273 results found
Van Roey GA, Arias MA, Tregoning JS, et al., 2012, Thymic stromal lymphopoietin (TSLP) acts as a potent mucosal adjuvant for HIV-1 gp140 vaccination in mice, European Journal of Immunology, Vol: 42, Pages: 353-363, ISSN: 1521-4141
The development of a successful vaccine against HIV is likely to require the induction of strong and long-lasting humoral immune responses at the mucosal portal of virus entry. Hence, the design of a vaccine strategy able to induce mucosal antibodies and in particular specific IgA, may be crucial to providing immune protection. Nasal immunisation is known to induce specific IgG and IgA responses in the cervicovaginal mucosa; however, there is an urgent need for the development of safe, effective and accessible mucosal adjuvants for nasal application in humans. To reduce the potential for adverse events associated with some nasal adjuvants, we have assessed whether the B-cell-activating cytokines APRIL, BAFF and TSLP enhance humoral immune responses to HIV-1 gp140. Following intranasal immunisation, TSLP but not APRIL or BAFF induced strong humoral responses both in serum and mucosa. The adjuvant effect of TSLP on humoral responses was similar to that of cholera toxin (CT). The use of TSLP as an adjuvant skewed both the cellular and humoral immune responses towards Th2 cells. This is the first time that TSLP has been demonstrated to have a positive effect as a mucosal adjuvant, and specifically to promote mucosal and systemic responses to HIV gp140.
Shattock RJ, Rosenberg Z, 2012, Microbicides: topical prevention against HIV., Cold Spring Harb Perspect Med, Vol: 2
Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral (ARV) products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. We discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape.
Veazey RS, Shattock RJ, Klasse PJ, et al., 2012, Animal Models for Microbicide Studies, CURRENT HIV RESEARCH, Vol: 10, Pages: 79-87, ISSN: 1570-162X
Herrera C, Shattock RJ, 2012, Potential Use of Protease Inhibitors as Vaginal and Colorectal Microbicides, CURRENT HIV RESEARCH, Vol: 10, Pages: 42-52, ISSN: 1570-162X
Shattock R, Rosenberg Z, 2012, Microbicides: Topical Prevention against HIV, HIV: From Biology to Prevention and Treatment, Editors: Bushman, Nabel, Swanstrom, Publisher: Cold Spring Harbor Laboratory Press, Pages: 505-521
Forbes CJ, Lowry D, Geer L, et al., 2011, Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc, JOURNAL OF CONTROLLED RELEASE, Vol: 156, Pages: 161-169, ISSN: 0168-3659
Kelly CG, Shattock RJ, 2011, Specific microbicides in the prevention of HIV infection, JOURNAL OF INTERNAL MEDICINE, Vol: 270, Pages: 509-519, ISSN: 0954-6820
Herrera C, Cranage M, McGowan I, et al., 2011, Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants, AIDS, Vol: 25, Pages: 1971-1979, ISSN: 0269-9370
Van Roey GA, Arias M, Tregoning JS, et al., 2011, TSLP: A Potential New Mucosal Adjuvant for Intranasal Immunisation with GP140, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT INC, Pages: A68-A68, ISSN: 0889-2229
Veazey R, Siddiqui AA, Buffa V, et al., 2011, Evaluation of Mucosal Immunization Routes for Induction of Vaginal Humoral Immunity in Macaques., Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT INC, Pages: A68-A68, ISSN: 0889-2229
Huang X, Jin W, Griffin GE, et al., 2011, Removal of two high-mannose N-linked glycans on gp120 renders human immunodeficiency virus 1 largely resistant to the carbohydrate-binding agent griffithsin, JOURNAL OF GENERAL VIROLOGY, Vol: 92, Pages: 2367-2373, ISSN: 0022-1317
Lewis DJ, Fraser CA, Mahmoud AN, et al., 2011, Phase I randomised clinical trial of an HIV-1(CN54), clade C, trimeric envelope vaccine candidate delivered vaginally, PLoS ONE, Vol: 6, ISSN: 1932-6203
We conducted a phase 1 double-blind randomised controlled trial (RCT) of a HIV-1 envelope protein (CN54 gp140) candidate vaccine delivered vaginally to assess immunogenicity and safety. It was hypothesised that repeated delivery of gp140 may facilitate antigen uptake and presentation at this mucosal surface. Twenty two healthy female volunteers aged 18–45 years were entered into the trial, the first receiving open-label active product. Subsequently, 16 women were randomised to receive 9 doses of 100 µg of gp140 in 3 ml of a Carbopol 974P based gel, 5 were randomised to placebo solution in the same gel, delivered vaginally via an applicator. Participants delivered the vaccine three times a week over three weeks during one menstrual cycle, and were followed up for two further months. There were no serious adverse events, and the vaccine was well tolerated. No sustained systemic or local IgG, IgA, or T cell responses to the gp140 were detected following vaginal immunisations. Repeated vaginal immunisation with a HIV-1 envelope protein alone formulated in Carbopol gel was safe, but did not induce local or systemic immune responses in healthy women.
