Imperial College London

ProfessorRobinShattock

Faculty of MedicineDepartment of Infectious Disease

Chair in Mucosal Infection and Immunity
 
 
 
//

Contact

 

+44 (0)20 7594 5206r.shattock

 
 
//

Location

 

453Wright Fleming WingSt Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

381 results found

Dastgerdi NK, Gumus N, Bayraktutan H, Jackson D, Polra K, McKay PF, Atyabi F, Dinarvand R, Shattock RJ, Martinez-Pomares L, Gurnani P, Alexander Cet al., 2024, Charge neutralized poly(β-amino ester) polyplex nanoparticles for delivery of self-amplifying RNA, Nanoscale Advances

Therapeutic self-amplifying RNA (saRNA) is a promising approach for disease treatment, as it can be administered in lower doses than messenger RNA (mRNA) to achieve comparable protein production levels. However, saRNA requires an appropriate delivery vehicle to protect it during transit and facilitate its transfection. A widely-adopted approach has been to use polycations to condense these large anionic macromolecules into polyplex nanoparticles, however their high charge density often elicits cytotoxic effects. In this study we postulated that we could improve the potency and tolerability of such delivery vehicles by co-formulating poly(β-amino ester)s saRNA polyplexes with a non-toxic anionic polymer, γ-polyglutamic acid (γ-PGA) to neutralize partially this positive charge. Accordingly, we prepared a poly(β-amino ester) from 1,6-hexanedioldiacrylate (HDDA) and 4-aminobutanol (ABOL) and initially evaluated the physicochemical properties of the binary polyplexes (i.e. formed from polymer and saRNA only). Optimised binary polyplex formulations were then taken forward for preparation of ternary complexes containing pHDDA-ABOL, saRNA and γ-PGA. Our findings demonstrate that γ-PGA integration into polyplexes significantly enhanced transfection efficacy in HEK293T and A431 cells without affecting polyplex size. Notably, γ-PGA incorporation leads to a pronounced reduction in zeta potential, which reduced the toxicity of the ternary complexes in moDC, NIH3T3, and A431 cells. Furthermore, the presence of γ-PGA contributed to colloidal stability, reducing aggregation of the ternary complexes, as evidenced by insignificant changes in polydispersity index (PDI) after freeze-thaw cycles. Overall, these results suggest that incorporating the appropriate ratio of a polyanion such as γ-PGA with polycations in RNA delivery formulations is a promising way to improve the in vitro delivery of saRNA.

Journal article

Shattock RJ, Andrianaivoarimanana V, Mckay PF, Randriantseheno LN, Murugaiah V, Samnuan K, Rogers P, Tregoning JS, Rajerison M, Moore KM, Laws TR, Williamson EDet al., 2023, A self-amplifying RNA vaccine provides protection in a murine model of bubonic plague, FRONTIERS IN MICROBIOLOGY, Vol: 14

Journal article

Zhou J, Sukhova K, Peacock TP, McKay PF, Brown JC, Frise R, Baillon L, Moshe M, Kugathasan R, Shattock RJ, Barclay WSet al., 2023, Omicron breakthrough infections in vaccinated or previously infected hamsters, Proceedings of the National Academy of Sciences of USA, Vol: 120, ISSN: 0027-8424

The ongoing SARS-CoV-2 epidemic was marked by the repeated emergence and replacement of “variants” with genetic and phenotypic distance from the ancestral strains, the most recent examples being viruses of the Omicron lineage. Here, we describe a hamster direct contact exposure challenge model to assess protection against reinfection conferred by either vaccination or prior infection. We found that two doses of self-amplifying RNA vaccine based on the ancestral Spike ameliorated weight loss following Delta infection and decreased viral loads but had minimal effect on Omicron BA.1 infection. Prior vaccination followed by Delta or BA.1 breakthrough infections led to a high degree of cross-reactivity to all tested variants, suggesting that repeated exposure to antigenically distinct Spikes, via infection and/or vaccination drives a cross-reactive immune response. Prior infection with ancestral or Alpha variant was partially protective against BA.1 infection, whereas all animals previously infected with Delta and exposed to BA.1 became reinfected, although they shed less virus than BA.1-infected naive hamsters. Hamsters reinfected with BA.1 after prior Delta infection emitted infectious virus into the air, indicating that they could be responsible for onwards airborne transmission. We further tested whether prior infection with BA.1 protected from reinfection with Delta or later Omicron sublineages BA.2, BA.4, or BA.5. BA.1 was protective against BA.2 but not against Delta, BA.4, or BA.5 reinfection. These findings suggest that cohorts whose only immune experience of COVID-19 is Omicron BA.1 infection may be vulnerable to future circulation of reemerged Delta-like derivatives, as well as emerging Omicron sublineages.

