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 Li, Z. Articles by Frankel, F. R. Search for Related Content PubMed PubMed Citation Articles by Li, Z. Articles by Frankel, F. R.

Novel Vaccination Protocol with Two Live Mucosal Vectors Elicits Strong Cell-Mediated Immunity in the Vagina and Protects against Vaginal Virus Challenge¹

Zhongxia Li^*, Manxin Zhang^*, Chenghui Zhou^*, Xinyan Zhao^*, Norifumi Iijima and Fred R. Frankel^2,*

^* Department of Microbiology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104; and Section of Immunobiology, Yale University, School of Medicine, New Haven, CT 06520

Most HIV infections result from heterosexual transmission to women. Because cellular immunity plays a key role in the control of the infection, we sought to strengthen cellular immune responses in vaginal tissue. We explored a novel prime-boost protocol that used two live mucosal agents that trigger different pathways of innate immunity and induce strong cellular immunity. Adenovirus serotype 5 (Ad5) has frequently been used as a boost for DNA vaccines. In this study we used attenuated, recombinant L. monocytogenes-gag (rLm-gag) to prime mice by various mucosal routes—oral, intrarectal, and intravaginally (ivag)—followed by a systemic or mucosal boost with replication-defective rAd5-gag. Mice primed with a single administration of rLm-gag by any route and then boosted with rAd5-gag intramuscularly exhibited abundant Gag-specific CD8 T cells in spleen and vaginal lamina propria. Conversely, when boosted with rAd5-gag ivag, the immune response was reoriented toward the vagina with strikingly higher CD8 T cell responses in that tissue, particularly after ivag immunization by both vectors (ivag/ivag). Five weeks to 5 mo later, ivag/ivag-immunized mice continued to show high levels of effector memory CD8 T cells in vagina, while the pool of memory T cells in spleen assumed a progressively more central memory T cell phenotype. The memory mice showed high in vivo CTL activity in vagina, a strong recall response, and robust protection after ivag vaccinia-gag challenge, suggesting that this prime-boost strategy can induce strong cellular immunity, especially in vaginal tissues, and might be able to block the heterosexual transmission of HIV-1 at the vaginal mucosa.

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 R01 AI42509 and P01 AI054558.

² Address correspondence and reprint requests to Dr. Fred R. Frankel, Department of Microbiology, University of Pennsylvania, School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104. E-mail address: frankelf{at}mail.med.upenn.edu

³ Abbreviations used in this paper: Lm, Listeria monocytogene; Ad5, adenovirus type 5; CD62L, CD62 ligand; ig, oral gavage; im, intramuscular(ly); ivag, intravaginal(ly); ivag/ivag, intravaginal administration of both vectors, rLm-gag and rAd5-gag; T_CM, central memory T cell; T_EM, effector memory T cell; vps, virus particles.