VAccine deveLopment for complex Intracellular neglecteD pAThogEns (VALIDATE)

Lead Research Organisation: University of Oxford

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Publications

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Dunachie S (2019) The double burden of diabetes and global infection in low and middle-income countries. in Transactions of the Royal Society of Tropical Medicine and Hygiene

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Eckold C (2021) Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Paarwater BA (2021) Inhaled particulate matter affects immune responsiveness of human lung phagocytes to mycobacteria. in American journal of physiology. Lung cellular and molecular physiology

 
Description Liaison with MPs
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
URL https://www.validate-network.org/un-high-level-tb-meeting-2018
 
Description Additional MRC funding for VALIDATE 2022
Amount £450,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2022 
End 03/2023
 
Description Developing a vaccine to prevent death from melioidosis in people with type 2 diabetes mellitus in low- and middle-income countries
Amount £1,956,321 (GBP)
Funding ID NIHR300791 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2021 
End 01/2026
 
Description Diabetes and infection: developing a network for using real-world datasets (Susanne Dunachie P016 outcome)
Amount £26,728 (GBP)
Organisation United Kingdom Research and Innovation 
Department Global Challenges Research Fund
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2020
 
Description Internal GCRF funding award to Panjaporn Chaichana (VALIDATE P007 output)
Amount £29,928 (GBP)
Organisation United Kingdom Research and Innovation 
Department Global Challenges Research Fund
Sector Public
Country United Kingdom
Start  
 
Description NIHR Senior Investigator - Prof Helen McShane (ref NIHR200225)
Amount £60,000 (GBP)
Funding ID NIHR200225 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2019 
End 03/2023
 
Description Optimization of lead melioidosis and glanders vaccine formulations (Brett, Dunachie; melioidosis workshop outcome)
Amount $733,976 (USD)
Organisation Defense Threat Reduction Agency 
Sector Public
Country United States
Start 01/2020 
End 12/2022
 
Description VALIDATE Network TB Vaccine Support
Amount $1,538,836 (USD)
Funding ID INV-031830 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2021 
End 03/2024
 
Title VALIDATE Data Sharing Portal and VALIDATE Research Data Analyst 
Description In January 2019 we launched the VALIDATE Data Sharing Portal, which aimed to facilitate and encourage the sharing of published and unpublished data amongst our members, to enable cross-comparisons (e.g. of similar assays across pathogens, or across assays for one pathogen, or across species or countries) that will accelerate vaccine development, as well as to avoid duplication of effort where unpublished negative data already exists. Our VALIDATE Research Data Analyst was in charge of the database and facilitated the uploading and analyses of data by our members. This has resulted in two publications to date: 1. Satti I et al 2022. Inflammation and immune activation are associated with risk of Mycobacterium tuberculosis infection in BCG-vaccinated infants | Nature Communications DOI 10.1038/s41467-022-34061-7 2. Tanner R et al 2020. Tools for Assessing the Protective Efficacy of TB Vaccines in Humans: in vitro Mycobacterial Growth Inhibition Predicts Outcome of in vivo Mycobacterial Infection. Frontiers in Immunology DOI: 10.3389/fimmu.2019.02983 Our Research Data Analyst, Dr Deniz Cizmeci, moved to a post-doc position at Harvard University in early May 2019 and we had significant challenges recruiting an appropriate replacement, with no appointable candidates in three rounds of advertisement. Our fourth round resulted in an appointable candidate, who started in post on 1 January 2020. This means we had a gap of eight months in this post that was beyond our control, but moved this area of the Network forwards with our new VALIDATE Bioinformatician/Computational Biologist, Dr Mirvat Surakhy, who was in post from March 2020 to Jan 2021. Sadly, it became clear that neither our Bioinformatician or the VALIDATE Data Portal were being used much by members, so we decided to close both. Before she left, Mirvat Surakhy added a comprehensive list of data resources (including free training options and free databases) to the VALIDATE website to support members (https://www.validate-network.org/bioinformatics). Instead of the data portal, we now have a list of data sets available via VALIDATE members from pump-priming/fellowship projects at https://www.validate-network.org/data-sharing for members. 20 data sets are listed as available for members, ranging from clinical trial data (e.g. microarray, RNAseq) to animal model lab data (e.g. ELISA, MGIA, flow cytometry). 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact List of data sets available via VALIDATE members from pump-priming/fellowship projects at https://www.validate-network.org/data-sharing for members. 
URL https://www.validate-network.org/data-sharing
 
