title: Mucosally delivered Salmonella typhi expressing the Yersinia pestis F1 antigen elicits mucosal and systemic immunity early in life and primes the neonatal immune system for a vigorous anamnestic response to parenteral F1 boost.
abstract: Neonates respond poorly to conventional vaccines. This has been attributed, in part, to the immaturity of neonatal dendritic cells that lack full capacity for Ag presentation and T cell stimulation. We engineered an attenuated Salmonella Typhi strain to express and export the F1 Ag of Y. pestis (S. Typhi(F1)) and investigated its immunogenicity early in life using a heterologous prime-boost regimen. Newborn mice primed intranasally with a single dose of S. Typhi(F1) elicited mucosal Ab- and IFN-gamma-secreting cells 1 wk after immunization. They also developed a potent and fast anamnestic response to a subsequent parenteral boost with F1-alum, which surpassed those of mice primed and boosted with S. Typhi(F1) or F1-alum. Neonatal priming with S. Typhi(F1), as opposed to priming with F1-alum, resulted in a more balanced IgG2a/IgG1 profile, enhanced avidity maturation and stimulation of B memory cells, and strong Th1-type cell-mediated immunity. S. Typhi(F1) enhanced the activation and maturation of neonatal CD11c+ dendritic cells, shown by increased expression of CD80, CD86, CD40, and MHC-II cell surface markers and production of proinflammatory cytokines IL-12, TNF-alpha, IL-6, and MCP-1. S. Typhi(F1)-stimulated neonatal DC had improved capacity for Ag presentation and T cell stimulation in vitro and induced F1-specific CD4+ and CD8+ T cell responses when adoptively transferred to newborn mice. Mucosal immunization with S. Typhi expressing a foreign Ag effectively primes the neonatal immune system for potent, fast, and broader responses to a parenteral Ag boost. Such a strategy can prevent infectious diseases, including those considered biowarfare threats, early in life.
authors.affiliation: Center for Vaccine Development, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Ramirez
authors.forename: Alejandra V E
authors.initials: AV
authors.lastname: Capozzo
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lloyd
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
authors.forename: James P
authors.initials: JP
authors.lastname: Nataro
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Pasetti
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000378:metabolism; D000915:Antibody Affinity / Q000235:genetics; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D016667:Bacterial Capsules / Q000096:biosynthesis / Q000235:genetics; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D003433:Crosses, Genetic; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D007110:Immunity, Active / Q000235:genetics; D018928:Immunity, Mucosal / Q000235:genetics; D007117:Immunization, Secondary; D007156:Immunologic Memory / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology* / Q000382:microbiology; D022562:Salmonella Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012485:Salmonella typhi / Q000235:genetics / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; C086725:caf1 protein, Yersinia pestis