In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity.
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.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.|Department of Oncology, University of Oxford, Oxford, UK.
Geoffrey M
GM
Lynn
Department of Oncology, University of Oxford, Oxford, UK.|Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Richard
R
Laga
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Patricia A
PA
Darrah
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Andrew S
http://orcid.org/0000-0002-3024-7536
AS
Ishizuka
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Alexandra J
AJ
Balaci
Imaging Probe Development Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland, USA.
Andrés E
AE
Dulcey
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Michal
M
Pechar
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Robert
R
Pola
Lymphocyte Biology Section, Laboratory of Systems Biology, NIAID, NIH, Bethesda, Maryland, USA.
Michael Y
MY
Gerner
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Ayako
A
Yamamoto
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Connor R
CR
Buechler
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Kylie M
KM
Quinn
Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, Maryland, USA.
Margery G
MG
Smelkinson
Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Ondrej
http://orcid.org/0000-0003-1190-8535
O
Vanek
Department of Oncology, University of Oxford, Oxford, UK.
Ryan
R
Cawood
Department of Oncology, University of Oxford, Oxford, UK.
Thomas
T
Hills
Imaging Probe Development Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland, USA.
Olga
O
Vasalatiy
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Kathrin
K
Kastenmüller
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Joseph R
JR
Francica
Department of Chemistry, University of California, Irvine, Irvine, California, USA.
Lalisa
L
Stutts
Department of Chemistry, University of California, Irvine, Irvine, California, USA.
Janine K
JK
Tom
Department of Chemistry, University of California, Irvine, Irvine, California, USA.
Keun Ah
KA
Ryu
Department of Chemistry, University of California, Irvine, Irvine, California, USA.
Aaron P
AP
Esser-Kahn
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Tomas
T
Etrych
Department of Oncology, University of Oxford, Oxford, UK.
Kerry D
KD
Fisher
Department of Oncology, University of Oxford, Oxford, UK.
Leonard W
LW
Seymour
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Robert A
RA
Seder
D000276:Adjuvants, Immunologic / Q000737:chemistry*; D000818:Animals; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*; D014612:Vaccines / Q000276:immunology*
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D051193:Toll-Like Receptors; D014612:Vaccines