title: Robust antigen-specific humoral immune responses to sublingually delivered adenoviral vectors encoding HIV-1 Env: association with mucoadhesion and efficient penetration of the sublingual barrier.
abstract: The efficient induction of virus-specific mucosal antibodies is an important unmet objective in Human Immunodeficiency Virus Type-1 (HIV-1) vaccine research. One promising approach is sublingual (SL) immunization. We examined the effectiveness of SL delivery of two different viral vectors: (i) a recombinant adenovirus (rAd5), and (ii) a Herpes Simplex Virus Type-1 amplicon vector (HSV-1). Initial in vitro videomicroscopy experiments showed that rAd5 particles were trapped in saliva (i.e., that Ad5 was mucoadhesive) - unlike HSV-1 virions, which migrated freely in both saliva and water. In vivo imaging studies in mice revealed that only the rAd5 vector efficiently transduced the SL epithelium. Consistent with this, SL delivery of an rAd5 encoding HIV-1 envelope glycoprotein (Env) resulted in robust antigen-specific antibody responses in plasma and in vaginal washes, whereas SL delivery of a HSV-1 amplicon vector encoding HIV-1 Env failed to elicit Env-specific antibodies. In contrast, both vectors elicited equivalent humoral responses following intramuscular (IM) delivery. Finally, SL delivery of the rAd5:Env vector resulted in elevated levels of Env-specific serum IgA, and vaginal IgA and IgG, when compared to IM delivery of the same vector. These results findings shed light on vector properties (mucoadhesion, penetration of the sublingual barrier) which may be important for the induction of potent humoral immune responses following sublingual vector administration. Our data also show that SL delivery of an Env-encoding rAd5 vector can elicit a potent antigen-specific mucosal antibody response in the absence of adjuvant. Overall, these findings support the further exploration of the SL delivery route for HIV-1 vaccine delivery.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14627, USA.
authors.forename: William
authors.initials: W
authors.lastname: Domm
authors.forename: Lauren
authors.initials: L
authors.lastname: Brooks
authors.forename: Hung Li
authors.initials: HL
authors.lastname: Chung
authors.forename: Changyong
authors.initials: C
authors.lastname: Feng
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
authors.forename: Gene
authors.initials: G
authors.lastname: Watson
authors.forename: James L
authors.initials: JL
authors.lastname: McGrath
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology* / Q000493:pharmacokinetics; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000286:Administration, Sublingual; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D012463:Saliva / Q000276:immunology; D014771:Virion / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D054299:env Gene Products, Human Immunodeficiency Virus