Imperial College London

ProfessorRobinShattock

Faculty of MedicineDepartment of Infectious Disease

Chair in Mucosal Infection and Immunity
 
 
 
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Contact

 

+44 (0)20 7594 5206r.shattock

 
 
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Location

 

453Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

285 results found

Forbes CJ, Mccoy CF, Murphy DJ, Woolfson AD, Moore JP, Evans A, Shattock RJ, Malcolm RKet al., 2014, Modified Silicone Elastomer Vaginal Gels for Sustained Release of Antiretroviral HIV Microbicides, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol: 103, Pages: 1422-1432, ISSN: 0022-3549

Journal article

Malcolm RK, Lowry D, Boyd P, Geer L, Veazey RS, Goldman L, Klasse PJ, Shattock RJ, Moore JPet al., 2014, Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 69, Pages: 1325-1329, ISSN: 0305-7453

Journal article

Herrera C, Shattock RJ, 2014, Candidate Microbicides and Their Mechanisms of Action, MICROBICIDES FOR PREVENTION OF HIV INFECTION, Vol: 383, Pages: 1-25, ISSN: 0070-217X

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

Jones C, Kaye S, Shattock R, Fidler Set al., 2014, Can we measure HIV viral load in mucosal secretions in men?, HIV MEDICINE, Vol: 15, Pages: 145-145, ISSN: 1464-2662

Journal article

Jones C, Quinn K, Miller A, O'Farrell S, Legg K, Shattock R, McCormack Set al., 2014, What are the best methods to recruit healthy volunteers into HIV vaccine trials?, HIV MEDICINE, Vol: 15, Pages: 146-146, ISSN: 1464-2662

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

Moog C, Dereuddre-Bosquet N, Teillaud J-L, Biedma ME, Holl V, Van Ham G, Heyndrickx L, Van Dorsselaer A, Katinger D, Vcelar B, Zolla-Pazner S, Mangeot I, Kelly C, Shattock RJ, Le Grand Ret al., 2014, Protective effect of vaginal application of neutralizing and nonneutralizing inhibitory antibodies against vaginal SHIV challenge in macaques, MUCOSAL IMMUNOLOGY, Vol: 7, Pages: 46-56, ISSN: 1933-0219

Journal article

Tregoning JS, Buffa V, Oszmiana A, Klein K, Walters AA, Shattock RJet al., 2013, A "Prime-Pull" Vaccine Strategy Has a Modest Effect on Local and Systemic Antibody Responses to HIV gp140 in Mice, PLOS One, Vol: 8, ISSN: 1932-6203

One potential strategy for the prevention of HIV infection is to induce virus specific mucosal antibody that can act as animmune barrier to prevent transmission. The mucosal application of chemokines after immunisation, termed ‘‘prime-pull’’,has been shown to recruit T cells to mucosal sites. We wished to determine whether this strategy could be used to increaseB cells and antibody in the vaginal mucosa following immunisation with an HIV antigen. BALB/c mice were immunisedintranasally with trimeric gp140 prior to vaginal application of the chemokine CCL28 or the synthetic TLR4 ligand MPLA,without antigen six days later. There was no increase in vaginal IgA, IgG or B cells following the application of CCL28,however vaginal application of MPLA led to a significant boost in antigen specific vaginal IgA. Follow up studies toinvestigate the effect of the timing of the ‘‘pull’’ stimulation demonstrated that when given 14 days after the initialimmunisation MPLA significantly increased systemic antibody responses. We speculate that this may be due to residualinflammation prior to re-immunisation. Overall we conclude that in contrast to the previously observed effect on T cells, theuse of ‘‘prime-pull’’ has only a modest effect on B cells and antibody.

Journal article

Klein K, Veazey RS, Warrier R, Hraber P, Doyle-Meyers LA, Buffa V, Liao H-X, Haynes BF, Shaw GM, Shattock RJet al., 2013, Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge, JOURNAL OF VIROLOGY, Vol: 87, Pages: 11604-11616, ISSN: 0022-538X

Journal article

Herrera C, Schuetz A, Olejniczak N, Assawadarachai V, Karasavva N, Nitayaphan S, Kaewkungwal J, Ngauy V, Pitisuttithum P, Rerks-Ngarm S, Michael NL, O'Connell RJ, Excler J, Shattock RJ, Kim JHet al., 2013, Preliminary Evaluation of Mucosal Immune Responses with Mucosal Explants in Humans Vaccinated with ALVAC/AIDSVAX B/E During the Ongoing RV305 Trial, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A181-A181, ISSN: 0889-2229

Conference paper

Herrera C, Olejniczak N, Karasavva N, Rasmussen TA, Rasmussen K, Veazey RS, Kim JH, Shattock RJet al., 2013, Use of Tissue Explants to Evaluate Mucosal Immune Responses in Non-Human Primates (NHPs) Vaccinated with ALVAC/AIDSVAX B/E, Conference on AIDS Vaccine, Publisher: MARY ANN LIEBERT, INC, Pages: A105-A105, 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

Klein K, Veazey RS, Warrier R, Hraber P, Doyle-Meyers LA, Buffa V, Liao HX, Haynes BF, Shaw GM, Shattock RJet al., 2013, Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge., Journal of virology, Vol: 87, Pages: 11604-11616

Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans.

Journal article

Mann JFS, McKay PF, Arokiasamy S, Patel RK, Klein K, Shattock RJet al., 2013, Pulmonary delivery of DNA vaccine constructs using deacylated PEI elicits immune responses and protects against viral challenge infection, JOURNAL OF CONTROLLED RELEASE, Vol: 170, Pages: 452-459, ISSN: 0168-3659

Journal article

Hu K, Luo S, Tong L, Huang X, Jin W, Huang W, Du T, Yan Y, He S, Griffin GE, Shattock RJ, Hu Qet al., 2013, CCL19 and CCL28 Augment Mucosal and Systemic Immune Responses to HIV-1 gp140 by Mobilizing Responsive Immunocytes into Secondary Lymph Nodes and Mucosal Tissue, JOURNAL OF IMMUNOLOGY, Vol: 191, Pages: 1935-1947, ISSN: 0022-1767

Journal article

Mann JFS, Mckay PF, Arokiasamy S, Patel RK, Tregoning JS, Shattock RJet al., 2013, Mucosal Application of gp140 Encoding DNA Polyplexes to Different Tissues Results in Altered Immunological Outcomes in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203

Journal article

Stieh DJ, Phillips JL, Rogers PM, King DF, Cianci GC, Jeffs SA, Gnanakaran S, Shattock RJet al., 2013, Dynamic electrophoretic fingerprinting of the HIV-1 envelope glycoprotein, Retrovirology, Vol: 10, ISSN: 1742-4690

Background: Interactions between the HIV-1 envelope glycoprotein (Env) and its primary receptor CD4 areinfluenced by the physiological setting in which these events take place. In this study, we explored the surfacechemistry of HIV-1 Env constructs at a range of pH and salinities relevant to mucosal and systemic compartmentsthrough electrophoretic mobility (EM) measurements. Sexual transmission events provide a more acidicenvironment for HIV-1 compared to dissemination and spread of infection occurring in blood or lymph node. Wehypothesize functional, trimeric Env behaves differently than monomeric forms.Results: The dynamic electrophoretic fingerprint of trimeric gp140 revealed a change in EM from strongly negativeto strongly positive as pH increased from that of the lower female genital tract (pHx) to that of the blood (pHy).Similar findings were observed using a trimeric influenza Haemagglutinin (HA) glycoprotein, indicating that thismay be a general attribute of trimeric viral envelope glycoproteins. These findings were supported bycomputationally modeling the surface charge of various gp120 and HA crystal structures. To identify the behaviorof the infectious agent and its target cells, EM measurements were made on purified whole HIV-1 virions andprimary T-lymphocytes. Viral particles had a largely negative surface charge, and lacked the regions of positivitynear neutral pH that were observed with trimeric Env. T cells changed their surface chemistry as a function ofactivation state, becoming more negative over a wider range of pH after activation. Soluble recombinant CD4(sCD4) was found to be positively charged under a wide range of conditions. Binding studies between sCD4 andgp140 show that the affinity of CD4-gp140 interactions depends on pH.Conclusions: Taken together, these findings allow a more complete model of the electrochemical forces involvedin HIV-1 Env functionality. These results indicate that the influence of the localized environment on the inter

Journal article

King DFL, Siddiqui AA, Buffa V, Fischetti L, Gao Y, Stieh D, McKay PF, Rogers P, Ochsenbauer C, Kappes JC, Arts EJ, Shattock RJet al., 2013, Mucosal Tissue Tropism and Dissemination of HIV-1 Subtype B Acute Envelope-Expressing Chimeric Virus, JOURNAL OF VIROLOGY, Vol: 87, Pages: 890-899, ISSN: 0022-538X

Journal article

Buffa V, Klein K, Fischetti L, Shattock RJet al., 2012, Evaluation of TLR Agonists as Potential Mucosal Adjuvants for HIV gp140 and Tetanus Toxoid in Mice, PLOS ONE, Vol: 7, ISSN: 1932-6203