Description VALIDATE Fellowships - Jomien Mouton 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution VALIDATE aims to encourage Continuing Professional Development (CPD) and career progression amongst its members. As part of this, two VALIDATE Fellowships were awarded in 2018. These VALIDATE Fellowships were open to Early Career Researcher (Associate) Members to fund two years' independent scientific research with the aim of producing initial/pilot data, and a funding and experience track record, that can be used by the Fellow to go on to obtain independent external funding and launch their career as a Principal Investigator and/or Group Leader. After competitive application to the Network Management Board, and subsequent interviews, the two fellowships were awarded to: 1. Dr Jomien Mouton, Stellenbosch University South Africa, "Identification of latency associated antigens and biosignatures associated with Mycobacterium tuberculosis" 2. Dr Rachel Tanner, University of Oxford, UK "Characterising the BCG-induced antibody response to inform the design of improved vaccines against M.tuberculosis, M.leprae and M.bovis" We are proud that both awardees happen to be female, and one is also LMIC. Both Jomien and Rachel joined our Network Management Board for the duration of their Fellowships, giving them experience at this senior level and in reviewing grant and membership applications made to VALIDATE, and giving VALIDATE valuable ECR input to our NMB.
Collaborator Contribution Fellowship Aims 1. Characterise the transcriptional profile of replicating and non-replicating Mycobacterium tuberculosis populations using a single-cell dual host-pathogen RNA sequencing approach. 2. Identify biosignatures associated with replicating and non-replicating M. tuberculosis in host cells. 3. Identify potential antigen candidates associated with non-replicating persister M. tuberculosis using bioinformatics analyses. 4. Assess the immunogenicity of selected candidate latency antigens in human populations in South Africa to which tuberculosis (TB) is endemic. Fellowship Outcomes To elucidate how macrophages interact with replicating and non-replicating mycobacterium, we employed a dual-fluorescent replication reporter in combination with flow cytometry to identify and isolate host cells containing either non-replicating or replicating mycobacteria for RNA sequencing and fluorophore-conjugated antibody staining. Our results indicate that macrophages containing differentially replicating mycobacteria are distinctly associated with either M1 or M2 macrophage polarisation. The VALIDATE Fellowship has had a tremendous impact on my career development. Specifically, it allowed me to be appointed as a researcher, which afforded me the opportunity to supervise my own students and apply for funding as a primary investigator. In addition, I have had the opportunity to serve on the Network Management Board (NMB) and expand my network by meeting new people at the annual meetings. The funding I have received as part of my fellowship has made high-end research possible that contributed to scarce skills development in RNA sequencing in South Africa. Progress during the course of this funding includes the following: 1. Intracellular M. tuberculosis H37Rv growth inside alveolar macrophages from black versus clear bronchoalveolar lavage samples has been monitored using a combination of the fluorescence dilution (FD) technology and flow cytometry. This data was combined with data from another research group in our department that looked at cytokine responses of black versus clear alveolar macrophages for a publication (Objective 1). We have prepared a manuscript (2nd co-author) entitled, "Inhaled particulate matter affects immune responsiveness of human lung phagocytes to mycobacterial species" that was accepted in July 2021 (objective 1). 2. A material transfer agreement between Stellenbosch University and Helmholtz Institute for RNA-based Infection Research (HIRI) in Wursburg, Germany for shipping of extracted bacterial and host RNA for dual and single-cell RNA sequencing were set up (Objective 1). Although RNA sequencing have been performed at the South African Medical Research Council for the proposed work (to avoid covid-related delays), we maintain our relationship with collaborators at Wursburg University for future projects and to provide support with RNA sequencing analyses. 3. The dual host-bacterial RNA extraction protocol resulted in low bacterial RNA yield. In the interest of limited time, and restrictions due to circumstances related to COVID-19 we focused on RNA extraction of macrophages containing differentially replicating mycobacteria for RNA sequencing. The RNA extraction protocol has been optimised and provides good quality and high yield RNA. RNA samples were prepared for sequencing in May 2021 at the South African Medical Research Council Sequencing Unit in Cape Town, South Africa (objective 1). The results will be included in the PhD thesis of Mrs. Zimvo Obasa (I am her co- supervisor), who is expected to graduate in March 2022. Additionally, the RNA sequencing results will be included in a manuscript that is in preparation. 4. Progress on objectives 2 - 4 have subsequently been delayed due to circumstances related to COVID-19, however related work to the proposed work included investigating the relation between persister formation and clinical outcome in TB patients. This study was undertaken by my MSc student, Mr. Julian Coetzee (who will graduate in December 2021, cum laude). He employed a combination of bioinformatics analyses and experimental research to determine whether M. tuberculosis strains from TB patients who were considered cured, but have relapsed, or failed treatment (based on PET-CT imaging), are more likely to be predisposed to persister formation than those who remained "cured" using phenotypic and genotypic approaches. To achieve this, persister proportions in all clinical isolates (taken at baseline) from cured, recurrent/failed patient groups using fluorescence dilution (FD) and flow cytometry were assessed. Additionally, comparative next generation sequencing analyses of the isolates were performed to determine whether sequence variation predisposes persister formation in clinical isolates (taken at baseline) from patient groups. Results from this work revealed a significantly higher proportion of persisters in clinical isolates from patients who have remaining lesion activity in the lung (post-treatment) based on PET-CT imaging. This result suggests that the inherent tendency to form persister-like cells may have an impact on pulmonary TB treatment outcome. Data suggests that persister-like cell formation may be strain dependent. Results from this research are currently being written up for a manuscript. 5. Ms Lesedi Dikhoba, a MSc student working on aspects of the project, utilised a more comprehensive cytokine panel for flow cytometry to assess macrophage polarisation in response to replicating and non-replicating M. tuberculosis. She has demonstrated that we are able to identify a distinct M1-like macrophage polarisation (inflammatory) associated with non-replicating M. tuberculosis (MHCII and CD274) and a M2-like macrophage polarisation (anti-inflammatory) associated with replicating M. tuberculosis (Arg-1) (objective 2). She submitted this work as part of her MSc thesis for examination in May 2021, she is expected to graduate in December 2021. [As a result of the COVID-19 pandemic and implementation of restrictions in the research environment in South Africa during 2020/2021, experimental work were severely affected. VALIDATE granted Jomien a no-cost extension for this.]
Impact Fellowship Outputs Student supervision: o 2 MSc students (primary supervisor), will graduate in Dec 2021 o 2 Hons students (co-supervision), graduated in Dec 2019/2020 o 1 PhD student (co-supervision), graduated March 2021 o 2 PhD students (co-supervision), expected to graduate in December 2021 Workshops Attended: o AMNIS® IMAGESTREAM®XMARKII Workshop, Cape Town, May 2019 Publications: o Apiyo D, Mouton JM, Louw C, Sampson SL, Louw TM. A rigorous approach to develop, validate and evaluate a dynamic mathematical model predicting Mycobacterium smegmatis growth in physiologically relevant conditions. Journal of Theoretical Biology. (under revision July 2021) o Paarwater B, Mouton JM, Sampson SL, Malherbe S, Kotze L, Walzl G, du Plessis N. Inhaled particulate matter affects immune responsiveness of human lung phagocytes to mycobacteria. American Journal of Physiology-Lung Cellular and Molecular Physiology. Accepted July 2021. Impact factor: 4.037. o Parbhoo T, Sampson SL, Mouton JM. Recent developments in the application of flow cytometry to advance our understanding of Mycobacterium tuberculosis physiology and pathogenesis. Cytometry Part A 2020. 97(7):783. Impact factor: 3.124. o Gallant J, Mouton JM, Ummels R, ten Hagen-Jongman C, Kriel N, Pain A, Warren RW, Bitter W, Heunis T, Sampson SL. Identification of gene fusion events in Mycobacterium tuberculosis that encode chimeric proteins. NAR Genomics and Bioinformatics 2020. 2(2): lqaa033. o Mouton JM, Heunis T, Dippenaar A, Gallant JL, Kleynhans L, Sampson SL. Comprehensive characterisation of the attenuated double auxotroph Mycobacterium tuberculosis ?leuD?panCD as an alternative to H37Rv. Frontiers in Microbiology 2019. 10: 1922. Impact factor: 4.259 Publications in preparation: o Obasa Z, Smith L, Mouton JM and Sampson SL. Different approaches to study Mycobacterium tuberculosis persister formation in vivo. BMC microbiology journal, submission in October 2021. Impact factor 3.19 Honours/Rewards: o Top 20 Post-doc award (Nov 2018) o Promotion to appointed as Researcher (Nov 2018) o NRF Y-rating (Nov 2020) Funding: o NRF Y-rating, incentive funding (Jan 2021) o Involved in a subsequent successful VALIDATE pump-priming grant application as co-investigator, with Samantha Sampson (SU) and Andrea Zelmar (LSHTM; a new collaborator), for £37,031. o As a result of being a SU staff member, Jomien was a co-investigator for a National Research Foundation National Equipment Fund application, to acquire an Amnis Imagestream Imaging Flow Cytometer. This grant was successful, with R12,000,000; the instrument is the first of its kind in Africa and arrived in July 2019, and Jomien subsequently capacity builds by presenting Amnis Imaging Flow Cytometer data analyses workshops in the division, teaching honours students, and leading a Joint Stellenbosch University-University of Cape Town bacterial flow cytometry interest group. o Submitted a R01 funding application to the National Institute of Health as PI in collaboration with VALIDATE fellow, Dr. Rachel Tanner from Oxford University, Prof. Sophie Helaine from Harvard Medical School and Prof. Samantha Sampson from Stellenbosch University entitled, "Evaluation of the interplay between host cells and mycobacteria in drug-resistant tuberculosis (DR-TB) patients from the Eastern Cape, South Africa" in July 2021 (outcome pending). o Jomien submitted a Dorothy Temple Cross Tuberculosis International collaboration grant as co-PI in collaboration with VALIDATE Fellow, Dr Rachel Tanner ( Oxford University) entitled, "Combining expertise in mycobacterial killing assays to evaluate functional immune and treatment responses in drug-resistant tuberculosis (DR-TB) patients" in October 2020. Although this was not funded, Jomien and Rachel aim to incorporate feedback and resubmit in 2021 and/or submit our application to another funding call. o As a member of VALIDATE Jomien also participated in a larger European COST funding application that included 97 VALIDATE members from 49 countries (unsuccessful). o Ms Lesedi Dikhoba, MSc student working on aspects of the project, received a bursary to support her 2nd year of studies from the National Research Foundation. New Collaborations: o Associate Professor Sean Wasserman, University of Cape Town, South Africa (consultant on NIH R01 application submitted in July 2021) o Alex Westermann, Antoine-Emmaneul Saliba, Helmholtz Institute for RNA-based infection research, Wursburg University, Germany o Sophie Helaine, Harvard Medical School, Boston, United States of America (co-investigator on NIH R01 application submitted in July 2021) o Rachel Tanner, University of Oxford, United Kingdom (co-investigator on NIH R01 application submitted in July 2021) Talks/Presentations: o Poster Presentation at the international Meeting 'Bacterial morphogenesis, survival and virulence: regulation in 4D' in Cape Town, Nov 2019 o Presentations at the VALIDATE 2018 and 2019 Annual Meetings Guest Lecturer: o What if I don't want to work in the BSL3? Departmental Year Day, Cape Town, November 2019. o M. tuberculosis in the host: Persisters and PE/PPE proteins, VALIDATE Winter Seminar Series, 24 November 2020. Student presentations: o Maqeda Z, Smith L, Mouton J, Sampson SL. CYTO2020 (International society for advanced cytometry), 04-05 August 2020, "Mycobacterium tuberculosis at the host-pathogen interface", ePoster o Maqeda Z, Smith L, Mouton J, Sampson SL. 63rd Annual Academic Day 2020, Faculty of Medicine and Health Sciences, Stellenbosch University, 26 - 27 August 2020, "Mycobacterium tuberculosis at the host-pathogen interface", ePoster o Coetzee J, Sampson SL, Mouton JM. 63rd Annual Academic Day, Faculty of Medicine and Health Sciences, Stellenbosch University, 26-27 August 2020, "The relation between persisters and clinical outcome in tuberculosis (TB) patients", ePoster o Coetzee JL, Sampson SL, Mouton JM. 6th SATB virtual conference. June 2021, "Investigating the relation between persister formation and clinical outcome in tuberculosis (TB) patients", ePoster o Dikhoba L, Gutschmidt A, Sampson SL, Mouton JM. Departmental Research Day, Faculty of Medicine and Health Sciences, Stellenbosch University, 21 November 2019, "Identification of biosignatures associated latent Mycobacterium tuberculosis.", ePoster o Dikhoba L, Gutschmidt A, Sampson SL, Mouton JM. The Conversation Africa Scientific Article Writing Competition, December 2019, "Identification of biosignatures associated latent Mycobacterium tuberculosis.", ePoster o Dikhoba L, Gutschmidt A, Sampson SL, Mouton JM. 63rd Annual Academic Day, Faculty of Medicine and Health Sciences, Stellenbosch University, 26-27 August 2020, "Identification of biosignatures associated latent Mycobacterium tuberculosis.", ePoster Scientific involvement: o Organizer of Bacterial Flow Cytometry Forum (Joint SU-UCT), March 2014 - March 2020 o VALIDATE Network Board Member, Nov 2018 - 2021 o SA Acid Fast Organizing Committee, August 2019 o Reviewer for PlosOne, Tuberculosis, Epigenetics o Examination of 2 MSc theses (Stellenbosch University, University of KwaZulu-Natal) Public engagement: o Participated in VALIDATE for Schools, by presenting a lecture to school pupils at a UK-based school about career path and research interests in May 2021. o Assisted 2 school pupils from local South Africa schools to "job shadow" in 2019, showing them the department, laboratory and campus and engaging with them about her science interests, experimental procedures that she use in the laboratory and discussing what our careers involve. o Students directly or indirectly involved in the project (2 MSc and 1 PhD students that Jomien either supervised/co-supervised) presented aspects of the project to other scientists at scientific conferences, or the general public at related meetings. For example, Ms Lesedi Dikhoba, the 2nd year MSc student working on aspects of the project presented at The Conversation Africa workshop in Stellenbosch on 3 December 2019. o Presented a lecture on "M. tuberculosis in the host: Persisters and PE/PPE proteins" at the VALIDATE Winter Seminar Series on 24 November 2020 o Jomien has applied for funding from the Faculty of Medicine and Health Science Social Impact Committee for an outreach project, entitled "Vaccines saves lives" that involves radio interviews and visits to local clinics to inform the community about vaccines and vaccine development. Following this, she has prepared a written brief for an interview with local radio stations in the Eastern Cape to communicate the importance of vaccines to the more rural communities in the region. The radio interviews will take place in early 2021. Capacity development During the course of the VALIDATE project funding Jomien contributed to capacity building and skills development in the following ways; o Had 2 final year school pupils visit for a day in the Division and laboratory to communicate her research to and convey what a career in science involves. o Supervised 2 MSc students on work related to the project. o Co-supervised 3 PhD students, 1 MSc student and 2 Honours students. o Presented an Amnis Imaging Flow Cytometer data analyses workshops in the division from 2019 - 2020. o Presented 3 lectures in 2 modules to honours students in 2018 - 2021. o Led a Joint Stellenbosch University - University of Cape Town bacterial flow cytometry interest group in 2018 - 2020. o As a result of moving to the Eastern Cape in June 2020, Jomien offered training to students to use the BD FACSJazz cell sorter in the BSL3 facility for cell sorting of infectious samples for downstream analyses. Other During the contracts process in November 2018, Jomien noticed that VALIDATE's grant conditions require employment for the duration of the award. At Stellenbosch University post-doctoral fellows are not employed and receive tax-free bursaries on a contract basis. She stated in an email to us "As a young researcher, employment by the university would be extremely beneficial e.g., allowing supervision of students as a primary supervisor, applying for funding otherwise not eligible to apply for." VALIDATE agreed to pay the FEC so that she could be made an employee at University of Stellenbosch, a promotion that would not have happened without her Fellowship. As an employed researcher at Stellenbosch University she was able to apply for rating in December 2019 in the Y category (young researchers) from the National Research Foundation that aims to benchmark the quality of South African researchers against the best in the world. NRF ratings are allocated based on a researcher's recent research outputs and impacts perceived by international peer reviewers. Several South African universities require NRF evaluation and rating for appointments, or provide incentives for their staff members to acquire or maintain a rating. The outcome of this application has been successful and she has received a Y-rating for the following 5 years. As a result of this appointment she has supervised two South African MSc students (one female, one male) for work related to her VALIDATE project, as their primary supervisor (prior to this Jomien had co-supervised students only) who aim to submit in April 2021. This has obviously further spread the local capacity building value of Jomien's VALIDATE Fellowship, as well as contributing to the development of important aspects of Jomien's scientific career e.g. mentoring, project management, interpersonal skills and teaching. She published her first senior author publication in March 2020. VALIDATE also supported Jomien through her maternity leave from 14 August to 13 December 2019; without her VALIDATE Fellowship she would have had to take unpaid maternity leave. She states, "Being supported and encouraged in this way has taught me that women in science have the opportunity to take up different roles (e.g. mothers, wives, professionals etc.)." As part of her Fellowship, Jomien has been mentored by Prof Paul Kaye, at the University of York, UK, since November 2018. As a result of this connection, they are working on a review together and Paul has connected Jomien with colleagues in his department at York. Jomien also received mentorship from her SU host, Prof Samantha Sampson, and Prof Helena Kuivaniemi at SU. The VALIDATE Fellows were made VALIDATE Network Management Board (NMB) full members. At the VALIDATE NMB bi-monthly meetings Jomien has participated in discussions about sustainability of the network, recruitment of new members, and management of funds. As part of the NMB, Fellows had the opportunity to review funding applications for training grants and pump-priming projects, which Jomien says has "provided incredible insight into how seasoned researchers that are experts in their field review, critique and score funding applications". Importantly, this improved her knowledge about what fundable grant applications should look like, what reviewers look for and also how to review grant applications. Her exposure to the discussions by internationally recognised scientists during the NMB meetings have been invaluable for her development as a young scientist. Jomien says: 'Receiving the VALIDATE Fellowship has had a tremendous impact on my research and career. Apart from being appointed as a researcher and being able to supervise my own students, I have had the opportunity to serve on the NMB and expand my network by meeting new people at the annual meeting. The funding I have received as part of my fellowship has made research possible (eg. dual RNA sequencing and single cell RNA sequencing) that has not yet been done in South Africa (to our knowledge). This has a large impact on capacity development and knowledge transfer in scarce skills and allows us to be able to use this data to apply for follow-on funding.'
Start Year 2018
 
