Imperial College London

Dr Alethea Cope (PhD)

Faculty of MedicineDepartment of Infectious Disease

Honorary Senior Research Fellow
 
 
 
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Contact

 

+44 (0)20 3315 5098a.cope

 
 
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Location

 

Human Immunology Lab (IAVI-HIL)Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Publication Type
Year
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47 results found

Haidari G, Day S, Wood M, Ridgers H, Cope A, Fleck S, Yan C, Reijonen K, Hannaman D, Spentzou A, Hayes P, Vogt A, Combadiere B, Cook A, McCormack S, Shattock RJet al., 2019, The safety and immunogenicity of GTU (R) MultiHIV DNA vaccine delivered by transcutaneous and intramuscular injection with or without electroporation in HIV-1 positive subjects on suppressive ART, Frontiers in Immunology, Vol: 10, Pages: 1-8, ISSN: 1664-3224

Previous studies have shown targeting different tissues via the transcutaneous (TC) and intramuscular injection (IM) with or without electroporation (EP) has the potential to trigger immune responses to DNA vaccination. The CUTHIVTHER 001 Phase I/II randomized controlled clinical trial was designed to determine whether the mode of DNA vaccination delivery (TC+IM or EP+IM) could influence the quality and function of induced cellular immune responses compared to placebo, in an HIV positive clade B cohort on antiretroviral therapy (ART). The GTU®MultiHIV B DNA vaccine DNA vaccine encoded a MultiHIV B clade fusion protein to target the cellular response. Overall the vaccine and regimens were safe and well-tolerated. There were robust pre-vaccination IFN-γ responses with no measurable change following vaccination compared to placebo. However, modest intracellular cytokine staining (ICS) responses were seen in the TC+IM group. A high proportion of individuals demonstrated potent viral inhibition at baseline that was not improved by vaccination. These results show that HIV positive subjects with nadir CD4+ counts ≥250 on suppressive ART display potent levels of cellular immunity and viral inhibition, and that DNA vaccination alone is insufficient to improve such responses. These data suggest that more potent prime-boost vaccination strategies are likely needed to improve pre-existing responses in similar HIV-1 cohorts (This study has been registered at http://ClinicalTrials.gov under registration no. NCT02457689).

Journal article

Nadai Y, Held K, Joseph S, Ahmed MIM, Hoffmann VS, Peterhoff D, Missange M, Bauer A, Joachim A, Reimer U, Zerweck J, McCormack S, Cope A, Tatoud R, Shattock RJ, Robb ML, Sandstroem EG, Hoelscher M, Maboko L, Bakari M, Kroidl A, Wagner R, Weber J, Pollakis G, Geldmacher Cet al., 2019, Envelope-specific recognition patterns of HIV vaccine-induced IgG antibodies are linked to immunogen structure and sequence, Frontiers in Immunology, Vol: 10, Pages: 1-14, ISSN: 1664-3224

Background: A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines.Methods: Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, n = 11 from UK) and TaMoVac01 (TMV01, n = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 μg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition.Results: After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG (p < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group.Conclusions: IgG recognition of linear antigenic Env regions differe

Journal article

Tran MGB, Neves JB, Stamati K, Redondo P, Cope A, Brew-Graves C, Williams NR, Grierson J, Cheema U, Loizidou M, Emberton Met al., 2019, Acceptability and feasibility study of patient-specific 'tumouroids' as personalised treatment screening tools: Protocol for prospective tissue and data collection of participants with confirmed or suspected renal cell carcinoma., Int J Surg Protoc, Vol: 14, Pages: 24-29