Journal article

Hayes G, Dias-Barbieri B, Yilmaz G, Shattock RJ, Becer CRet al., 2023, Poly(2-oxazoline)/saRNA Polyplexes for Targeted and Nonviral Gene Delivery, BIOMACROMOLECULES, ISSN: 1525-7797

Journal article

Kitonsa J, Kamacooko O, Ruzagira E, Nambaziira F, Abaasa A, Serwanga J, Gombe B, Lunkuse J, Naluyinda H, Tukamwesiga N, Namata T, Kigozi A, Kafeero P, Basajja V, Joseph S, Pierce BF, Shattock R, Kaleebu Pet al., 2023, A phase I COVID-19 vaccine trial among SARS-CoV-2 seronegative and seropositive individuals in Uganda utilizing a self-amplifying RNA vaccine platform: screening and enrollment experiences, Human Vaccines and Immunotherapeutics, Vol: 19, Pages: 1-8, ISSN: 1554-8600

We report the screening and enrollment process for a phase I vaccine trial in Masaka, Uganda that investigated the safety and immunogenicity of a self-amplifying SARS-CoV-2 RNA vaccine amongst individuals with and without antibodies to SARS-CoV-2. Participant screening and enrollment were conducted between December 2021 and April 2022. Individuals were eligible if they were aged between 18 and 45 years, healthy, and never vaccinated against COVID-19. SARS-CoV-2 antibody status was determined using two point-of-care rapid tests, i.e. Multi G (MGFT3) and Standard Q (Standard Q COVID-19 IgM/IgG Plus). Data were entered and managed in OpenClinica. Analyses were performed and presented descriptively. A total of 212 individuals were screened and 43(20.3%) enrolled. The most common reasons for exclusion were ≥ grade 1 laboratory abnormalities (39, 18.4%), followed by discordant SARS-CoV-2 antibody results (23, 10.9%). While the first 38 participants were quickly enrolled over a period of 9 weeks, it took another 9 weeks to enroll the remaining five, as antibody negative participants became scarce during the surge of the Omicron variant. The SARS-CoV-2 antibody positivity rate was determined to be 60.8% and 84.4% in each half of the 18 months of screening respectively. The mean age (±Standard Deviation, SD) of screened and enrolled participants was 27.7 (±8.1) and 30.2 (±8.3) years respectively. We demonstrated that it is feasible to successfully screen and enroll participants for COVID-19 vaccine trials in Uganda in the time of a pandemic. Our experiences may be useful for investigators planning to undertake similar work in Africa.

Journal article

Martin GM, Russell RA, Mundsperger P, Harris S, Jovanoska L, Trajano LF, Schiffner T, Fabian K, Tolazzi M, Scarlatti G, McFarlane L, Cheeseman H, Aldon Y, Schermer EE, Breemen M, Sliepen K, Katinger D, Kunert R, Sanders RW, Shattock R, Ward AB, Sattentau QJet al., 2023, Profound structural conservation of chemically cross-linked HIV-1 envelope glycoprotein experimental vaccine antigens., npj Vaccines, Vol: 8, ISSN: 2059-0105

Chemical cross-linking is used to stabilize protein structures with additional benefits of pathogen and toxin inactivation for vaccine use, but its use has been restricted by the potential for local or global structural distortion. This is of particular importance when the protein in question requires a high degree of structural conservation for inducing a biological outcome such as the elicitation of antibodies to conformationally sensitive epitopes. The HIV-1 envelope glycoprotein (Env) trimer is metastable and shifts between different conformational states, complicating its use as a vaccine antigen. Here we have used the hetero-bifunctional zero-length reagent 1-Ethyl-3-(3-Dimethylaminopropyl)-Carbodiimide (EDC) to cross-link two soluble Env trimers, selected well-folded trimer species using antibody affinity, and transferred this process to good manufacturing practice (GMP) for experimental medicine use. Cross-linking enhanced trimer stability to biophysical and enzyme attack. Cryo-EM analysis revealed that cross-linking retained the overall structure with root-mean-square deviations (RMSDs) between unmodified and cross-linked Env trimers of 0.4-0.5 Å. Despite this negligible distortion of global trimer structure, we identified individual inter-subunit, intra-subunit, and intra-protomer cross-links. Antigenicity and immunogenicity of the trimers were selectively modified by cross-linking, with cross-linked ConS retaining bnAb binding more consistently than ConM. Thus, the EDC cross-linking process improves trimer stability whilst maintaining protein folding, and is readily transferred to GMP, consistent with the more general use of this approach in protein-based vaccine design.