Description VALIDATE Fellowships - Rachel Tanner 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution VALIDATE aims to encourage Continuing Professional Development (CPD) and career progression amongst its members. As part of this, two VALIDATE Fellowships were awarded in 2018. These VALIDATE Fellowships were open to Early Career Researcher (Associate) Members to fund two years' independent scientific research with the aim of producing initial/pilot data, and a funding and experience track record, that can be used by the Fellow to go on to obtain independent external funding and launch their career as a Principal Investigator and/or Group Leader. After competitive application to the Network Management Board, and subsequent interviews, the two fellowships were awarded to: 1. Dr Jomien Mouton, Stellenbosch University South Africa, "Identification of latency associated antigens and biosignatures associated with Mycobacterium tuberculosis" 2. Dr Rachel Tanner, University of Oxford, UK "Characterising the BCG-induced antibody response to inform the design of improved vaccines against M.tuberculosis, M.leprae and M.bovis" We are proud that both awardees happen to be female, and one is also LMIC. Both Jomien and Rachel joined our Network Management Board for the duration of their Fellowships, giving them experience at this senior level and in reviewing grant and membership applications made to VALIDATE, and giving VALIDATE valuable ECR input to our NMB.
Collaborator Contribution Fellowship Aims This project aimed to characterise the antibody response to BCG vaccination by identifying mycobacterial proteins that are potent inducers of protective antibodies, and testing these proteins as potential vaccine candidates. The findings could inform the design of new, efficacious vaccines against M.tb, M.leprae and M.bovis that may benefit from targeting humoral as well as cell- mediated immunity. Serum samples were selected from n=10 humans, n=10 non-human primates (NHP) and n=10 cattle at pre- and post-BCG vaccination time-points. In collaboration with Antigen Discovery Inc. (ADI), we employed a comprehensive, high-throughput and unbiased approach to antigen discovery, applying protein microarrays spanning the entire proteome of M.tb to identify targets recognised by BCG vaccine-induced antibodies. A large number of proteins showed increased reactivity following BCG vaccination across species, with a higher magnitude of response to BCG in NHPs compared with humans (possibly associated with the lower baseline reactivity resulting in less blocking/masking effect). Interestingly, many top- ranked proteins differed by species and by route of BCG administration in NHP, with higher reactivity in the intravenous (IV) vaccinated compared with intradermal (ID) vaccinated NHP, and in particular the two most protected animals. This suggests that route of vaccination alters target antigen repertoire and indicates potential associations between IgG antigen specificity and improved protection from in vivo M.tb challenge. 14 proteins of interest were selected based on i) higher array reactivity in animals showing superior protection from mycobacterial challenge in vivo, ii) ranking of reactivity in the array based on magnitude of response increase between pre- and post-vaccination time-points, iii) high ranking across more than one species, iv) high degree of homology across M.tb and one or more of M.bovis and M.leprae, v) low homology to human proteins, and vi) surface or secreted protein available for antibody recognition in vivo. 8 of these were successfully synthesised in collaboration with Deepa Paliwal and Ian Jones at the University of Reading, and 7 were taken forward to testing in mice. Antigens were tested in a protein + adjuvant formulation with 3 homologous vaccinations at 2 weekly intervals. Spleen and serum were collected and the ex vivo mycobacterial growth inhibition assay (MGIA) conducted as a high-throughput surrogate of protective efficacy. 3 of the proteins conferred significantly improved ability to control mycobacterial growth in the MGIA following correction for multiple comparisons and will be progressed to further in vivo efficacy studies. The pandemic, associated lockdown and lack of lab capacity since has had a significant impact on this work in 2020 and Rachel was granted a no-cost extension to compensate for this and enable her to finish her research.
Impact New Collaborations • Collaborated with Antigen Discovery Inc on this project, which is a new industry collaboration, and who have subsequently been involved in her follow-up grant applications • Sally Sharpe (PHE, UK - VALIDATE member) • Martin Vordermeier (APHA, UK - VALIDATE member) • Bernardo Villarreal-Ramos (University of Aberystwyth - VALIDATE member) • Ian Jones and Deepa Paliwal (University of Reading & VALIDATE members) • In discussions to set up new collaborations with researchers at Albert Einstein College of Medicine in New York and Leiden University Medical Centre in the Netherlands to explore the functional and biophysical characteristics of the antibody responses induced by antigens identified during her fellowship. Publications • Review on the humoral immune response to BCG vaccination as a basis to this project: Tanner R, Villarreal-Ramos B, Vordermeier M, McShane H. "The humoral immune response to BCG vaccination." Front Immunol. 2019; 10:1317 • Preprint of a primary data paper on the humoral response to BCG vaccination as senior author: "Induction of specific antibodies, IgG-secreting plasmablasts and memory B cells following BCG vaccination." BioRxiv, 2021. • In writing: main data paper from this work • In writing: a VALIDATE review entitled 'Shared challenges to the control of complex intracellular neglected pathogens'. Funding • Submitted a VALIDATE pump-priming application with VALIDATE member Dr Hao Li who hopes to conduct some of his research with Rachel in Oxford in March 2022 (successful - £57,500). • Submitted an R01 NIH grant as co-applicant with VALIDATE Fellow, Dr Jomien Mouton (Stellenbosch University) entitled, "Evaluation of the interplay between host cells and mycobacteria in drug-resistant tuberculosis (DR-TB) patients from the Eastern Cape, South Africa" in July 2021. • Submitted a Dorothy Temple Cross Tuberculosis International collaboration grant as co-PI in collaboration with VALIDATE Fellow, Dr Jomien Mouton (Stellenbosch University) entitled, "Combining expertise in mycobacterial killing assays to evaluate functional immune and treatment responses in drug-resistant tuberculosis (DR-TB) patients" in October 2020. Although this was not funded, Jomien and Rachel aim to incorporate feedback and resubmit in 2021 and/or submit our application to another funding call. • As a member of VALIDATE Jomien and Rachel also participated in a larger European COST funding application that included 97 VALIDATE members from 49 countries (unsuccessful). • Building on the preliminary data generated and experience gained during this fellowship, Rachel recently submitted an application for a £1.5m UKRI Future Leaders Fellowship, as well as for an ERC Starting Grant and a Wellcome Trust Sir Henry Dale Fellowship. • In January 2021, Rachel was awarded a £5,000 grant from the University of Oxford John Fell Fund to rebuild research momentum after COVID-19 and support the completion of the murine studies. • 2021 received a £21,500 grant from the Health Research Bridging Salary Scheme to support her salary for the period between completing this fellowship and hearing the outcome of her pending follow-on grant applications. • Shortlisted for an Oxford NIHR BRC Senior Fellowship but was unsuccessful following interview. • Co-Investigator on a successful grant application from the Songklanagarind Hospital Research Fund, Thailand. • Received a BSI Travel award (£1000) to present this project at the 'Tuberculosis: Immunity and Immune Evasion' Keystone Symposium in Santa Fe, USA in January 2020 Presentations • 6th Global Forum on TB Vaccines in Toulouse France (this meeting became virtual due to COVID) in February 2022: Project abstract was selected for an oral presentation. • Keystone Symposium in Santa Fe, USA in January 2020: project abstract was selected for an oral presentation and a poster. Presenting at such a large international forum was an excellent opportunity for Rachel to reach a wider audience and make new connections, and she met several new contacts who have relevant sample sets to offer or are otherwise interested in collaborating on antibody-related projects. • Presented the protein array findings at the TBScience2020 meeting as part of the 51st Union World Conference on Lung Health. • Received a Collaboration for TB Vaccine Discovery (CTVD) Early Career Investigator Award to present a poster of this work at the CTVD annual meeting in Seattle in June 2020 (this meeting became virtual due to COVID). • Presented preliminary data at the International BCG Symposium (Lille, Dec 2018) and the TBVAC2020 Annual Meeting (Switzerland, Feb 2019), which also opened up new networks and discussions on the project. • Presented her research project to VALIDATE members at the 2018 and 2019 VALIDATE Annual Meetings, as a poster at the VALIDATE-BSI 2019 Conference, and as a virtual seminar "Developing a better vaccine against TB" in February 2019. Continuing professional development In 2018, Rachel joined the Acid Fast Club committee and the Editorial Board of Scientific Reports, and in 2022 was invited to join the Editorial Board of Frontiers in Immunology. In 2019 she joined the British Society of Immunology Vaccine Affinity Group (BSI-VAG) committee, which came about as a result of networking during the VALIDATE-BSI annual meeting. In Jan. 2020, she was elected a Research Fellow of Wolfson College, Oxford, and presented work from this fellowship as part of the interview process. She is currently primary supervisor to a DPhil student and has examined four transfer/confirmation of status vivas and one final DPhil viva in the past 2 years. She has been asked to be external examiner for a further final DPhil viva. In 2021, she completed training on Mental Health Awareness (MFHA England); Equality, Diversity and Inclusion; Safeguarding; and Supporting Student Mental Health. She holds a Lectureship position at Wadham College and is Access and Outreach Officer for the Institute of Human Sciences. In 2019, she completed the Oxford Learning Institute Enhancing Teaching Program (ETP) with a Special Commendation, and a SEDA-PDF Learning, Teaching and Assessing Award (aligned against the UKPSF). Secondments/placements/internships From April to Nov. 2020 Rachel was partially seconded to the Oxford COVID-19 vaccine trial group, testing the safety and efficacy of the ChAdOx1 nCoV-19 vaccine. This has resulted in co-authorship on 59 publications. Outreach In 2019 Rachel contributed to a VALIDATE blog for World Leprosy Day, was recorded by Film Oxford for a film entitled 'Women in Vaccine Research' for International Women's Day, and volunteered at Oxford Open Doors, discussing her research with the public, as well as the Oxford Science and Ideas Festival and 'Uncultured: Late night at the Museum of Natural History'. She also provides regular outreach talks for the university during term time at Wadham College and as Access Officer for the Institute of Human Sciences, giving school talks to groups from over 20 different secondary schools. She also gave a talk as part of the Oxford University 'Meeting Minds' alumni event. In 2020 Rachel filmed clips from a day in the laboratory for the YouTube 'Life in a Day' movie directed by Ridley Scott and Kevin McDonald which premiered at Sundance Film Festival; her submission was featured as part of the press release. She took part in the BSI 'A day in the life of a vaccine researcher' blog, and was interviewed for a 500 Women Scientists article. Rachel was contacted by a school student in California who interviewed her for a presentation on "Scientists that don't fit the conventional mold", and in 2020 took part in 'I'm a Scientist, Stay at Home!' to help school pupils stay connected with STEM during the lockdown. She gave a 'VALIDATE for Schools' virtual talk in December 2020, discussing her research and career in science, to over 200 school children across the UK, and also contributed a 'Useful Resources' section to the VALIDATE Outreach Guide. She published a paper for children on BCG vaccination in Frontiers for Young Minds as part of the VALIDATE BCG100 celebrations. Rachel was invited as a panellist to talk about her work and experience as a female scientist for the 2020 Women of the Future Awards and the 2021 Oxford Women in Engineering, Science and Technology (OxWEST) Annual Symposium. In 2021, Rachel gave a talk at the UNIQ Summer School and the University of Oxford 'Meeting Minds' alumni event. In 2022, she was invited as a panellist for a Wadham College 'Towards Vaccine Equity' event and to chair the 'Two years of COVID-19 - did we follow the science?' event at UCL. Rachel was featured in the 'Wonderful Women' campaign by Wolfson College in celebration of International Women's Day 2022. Awards Rachel was awarded the 2019 Women of the Future Award for Science, partly in recognition of her VALIDATE Fellowship research. In 2021, she was elected a Research Fellow of Wolfson College, Oxford, was awarded a divisional Teaching Excellence Award, the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) International Global 3Rs Award, and a Justice, Equality, Diversity and Inclusion (JEDI) award from the Life Sciences Editors Foundation. Career Development In 2022 Rachel gained an Assistant Professor position at University of Oxford, to start her own research group.
Start Year 2018
 
