Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination.

Autor:	Tam HH; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139., Melo MB; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, & Harvard, Cambridge, MA 02139., Kang M; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139., Pelet JM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139., Ruda VM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139., Foley MH; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139., Hu JK; Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037., Kumari S; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, & Harvard, Cambridge, MA 02139., Crampton J; Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037., Baldeon AD; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139., Sanders RW; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam-Zuidoost, The Netherlands., Moore JP; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021., Crotty S; Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037., Langer R; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139., Anderson DG; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139; djirvine@mit.edu dgander@mit.edu arupc@mit.edu., Chakraborty AK; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, & Harvard, Cambridge, MA 02139; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; djirvine@mit.edu dgander@mit.edu arupc@mit.edu., Irvine DJ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, & Harvard, Cambridge, MA 02139; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Howard Hughes Medical Institute, Chevy Chase, MD 20815 djirvine@mit.edu dgander@mit.edu arupc@mit.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Oct 25; Vol. 113 (43), pp. E6639-E6648. Date of Electronic Publication: 2016 Oct 04.
DOI:	10.1073/pnas.1606050113
Abstrakt:	Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1-2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higher-affinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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