Introduction: 'Personalised medicine' aims to tailor interventions to the individual, and has become one of the fastest growing areas of cancer research. One of these approaches is to harvest cancer cells from patients and grow them in the laboratory, which can then be subjected to treatments and the response assessed. We have developed a 3D tumour model with a complex protein matrix that mimics the tumour stroma, cell to cell and cell-matrix interactions seen in vivo, called a tumouroid. In this study, we test the acceptability and feasibility of using this model to establish patient-derived tumouroids. Methods and analysis: This is a first in-human study using prospective tissue and data collection of adult participants with confirmed or suspected renal cell carcinoma. The goals of the study are to assess patient acceptability to the use of patient-derived tumour models for future treatment decisions, and to assess the feasibility of generating patient-specific renal cancer tumouroids that can be challenged with drugs. These goals will be realised through the collection of tumour samples (expected n = 10), participant-completed questionnaires (expected n = 10), and in-depth semi-structured interviews with patients (expected n = 5). Collected multiregional tumour samples will be dissociated to isolate primary cells which are then expanded in vitro and incorporated into tumouroids. Drug challenge will ensue and the response will be categorised into "responder", "weak responder", and "non-responder". Statistical analysis will be descriptive. Ethics and dissemination: The study has ethical approval (REC reference 17/LO/1744). Findings will be made available to patients, clinicians, funders, and the National Health Service (NHS) through presentations at national and international meetings, peer-reviewed publications, social media and patient support groups. Trial registration: Registered on ClinicalTrials.gov (NCT03300102).

Journal article

Cheeseman H, Day S, McFarlane L, Fleck S, Miller A, Cole T, Cope A, Tolazzi M, Hannaman D, Kratochvil S, McKay P, Kent S, Chung A, Cook A, Scarlatti G, Combadiere B, Abraham S, McCormack S, Lewis D, Shattock Ret al., 2018, Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to an HIV-1 Clade C Envelope Vaccine, HIV Research for Prevention Meeting (HIVR4P) - AIDS Vaccine, Microbicide and ARV-Based Prevention Science, Publisher: MARY ANN LIEBERT, INC, Pages: 43-43, ISSN: 0889-2229

Conference paper

Cheeseman HM, Day S, McFarlane LR, Fleck S, Miller A, Cole T, Sousa-Santos N, Cope A, Cizmeci D, Tolazzi M, Hwekwete E, Hannaman D, Kratochvil S, McKay PF, Chung AW, Kent SJ, Cook A, Scarlatti G, Abraham S, Combadiere B, McCormack S, Lewis DJ, Shattock RJet al., 2018, Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine, Human Gene Therapy, Vol: 29, Pages: 1011-1028, ISSN: 1043-0342

© Copyright 2018, Mary Ann Liebert, Inc., publishers2018. Intradermal (i.d.) and intramuscular (i.m.) injections when administered with or without electroporation (EP) have the potential to tailor the immune response to DNA vaccination. This Phase I randomized controlled clinical trial in human immunodeficiency virus type 1-negative volunteers investigated whether the site and mode of DNA vaccination influences the quality of induced cellular and humoral immune responses following the DNA priming phase and subsequent protein boost with recombinant clade C CN54 gp140. A strategy of concurrent i.d. and i.m. DNA immunizations administered with or without EP was adopted. Subtle differences were observed in the shaping of vaccine-induced virus-specific CD4+ and CD8+ T cell-mediated immune responses between groups receiving: i.d.EP+ i.m., i.d. + i.m.EP, and i.d.EP+ i.m.EPregimens. The DNA priming phase induced 100% seroconversion in all of the groups. A single, non-adjuvanted protein boost induced a rapid and profound increase in binding antibodies in all groups, with a trend for higher responses in i.d.EP+ i.m.EP. The magnitude of antigen-specific binding immunoglobulin G correlated with neutralization of closely matched clade C 93MW965 virus and Fc-dimer receptor binding (FcγRIIa and FcγRIIIa). These results offer new perspectives on the use of combined skin and muscle DNA immunization in priming humoral and cellular responses to recombinant protein.

Journal article

Haidari G, Cope A, Miller A, Venables S, Yan C, Ridgers H, Reijonen K, Hannaman D, Spentzou A, Hayes P, Bouliotis G, Vogt A, Joseph S, Combadiere B, McCormack S, Shattock RJet al., 2017, Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers.

