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Journal articleHolmes AH, Gill SK, Hui K, et al., 2016,
Increased airway glucose increases airway bacterial load in hyperglycaemia
, Scientific Reports, Vol: 6, ISSN: 2045-2322Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection.We hypothesize that increased airway glucose caused by hyperglycaemia leads to increasedbacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisationis significantly more likely when blood glucose is high. We engineered mutants in genesaffecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa,strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented withglucose as the sole carbon source. The effect of glucose on growth in vivo was tested usingstreptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose.Bacterial burden in hyperglycaemic animals was greater than control animals when infected withwild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reducedboth airway glucose and bacterial load. These data support airway glucose as a criticaldeterminant of increased bacterial load during diabetes.
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Journal articleCheeseman HM, Carias AM, Evans AB, et al., 2016,
Expression profile of human Fc receptors in mucosal tissue: implications for antibody-dependent cellular effector functions targeting HIV-1 transmission
, PLOS One, Vol: 11, ISSN: 1932-6203The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) of the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting the V1V2 region of the HIV-1 envelope. This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events will depend on a variety of parameters including effector cell type, frequency, the class of Fc-Receptor (FcR) expressed, the number of FcR per cell and the glycoslyation pattern of the induced antibodies. In this study, we characterize and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and red blood cell-lysed whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Of the three tissues tested, penile tissue had the highest percentage of FcR positive effector cells. Immunofluorescent staining was used to determine the location of CD14+, CD11c+ and CD56+ cells within the three mucosal tissues. We show that the majority of effector cells across the different mucosal locations reside within the subepithelial lamina propria. The potential implication of the observed FcR expression patterns on the effectiveness of FcR-dependent cellular effector functions to impact on the ini
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Journal articleCosgrove CA, Lacey CJ, Cope AV, et al., 2016,
Comparative immunogenicity of HIV-1 gp140 vaccine delivered by parenteral, and mucosal routes in female volunteers; MUCOVAC2, a randomized two centre study
, PLOS One, Vol: 11, ISSN: 1932-6203BackgroundDefining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.MethodsIn this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.ResultsThree IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.ConclusionsThese data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.
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Journal articleHerrera C, Armanasco N, García-Pérez J, et al., 2016,
Maraviroc and reverse transcriptase inhibitors combinations as potential pre-exposure prophylaxis candidates
, AIDS, Vol: 30, Pages: 1015-1025, ISSN: 0269-9370Objective: Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a program to develop an effective prevention strategy, we performed an ex-vivo preclinical evaluation to determine the efficacy of multiple double combinations of maraviroc (MVC) and reverse transcriptase inhibitors (RTIs).Design: The entry inhibitor, MVC, a nucleotide RTI, tenofovir and two non-nucleoside RTIs, UC781 and TMC120 (dapivirine, DPV), were used in double, combinations against a panel of CCR5-using clade B and clade C HIV-1 isolates and against MVC-escape variants. A gel-formulated version of MVC-DPV combination was also tested.Methods: Indicator cells, cocultures of immature dendritic cells with CD4+T cells, and colorectal tissue explants were used to assess antiviral activity of drug combinations.Results: All dual MVC-RTI combinations tested inhibited MVC-sensitive and resistant isolates in cellular and colorectal explants models. All the combinations were positive with no reduction in the activity of MVC. In tissue explants, the combinations against all viral isolates tested produced an increase in the activity of MVC. An initial gel-formulation of MVC-DPV combination showed greater and prolonged antiviral activity of MVC in mucosal tissue explants.Conclusion: This study demonstrates that combinations based on antiretroviral drugs inhibiting HIV transmission at viral entry and reverse transcription have potential as prevention strategies against colorectal transmission of HIV-1 including MVC-resistant isolates. Preclinical evaluation with colorectal tissue explants indicates that a gel-formulation of MVC-DPV is an effective candidate colorectal microbicide.
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Journal articleMann JF, Tregoning JS, Aldon Y, et al., 2016,
CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice.