Description VALIDATE Pump-priming project P004 
Organisation Brunel University London
Country United Kingdom 
Sector Academic/University 
PI Contribution VALIDATE funded project
Collaborator Contribution How do functional and metabolic characteristics of trained monocytes affect their anti-bacterial activity? Led by Asst Prof Steven Smith (LSHTM (now Brunel University)), with Dr Javier Sanchez-Garcia (Instituto Politécnico Nacional), Prof Jo Prior (dstl), and Prof Gregory Bancroft (LSHTM) Project Aims The human immune response has two components, the innate and the adaptive responses. This project will investigate the potential of the innate response to contribute to protection against tuberculosis (TB) and melioidosis. TB remains a major global problem being one of the world's leading causes of death from infectious disease. In addition to better drugs and better means of diagnosing TB, we also need a better vaccine. The current vaccine, BCG, is only partially effective and an improved version is needed. However, many novel TB vaccine candidates focus on the adaptive immune response involving T-lymphocytes as this is where immune memory is found which is essential for vaccine-induced protection. We think that an optimal innate response is also essential. It has recently been discovered that the innate response can be "trained" by some vaccines to respond better to later infections. In this project, we aim to investigate this training effect on the innate response to a) determine how best to train innate cells to prevent the growth of the causative organisms of TB and melioidosis; b) characterise these trained innate cells to find which immune molecules are important for their protective effect and how the metabolism (or biochemical energy production pathways) of these cells affects the trained response and c) to investigate why innate cells from different people do not respond in the same way to training - to do this we will look at differences in the DNA of immune cells (termed epigenetic marks) which cause these cells to produce different immune molecules when exposed to the same microorganism. The data produced by this project should help us understand better how different components of the immune response contribute to protection against TB and melioidosis and should aid the design of better vaccination regimes for bacterial diseases. Project Outcomes Tuberculosis remains the deadliest infectious disease worldwide and thus, any effort to understand the biological basis of disease progression as well as to provide the means to boost anti-Mycobacterium tuberculosis immune responses should be considered, as it might have a positive impact on overcoming this human health burden. Innate immune training offers an interesting theoretical framework for the understanding of tuberculosis, since monocyte/macrophages are the main target cells for infection by M. tuberculosis. Innate immune training allow these cells to respond faster and better to a second antigenic challenge, even if the first and second challenges are qualitatively different. An in vitro model of trained immunity in human monocytes was established in the laboratory based on a previous publication. This involved the isolation of CD14+ monocytes from peripheral blood and co-culture with training stimuli including live BCG, heat-killed BCG or beta-glucan followed by a rest period of 6 days. Training of monocytes was demonstrated by their enhanced ability to produce cytokines (TNF and IL-6) in response to heterologous ligands. Trained monocytes were also cocultured with BCG to determine their capacity to inhibit the growth of mycobacteria which was observed for some, but not all donor monocytes. Monocyte aliquots were stored for analysis of DNA methylation patterns. Recent developments in the field show that, in some instances, innate immune training correlates with intracellular fumarate accumulation. Of note, fumarate-stimulation of monocyte/macrophages induces the functional and epigenetic signatures of innate immune training. As part of this project we aimed to characterize the ''mitochondrial signature'' of this training, as well as to explore some other monocyte/macrophage functions relevant for the control of mycobacterial infection. Human peripheral blood monocytes were first stimulated with monomethyl fumarate and then with LPS or BCG, and mitochondrial dynamics; mitochondrial membrane potential was followed for 3 h post-stimulation and mitochondrial calcium uptake followed for 15min after the addition of BCG. These three functional activities of mitochondria were increased in fumarate-treated monocytes as compared to un-treated cells. Fumarate-stimulated monocyte/macrophages (plus the appropriate controls) were subjected to transmission electron microscopy in order to analyse the mitochondrial cristae. In addition, RAW 264.7 cells (a murine macrophage cell line) were stimulated with monomethyl fumarate in order to study mitochondria and then mitochondrial proteins. Anti-phosphoserine Western blot analyses showed a different pattern of serine-phosphorylated mitochondrial proteins in cells stimulated with a fumarate as compared to un-stimulated cells. All these mitochondrial functional parameters contribute to define the ''mitochondrial signature'' of innate training. As for the function of trained versus non-trained monocytes, the ability of these cells to process antigen was explored. Results showed that fumarate-treated cells have an increased capacity for antigen processing. Taken together, these results provide evidence of a distinctive mitochondrial function (''mitochondrial signature'') in trained monocytes and also show that trained monocytes process exogenous antigens more efficiently that un-trained monocytes. Such a ''mitochondrial signature'' may identify one way to boost anti-mycobacterial immune responses, maintain innate immune training, and understand the basis of mycobacterial dormancy and reactivation.
Impact - This was a new collaboration of the partners with dstl. - New collaboration with the group of Prof Michael Duchen (UCL; expert on mitochondrial calcium) and the group of Carina Kern (UCL; working on C.elegans). - Establishment of scientific collaboration between the groups of LSHTM and ENCB-IPN (Mexico), particularly through Prof Sanchez-Garcia's sabbatical visit to LSHTM. - During the 2018 VALIDATE Annual Meeting this team established a new collaboration with Dr Barbara Kronsteiner-Dobramysl (University of Oxford), leading to a successfully funded new pump-priming project "Metabolic reprogramming of skin microenvironment for improved BCG vaccine efficacy" (P020). - Butkeviciute E, Jones CE, Smith SG. Heterologous effects of infant BCG vaccination: potential mechanisms of immunity. Future Microbiol. 2018 Aug; 13:1193-1208. - C Angélica Pérez-Hernández et al 2020. Mitochondrial signature in human monocytes and resistance to infection in C.elegans during fumarate-induced innate immune training. Frontiers in Immunology 11: 1715 - In 2020, the work and partnerships established during this project led to the submission of a Newton Fund Institutional Links grant application for which Dr Smith and Prof Sanchez-Garcia were co-applicants. The outcome is still pending for this application but if successful would lead to the strengthening of the partnership established during this VALIDATE project, in particular to the benefit of the Division of Biosciences at Brunel University as members of this division are co-applicants. - In 2020 Dr Steven Smith was appointed Senior Lecturer in Biomedical Sciences at Brunel University London, his application for which was strengthen by having received VALIDATE funding for a project in his area of interest, as well as by the VALIDATE network overall and the collaborations it has been possible to develop. - Prof Javier Sanchez-Garcia states 'The VALIDATE impact on my career is not small. This VALIDATE grant allowed me to spend sabbatical leave at LSHTM, hosted by Professor Hazel Dockrell. While in the UK, I had the opportunity to attend the 2nd annual VALIDATE meeting where I met Dr Barbara Kronsteiner-Dobramysl, who shares our research interest on immunometabolism, as a result we all presented a new research proposal, which luckily received VALIDATE funding. In the same meeting I met some other colleagues and it is likely that in the near future we will establish new collaborations. While in professor Dockrell´s lab, carrying on the experiments for this VALIDATE project, I strengthened collaboration with the group of Professor Michael Duchen at UCL and, while doing some experiments at UCL, I met other colleagues from a different UCL department, soon and quite naturally our respective works merged. In addition, a completely unexpected outcome of all this is that a new experimental animal model for the study of immunometabolism is now available in our lab in Mexico.' - 2022: Dr Steven Smith co-applicant on a proposal led by Dr Luciana Balboa (VALIDATE member, CONICET, Argentina) for a VALIDATE Pump-priming grant "Pro-Solving Lipids: New Players that regulate Local Protection against Mycobacterium tuberculosis". This came about as Dr Balboa was aware of the work done on trained immunity responses in macrophages as part of the P004 project.
Start Year 2017
 