Journal article

de Silva TI, Gould V, Mohammed NI, Cope A, Meijer A, Zutt I, Reimerink J, Kampmann B, Hoschler K, Zambon M, Tregoning JSet al., 2017, Comparison of mucosal lining fluid sampling methods and influenza-specific IgA detection assays for use in human studies of influenza immunity, Journal of Immunological Methods, Vol: 449, Pages: 1-6, ISSN: 0022-1759

We need greater understanding of the mechanisms underlying protection against influenza virus to develop more effective vaccines. To do this, we need better, more reproducible methods of sampling the nasal mucosa. The aim of the current study was to compare levels of influenza virus A subtype-specific IgA collected using three different methods of nasal sampling. Samples were collected from healthy adult volunteers before and after LAIV immunization by nasal wash, flocked swabs and Synthetic Absorptive Matrix (SAM) strips. Influenza A virus subtype-specific IgA levels were measured by haemagglutinin binding ELISA or haemagglutinin binding microarray and the functional response was assessed by microneutralization. Nasosorption using SAM strips lead to the recovery of a more concentrated sample of material, with a significantly higher level of total and influenza H1-specific IgA. However, an equivalent percentage of specific IgA was observed with all sampling methods when normalized to the total IgA. Responses measured using a recently developed antibody microarray platform, which allows evaluation of binding to multiple influenza strains simultaneously with small sample volumes, were compared to ELISA. There was a good correlation between ELISA and microarray values. Material recovered from SAM strips was weakly neutralizing when used in an in vitro assay, with a modest correlation between the level of IgA measured by ELISA and neutralization, but a greater correlation between microarray-measured IgA and neutralizing activity. In conclusion we have tested three different methods of nasal sampling and show that flocked swabs and novel SAM strips are appropriate alternatives to traditional nasal washes for assessment of mucosal influenza humoral immunity.

Journal article

Gould VMW, Francis JN, Anderson KJ, Georges B, Cope AV, Tregoning JSet al., 2017, Nasal IgA provides protection against human influenza challenge in volunteers with low serum influenza antibody titre, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X

In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.

Journal article

Joseph S, Quinn K, Greenwood A, Cope A, McKay P, Hayes P, Kopycinski J, Gilmour J, Miller A, Geldmacher C, Nadai Y, Ahmed M, Montefiori D, Dally L, Bouliotis G, Lewis D, Tatoud R, Wagner R, Esteban M, Shattock R, McCormack S, Weber Jet al., 2017, A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 protein/adjuvant HIV vaccines in two immunization regimes, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The ap

Journal article

Joseph S, Quinn K, Greenwood A, Miller A, Cope AV, Mckay PF, Hayes P, Kopycinski J, Bouliotis G, Gilmour J, McFarlane L, Tatoud R, Shattock RJ, Lewis D, Montefiore D, Esteban M, Wagner R, McCormack S, Weber Jet al., 2016, UK HVC 003: A Phase I Clinical Trial Exploring a Strategy to Maximise HIV Antibody Responses using Subtype C DNA, MVA and GLA Adjuvanted gp140, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 99-99, ISSN: 0889-2229

Conference paper

Nadai Y, Ahmed MIM, Joseph S, Missanga M, Bauer A, Cope AV, Joachim A, Reimer U, Pollakis G, McCormack S, Tatoud R, Shattock RJ, Robb M, Sandstroem E, Hoelscher M, Bakari M, Maboko L, Kroidl A, Weber J, Geldmacher C, Held Ket al., 2016, Env-specific IgG Responses Induced by Identical and None-identical Immunogen Prime-boost Vaccination Strategies Target Different Antigenic Regions, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 392-392, ISSN: 0889-2229

Conference paper

Haidari G, Cope A, Miller A, Ridgers H, Venables S, Yan C, Reijonen K, Hannaman D, Spentzou A, Hayes P, Bouliotis G, Joseph S, Combadiere B, McCormack S, Shattock RJet al., 2016, CUTHIVAC 001: Results from a Phase I Clinical Trial of a Prophylactic Clade B HIV-1 DNA Vaccine Comparing Multiple Routes of Administration, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 391-391, ISSN: 0889-2229

Conference paper

Cosgrove CA, Lacey CJ, Cope AV, Bartolf A, Morris G, Yan C, Baden S, Cole T, Carter D, Brodnicki E, Shen X, Joseph S, DeRosa SC, Peng L, Yu X, Ferrari G, Seaman M, Montefiori DC, Frahm N, Tomaras GD, Stöhr W, McCormack S, Shattock RJet 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: 1932-6203

BackgroundDefining 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.

