title: TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth.
abstract: Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197-specific neonatal CD4+cells, activation of newborn and infantStreptococcus pneumoniaepolysaccharide-specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10-100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Precision Vaccines Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Simon D
authors.initials: SD
authors.lastname: van Haren
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Precision Vaccines Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Division of Newborn Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Scheid
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Bergelson
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Dhohyung
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Mancuso
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Willemina
authors.initials: W
authors.lastname: Foppen
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Precision Vaccines Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Center for Patient Safety and Quality Research, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Al
authors.initials: A
authors.lastname: Ozonoff
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Fresh
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Terese B
authors.initials: TB
authors.lastname: Theriot
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lackner
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.affiliation: 3M Drug Delivery Systems, Saint Paul, Minnesota, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Smirnov
authors.affiliation: 3M Drug Delivery Systems, Saint Paul, Minnesota, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Vasilakos
authors.affiliation: 3M Drug Delivery Systems, Saint Paul, Minnesota, USA.
authors.forename: Joe M
authors.initials: JM
authors.lastname: Beaurline
authors.affiliation: 3M Drug Delivery Systems, Saint Paul, Minnesota, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Cecily C
authors.initials: CC
authors.lastname: Midkiff
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Blanchard
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Gilbert
authors.affiliation: Tulane National Primate Research Center (TNPRC), Covington, Louisiana, USA.
authors.forename: Pyone Pyone
authors.initials: PP
authors.lastname: Aye
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Precision Vaccines Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007231:Infant, Newborn; D008253:Macaca mulatta; D022242:Pneumococcal Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D018074:Vaccines, Conjugate / Q000008:administration & dosage* / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D022242:Pneumococcal Vaccines; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018074:Vaccines, Conjugate