Description VALIDATE Pump-priming project P004 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution VALIDATE funded project
Collaborator Contribution How do functional and metabolic characteristics of trained monocytes affect their anti-bacterial activity? Led by Asst Prof Steven Smith (LSHTM (now Brunel University)), with Dr Javier Sanchez-Garcia (Instituto Politécnico Nacional), Prof Jo Prior (dstl), and Prof Gregory Bancroft (LSHTM) Project Aims The human immune response has two components, the innate and the adaptive responses. This project will investigate the potential of the innate response to contribute to protection against tuberculosis (TB) and melioidosis. TB remains a major global problem being one of the world's leading causes of death from infectious disease. In addition to better drugs and better means of diagnosing TB, we also need a better vaccine. The current vaccine, BCG, is only partially effective and an improved version is needed. However, many novel TB vaccine candidates focus on the adaptive immune response involving T-lymphocytes as this is where immune memory is found which is essential for vaccine-induced protection. We think that an optimal innate response is also essential. It has recently been discovered that the innate response can be "trained" by some vaccines to respond better to later infections. In this project, we aim to investigate this training effect on the innate response to a) determine how best to train innate cells to prevent the growth of the causative organisms of TB and melioidosis; b) characterise these trained innate cells to find which immune molecules are important for their protective effect and how the metabolism (or biochemical energy production pathways) of these cells affects the trained response and c) to investigate why innate cells from different people do not respond in the same way to training - to do this we will look at differences in the DNA of immune cells (termed epigenetic marks) which cause these cells to produce different immune molecules when exposed to the same microorganism. The data produced by this project should help us understand better how different components of the immune response contribute to protection against TB and melioidosis and should aid the design of better vaccination regimes for bacterial diseases. Project Outcomes Tuberculosis remains the deadliest infectious disease worldwide and thus, any effort to understand the biological basis of disease progression as well as to provide the means to boost anti-Mycobacterium tuberculosis immune responses should be considered, as it might have a positive impact on overcoming this human health burden. Innate immune training offers an interesting theoretical framework for the understanding of tuberculosis, since monocyte/macrophages are the main target cells for infection by M. tuberculosis. Innate immune training allow these cells to respond faster and better to a second antigenic challenge, even if the first and second challenges are qualitatively different. An in vitro model of trained immunity in human monocytes was established in the laboratory based on a previous publication. This involved the isolation of CD14+ monocytes from peripheral blood and co-culture with training stimuli including live BCG, heat-killed BCG or beta-glucan followed by a rest period of 6 days. Training of monocytes was demonstrated by their enhanced ability to produce cytokines (TNF and IL-6) in response to heterologous ligands. Trained monocytes were also cocultured with BCG to determine their capacity to inhibit the growth of mycobacteria which was observed for some, but not all donor monocytes. Monocyte aliquots were stored for analysis of DNA methylation patterns. Recent developments in the field show that, in some instances, innate immune training correlates with intracellular fumarate accumulation. Of note, fumarate-stimulation of monocyte/macrophages induces the functional and epigenetic signatures of innate immune training. As part of this project we aimed to characterize the ''mitochondrial signature'' of this training, as well as to explore some other monocyte/macrophage functions relevant for the control of mycobacterial infection. Human peripheral blood monocytes were first stimulated with monomethyl fumarate and then with LPS or BCG, and mitochondrial dynamics; mitochondrial membrane potential was followed for 3 h post-stimulation and mitochondrial calcium uptake followed for 15min after the addition of BCG. These three functional activities of mitochondria were increased in fumarate-treated monocytes as compared to un-treated cells. Fumarate-stimulated monocyte/macrophages (plus the appropriate controls) were subjected to transmission electron microscopy in order to analyse the mitochondrial cristae. In addition, RAW 264.7 cells (a murine macrophage cell line) were stimulated with monomethyl fumarate in order to study mitochondria and then mitochondrial proteins. Anti-phosphoserine Western blot analyses showed a different pattern of serine-phosphorylated mitochondrial proteins in cells stimulated with a fumarate as compared to un-stimulated cells. All these mitochondrial functional parameters contribute to define the ''mitochondrial signature'' of innate training. As for the function of trained versus non-trained monocytes, the ability of these cells to process antigen was explored. Results showed that fumarate-treated cells have an increased capacity for antigen processing. Taken together, these results provide evidence of a distinctive mitochondrial function (''mitochondrial signature'') in trained monocytes and also show that trained monocytes process exogenous antigens more efficiently that un-trained monocytes. Such a ''mitochondrial signature'' may identify one way to boost anti-mycobacterial immune responses, maintain innate immune training, and understand the basis of mycobacterial dormancy and reactivation.
Impact - This was a new collaboration of the partners with dstl. - New collaboration with the group of Prof Michael Duchen (UCL; expert on mitochondrial calcium) and the group of Carina Kern (UCL; working on C.elegans). - Establishment of scientific collaboration between the groups of LSHTM and ENCB-IPN (Mexico), particularly through Prof Sanchez-Garcia's sabbatical visit to LSHTM. - During the 2018 VALIDATE Annual Meeting this team established a new collaboration with Dr Barbara Kronsteiner-Dobramysl (University of Oxford), leading to a successfully funded new pump-priming project "Metabolic reprogramming of skin microenvironment for improved BCG vaccine efficacy" (P020). - Butkeviciute E, Jones CE, Smith SG. Heterologous effects of infant BCG vaccination: potential mechanisms of immunity. Future Microbiol. 2018 Aug; 13:1193-1208. - C Angélica Pérez-Hernández et al 2020. Mitochondrial signature in human monocytes and resistance to infection in C.elegans during fumarate-induced innate immune training. Frontiers in Immunology 11: 1715 - In 2020, the work and partnerships established during this project led to the submission of a Newton Fund Institutional Links grant application for which Dr Smith and Prof Sanchez-Garcia were co-applicants. The outcome is still pending for this application but if successful would lead to the strengthening of the partnership established during this VALIDATE project, in particular to the benefit of the Division of Biosciences at Brunel University as members of this division are co-applicants. - In 2020 Dr Steven Smith was appointed Senior Lecturer in Biomedical Sciences at Brunel University London, his application for which was strengthen by having received VALIDATE funding for a project in his area of interest, as well as by the VALIDATE network overall and the collaborations it has been possible to develop. - Prof Javier Sanchez-Garcia states 'The VALIDATE impact on my career is not small. This VALIDATE grant allowed me to spend sabbatical leave at LSHTM, hosted by Professor Hazel Dockrell. While in the UK, I had the opportunity to attend the 2nd annual VALIDATE meeting where I met Dr Barbara Kronsteiner-Dobramysl, who shares our research interest on immunometabolism, as a result we all presented a new research proposal, which luckily received VALIDATE funding. In the same meeting I met some other colleagues and it is likely that in the near future we will establish new collaborations. While in professor Dockrell´s lab, carrying on the experiments for this VALIDATE project, I strengthened collaboration with the group of Professor Michael Duchen at UCL and, while doing some experiments at UCL, I met other colleagues from a different UCL department, soon and quite naturally our respective works merged. In addition, a completely unexpected outcome of all this is that a new experimental animal model for the study of immunometabolism is now available in our lab in Mexico.' - 2022: Dr Steven Smith co-applicant on a proposal led by Dr Luciana Balboa (VALIDATE member, CONICET, Argentina) for a VALIDATE Pump-priming grant "Pro-Solving Lipids: New Players that regulate Local Protection against Mycobacterium tuberculosis". This came about as Dr Balboa was aware of the work done on trained immunity responses in macrophages as part of the P004 project.
Start Year 2017
 
