HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ramirez, K. Articles by Pasetti, M. F. Search for Related Content PubMed PubMed Citation Articles by Ramirez, K. Articles by Pasetti, M. F.

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 Boost¹

Karina Ramirez^*,, Alejandra V. E. Capozzo^2,*,, Scott A. Lloyd^*,, Marcelo B. Sztein^*,, James P. Nataro^*, and Marcela F. Pasetti^3,*,

^* Center for Vaccine Development, Department of Medicine, and Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201

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--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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants U19-AI-56578 (to J.P.N.) and R01-AI065760 (to M.F.P.).

² Current address: Instituto de Ciencia y Tecnología, Dr. Cesar Milstein – Consejo Nacional de Investigaciones Cientificas y Tecnicas de Argentina, Saladillo 2468 (C1440FFX), Buenos Aires, Argentina.

³ Address correspondence and reprint requests to Dr. Marcela F. Pasetti, Center for Vaccine Development, University of Maryland, 685 West Baltimore Street, Room 480, Baltimore, MD 21201. E-mail address: mpasetti{at}medicine.umaryland.edu

⁴ Abbreviations used in this paper: Frag C, Fragment C; ASC, Ab-secreting cell; BM, bone marrow; CBA, Cytometric Bead Array; DC, dendritic cell; GMT, geometric mean titer; i.n., intranasally; m.o.i., multiplicity of infection; PBA, PBS containing 0.1% BSA and 0.01% NaN₃; PBST, PBS containing 0.05% Tween 20; SFC, spot-forming cell.