Journal article

Herrera C, Serwanga J, Else L, Limakatso L, Opoka D, Ssemata AS, Pillay A-D, Namubiru P, Seiphetlo TB, Odoch G, Mugaba S, Seatlholo P, Alieu A, Penchala SD, Muhumuza R, Alinde B, Petkov S, O'Hagan K, Callebaut C, Seeley J, Weiss H, Khoo S, Chiodi F, Gray CM, Kaleebu P, Webb EL, Martinson N, Fox J, CHAPSet al., 2023, Dose finding study for on-demand HIV pre-exposure prophylaxis for insertive sex in sub-Saharan Africa: results from the CHAPS open label randomised controlled trial, EBIOMEDICINE, Vol: 93, ISSN: 2352-3964

Journal article

Monaco A, Barbieri BD, Yilmaz G, Shattock RJ, Becer CRet al., 2023, Degradable glycopolymers for saRNA transfection, POLYMER CHEMISTRY, Vol: 14, Pages: 2750-2761, ISSN: 1759-9954

Journal article

Siris S, Gladstone CA, Guo Y, Patel R, Pinder CL, Shattock RJ, McKay PF, Langford PR, Bidmos Fet al., 2023, Increasing human monoclonal antibody cloning efficiency with whole-cell modified Immunoglobulin-Capture Assay (mICA), Frontiers in Immunology, Vol: 14, Pages: 1-15, ISSN: 1664-3224

Expression cloning of fully human monoclonal antibodies (hmAbs) is seeing powerful utility in the field of vaccinology, especially for elucidating vaccine-induced B-cell responses and novel vaccine candidate antigen discovery. Precision of the hmAb cloning process relies on efficient isolation of hmAb-producing plasmablasts of interest. Previously, a novel immunoglobulin-capture assay (ICA) was developed, using single protein vaccine antigens, to enhance the pathogen-specific hmAb cloning output. Here, we report a novel modification of this single-antigen ICA using formalin-treated, fluorescently stained whole cell suspensions of the human bacterial invasive pathogens, Streptococcus pneumoniae and Neisseria meningitidis. Sequestration of IgG secreted by individual vaccine antigen-specific plasmablasts was achieved by the formation of an anti-CD45-streptavidin and biotin anti-IgG scaffold. Suspensions containing heterologous pneumococcal and meningococcal strains were then used to enrich for polysaccharide- and protein antigen-specific plasmablasts, respectively, during single cell sorting. Following application of the modified whole-cell ICA (mICA), ~61% (19/31) of anti-pneumococcal polysaccharide hmAbs were cloned compared to 14% (8/59) obtained using standard (non-mICA) methods – representing a ~4.4-fold increase in hmAb cloning precision. A more modest ~1.7-fold difference was obtained for anti-meningococcal vaccine hmAb cloning; ~88% of hmAbs cloned via mICA versus ~53% cloned via the standard method were specific for a meningococcal surface protein. VDJ sequencing revealed that cloned hmAbs reflected an anamnestic response to both pneumococcal and meningococcal vaccines; diversification within hmAb clones occurred by positive selection for replacement mutations. Thus, we have shown successful utilisation of whole bacterial cells in the ICA protocol enabling isolation of hmAbs targeting multiple disparate epitopes, thereby increasing the power of approache

Journal article

Short C-E, 2023, Comparative analysis of vaginal microbiota sampling using menstrual cups and high vaginal swabs in pregnant women living with HIV-1 infection, Frontiers in Cellular and Infection Microbiology, Vol: 13, ISSN: 2235-2988

Background: Menstrual cups (MCs) are increasingly used to collect cervicovaginal secretions to characterise vaginal mucosal immunology, in conjunction with high vaginal swabs (HVS) for metataxonomics, particularly in HIV transmission studies. We hypothesised that both methods of collecting bacterial biomass are equivalent for 16S rRNA gene sequencing.Material and Methods: Cervicovaginal fluid (CVF) samples from 16 pregnant women with HIV-1 (PWWH) were included to represent the major vaginal bacterial community state types (CST I-V). Women underwent sampling during the second trimester by liquid amies HVS followed by a MC (Soft disc™) and samples were stored at -80°C. Bacterial cell pellets obtained from swab elution and MC (500 µL, 1 in 10 dilution) were resuspended in 120 µL PBS for DNA extraction. Bacterial 16S rRNA gene sequencing was performed using V1-V2 primers and were analysed using MOTHUR. Paired total DNA, bacterial load, amplicon read counts, diversity matrices and bacterial taxa were compared by sampling method using MicrobiomeAnalyst, SPSS and R.Results: The total DNA eluted from one aliquot of diluted CVF from an MC was similar to that of a HVS (993ng and 609ng, p=0.18); the mean bacterial loads were also comparable for both methods (MC: 8.0 log10 16S rRNA gene copies versus HVS: 7.9 log10 16S rRNA gene copies, p=0.27). The mean number of sequence reads generated from MC samples was lower than from HVS (MC: 12730; HVS:14830, p=0.05). The α-diversity metrices were similar for both techniques; MC Species Observed: 41 (range 12-96) versus HVS: 47 (range 16-96), p=0.15; MC Inverse Simpson Index: 1.98 (range 1.0-4.0) versus HVS: 0.48 (range 1.0-4.4), p=0.22). The three most abundant species observed were: Lactobacillus iners, Lactobacillus crispatus and Gardnerella vaginalis. Hierarchical clustering of relative abundance data showed that samples obtained using different techniques in an individual clustered in the same CST group.

Journal article

Prudden H, Tatoud R, Slack C, Shattock R, Anklesaria P, Bekker LG, Buchbinder Set al., 2023, Experimental Medicine for HIV Vaccine Research and Development, Vaccines, Vol: 11

The development of safe and effective HIV vaccines has been a scientific challenge for more than 40 years. Despite disappointing results from efficacy clinical trials, much has been learnt from years of research and development. In a rapidly evolving HIV prevention landscape, swift evaluation of multiple vaccine approaches eliciting cross-reactive humoral and cellular responses is needed to ensure the development of efficacious vaccine candidates. To contain increasing costs, innovative clinical research methods are required. Experimental medicine has the potential to accelerate vaccine discovery by iterating early stages of clinical testing faster and by selecting the most promising immunogen combinations for further clinical evaluation. As part of its mission to unite diverse stakeholders involved in the response to the HIV epidemic, the Global HIV Vaccine Enterprise at IAS—the International AIDS Society—hosted a series of online events between January and September 2022 to discuss the merits and challenges of experimental medicine studies to accelerate the development of safe and effective HIV vaccines. This report summarizes key questions and discussions across the series of events, which brought together scientists, policy makers, community stakeholders, advocates, bioethicists, and funders.

Journal article

Tregoning JS, Stirling DC, Wang Z, Flight KE, Brown JC, Blakney AK, McKay PF, Cunliffe RF, Murugaiah V, Fox CB, Beattie M, Tam YK, Johansson C, Shattock RJet al., 2023, Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines, Molecular Therapy : Nucleic Acids, Vol: 31, Pages: 29-42, ISSN: 2162-2531

To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response.

Journal article

Szubert AJ, Pollock KM, Cheeseman HM, Alagaratnam J, Bern H, Bird O, Boffito M, Byrne R, Cole T, Cosgrove CA, Faust SN, Fidler S, Galiza E, Hassanin H, Kalyan M, Libri V, McFarlane LR, Milinkovic A, O'Hara J, Owen DR, Owens D, Pacurar M, Rampling T, Skene S, Winston A, Woolley J, Yim YTN, Dunn DT, McCormack S, Shattock RJ, COVAC 1 Study Teamet al., 2023, COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2., EClinicalMedicine, Vol: 56, Pages: 1-13, ISSN: 2589-5370

BACKGROUND: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18-75. METHODS: A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1 μg then 10 μg of LNP-nCoVsaRNA, ∼14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). FINDINGS: 216 healthy individuals (median age 51 years) received 1.0 μg followed by 10.0 μg of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naïve individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18-75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0 μg dose with a ≥0.5log10 increase in 71% (22/31). INTERPRETATION: Encapsulated saRNA was well tolerated and immunogenic in adults aged 18-75 years. Seroconversion rates in antigen naïve were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0 μg followed by 10.0 μg. Boosting of S IgG an