Description VALIDATE Pump-priming project P004 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution VALIDATE funded project
Collaborator Contribution How do functional and metabolic characteristics of trained monocytes affect their anti-bacterial activity? Led by Asst Prof Steven Smith (LSHTM (now Brunel University)), with Dr Javier Sanchez-Garcia (Instituto Politécnico Nacional), Prof Jo Prior (dstl), and Prof Gregory Bancroft (LSHTM) Project Aims The human immune response has two components, the innate and the adaptive responses. This project will investigate the potential of the innate response to contribute to protection against tuberculosis (TB) and melioidosis. TB remains a major global problem being one of the world's leading causes of death from infectious disease. In addition to better drugs and better means of diagnosing TB, we also need a better vaccine. The current vaccine, BCG, is only partially effective and an improved version is needed. However, many novel TB vaccine candidates focus on the adaptive immune response involving T-lymphocytes as this is where immune memory is found which is essential for vaccine-induced protection. We think that an optimal innate response is also essential. It has recently been discovered that the innate response can be "trained" by some vaccines to respond better to later infections. In this project, we aim to investigate this training effect on the innate response to a) determine how best to train innate cells to prevent the growth of the causative organisms of TB and melioidosis; b) characterise these trained innate cells to find which immune molecules are important for their protective effect and how the metabolism (or biochemical energy production pathways) of these cells affects the trained response and c) to investigate why innate cells from different people do not respond in the same way to training - to do this we will look at differences in the DNA of immune cells (termed epigenetic marks) which cause these cells to produce different immune molecules when exposed to the same microorganism. The data produced by this project should help us understand better how different components of the immune response contribute to protection against TB and melioidosis and should aid the design of better vaccination regimes for bacterial diseases. Project Outcomes Tuberculosis remains the deadliest infectious disease worldwide and thus, any effort to understand the biological basis of disease progression as well as to provide the means to boost anti-Mycobacterium tuberculosis immune responses should be considered, as it might have a positive impact on overcoming this human health burden. Innate immune training offers an interesting theoretical framework for the understanding of tuberculosis, since monocyte/macrophages are the main target cells for infection by M. tuberculosis. Innate immune training allow these cells to respond faster and better to a second antigenic challenge, even if the first and second challenges are qualitatively different. An in vitro model of trained immunity in human monocytes was established in the laboratory based on a previous publication. This involved the isolation of CD14+ monocytes from peripheral blood and co-culture with training stimuli including live BCG, heat-killed BCG or beta-glucan followed by a rest period of 6 days. Training of monocytes was demonstrated by their enhanced ability to produce cytokines (TNF and IL-6) in response to heterologous ligands. Trained monocytes were also cocultured with BCG to determine their capacity to inhibit the growth of mycobacteria which was observed for some, but not all donor monocytes. Monocyte aliquots were stored for analysis of DNA methylation patterns. Recent developments in the field show that, in some instances, innate immune training correlates with intracellular fumarate accumulation. Of note, fumarate-stimulation of monocyte/macrophages induces the functional and epigenetic signatures of innate immune training. As part of this project we aimed to characterize the ''mitochondrial signature'' of this training, as well as to explore some other monocyte/macrophage functions relevant for the control of mycobacterial infection. Human peripheral blood monocytes were first stimulated with monomethyl fumarate and then with LPS or BCG, and mitochondrial dynamics; mitochondrial membrane potential was followed for 3 h post-stimulation and mitochondrial calcium uptake followed for 15min after the addition of BCG. These three functional activities of mitochondria were increased in fumarate-treated monocytes as compared to un-treated cells. Fumarate-stimulated monocyte/macrophages (plus the appropriate controls) were subjected to transmission electron microscopy in order to analyse the mitochondrial cristae. In addition, RAW 264.7 cells (a murine macrophage cell line) were stimulated with monomethyl fumarate in order to study mitochondria and then mitochondrial proteins. Anti-phosphoserine Western blot analyses showed a different pattern of serine-phosphorylated mitochondrial proteins in cells stimulated with a fumarate as compared to un-stimulated cells. All these mitochondrial functional parameters contribute to define the ''mitochondrial signature'' of innate training. As for the function of trained versus non-trained monocytes, the ability of these cells to process antigen was explored. Results showed that fumarate-treated cells have an increased capacity for antigen processing. Taken together, these results provide evidence of a distinctive mitochondrial function (''mitochondrial signature'') in trained monocytes and also show that trained monocytes process exogenous antigens more efficiently that un-trained monocytes. Such a ''mitochondrial signature'' may identify one way to boost anti-mycobacterial immune responses, maintain innate immune training, and understand the basis of mycobacterial dormancy and reactivation.
Impact - This was a new collaboration of the partners with dstl. - New collaboration with the group of Prof Michael Duchen (UCL; expert on mitochondrial calcium) and the group of Carina Kern (UCL; working on C.elegans). - Establishment of scientific collaboration between the groups of LSHTM and ENCB-IPN (Mexico), particularly through Prof Sanchez-Garcia's sabbatical visit to LSHTM. - During the 2018 VALIDATE Annual Meeting this team established a new collaboration with Dr Barbara Kronsteiner-Dobramysl (University of Oxford), leading to a successfully funded new pump-priming project "Metabolic reprogramming of skin microenvironment for improved BCG vaccine efficacy" (P020). - Butkeviciute E, Jones CE, Smith SG. Heterologous effects of infant BCG vaccination: potential mechanisms of immunity. Future Microbiol. 2018 Aug; 13:1193-1208. - C Angélica Pérez-Hernández et al 2020. Mitochondrial signature in human monocytes and resistance to infection in C.elegans during fumarate-induced innate immune training. Frontiers in Immunology 11: 1715 - In 2020, the work and partnerships established during this project led to the submission of a Newton Fund Institutional Links grant application for which Dr Smith and Prof Sanchez-Garcia were co-applicants. The outcome is still pending for this application but if successful would lead to the strengthening of the partnership established during this VALIDATE project, in particular to the benefit of the Division of Biosciences at Brunel University as members of this division are co-applicants. - In 2020 Dr Steven Smith was appointed Senior Lecturer in Biomedical Sciences at Brunel University London, his application for which was strengthen by having received VALIDATE funding for a project in his area of interest, as well as by the VALIDATE network overall and the collaborations it has been possible to develop. - Prof Javier Sanchez-Garcia states 'The VALIDATE impact on my career is not small. This VALIDATE grant allowed me to spend sabbatical leave at LSHTM, hosted by Professor Hazel Dockrell. While in the UK, I had the opportunity to attend the 2nd annual VALIDATE meeting where I met Dr Barbara Kronsteiner-Dobramysl, who shares our research interest on immunometabolism, as a result we all presented a new research proposal, which luckily received VALIDATE funding. In the same meeting I met some other colleagues and it is likely that in the near future we will establish new collaborations. While in professor Dockrell´s lab, carrying on the experiments for this VALIDATE project, I strengthened collaboration with the group of Professor Michael Duchen at UCL and, while doing some experiments at UCL, I met other colleagues from a different UCL department, soon and quite naturally our respective works merged. In addition, a completely unexpected outcome of all this is that a new experimental animal model for the study of immunometabolism is now available in our lab in Mexico.' - 2022: Dr Steven Smith co-applicant on a proposal led by Dr Luciana Balboa (VALIDATE member, CONICET, Argentina) for a VALIDATE Pump-priming grant "Pro-Solving Lipids: New Players that regulate Local Protection against Mycobacterium tuberculosis". This came about as Dr Balboa was aware of the work done on trained immunity responses in macrophages as part of the P004 project.
Start Year 2017
 
