title: Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hok Hei
authors.identifier: 0000-0002-2358-0330
authors.initials: HH
authors.lastname: Tam
authors.affiliation: 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.
authors.forename: Mariane B
authors.identifier: 0000-0002-0409-2454
authors.initials: MB
authors.lastname: Melo
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Myungsun
authors.initials: M
authors.lastname: Kang
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Jeisa M
authors.initials: JM
authors.lastname: Pelet
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Ruda
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Foley
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037.
authors.forename: Joyce K
authors.initials: JK
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037.
authors.forename: Jordan
authors.initials: J
authors.lastname: Crampton
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Alexis D
authors.initials: AD
authors.lastname: Baldeon
authors.affiliation: 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.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: 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.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
authors.affiliation: 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.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016466:CHO Cells; D003412:Cricetulus; D004334:Drug Administration Schedule; D005260:Female; D018858:Germinal Center / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage* / Q000096:biosynthesis; D006801:Humans; D000071497:Immunogenicity, Vaccine; D015918:Infusion Pumps, Implantable; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D008810:Mice, Inbred C57BL; D009997:Osmotic Pressure; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000096:biosynthesis; D014611:Vaccination / Q000295:instrumentation / Q000379:methods*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D015699:HIV Envelope Protein gp120; D008050:Lipid A; D011993:Recombinant Fusion Proteins; C514793:gp120 protein, Human immunodeficiency virus 1; C048436:monophosphoryl lipid A
keywords: antigen retention; computational immunology; germinal center formation; humoral response; vaccination kinetics