Journal article

Shattock R, Cope A, Bouliotis G, Haidari G, Miller A, Ridgers H, Venables S, Yan C, Spentzou A, Hayes P, Joseph S, McCormack Set al., 2016, The quest for a prophylactic HIV vaccine continues: results from a Phase I trial using novel routes of DNA vaccination in HIV-uninfected volunteers, HIV MEDICINE, Vol: 17, Pages: 28-28, ISSN: 1464-2662

Journal article

Le Grand R, Dereuddre-Bosquet N, Dispinseri S, Gosse L, Desjardins D, Shen X, Tolazzi M, Ochsenbauer C, Saidi H, Tomaras G, Prague M, Barnett SW, Thiebaut R, Cope A, Scarlatti G, Shattock RJet 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: 1098-5514

Although 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

Journal article

Shen X, Duffy R, Howington R, Cope A, Sadagopal S, Park H, Pal R, Kwa S, Ding S, Yang OO, Fouda GG, Le Grand R, Bolton D, Esteban M, Phogat S, Roederer M, Amara RR, Picker LJ, Seder RA, McElrath MJ, Barnett S, Permar SR, Shattock R, DeVico AL, Felber BK, Pavlakis GN, Pantaleo G, Korber BT, Montefiori DC, Tomaras GDet al., 2015, Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates, JOURNAL OF VIROLOGY, Vol: 89, Pages: 8643-8650, ISSN: 0022-538X

Journal article

Cope AV, Moog C, Shattock RJ, Chawda MM, Czyzewska-Khan J, Kat P, Venables S, Yan C, Williams M, Cobb K, Singh M, Oehlmann W, Elamin A, Katinger D, Wagner A, Joshi P, Lewis DJMet al., 2014, A Phase I Clinical Trial with a Novel gp41 HIV Vaccine (EN41-FPA2) in Healthy Female Volunteers: A Mucosal Prime and Intramuscular Boost Regimen, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A187-A188, ISSN: 0889-2229

Journal article

Le Grand R, Bosquet NN, Dispinseri S, Gosse L, Des Jardins D, Shen S, Tomaras G, Hopewell N, Barnett S, Saidi H, Thiebaut R, Scarlatti G, Cope A, Shattock RJet al., 2014, Microbicide-vaccine Combination Provides Significant Protection against Vaginal SHIV-162P3 Challenge in Cynomolgous Monkeys, AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: A26-A26, ISSN: 0889-2229

Journal article

Mann JFS, Mckay PF, Fiserova A, Klein K, Cope A, Rogers P, Swales J, Seaman MS, Combadiere B, Shattock RJet al., 2014, Enhanced immunogenicity of an HIV-1 DNA vaccine delivered with electroporation via combined intramuscular and intradermal routes, Journal of Virology, Vol: 88, Pages: 6959-6969, ISSN: 1098-5514

It is accepted that an effective prophylactic HIV-1 vaccine is likely to have the greatest impact on viral transmission rates. As previous reports have implicated DNA-priming, protein boost regimens to be efficient activators of humoral responses, we sought to optimize this regimen to further augment vaccine immunogenicity. Here we evaluated single versus concurrent intradermal (i.d.) and intramuscular (i.m.) vaccinations as a DNA-priming strategy for their abilities to elicit humoral and cellular responses against a model HIV-1 vaccine antigen, CN54-gp140. To further augment vaccine-elicited T and B cell responses, we enhanced cellular transfection with electroporation and then boosted the DNA-primed responses with homologous protein delivered subcutaneously (s.c.), intranasally (i.n.), i.m., or transcutaneously (t.c.). In mice, the concurrent priming regimen resulted in significantly elevated gamma interferon T cell responses and high-avidity antigen-specific IgG B cell responses, a hallmark of B cell maturation. Protein boosting of the concurrent DNA strategy further enhanced IgG concentrations but had little impact on T cell reactivity. Interestingly protein boosting by the subcutaneous route increased antibody avidity to a greater extent than protein boosting by either the i.m., i.n., or t.c. route, suggesting that this route may be preferential for driving B cell maturation. Using an alternative and larger animal model, the rabbit, we found the concurrent DNA-priming strategy followed by s.c. protein boosting to again be capable of eliciting high-avidity humoral responses and to also be able to neutralize HIV-1 pseudoviruses from diverse clades (clades A, B, and C). Taken together, we show that concurrent multiple-route DNA vaccinations induce strong cellular immunity, in addition to potent and high-avidity humoral immune responses.