Description VALIDATE Pump-priming project P016 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution VALIDATE funded project
Collaborator Contribution Vaccines to target people with diabetes: characterising the pathways of immune response to M. tuberculosis and B. pseudomallei in people with diabetes compared to non-diabetics Led by Prof Susanna Dunachie (University of Oxford), with Assistant Prof Jacqueline Cliff (LSHTM), and Prof Gregory Bancroft (LSHTM) Project Aims A better vaccine is urgently required for tuberculosis (TB), and there is no vaccine at all for the neglected tropical disease melioidosis. Both diseases are caused by bacteria that live inside cells, and there are shared defence mechanisms. People with diabetes are at increased risk of getting ill with TB (three-fold increased risk) and are twelve time more likely to develop melioidosis than non-diabetics. We therefore need to understand why people with diabetes get ill with these bacteria, and how diabetes prevents the body from clearing the infection. We will combine expertise at the London School of Hygiene and Tropical Medicine, Mahidol- Oxford Tropical Medicine Unit in Bangkok and the University of Oxford, to study the pattern of human immune response to TB and melioidosis in people with and without diabetes. To do this, we will use "transcriptomics" - the big-scale study of the gene readouts from the body's DNA ("transcripts") which are instruction messages for protein manufacture carried as ribonucleic acid (RNA). By measuring the pattern of RNA in a person's blood, we can compare which immune pathways are active in different groups of people. We will identify differences in the pattern of responses in TB patients with and without diabetes, see how they relate to cure from TB, and then compare the results with responses in melioidosis patients with and without diabetes. We will detect the most important protective immune response pathways which are seen in nondiabetic patients but are lacking in people with diabetes. This will allow us to design better vaccines for TB and melioidosis that work well in people with diabetes, and can also help us develop ways to use medicines at the time of vaccination to boost immune responses in people with diabetes. Project Outcomes Diabetes mellitus (DM) currently affects over 425 million people worldwide, of which almost 80% live in low- and middle-income countries (LMICs). The majority of people with diabetes in LMICs are thought to have Type 2 diabetes. Diabetes increases susceptibility to many global infections including Escherichia coli, Staphylococcus aureus and dengue, but the most established susceptibility relationships are for melioidosis and tuberculosis (TB). Melioidosis is a deadly infectious disease caused by the Gram-negative bacterium, Burkholderia pseudomallei (BP). The current estimation of melioidosis cases is 165,000 cases worldwide with 89,000 deaths. Mortality in severe melioidosis cases presenting with sepsis can reach 50% in Thailand. Diabetes is a major risk factor for melioidosis with a 12-fold increased susceptibility to the infection. Tuberculosis (TB) is a major global killer. In 2018, an estimated 10 million people were infected with Mycobacterium tuberculosis and over a million people died from TB. Moreover, DM confers a 3-fold increased susceptibility to TB. Tuberculosis and melioidosis share many key features including an overlap of clinical manifestations, immunopathology, and host immune responses. A previous study in Thailand demonstrated that transcriptomic profiles between tuberculosis and melioidosis were indistinguishable. Host-immune responses to the infections are dysregulated in people with diabetes including killing mechanisms, cell-cell communication, and migration. However, mechanisms involved in the increased susceptibility in DM to intracellular pathogens are to be elucidated. In this project we used RNA sequencing to study transcriptomics in melioidosis and tuberculosis patients in order to characterise the difference in host response to infection for those with and without DM. Differential gene expression analysis between melioidosis patients with (n = 49) and without DM (n = 32) identified two genes CD163L1 (scavenger-receptor cytokine-rich protein) and FAM1932 (a member of the CC chemokine family) were differentially expressed with a false discovery rate < 0.05. However, gene set enrichment analysis using hallmark gene sets showed distinctive profiles in several comparisons. A comparison between melioidosis cases with and without DM showed a number of enriched gene sets dominated by immune, proliferation, and signalling in the DM group only. We identified gene signatures in people with diabetes indicative of endoplasmic reticulum stress and are now confirming this finding in validation experiments in peripheral blood mononuclear cells. Further analysis comparing the impact of diabetes in acute melioidosis with tuberculosis revealed shared transcriptomic signatures of increased inflammatory responses, increased neutrophil degranulation and increased platelet degranulation. However, looking at the whole blood transcriptome we saw opposite effects of diabetes on interferon-gamma signalling, with an increase in acute melioidosis (which may represent non-specific neutrophil activation) and a decrease in tuberculosis. Using an additional sample set from a collaboration with Eoin West at University of Washington, USA, we compared patients who went on to survive melioidosis in Ubon Ratchathani (n = 80) with fatal cases (n = 84) and found dominance in fatal cases for non-specific pro-inflammatory pathways but down-regulation of T cell signalling pathways, especially in those with diabetes. Overall, our data shows that excessive pro-inflammatory immune responses with reduced T cell signalling are associated with poor clinical outcomes, and people with diabetes have an excessive non-specific pro-inflammatory response to both melioidosis and tuberculosis, with increased neutrophil and platelet activation. The massive neutrophil activation in sepsis from acute melioidosis is associated with increased interferon-gamma pathway activation, in contrast to tuberculosis where overall interferon-gamma activity is reduced in diabetes - most likely reflecting the less acute nature of disease from M. tuberculosis. Vaccines targeting T cells for these intracellular pathogens may be especially important to correct the increased susceptibility seen in diabetes.
Impact Collaborations: • This project allowed the building of a collaboration between S. Dunachie and J. Cliff, which we aim to be a foundation for further work. • Further collaborations that this project was a springboard for: 1. Paul Brett and Mary Burtnick, University of Nevada in Reno, USA - planning a Phase 1 vaccine trial of a public health melioidosis vaccine to target people with diabetes 2. Helen McShane and Elena Stylianou, U. Oxford, UK - establishing a mouse model of diabetes for vaccine testing 3. Claire Chewapreecha, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand - "Dissecting the genetic basis of melioidosis infection" 4. Eoin West, University of Washington, Seattle, USA (extension from previous collaboration on sepsis and Toll-like receptors) - transcriptomic signatures of melioidosis and sepsis 5. Chiranjay Mukhopadhyay, Manipal Academy of Higher Education, India - cellular immunity in TB and melioidosis (which has been awarded a subsequent VALIDATE pump-priming grant, P033) 6. Mohammad Ali, Dhaka Medical College, Bangladesh - metabolism, DM and TB 7. Vivek Jha, George Institute, New Delhi, India - diabetes and infection database research 8. Prof. Chang-Hwa Song, Chungman National University, South Korea - macrophage immunology in TB +/- DM As a result of the VALIDATE networking session in 2018, a team assembled with an interest in developing a diabetic mouse model for testing of immune response to disease and vaccination, and this was a successful pump-priming award from VALIDATE in early 2019 (PI Elena Stylianou, P022 - further details below). Papers: This project influenced the following manuscripts: • Dunachie, S. and P. Chamnan, The double burden of diabetes and global infection in low and middle-income countries. Trans R Soc Trop Med Hyg, 2019. 113(2): p. 56-64. https://doi.org/10.1093/trstmh/try124 • Kronsteiner, B., et al., Diabetes alters immune response patterns to acute melioidosis in humans. Eur J Immunol, 2019. 49(7): p. 1092-1106 https://doi.org/10.1002/eji.201848037 • Eckold, C. et al., Impact of intermediate hyperglycaemia as well as diabetes on immune dysfunction in tuberculosis. Clinical Infectious Diseases 2021 https://doi.org/10.1093/cid/ciaa751 • Eckold et al., Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity MedRxiv 2022 https://doi.org/10.1101/2022.02.07.22269422 • Tomás-Cortázar, J., Bossi, L., Quinn, C., Reynolds, C.J., Butler, D.K., Corcoran, N., . . . McClean, S. BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis. Front. Immunol. 12, 767359-767359 (2021). 10.3389/fimmu.2021.767359. https://pubmed.ncbi.nlm.nih.gov/34966388 • Chewapreecha, C., Pensar, J., Chattagul, S., Pesonen, M., Sangphukieo, A., Boonklang, P., . . . Corander, J. Co-evolutionary Signals Identify Burkholderia pseudomallei Survival Strategies in a Hostile Environment. Mol. Biol. Evol. 39, msab306 (2022). 10.1093/molbev/msab306. https://pubmed.ncbi.nlm.nih.gov/34662416 Two manuscripts are in preparation directly from this work: 1. Rongkard, P., Kronsteiner B., Hantrakunb, V., Teparrukkul, P., Wongsuvanb, G., Limmathurotsakul, D., Lovelace-Macon, L., Day, N.P., Klenerman, P., Chantratita, N., Gharib, S., Dunachie S., West, T.E. Transcriptomic signatures in fatal melioidosis. Manuscript in preparation 2. Rongkard, P., Hantrakunb, V., Teparrukkul, P., Wongsuvanb, G., Limmathurotsakul, D., Lovelace-Macon, L., Day, N.P., Gharib, S., West, T.E, Cliff, J., Klenerman, P., Kronsteiner B., Dunachie S. The impact of type 2 Diabetes on the immune response to melioidosis and tuberculosis. Manuscript in preparation Related funding: 1. 2021-2026 NIHR Professorship in Global Health "Developing a vaccine to prevent death from melioidosis in people with type 2 diabetes mellitus in low- and middle-income countries" (Dunachie PI), £1,951,296 2. 2020-2022 US Defense Threat Reduction Agency award "Optimization of lead melioidosis and glanders vaccine formulations" Prof Paul Brett University of Nevada, Reno PI with sub-contract award to Dunachie, Oxford PI, $733,976.61 USD (£524,269) to Dunachie lab. 3. 2022-2025 MRC Biomedical Catalyst Developmental Pathway Funding Scheme (DPFS) / US Defense Threat reduction Agency award, "Developing a vaccine for Burkholderia pseudomallei - a Phase I Clinical Trial" (Dunachie PI) £3,238,214. 4. 2019-2020 VALIDATE pump-priming project: "Characterising the cellular immunity and metabolic response to Mycobacterium tuberculosis and Burkholderia pseudomallei in Indian patients for vaccine design". (Mukhopadhyay, Manipal Academy of Higher Education, India PI, Dunachie Co-PI) £48,993 (£7,000 to Dunachie lab). 5. 2019-2020 Global Challenges Research Fund (GCRF) "Diabetes and Infection: Developing a network for using real-world datasets to evaluate the relationship between diabetes and infection in low and middle income countries?" (Dunachie PI) £?26,728.50. 6. 2019-2022 Bangladesh Prime Minister's PhD Scholarship for DPhil study at U. Oxford for "Metabolic changes in immune cells of diabetic patients and their impact on immune responses to tuberculosis"(Mohammad Ali, Dhaka Medical College, Bangladesh applicant, Dunachie supervisor) $258,823 USD (£184,874). 7. 2019-2020 MRC VALIDATE "Developing a mouse model of diabetes to evaluate vaccines for TB and melioidosis' (Stylianou PI, Dunachie Co-PI) £49,733.91 - £5,500 to Dunachie lab). In addition, S.Dunachie has been PI or Co-Investigator for grants totalling £5.7 million addressing the immune response to SARS-CoV-2 from infection and vaccination. The immunology expertise developed in her melioidosis work was rapidly applicable to SARS-CoV-2 due to similarity of vulnerable patient group (increased age, diabetes, immunocompromise). Capacity building: • This was Prof Susanna Dunachie's first formal funding to look at the relationship between diabetes and infection (although it was already an interest), and has sparked a whole programme of work (see collaborations and funding). She is now leading the world's first clinical trial of a vaccine for melioidosis. • Mr Patpong Rongkard, Mahidol-Oxford Tropical Medicine Research Unit (MORU), Bangkok - came to Oxford to undertake this project, and was able to register for a DPhil "Understanding how type II diabetes increases susceptibility to intracellular infections". This VALIDATE project has enabled him to receive extensive training in bioinformatics for analysis of RNAseq data, all using open-source software in R. He passed his DPhil viva in November 2022 and has now been awarded the DPhil. • Susanna Dunachie is supporting development of immunology research in India and Bangladesh, by supporting a new collaboration with Dr Mukhopadhyay at Manipal Academy of Higher Education, India, and supported the writing of a successful PhD scholarship application by Dr Ali of Dhaka Medical College, who is now undertaking a DPhil at U Oxford. • Dr Lee (LSHTM) was instrumental in writing her first grant application "Building investigator links for studies on the roles of complement C1q and endoplasmicreticulum (ER) stress in macrophage polarisation during Mycobacterium tuberculosis infection for a successfully funded MRC-KHIDI UK-Korea Partnering Award. • Secondments: Mr Rongkard was unable to undertake the planned secondment at U. Washington, Seattle, USA, in May 2020 due to the pandemic. However, using Microsoft Teams we have been able to build a close collaboration and he has used the skills acquired in this project to analyse the raw RNAseq data generated in an independent cohort of melioidosis patients as part of a sepsis study in the same region of Northeast Thailand as our study (see results). • Susanna organised the VALIDATE Melioidosis Vaccine Symposium: Moving from animal models to man on February 26th 2019, with support from the VALIDATE team (see separate section on this Symposium). Outreach: March 2022. Talk to local 6th form college about careers in tropical medicine. 2022 Dunachie S. Vaccines against melioidosis: How far are we? European Melioidosis Congress, Gratz, Austria, May 2022 2022 Rongkard P. T-cell dysfunction is associated with fatality in community-acquired melioidosis 2019 Dunachie S. Diabetes and melioidosis: What do we know, and what can we do? Invited plenary speaker at World Melioidosis Congress, Hanoi, October 2019 This project was presented at the 2018, 2019 and 2021 VALIDATE Annual Meetings. As a result of the VALIDATE networking session in 2018, a team assembled with an interest in developing a diabetic mouse model for testing of immune response to disease and vaccination, and this was a successful pump-priming award from VALIDATE in early 2019 (PI Elena Stylianou, P022). New datasets of RNAseq data in acute melioidosis have been generated from this project and will be available to VALIDATE members. Awards/Recognition: Susanna Dunachie: - Professor of Infectious Diseases - NIHR Global Research Professorship - Medical Fellow, Corpus Christi College, Oxford Product Development We organised a VALIDATE workshop on vaccines for melioidosis in February 2019, and as a result submitted a successful application to MRC's DPFS grant call to undertake the first human Phase I Vaccine Trial of a melioidosis vaccine, in Oxford using Paul Brett and Mary Burtnick's melioidosis vaccine candidate. The subunit vaccine has been developed at University of Nevada, Reno (UNR) and combines the bacterial capsule polysaccharide (CPS) conjugated to the immunogenic diphtheria toxin mutant CRM197, with recombinant B. pseudomallei Hcp1 protein in an Alhydrogel-CpG adjuvant. In a mouse model, the combined vaccine generated high levels of opsonising anti-CPS antibodies, alongside high T-cell responses to Hcp1, and protected 100% of mice against a robust lethal inhalational B. pseudomallei challenge. We plan to develop the vaccine as a public health vaccine for people with diabetes in low- and middle-income countries (LMICs). The group of investigators in UK (Dunachie, McShane, Kronsteiner), USA (Brett, Burtnick) and Thailand (Chantratita), brought together by the MRC VALIDATE Network, are planning a first-in-man study of 36 healthy human volunteer subjects in Oxford, UK, randomised to receive either the CPS-CRM197 alone, Hcp1 alone, or the CPS-CRM197 / Hcp1 combination. This will be followed by 12 subjects aged 40-60 years with Type II diabetes in Oxford receiving the CPS-CRM197 / Hcp1 combination. Endpoints will be safety and immunogenicity (antibody and T cell responses). The team seeks to define the key immune correlates of protection for monitoring vaccine efficacy in subsequent field trials, using functional growth inhibition assays and transcriptomics in the vaccinated population, existing melioidosis patient cohort studies, and animal models in collaboration with UNR. The vaccine is currently completing manufacture at Resilience Corp, Florida, USA (funded by US Defense Threat Reduction Agency) and we will commence the Phase 1 clinical trial in Oxford, UK in early 2023. Next we plan to undertake a Phase 1b study in Thailand (will require future funding). Ultimately we seek to accelerate production of a vaccine for the 280 million people with diabetes and the many with other risk factors for melioidosis including older age, chronic renal disease and immunosuppression who live in melioidosis-endemic regions in 83 countries across the globe.
Start Year 2018
 
