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Infection and Immunity, August 2007, p. 3769-3779, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00356-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Enhanced Immunity to Plasmodium falciparum Circumsporozoite Protein (PfCSP) by Using Salmonella enterica Serovar Typhi Expressing PfCSP and a PfCSP-Encoding DNA Vaccine in a Heterologous Prime-Boost Strategy{triangledown} ,{dagger}

Magaly Chinchilla,1,3 Marcela F. Pasetti,1,2 Sandra Medina-Moreno,1,3,{ddagger} Jin Yuan Wang,1 Oscar G. Gomez-Duarte,1,§ Rick Stout,4 Myron M. Levine,1,2,3 and James E. Galen1,3*

Center for Vaccine Development,1 Departments of Pediatrics,2 Medicine, University of Maryland School of Medicine, Baltimore, Maryland,3 Bioject Inc., Portland, Oregon4

Received 7 March 2007/ Returned for modification 4 April 2007/ Accepted 2 May 2007

Two Salmonella enterica serovar Typhi strains that express and export a truncated version of Plasmodium falciparum circumsporozoite surface protein (tCSP) fused to Salmonella serovar Typhi cytolysin A (ClyA) were constructed as a first step in the development of a preerythrocytic malaria vaccine. Synthetic codon-optimized genes (t-csp1 and t-csp2), containing immunodominant B- and T-cell epitopes present in native P. falciparum circumsporozoite surface protein (PfCSP), were fused in frame to the carboxyl terminus of the ClyA gene (clyA::t-csp) in genetically stabilized expression plasmids. Expression and export of ClyA-tCSP1 and ClyA-tCSP2 by Salmonella serovar Typhi vaccine strain CVD 908-htrA were demonstrated by immunoblotting of whole-cell lysates and culture supernatants. The immunogenicity of these constructs was evaluated using a "heterologous prime-boost" approach consisting of mucosal priming with Salmonella serovar Typhi expressing ClyA-tCSP1 and ClyA-tCSP2, followed by parenteral boosting with PfCSP DNA vaccines pVR2510 and pVR2571. Mice primed intranasally on days 0 and 28 with CVD 908-htrA(pSEC10tcsp2) and boosted intradermally on day 56 with PfCSP DNA vaccine pVR2571 induced high titers of serum NANP immunoglobulin G (IgG) (predominantly IgG2a); no serological responses to DNA vaccination were observed in the absence of Salmonella serovar Typhi-PfCSP priming. Mice primed with Salmonella serovar Typhi expressing tCSP2 and boosted with PfCSP DNA also developed high frequencies of gamma interferon-secreting cells, which surpassed those produced by PfCSP DNA in the absence of priming. A prime-boost regimen consisting of mucosal delivery of PfCSP exported from a Salmonella-based live-vector vaccine followed by a parenteral PfCSP DNA boosting is a promising strategy for the development of a live-vector-based malaria vaccine.

* Corresponding author. Mailing address: Center for Vaccine Development, University of Maryland, 685 W. Baltimore St., HSF I, Room 480, Baltimore, MD 21201. Phone: (410) 706-5328. Fax: (410) 706-6205. E-mail: jgalen{at}medicine.umaryland.edu

{triangledown} Published ahead of print on 14 May 2007.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: D. L. Burns

{ddagger} Present address: Institute of Human Virology, Division of Clinical Research, University of Maryland, 725 Lombard St., Baltimore, MD 21201.

§ Present address: Department of Pediatrics, University of Iowa Children's Hospital, 200 Hawkins Dr., Iowa City, IA 52242.

Infection and Immunity, August 2007, p. 3769-3779, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00356-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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