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Journal of Virology, September 2003, p. 10078-10087, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.10078-10087.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Enhanced Mucosal Immunoglobulin A Response of Intranasal Adenoviral Vector Human Immunodeficiency Virus Vaccine and Localization in the Central Nervous System

Franck Lemiale,1 Wing-pui Kong,1 Levent M. Akyürek,2,{dagger} Xu Ling,1 Yue Huang,1 Bimal K. Chakrabarti,1 Michael Eckhaus,3 and Gary J. Nabel1*

Vaccine Research Center, NIAID,1 Vascular Biology Branch, NHLBI, National Institutes of Health,2 Pathology Section, Office of Research Services, Bethesda, Maryland 208923

Received 17 March 2003/ Accepted 19 June 2003

Replication-defective adenovirus (ADV) vectors represent a promising potential platform for the development of a vaccine for AIDS. Although this vector is typically administered intramuscularly, it would be desirable to induce mucosal immunity by delivery through alternative routes. In this study, the immune response and biodistribution of ADV vectors delivered by different routes were evaluated. ADV vectors expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pol, and Env were delivered intramuscularly or intranasally into mice. Intranasal immunization induced greater HIV-specific immunoglobulin A (IgA) responses in mucosal secretions and sera than in animals with intramuscular injection, which showed stronger systemic cellular and IgG responses. Administration of the vaccine through an intranasal route failed to overcome prior ADV immunity. Animals exposed to ADV prior to vaccination displayed substantially reduced cellular and humoral immune responses to HIV antigens in both groups, though the reduction was greater in animals immunized intranasally. This inhibition was partially overcome by priming with a DNA expression vector expressing HIV-1 Gag, Pol, and Env before boosting with the viral vector. Biodistribution of recombinant adenovirus (rADV) vectors administered intranasally revealed infection of the central nervous system, specifically in the olfactory bulb, possibly via retrograde transport by olfactory neurons in the nasal epithelium, which may limit the utility of this route of delivery of ADV vector-based vaccines.

* Corresponding author. Mailing address: Vaccine Research Center, NIAID, National Institutes of Health, Bldg. 40, Room 4502, MSC 3005, 40 Convent Dr., Bethesda, MD 20892-3005. Phone: (301) 496-1852. Fax: (301) 480-0274. E-mail: gnabel{at}nih.gov.

{dagger} Present address: The Wallenberg Laboratory, Göteberg University, SE-413 45 Göteberg, Sweden.

Journal of Virology, September 2003, p. 10078-10087, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.10078-10087.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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