Van Roey G, Arias M, Tregoning J, et al., 2011, TSLP, a potential new mucosal adjuvant for intranasal immunisation with HIV-1 gp140, AIDS Vaccine Conference, Bangkok, Thailand
Liard C, Munier S, Arias M, et al., 2011, Targeting of HIV-p24 particle-based vaccine into differential skin layers induces distinct arms of the immune responses, VACCINE, Vol: 29, Pages: 6379-6391, ISSN: 0264-410X
Veazey RS, Klasse PJ, Shattock RJ, et al., 2011, Vaginal application of anti-gp120 monocloncal antibody b12 prevents SHIV-162P vaginal transmission to macaques., Pages: 51-57
Donnelly L, Curran RM, Tregoning JS, et al., 2011, Intravaginal immunization using the recombinant HIV-1 clade-C trimeric envelope glycoprotein CN54gp140 formulated within lyophilized solid dosage forms, Vaccine, Vol: 29, Pages: 4512-4520, ISSN: 1873-2518
Vaccine-mediated prevention of primary HIV-1 infection at the heterosexual mucosal portal of entry may be facilitated by highly optimised formulations or drug delivery devices for intravaginal (i.vag) immunization. Previously we described hydroxyethylcellulose (HEC)-based rheologically structured gel vehicles (RSVs) for vaginal immunization of an HIV-1 vaccine candidate, a soluble recombinant trimeric HIV-1 clade-C envelope glycoprotein designated CN54gp140. Here we investigated the efficacy of lyophilized solid dosage formulations (LSDFs) for prolonging antigen stability and as i.vag delivery modalities. LSDFs were designed and developed that upon i.vag administration they would reconstitute with the imbibing of vaginal fluid to mucoadhesive, site-retentive semi-solids. Mice were immunized with lyophilized equivalents of (i) RSVs, (ii) modified versions of the RSVs more suited to lyophilization (sodium carboxymethyl cellulose (NaCMC)-based gels) and (iii) Carbopol® gel, all containing CN54gp140. NaCMC-based LSDFs provided significantly enhanced antigen stability compared to aqueous-based RSVs. Rheological analysis indicated the NaCMC-based LSDFs would offer enhanced vaginal retention in woman compared to more conventional vaginal gel formulations. All LSDFs were well tolerated in the mouse model. Following i.vag administration, all LSDFs boosted systemic CN54gp140-specific antibody responses in sub-cutaneously primed mice. Induction of CN54gp140-specific antibody responses in the female genital tract was evident. Of all the LSDFs the fastest releasing which was lyophilized Carbopol® gel elicited immune responses comparable to buffer instillation of antigen suggesting that rather than slower sustained release, initial high burst release from the LSDFs may suffice. The boosting of specific immune responses upon i.vag administration indicates that LSDFs are viable mucosal vaccine delivery modalities promoting antigen stability and facilitating intimate exposur
Cranage MP, Fraser CA, Cope A, et al., 2011, Antibody responses after intravaginal immunisation with trimeric HIV-1(CN54) clade C gp140 in Carbopol gel are augmented by systemic priming or boosting with an adjuvanted formulation, Vaccine, Vol: 29, Pages: 1421-1430, ISSN: 0264-410X
Optimum strategies to elicit and maintain antibodies at mucosal portals of virus entry are critical for the development of vaccines against human immunodeficiency virus (HIV). Here we show in non-human primates that a novel regimen of repeated intravaginal delivery of a non-adjuvanted, soluble recombinant trimeric HIV-1(CN54) clade C envelope glycoprotein (gp140) administered in Carbopol gel can prime for B-cell responses even in the absence of seroconversion. Following 3 cycles of repeated intravaginal administration, throughout each intermenses interval, 3 of 4 macaques produced or boosted systemic and mucosally-detected antibodies upon intramuscular immunisation with gp140 formulated in AS01 adjuvant. Reciprocally, a single intramuscular immunisation primed 3 of 4 macaques for antibody boosting after a single cycle of intravaginal immunisation. Virus neutralising activity was detected against clade C and clade B HIV-1 envelopes but was restricted to highly neutralisation sensitive pseudoviruses. (C) 2010 Elsevier Ltd. All rights reserved.
