Competing interests

D.J.M. received sponsored research funding from Novartis, and has equity in Lyell and Attivare Therapeutics. D.E.I. is a founder, member of the board of directors and scientific advisory board, and equity holder in Boa Biomedical, Inc. M.S. is a founder and equity holder in BOA Biomedical. E.J.D., F.L. and B.T.S. are founders and have equity in Attivare Therapeutics. Inventors, patent applications: D.J.M., D.E.I., M.S., M.J.C., E.J.D., B.T.S., F.L., A.G.S., A.R.G., J.M.S. and D.A.W. For each patent, the serial number, country and patent number are provided: (1) 15/434,781; US; 10,813,988; (2) 17/015,177; US; (3) 2018-543154; Japan; 6854530; (4) 17753811; EPO; and (5) 202000000000; China. All other authors declare that they have no competing interests.

Additional information

Peer review information Nature Biomedical Engineering thanks Tarek Fahmy, Michael Mitchell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Super, M., Doherty, E.J., Cartwright, M.J. et al. Biomaterial vaccines capturing pathogen-associated molecular patterns protect against bacterial infections and septic shock. Nat Biomed Eng 6, 8–18 (2022). https://doi.org/10.1038/s41551-021-00756-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41551-021-00756-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology