title: Intravaginal immunisation using a novel antigen-releasing ring device elicits robust vaccine antigen-specific systemic and mucosal humoral immune responses.
abstract: The generation of effective levels of antigen-specific immunity at the mucosal sites of pathogen entry is a key goal for vaccinologists. We explored topical vaginal application as an approach to initiate local antigen-specific immunity, enhance previously existing systemic immunity or re-target responses to the mucosae. To deliver a protein vaccine formulation to the vaginal mucosal surface, we used a novel vaginal ring device comprising a silicone elastomer body into which three freeze-dried, rod-shaped, hydroxypropylmethylcellulose inserts were incorporated. Each rod contained recombinant HIV-1 CN54gp140 protein (167μg)±R848 (167μg) adjuvant. The inserts were loaded into cavities within each ring such that only the ends of the inserts were initially exposed. Sheep received a prime-boost vaccination regime comprising intramuscular injection of 100μg CN54gp140+200μg R848 followed by three successive ring applications of one week duration and separated by one month intervals. Other sheep received only the ring devices without intramuscular priming. Serum and vaginal mucosal fluids were sampled every two weeks and analysed by CN54gp140 ELISA and antigen-specific B cells were measured by flow cytometry at necropsy. Vaccine antigen-specific serum antibody responses were detected in both the intramuscularly-primed and vaginal mucosally-primed groups. Those animals that received only vaginal vaccinations had identical IgG but superior IgA responses. Analysis revealed that all animals exhibited mucosal antigen-specific IgG and IgA with the IgA responses 30-fold greater than systemic levels. Importantly, very high numbers of antigen-specific B cells were detected in local genital draining lymph nodes. We have elicited local genital antigen-specific immune responses after topical application of an adjuvanted antigen formulation within a novel vaginal ring vaccine release device. This regimen and delivery method elicited high levels of antigen-specific mucosal IgA and large numbers of local antigen-reactive B cells, both likely essential for effective mucosal protection.
authors.affiliation: Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK. Electronic address: p.mckay@imperial.ac.uk.
authors.forename: Paul F
authors.initials: PF
authors.lastname: McKay
authors.affiliation: Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK.
authors.forename: Jamie F S
authors.initials: JF
authors.lastname: Mann
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Aditya
authors.initials: A
authors.lastname: Pattani
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Vicky
authors.initials: V
authors.lastname: Kett
authors.affiliation: Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Aldon
authors.affiliation: Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: King
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
authors.affiliation: Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000282:Administration, Intravaginal; D000818:Animals; D000917:Antibody Formation; D003274:Contraceptive Devices, Female; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000276:immunology; D056724:Immunity, Humoral; D018928:Immunity, Mucosal; D007114:Immunization / Q000295:instrumentation*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D012756:Sheep; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D007093:Imidazoles; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1; C402365:resiquimod