, Journal of Controlled Release, Vol: 232, Pages: 75-82, ISSN: 1873-4995The delivery of vaccines to the sublingual mucosa is an attractive prospect due to the ease and acceptability of such an approach. However, novel adjuvant and delivery approaches are required to optimally vaccinate at this site. We have previously shown that conjugation of protein antigen to the iron transport molecule, transferrin, can significantly enhance mucosal immune responses. We tested whether conjugating influenza haemagglutinin to transferrin could improve the immune response to sublingually delivered antigen. Transferrin conjugated haemagglutinin induced a significant antibody and T cell response in both naïve animals and previously immunized animals. The immune response generated was able to protect mice against influenza virus challenge. Sublingually administered antigen dispersed more widely through the gastro-intestinal tract than intranasally delivered antigen and transferrin conjugation had a more marked effect on sublingually delivered antigen than intranasal immunisation. From these studies we conclude that transferrin conjugation of antigen is effective at boosting immune responses to sublingually delivered antigen and may be an attractive approach for influenza vaccines, particularly when mass campaigns are required.
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Journal articleBadamchi-Zadeh A, McKay PF, Korber BT, et al., 2016,
A multi-component prime-boost vaccination regimen with a consensus MOMP antigen enhances Chlamydia trachomatis clearance
, Frontiers in Immunology, Vol: 7, ISSN: 1664-3224Background: A vaccine for Chlamydia trachomatis is of urgent medical need. We explored bioinformatic approaches to generate an immunogen against C. trachomatis that would induce cross-serovar T cell responses as (i) CD4+ T cells have been shown in animal models and human studies to be important in chlamydial protection, and (ii) antibody responses may be restrictive and serovar-specific.Methods: A consensus antigen based on over 1,500 MOMP sequences provided high epitope coverage against the most prevalent C. trachomatis strains in silico. Having designed the T cell immunogen, we assessed it for immunogenicity in prime-boost regimens. This consensus MOMP transgene was delivered using plasmid DNA, Human Adenovirus-5 (HuAd5) or modified vaccinia Ankara (MVA) vectors with or without MF59® adjuvanted recombinant MOMP protein. Results: Different regimens induced distinct immune profiles. The DNA-HuAd5-MVA-Protein (DAMP) vaccine regimen induced a cellular response with a Th1 biased serum antibody response, alongside high serum and vaginal MOMP-specific antibodies. This regimen significantly enhanced clearance against intravaginal C. trachomatis serovar D infection in both BALB/c and B6C3F1 mouse strains. This enhanced clearance was shown to be CD4+ T cell dependent. Future studies will need to confirm the specificity and precise mechanisms of protection. Conclusions: A C. trachomatis vaccine needs to induce a robust cellular response with broad cross-serovar coverage and that a heterologous prime-boost regimen may be an approach to achieve this.
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Journal articleFletcher P, Herrera C, Armanasco N, et al., 2016,
Short Communication: Limited Anti-HIV-1 Activity of Maraviroc in Mucosal Tissues
, AIDS Research and Human Retroviruses, Vol: 32, Pages: 334-338, ISSN: 0889-2229The potential of maraviroc (MVC), a small-molecule CCR5 antagonist, as a candidate to prevent HIV-1 sexual transmission by oral or topical dosing has not yet been completely established. Using relevant cellular and mucosal tissue explant models, we show partial antiviral activity of MVC when tested in multiple preclinical dosing strategies.