Journal article

Myatt DP, Wharram L, Graham C, Liddell J, Branton H, Pizzey C, Cowieson N, Rambo R, Shattock RJet al., 2023, Biophysical characterization of the structure of a SARS-CoV-2 self-amplifying RNA (saRNA) vaccine, BIOLOGY METHODS & PROTOCOLS, Vol: 8

Journal article

Horvath A, Rogers L, Pollakis G, Baranov O, Pieroth N, Joseph S, Chachage M, Heitzer A, Maganga L, Msafiri F, Joachim A, Viegas E, Eller L-A, Kibuuka H, Rerks-Ngarm S, Pitisuttithum P, Nitayapan S, Dhitavat J, Premsri N, Fidler S, Shattock RJJ, Robb ML, Weber J, McCormack S, Munseri PJ, Lyamuya E, Nilsson C, Kroidl A, Hoelscher M, Wagner R, Geldmacher C, Held Ket al., 2023, Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?, Frontiers in Immunology, Vol: 13, Pages: 1-16, ISSN: 1664-3224

Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.

Journal article

Reiss EIMM, van Haaren MM, van Schooten J, Claireaux MAF, Maisonnasse P, Antanasijevic A, Allen JD, Bontjer I, Torres JL, Lee W-H, Ozorowski G, Bernat NV, Kaduk M, Aldon Y, Burger JA, Chawla H, Aartse A, Tolazzi M, Gao H, Mundsperger P, Crispin M, Montefiori DC, Hedestam GBK, Scarlatti G, Ward AB, Le Grand R, Shattock R, Dereuddre-Bosquet N, Sanders RW, van Gils MJet al., 2022, Fine-mapping the immunodominant antibody epitopes on consensus sequence-based HIV-1 envelope trimer vaccine candidates, NPJ VACCINES, Vol: 7

Journal article

Lorenzen E, Contreras V, Olsen AW, Andersen P, Desjardins D, Rosenkrands I, Juel HB, Delache B, Langlois S, Delaugerre C, Joubert C, Dereuddre-Bosquet N, Bebear C, De Barbeyrac B, Touati A, McKay PF, Shattock RJ, Le Grand R, Follmann F, Dietrich Jet al., 2022, Multi-component prime-boost <i>Chlamydia trachomatis</i> vaccination regimes induce antibody and T cell responses and accelerate clearance of infection in a non-human primate model, FRONTIERS IN IMMUNOLOGY, Vol: 13, ISSN: 1664-3224

Journal article

Kitandwe PK, McKay PF, Kaleebu P, Shattock RJet al., 2022, An Overview of Rift Valley Fever Vaccine Development Strategies, VACCINES, Vol: 10

Journal article

Hu K, Palmieri E, Samnuan K, Ricchetti B, Oldrini D, McKay PF, Wu G, Thorne L, Fooks AR, McElhinney LM, Goharriz H, Golding M, Shattock RJ, Micoli Fet al., 2022, Generalized Modules for Membrane Antigens (GMMA), an outer membrane vesicle-based vaccine platform, for efficient viral antigen delivery, JOURNAL OF EXTRACELLULAR VESICLES, Vol: 11

Journal article

Van Tilbeurgh M, Maisonnasse P, Palgen J-L, Tolazzi M, Aldon Y, Dereuddre-Bosquet N, Cavarelli M, Beignon A-S, Marcos-Lopez E, Gallouet A-S, Gilson E, Ozorowski G, Ward AB, Bontjer I, McKay PF, Shattock RJ, Scarlatti G, Sanders RW, Le Grand Ret al., 2022, Innate cell markers that predict anti-HIV neutralizing antibody titers in vaccinated macaques, CELL REPORTS MEDICINE, Vol: 3, ISSN: 2666-3791

Journal article

Day S, Kaur C, Cheeseman H, de Groot E, McFarlane L, Tanaka M, Coelho S, Cole T, Lemm N-M, Lim A, Sanders R, Asquith B, Shattock R, Pollock Ket al., 2022, Comparison of blood and lymph node cells after intramuscular injection with HIV envelope immunogens, Frontiers in Immunology, Vol: 13, Pages: 1-17, ISSN: 1664-3224