Journal article

McKay PF, Cope AV, Mann JFS, Joseph S, Esteban M, Tatoud R, Carter D, Reed SG, Weber J, Shattock RJet al., 2014, Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen, PLOS One, Vol: 9, ISSN: 1932-6203

Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNApoxvirus-proteinstrategy in mice and rabbits, administering MVA and protein immunizations either sequentially orsimultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/2GLA-AF adjuvant) andeither co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. TheDNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to theboost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccinecomponents. Moreover, a high proportion of the total mucosal IgG (20 – 50%) present in the vaginal vault of thesevaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccinemodality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIVCN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene productexpressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA andGLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequentialvaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit ofthe condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced,an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF.

Journal article

Shen X, Howington R, Park H, Sadagopal S, Kwa S, Cope A, Ding S, Bolton D, Roederer M, Amara R, Picker L, Seder R, McElrath J, Barnett S, Shattock R, Felber B, Pavlakis G, Pantaleo G, Montefiori D, Tomaras Get al., 2013, Vaccine Induced Epitope Specific Antibodies to the SIV Envelope Are Distinct from Those Induced to the HIV-1 Envelope, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A10-A11, ISSN: 0889-2229

Conference paper

Cosgrove CA, Lacey C, Cope AV, Bartolf A, Morris G, Yan C, Baden S, Cole T, Carter D, Brodnicki E, Stoehr W, McCormack S, Shattock RJet al., 2013, A Phase I Clinical Trial of an HIV-1(CN54), Clade C, Trimeric Envelope Vaccine Delivered by Parenteral, Nasal and Vaginal Routes of Immunisation, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A9-A9, ISSN: 0889-2229

Conference paper

Katinger D, Wagner A, Luque I, Crespillo S, Conejero-Lara F, Roger M, Martin C, Mouz N, Mourao S, Farsang A, Notka F, Malcolm K, Bosquet N, Le Grand R, Moog C, Cope A, Shattock R, Lewis DJ, El Habib Ret al., 2012, Liposomal formulation of Gp41 derivate with adjuvant MPLA: vaccine design, immunogenicity in animals and safety in humans, RETROVIROLOGY, Vol: 9, ISSN: 1742-4690

Journal article

Mann JF, McKay PF, Swales J, Klein K, Fiserova A, Cope A, Shattock RJet al., 2012, Optimising CN54gp140 plasmid delivery by comparing intramuscular and intradermal vaccination combinations with and without electroporation, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690

Conference paper

McKay PF, Cope AV, Swales J, Joseph S, Esteban M, Tatoud R, Carter D, Weber J, Shattock RJet al., 2012, Antigen-specific T lymphocyte responses elicited by a DNA - MVA HIV CN54gp140 immunization regime are significantly altered by the TLR4 adjuvant GLA, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690

Conference paper

Katinger D, Jeffs S, Altmann F, Cope A, McKay P, Almond N, Sandstrom E, Hejdeman B, Biberfeld G, Nilsson C, Hallengard D, Wahren B, Lehner T, Singh M, Lewis DJ, Lacey C, Shattock Ret al., 2012, CN54gp140: product characteristics, peclinical and clinical use - recombinant glycoprotein for HIV immunization, RETROVIROLOGY, Vol: 9, ISSN: 1742-4690

Journal article

Lewis DJ, Fraser CA, Mahmoud AN, Wiggins RC, Woodrow M, Cope A, Cai C, Giemza R, Jeffs SA, Manoussaka M, Cole T, Cranage MP, Shattock RJ, Lacey CJet 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.

Journal article

Cranage MP, Fraser CA, Cope A, Mckay PF, Seaman MS, Cole T, Mahmoud AN, Hall J, Giles E, Voss G, Page M, Almond N, Shattock RJet 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.

Journal article

McKay PF, Cope A, Swales J, Joseph S, Esteban M, Tatoud R, Carter D, Weber J, Shattock RJet 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.

Conference paper

McKay PF, Mann JFS, Cope AV, Shattock RJet 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

Conference paper

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