Abstract

Fully effective vaccines for complex infections must elicit a diverse repertoire of antibodies (humoral immunity) and CD8+ T-cell responses (cellular immunity). Here, we present a synthetic glyco-adjuvant named p(Man–TLR7), which, when conjugated to antigens, elicits robust humoral and cellular immunity. p(Man–TLR7) is a random copolymer composed of monomers that either target dendritic cells (DCs) via mannose-binding receptors or activate DCs via Toll-like receptor 7 (TLR7). Protein antigens are conjugated to p(Man–TLR7) via a self-immolative linkage that releases chemically unmodified antigen after endocytosis, thus amplifying antigen presentation to T cells. Studies with ovalbumin (OVA)–p(Man–TLR7) conjugates demonstrate that OVA–p(Man–TLR7) generates greater humoral and cellular immunity than OVA conjugated to polymers lacking either mannose targeting or TLR7 ligand. We show significant enhancement of Plasmodium falciparum-derived circumsporozoite protein (CSP)-specific T-cell responses, expansion in the breadth of the αCSP IgG response and increased inhibition of sporozoite invasion into hepatocytes with CSP–p(Man–TLR7) when compared with CSP formulated with MPLA/QS-21-loaded liposomes—the adjuvant used in the most clinically advanced malaria vaccine. We conclude that our antigen–p(Man–TLR7) platform offers a strategy to enhance the immunogenicity of protein subunit vaccines.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the Flow Cytometry Core Facility of EPFL for technical assistance, and Dr E. Simeoni of EPFL for discussion of the research and guidance on animal work. D.S.W. was supported by a fellowship from the Whitaker Foundation. We would like to thank PATH for donating the CSP used in our studies. This study was supported by the School of Life Sciences, EPFL, and the University of Chicago. This work benefited from equipment and services from the CELIS cell culture core facility (Institut du Cerveau et de la Moelle Epinière, Paris), a platform supported through the ANR grants ANR-10-IAIHU-06 and ANR-11-INBS-0011-NeurATRIS. We are particularly grateful to D. Akbar for his assistance regarding automated fluorescence.

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  1. Institute for Bioengineering, School of Life Science and School of Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    • D. Scott Wilson
    • , Sachiko Hirosue
    • , Michal M. Raczy
    • , Laura Jeanbart
    • , Maria A. S. Broggi
    • , Giacomo Diaceri
    • , Xavier Quaglia-Thermes
    • , Melody A. Swartz
    •  & Jeffrey A. Hubbell
  2. Institute for Molecular Engineering, University of Chicago, Chicago, IL, USA

    • D. Scott Wilson
    • , Michal M. Raczy
    • , Ruyi Wang
    • , Marcin Kwissa
    • , Maria A. S. Broggi
    • , Melody A. Swartz
    •  & Jeffrey A. Hubbell
  3. Sorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, CIMI, Paris, France

    • Leonardo Bonilla-Ramirez
    • , Jean-Francois Franetich
    •  & Dominique Mazier

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Contributions

J.A.H. and M.A.S. oversaw all research; D.S.W. conceptualized materials; D.S.W., M.M.R. and R.W. performed the synthesis; D.S.W., S.H. and J.A.H designed animal studies; D.S.W., S.H., M.A.S.B., L.J., G.D. and X.Q.T. performed animal studies; S.H., L.J., D.S.W. and M.K. designed and carried out in vitro studies; D.M., J.-F.F. and L.B.R. designed hepatic invasion studies; J.-F.F. and L.B.R. carried out hepatic invasion studies; D.S.W., S.H. and J.A.H. wrote the manuscript; all authors proofread the manuscript.

Competing interests

The University of Chicago has filed for patent protection on the p(Man-TLRx) delivery platform, and J.A.H., S.H. and D.S.W. are named as inventors on these patents.

Corresponding author

Correspondence to Jeffrey A. Hubbell.

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https://doi.org/10.1038/s41563-018-0256-5

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