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Infection and Immunity, August 2004, p. 4637-4646, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4637-4646.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mucosally Delivered Salmonella Live Vector Vaccines Elicit Potent Immune Responses against a Foreign Antigen in Neonatal Mice Born to Naive and Immune Mothers

Alejandra V. E. Capozzo,1 Lilian Cuberos,1 Myron M. Levine,1,2 and Marcela F. Pasetti2*

Center for Vaccine Development, Departments of Pediatrics,2 Medicine, University of Maryland School of Medicine, Baltimore, Maryland 212011

Received 15 January 2004/ Returned for modification 17 February 2004/ Accepted 21 April 2004

The development of effective vaccines for neonates and very young infants has been impaired by their weak, short-lived, and Th-2 biased responses and by maternal antibodies that interfere with vaccine take. We investigated the ability of Salmonella enterica serovars Typhi and Typhimurium to mucosally deliver tetanus toxin fragment C (Frag C) as a model antigen in neonatal mice. We hypothesize that Salmonella, by stimulating innate immunity (contributing to adjuvant effects) and inducing Th-1 cytokines, can enhance neonatal dendritic cell maturation and T-cell activation and thereby prime humoral and cell-mediated immunity. We demonstrate for the first time that intranasal immunization of newborn mice with 109 CFU of S. enterica serovar Typhi CVD 908-htrA and S. enterica serovar Typhimurium SL3261 carrying plasmid pTETlpp on days 7 and 22 after birth elicits high titers of Frag C antibodies, previously found to protect against tetanus toxin challenge and similar to those observed in adult mice. Salmonella live vectors colonized and persisted primarily in nasal tissue. Mice vaccinated as neonates induced Frag C-specific mucosal and systemic immunoglobulin A (IgA)- and IgG-secreting cells, T-cell proliferative responses, and gamma interferon secretion. A mixed Th1- and Th2-type response to Frag C was established 1 week after the boost and was maintained thereafter. S. enterica serovar Typhi carrying pTETlpp induced Frag C-specific antibodies and cell-mediated immunity in the presence of high levels of maternal antibodies. This is the first report that demonstrates the effectiveness of Salmonella live vector vaccines in early life.

* Corresponding author. Mailing address: Center for Vaccine Development, University of Maryland, 685 West Baltimore St., Room 480, Baltimore, MD 21201. Phone: (410) 706-2341. Fax: (410) 706-6205. E-mail: mpasetti{at}medicine.umaryland.edu.

Editor: D. L. Burns

Infection and Immunity, August 2004, p. 4637-4646, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4637-4646.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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