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Journal articleLe Grand R, Dereuddre-Bosquet N, Dispinseri S, et al., 2016,
Superior efficacy of a human immunodeficiency virus vaccine combined with antiretroviral prevention in simian-human immunodeficiency virus-challenged nonhuman primates
, Journal of Virology, Vol: 90, Pages: 5315-5328, ISSN: 1098-5514Although vaccines and antiretroviral (ARV) prevention have demonstrated partial success against human immunodeficiency virus (HIV) infection in clinical trials, their combined introduction could provide more potent protection. Furthermore, combination approaches could ameliorate the potential increased risk of infection following vaccination in the absence of protective immunity. We used a nonhuman primate model to determine potential interactions of combining a partially effective ARV microbicide with an envelope-based vaccine. The vaccine alone provided no protection from infection following 12 consecutive low-dose intravaginal challenges with simian-HIV strain SF162P3, with more animals infected compared to naive controls. The microbicide alone provided a 68% reduction in the risk of infection relative to that of the vaccine group and a 45% reduction relative to that of naive controls. The vaccine-microbicide combination provided an 88% reduction in the per-exposure risk of infection relative to the vaccine alone and a 79% reduction relative to that of the controls. Protected animals in the vaccine-microbicide group were challenged a further 12 times in the absence of microbicide and demonstrated a 98% reduction in the risk of infection. A total risk reduction of 91% was observed in this group over 24 exposures (P = 0.004). These important findings suggest that combined implementation of new biomedical prevention strategies may provide significant gains in HIV prevention.IMPORTANCE There is a pressing need to maximize the impact of new biomedical prevention tools in the face of the 2 million HIV infections that occur each year. Combined implementation of complementary biomedical approaches could create additive or synergistic effects that drive improved reduction of HIV incidence. Therefore, we assessed a combination of an untested vaccine with an ARV-based microbicide in a nonhuman primate vaginal challenge model. The vaccine alone provided no protection (and ma
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Journal articleVamvaka E, Evans A, Ramessar K, et al., 2016,
Cyanovirin-N produced in rice endosperm offers effective pre-exposure prophylaxis against HIV-1BaL infection in vitro
, Plant Cell Reports, Vol: 35, Pages: 1309-1319, ISSN: 1432-203XCyanovirin-N (CV-N) is a lectin with potent antiviral activity that has been proposed as a component of microbicides for the prevention of infection with Human immunodeficiency virus (HIV). The production of protein-based microbicide components requires a platform that is sufficiently economical and scalable to meet the demands of the large at-risk population, particularly in resource poor developing countries. We, therefore, expressed CV-N in rice endosperm, because the dried seed is ideal for storage and transport and crude extracts could be prepared locally and used as a microbicide component without further purification. We found that crude extracts from rice seeds expressing up to 10 µg CV-N per gram dry seed weight showed dose-dependent gp120 binding activity, confirming that the protein was soluble, correctly folded and active. The recombinant lectin (OSCV-N) reduced the infectivity of HIV-1BaL (an R5 virus strain representing the majority of transmitted infections) by ~90 % but showed only weak neutralization activity against HIV-1RF (representative of X4 virus, rarely associated with transmission), suggesting it would be highly effective for pre-exposure prophylaxis against the vast majority of transmitted strains. Crude extracts expressing OSCV-N showed no toxicity towards human cells at working dilutions indicating that microbicide components produced in rice endosperm are safe for direct application as topical microbicides in humans.
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Journal articleRussell RF, McDonald JU, Lambert L, et al., 2016,
Use of the microparticle Nano-SiO2 as an adjuvant to boost vaccine immune responses in neonatal mice against influenza.
, Journal of Virology, Vol: 90, Pages: 4735-4744, ISSN: 1098-5514Neonates are at a high risk of infection, but vaccines are less effective in this age group; tailored adjuvants could potentially improve vaccine efficacy. Increased understanding about danger sensing by the innate immune system has led to the rational design of novel adjuvants. But differences in the neonatal innate immune response, for example to TLR agonists, can reduce the efficacy of these adjuvants in early life. We therefore targeted alternative danger sensing pathways, focusing on a range of compounds described as inflammasome agonists, including Nanoscale SiO2 (NanoSiO2), Calcium pyrophosphate dihydrate (CPPD) crystals and muramyl tripeptide (M-Tri-DAP), for their ability to act as adjuvants. In vitro these compounds induced an interleukin 1-beta (IL-1β) response in the macrophage-like cell line THP1. In vivo, adult CB6F1 female mice were immunised intramuscularly with H1N1 influenza vaccine antigens in combination with NanoSiO2, CPPD or M-Tri-DAP and subsequently challenged with H1N1 influenza (A/England/195/2009). The adjuvants boosted anti-haemagglutinin IgG and IgA antibody levels. Both adult and neonatal animals that received NanoSiO2 adjuvanted vaccines lost significantly less weight and recovered earlier after infection than control animals treated with antigen alone. Administration of the adjuvants led to an influx of activated inflammatory cells into the muscle, but little systemic inflammation measured by serum cytokines. Blocking IL-1β or caspase 1 in vivo had little effect on NanoSiO2 adjuvant function, suggesting it may work through other pathways than the inflammasome. Here we demonstrate that NanoSiO2 can act as an adjuvant and is effective in early life. IMPORTANCE: Vaccines can fail to protect the most at-risk populations, including the very young, elderly and immunocompromised. There is a gap in neonatal immunity between the waning of maternal protection and routine infant immunisation schedules, exacerbated by the failure of vac
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