Background:Harnessing CD4+ T cell help in the lymph nodes through rational antigen design could enhance formation of broadly neutralising antibodies (bNAbs) during experimental HIV immunisation. This process has remained hidden due to difficulty with direct study, with clinical studies instead focusing on responses in the blood as a proxy for the secondary lymphoid tissue. Methods:To address this, lymph node cells (LNC) were collected using ultrasound guided fine needle aspiration of axillary lymph nodes from 11 HIV negative participants in an experimental HIV immunogen study (European AIDS Vaccine Initiative EAVI2020_01 study, NCT04046978). Cells from lymph node and blood (PBMC), were collected after intramuscular injection with HIV Env Mosaic immunogens based on HIV Envelope glycoprotein and combined with a liposomal toll-like receptor-4 adjuvant; monophosphoryl lipid A. Simultaneously sampled cells from both blood and lymph node in the same donors were compared for phenotype, function, and antigen-specificity. Results:Unsupervised cluster analysis revealed tissue-specific differences in abundance, distribution, and functional response of LNC compared with PBMC. Monocytes were virtually absent from LNC, which were significantly enriched for CD4+ T cells compared with CD8+ T cells. T follicular helper cells with germinal centre features were enriched in LNC, which contained specific CD4+ and CD8+ T cell subsets including CD4+ T cells that responded after a single injection with HIV Env Mosaic immunogens combined with adjuvant. Tissue-specific differences in response to an MHC-II dependent superantigen, staphylococcal enterotoxin B, indicated divergence in antigen presentation function between blood and lymph node. Conclusions:LNC are phenotypically and functionally distinct from PBMC, suggesting that whole blood is only a limited proxy of the T cell lymphatic response to immunisation. HIV-specific CD4+ T cells in the lymph node are rapidly inducible upon experimen

Journal article

Elliott T, Cheeseman HM, Evans AB, Day S, McFarlane LR, O'Hara J, Kalyan M, Amini F, Cole T, Winston A, Fidler S, Pollock KM, Harker JA, Shattock RJet al., 2022, Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines, PLoS Pathogens, Vol: 18, Pages: 1-20, ISSN: 1553-7366

The optimal vaccination strategy to boost responses in the context of pre-existing immune memory to the SARS-CoV-2 spike (S) glycoprotein is an important question for global public health. To address this, we explored the SARS-CoV-2-specific humoral and cellular immune responses to a novel self-amplifying RNA (saRNA) vaccine followed by a UK authorised mRNA vaccine (BNT162b2) in individuals with and without previous COVID-19, and compared these responses with those who received an authorised vaccine alone. 35 subjects receiving saRNA (saRNA group) as part of the COVAC1 clinical trial and an additional 40 participants receiving an authorised SARS-CoV-2 vaccine only (non-saRNA group) were recruited. Antibody responses were measured by ELISA and a pseudoneutralisation assay for wildtype, Delta and Omicron variants. Cellular responses were measured by IFN-ƴ ELISpot and an activation induced marker (AIM) assay. Approximately 50% in each group had previous COVID-19 prior to vaccination, confirmed by PCR or antibody positivity on ELISA. All of those who received saRNA subsequently received a full course of an authorised vaccine. The majority (83%) of those receiving saRNA who were COVID-19 naïve at baseline seroconverted following the second dose, and those with previous COVID-19 had an increase in antibody titres two weeks following saRNA vaccination (median 27-fold), however titres were lower when compared to mRNA vaccination. Two weeks following the 2nd authorised mRNA vaccine dose, binding and neutralising antibody titres were significantly higher in the saRNA participants with previous COVID-19, compared to non-saRNA, or COVID-19 naive saRNA participants. Cellular responses were again highest in this group, with a higher proportion of spike specific CD8+ than CD4+ T cells when compared to those receiving the mRNA vaccine only. These findings suggest an immunological benefit of increased antigen exposure, both from natural infection and vaccination, particularly e

Journal article

McKay PF, Zhou J, Frise R, Blakney AK, Bouton CR, Wang Z, Hu K, Samnuan K, Brown JC, Kugathasan R, Yeow J, Stevens MM, Barclay WS, Tregoning JS, Shattock RJet al., 2022, Polymer formulated self-amplifying RNA vaccine is partially protective against influenza virus infection in ferrets, Oxford Open Immunology, Vol: 3, ISSN: 2633-6960