Journal article

Merbah M, Arakelyan A, Edmonds T, Ochsenbauer C, Kappes JC, Shattock RJ, Grivel J-C, Margolis LBet al., 2012, HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue Ex Vivo, PLOS ONE, Vol: 7, ISSN: 1932-6203

Journal article

Dereuddre-Bosquet N, Morellato-Castillo L, Brouwers J, Augustijns P, Bouchemal K, Ponchel G, Ramos OHP, Herrera C, Stefanidou M, Shattock R, Heyndrickx L, Vanham G, Kessler P, Le Grand R, Martin Let al., 2012, MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV162P3 in cynomolgus macaques, PLoS Pathogens, Vol: 8, ISSN: 1553-7366

In complement to an effective vaccine, development of potent anti-HIV microbicides remains an important priority. Wehave previously shown that the miniCD4 M48U1, a functional mimetic of sCD4 presented on a 27 amino-acid stable scaffold,inhibits a broad range of HIV-1 isolates at sub-nanomolar concentrations in cellular models. Here, we report that M48U1inhibits efficiently HIV-1Ba-L in human mucosal explants of cervical and colorectal tissues. In vivo efficacy of M48U1 wasevaluated in nonhuman primate (NHP) model of mucosal challenge with SHIV162P3 after assessing pharmacokinetics andpharmacodynamics of a miniCD4 gel formulation in sexually matured female cynomolgus macaques. Among 12 females,half were treated with hydroxyethylcellulose-based gel (control), the other half received the same gel containing 3 mg/g ofM48U1, one hour before vaginal route challenge with 10 AID50 of SHIV162P3. All control animals were infected with a peakplasma viral load of 105–106 viral RNA (vRNA) copies per mL. In animals treated with miniCD4, 5 out of 6 were fully protectedfrom acquisition of infection, as assessed by qRT-PCR for vRNA detection in plasma, qPCR for viral DNA detection in PBMCand lymph node cells. The only infected animal in this group had a delayed peak of viremia of one week. These resultsdemonstrate that M48U1 miniCD4 acts in vivo as a potent entry inhibitor, which may be considered in microbicidedevelopments.

Journal article

Pattani A, McKay PF, Garland MJ, Curran RM, Migalska K, Cassidy CM, Malcolm RK, Shattock RJ, McCarthy HO, Donnelly RFet al., 2012, Microneedle mediated intradermal delivery of adjuvanted recombinant HIV-1 CN54gp140 effectively primes mucosal boost inoculations, JOURNAL OF CONTROLLED RELEASE, Vol: 162, Pages: 529-537, ISSN: 0168-3659

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, Mann JF, Pattani A, Kett VL, Malcolm K, Shattock RJet al., 2012, Intravaginal immunization using a novel antigen delivery device elicits robust vaccine antigen-specific systemic and mucosal humoral immune responses, 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

Du T, Hu K, Yang J, Jin J, Li C, Stieh D, Griffin GE, Shattock RJ, Hu Qet al., 2012, Bifunctional CD4-DC-SIGN Fusion Proteins Demonstrate Enhanced Avidity to gp120 and Inhibit HIV-1 Infection and Dissemination, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 56, Pages: 4640-4649, ISSN: 0066-4804

Journal article

Stefanidou M, Herrera C, Armanasco N, Shattock RJet al., 2012, Saquinavir Inhibits Early Events Associated with Establishment of HIV-1 Infection: Potential Role for Protease Inhibitors in Prevention, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 56, Pages: 4381-4390, ISSN: 0066-4804

Journal article

Arias MA, Van Roey GA, Tregoning JS, Moutaftsi M, Coler RN, Windish HP, Reed SG, Carter D, Shattock RJet al., 2012, Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 Agonist, Promotes Potent Systemic and Mucosal Responses to Intranasal Immunization with HIVgp140, PLOS One, Vol: 7, ISSN: 1932-6203

Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellularimmune responses in both the systemic and mucosal compartments. Based on the known immunological linkage betweenthe upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for theinduction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 togetherwith micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA) and responseswere compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatlyenhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG andIgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with highnumbers of gp140-specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cellresponses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Ourresults show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses,both systemically and mucosally.

Journal article

Ruffin N, Borggren M, Euler Z, Fiorino F, Grupping K, Hallengard D, Javed A, Mendonca K, Pollard C, Reinhart D, Saba E, Sheik-Khalil E, Skold A, Ziglio S, Scarlatti G, Gotch F, Wahren B, Shattock RJet al., 2012, Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 10, ISSN: 1479-5876

Journal article

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