Abstract

The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer–TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer–TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer–TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer–TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

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Acknowledgements

The authors wish to acknowledge M. Dillon, K. Wuddie and C. Chiedi at the Vaccine Research Center and B. Klaunberg and V. Diaz at the Mouse Imaging Facility (MIF) for their valuable support and assistance with the animal studies. We would also like to thank K. Ulbrich, R. Swenson and G. Griffiths for their support and helpful insights. This work was supported in part by the BIOPOL project (Grant of the Ministry of Education, Youth and Sports of the Czech Republic, no. EE2.3.30.0029); by the Czech Science Foundation (15-15181S); by Charles University (UNCE 204025/2012); by a Cancer Research UK grant (C552/A17720); and by the Office of AIDS Research and the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

Author information

Author notes

    • Geoffrey M Lynn
    •  & Richard Laga

    These authors contributed equally to this work.

    • Leonard W Seymour
    •  & Robert A Seder

    These authors jointly supervised this work.

Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Geoffrey M Lynn
    • , Patricia A Darrah
    • , Andrew S Ishizuka
    • , Alexandra J Balaci
    • , Ayako Yamamoto
    • , Connor R Buechler
    • , Kylie M Quinn
    • , Kathrin Kastenmüller
    • , Joseph R Francica
    •  & Robert A Seder
  2. Department of Oncology, University of Oxford, Oxford, UK.

    • Geoffrey M Lynn
    • , Richard Laga
    • , Ryan Cawood
    • , Thomas Hills
    • , Kerry D Fisher
    •  & Leonard W Seymour
  3. Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.

    • Richard Laga
    • , Michal Pechar
    • , Robert Pola
    •  & Tomas Etrych
  4. Imaging Probe Development Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland, USA.

    • Andrés E Dulcey
    •  & Olga Vasalatiy
  5. Lymphocyte Biology Section, Laboratory of Systems Biology, NIAID, NIH, Bethesda, Maryland, USA.

    • Michael Y Gerner
  6. Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, Maryland, USA.

    • Margery G Smelkinson
  7. Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.

    • Ondrej Vanek
  8. Department of Chemistry, University of California, Irvine, Irvine, California, USA.

    • Lalisa Stutts
    • , Janine K Tom
    • , Keun Ah Ryu
    •  & Aaron P Esser-Kahn

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Contributions

G.M.L., R.L., K.D.F., L.W.S. and R.A.S were involved in experimental planning, interpreting data and writing the manuscript. G.M.L., R.L., A.E.D., O. Vasalatiy, J.K.T., L.S., K.A.R. and A.P.E.-K. planned and carried out the synthesis, purification and characterization of small molecules. R.L., R.P., M.P., T.E., O. Vanek and G.M.L. planned and completed the synthesis, purification and characterization of the polymer precursors and polymer conjugates. P.A.D, A.S.I., A.J.B., A.Y., K.M.Q., C.R.B., K.K. and J.R.F. planned and conducted many of the biological studies. M.Y.G. and M.G.S. carried out the confocal microscopy studies on lymph node sections and polymer particles, respectively. T.H. and R.C. developed the plasmids to express the HIV Gag-coil fusion protein. R.L., M.P., R.P. and T.E. devised the coil-coil strategy. A.P.E.-K., T.E., K.D.F., L.W.S. and R.A.S. are principal investigators who advised the studies.

Competing interests

G.M.L., R.L., K.D.F., L.W.S. and R.A.S. are listed as inventors on patents describing polymer-based vaccines. K.D.F. and L.W.S. are scientific founders and equity holders in PsiOxus Therapeutics, Ltd. (Oxford, UK). G.M.L. and J.R.F. are scientific founders and equity holders in Avidea Technologies, Inc., which is developing polymer-based technologies for immunotherapeutic applications (Baltimore, Maryland, USA).

Corresponding author

Correspondence to Robert A Seder.

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https://doi.org/10.1038/nbt.3371

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