COVID-19 has demonstrated the power of RNA vaccines as part of a pandemic response toolkit. Another virus with pandemic potential is influenza. Further development of RNA vaccines in advance of a future influenza pandemic will save time and lives. As RNA vaccines require formulation to enter cells and induce antigen expression, the aim of this study was to investigate the impact of a recently developed bioreducible cationic polymer, pABOL for the delivery of a self-amplifying RNA (saRNA) vaccine for seasonal influenza virus in mice and ferrets. Mice and ferrets were immunized with pABOL formulated saRNA vaccines expressing either haemagglutinin (HA) from H1N1 or H3N2 influenza virus in a prime boost regime. Antibody responses, both binding and functional were measured in serum after immunization. Animals were then challenged with a matched influenza virus either directly by intranasal inoculation or in a contact transmission model. While highly immunogenic in mice, pABOL-formulated saRNA led to variable responses in ferrets. Animals that responded to the vaccine with higher levels of influenza virus-specific neutralizing antibodies were more protected against influenza virus infection. pABOL-formulated saRNA is immunogenic in ferrets, but further optimization of RNA vaccine formulation and constructs is required to increase the quality and quantity of the antibody response to the vaccine.

Journal article

Herrera C, Cottrell ML, Prybylski J, Kashuba ADM, Veazey RS, García-Pérez J, Olejniczak N, McCoy CF, Ziprin P, Richardson-Harman N, Alcami J, Malcolm KR, Shattock RJet al., 2022, The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans, iScience, Vol: 25, ISSN: 2589-0042

Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (p = 0.042). In humans, this relationship was inverted with lower levels in colorectal tissue (p = 0.027). TFV-resistance caused greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

Journal article

Frise R, Baillon L, Zhou J, Kugathasan R, Peacock TP, Brown JC, Samnuan K, McKay PF, Shattock RJ, Barclay WSet al., 2022, A self-amplifying RNA vaccine protects against SARS-CoV-2 (D614G) and Alpha variant of concern (B.1.1.7) in a transmission-challenge hamster model, VACCINE, Vol: 40, Pages: 2848-2855, ISSN: 0264-410X

Journal article

Hannah S, Chinyenze K, Shattock R, Yola N, Warren Met al., 2022, HIV vaccines in 2022: where to from here?, J Int AIDS Soc, Vol: 25

Journal article

Peter AS, Roth E, Schulz SR, Fraedrich K, Steinmetz T, Damm D, Hauke M, Richel E, Mueller-Schmucker S, Habenicht K, Eberlein V, Issmail L, Uhlig N, Dolles S, Gruner E, Peterhoff D, Ciesek S, Hoffmann M, Pohlmann S, McKay PF, Shattock RJ, Wolfel R, Socher E, Wagner R, Eichler J, Sticht H, Schuh W, Neipel F, Ensser A, Mielenz D, Tenbusch M, Winkler TH, Grunwald T, Uberla K, Jack H-Met al., 2022, A pair of noncompeting neutralizing human monoclonal antibodies protecting from disease in a SARS-CoV-2 infection model, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 52, Pages: 770-783, ISSN: 0014-2980

Journal article

Gallinaro A, Pirillo MF, Aldon Y, Cecchetti S, Michelini Z, Tinari A, Borghi M, Canitano A, McKay PF, Bona R, Vescio MF, Grasso F, Blasi M, Baroncelli S, Scarlatti G, LaBranche C, Montefiori D, Klotman ME, Sanders RW, Shattock RJ, Negri D, Cara Aet al., 2022, Persistent immunogenicity of integrase defective lentiviral vectors delivering membrane-tethered native-like HIV-1 envelope trimers, NPJ VACCINES, Vol: 7

Journal article

Thomas A, Nazaripour C, Higgins R, Abraham S, Abbina S, Son H, Sadat S, Yee L, Boyer E, Tsai S, Anantha M, Chemmannur S, Blakney A, Shattock R, Geall A, Jeffs Let al., 2022, Lipid Nanoparticle Library for Non-Viral Delivery of mRNA and saRNA Towards Vaccine and Cell & Gene Therapy Applications, 25th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 464-465, ISSN: 1525-0016

Conference paper

Day S, de Groot E, Cheeseman H, McFarlane L, Cole T, Tanaka M, Lemm N-M, Lim A, Shattock R, Pollock Ket al., 2022, Towards a prophylactic HIV vaccine: fine needle aspiration reveals cellular features of human lymph nodes compared with blood in the EAVI2020_01 study, Publisher: WILEY, Pages: 39-40, ISSN: 1464-2662

Conference paper

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00698655&limit=30&person=true