Arias MA, Loxley A, Eatmon C, et al., 2011, Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen, VACCINE, Vol: 29, Pages: 1258-1269, ISSN: 0264-410X
Grivel J-C, Shattock RJ, Margolis LB, 2011, Selective transmission of R5 HIV-1 variants: where is the gatekeeper?, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 9, ISSN: 1479-5876
Wegmann F, Krashias G, Luehn K, et al., 2011, A Novel Strategy for Inducing Enhanced Mucosal HIV-1 Antibody Responses in an Anti-Inflammatory Environment, PLOS ONE, Vol: 6, ISSN: 1932-6203
McKay PF, Cope A, Swales J, et al., 2011, HIV CN54gp140 +GLA Significantly Enhances VaccineAntigen-Specific T and B Cell Immune Responses After Priming with DNA and MVA, AIDS Vaccine 2011, Publisher: Mary Ann Liebert, Inc.
Mann JF, McKay PF, Patel RK, et al., 2011, Mucosally Applied HIV gp140 DNA Prime/Protein Boost Strategies Generate Strong Serum and Mucosal Antigen-Specific Humoral Responses in Mice, AIDS Vaccine 2011, Publisher: Mary Ann Liebert, Inc.
Pattani A, McKay PF, Donnelly RF, et al., 2011, Microneedle Mediated Intradermal Delivery of Adjuvanted Recombinant HIV-1 CN54gp140 Effectively Primes Mucosal Boost Inoculations, AIDS Vaccine 2011, Publisher: Mary Ann Liebert, Inc.
McKay PF, King DF, Carter D, et al., 2011, Vaccine Antigen Immunity Is Enhanced by Optimized TLR4 and TLR7/8 Adjuvant Combinations in Mini-Pigs Inoculated via a Systemic but not a Mucosal Route, AIDS Vaccine 2011, Publisher: Mary Ann Liebert, Inc.
Hu Q, Huang X, Shattock RJ, 2010, C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors, JOURNAL OF GENERAL VIROLOGY, Vol: 91, Pages: 2965-2973, ISSN: 0022-1317
Whaley KJ, Hanes J, Shattock R, et al., 2010, Novel approaches to vaginal delivery and safety of microbicides: biopharmaceuticals, nanoparticles, and vaccines., Antiviral Res, Vol: 88 Suppl 1, Pages: S55-S66
The HIV-1 epidemic remains unchecked despite existing technology; vaccines and microbicides in development may help reverse the epidemic. Reverse transcriptase inhibitors (RTIs) formulated in gels tenofovir (TFV) and IVRs (dapivirine) are under clinical development. While TFV or similar products may prove successful for HIV-1, alternatives to RTIs may provide additional benefits, e.g., broader STI prevention. Biopharmaceutical agents under development as microbicides include cyanovirin, RANTES analogues, commensals, and Mabs. Cost of manufacturing biopharmaceuticals has been reduced and they can be formulated into tablets, films, and IVRs for vaginal delivery. Nanotechnology offers a novel approach to formulate microbicides potentially leading to uniform epithelial delivery. Delivery through vaginal mucus may be possible by controlling nanoparticle size and surface characteristics. Combining prevention modalities may be the most effective means of preventing STI transmission, importantly, codelivery of microbicides and vaccines has demonstrated. Finally, the safety of microbicide preparations and excipients commonly used can be assessed using a mouse/HSV-2 susceptibility model. Screening of new microbicide candidates and formulation excipients may avoid past issues of enhancing HIV-1 transmission. This article forms part of a special supplement covering several presentations on novel microbicide formulations from the symposium on "Recent Trends in Microbicide Formulations" held on 25 and 26 January 2010, Arlington, VA.
Patel R, Mann JFS, McKay PF, et al., 2010, Optimisation of different cationic complexes for mucosal delivery of an HIV-1 gp140 plasmid DNA vaccine, EUROPRISE - Rational Design of HIV Vaccines and Microbicides
McKay PF, Mann JFS, Cope AV, et al., 2010, Dramatic enhancement of gp140-specific mucosal IgA responses in mice following intramuscular DNA prime-intranasal adjuvant-free protein boost., 6th Annual Grand Challenges in Global Health Meeting
Borrow P, Shattock RJ, Vyakarnam A, 2010, Innate immunity against HIV: a priority target for HIV prevention research, RETROVIROLOGY, Vol: 7, ISSN: 1742-4690
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