Description VALIDATE Pump-priming project P016 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution VALIDATE funded project
Collaborator Contribution Vaccines to target people with diabetes: characterising the pathways of immune response to M. tuberculosis and B. pseudomallei in people with diabetes compared to non-diabetics Led by Prof Susanna Dunachie (University of Oxford), with Assistant Prof Jacqueline Cliff (LSHTM), and Prof Gregory Bancroft (LSHTM) Project Aims A better vaccine is urgently required for tuberculosis (TB), and there is no vaccine at all for the neglected tropical disease melioidosis. Both diseases are caused by bacteria that live inside cells, and there are shared defence mechanisms. People with diabetes are at increased risk of getting ill with TB (three-fold increased risk) and are twelve time more likely to develop melioidosis than non-diabetics. We therefore need to understand why people with diabetes get ill with these bacteria, and how diabetes prevents the body from clearing the infection. We will combine expertise at the London School of Hygiene and Tropical Medicine, Mahidol- Oxford Tropical Medicine Unit in Bangkok and the University of Oxford, to study the pattern of human immune response to TB and melioidosis in people with and without diabetes. To do this, we will use "transcriptomics" - the big-scale study of the gene readouts from the body's DNA ("transcripts") which are instruction messages for protein manufacture carried as ribonucleic acid (RNA). By measuring the pattern of RNA in a person's blood, we can compare which immune pathways are active in different groups of people. We will identify differences in the pattern of responses in TB patients with and without diabetes, see how they relate to cure from TB, and then compare the results with responses in melioidosis patients with and without diabetes. We will detect the most important protective immune response pathways which are seen in nondiabetic patients but are lacking in people with diabetes. This will allow us to design better vaccines for TB and melioidosis that work well in people with diabetes, and can also help us develop ways to use medicines at the time of vaccination to boost immune responses in people with diabetes. Project Outcomes Diabetes mellitus (DM) currently affects over 425 million people worldwide, of which almost 80% live in low- and middle-income countries (LMICs). The majority of people with diabetes in LMICs are thought to have Type 2 diabetes. Diabetes increases susceptibility to many global infections including Escherichia coli, Staphylococcus aureus and dengue, but the most established susceptibility relationships are for melioidosis and tuberculosis (TB). Melioidosis is a deadly infectious disease caused by the Gram-negative bacterium, Burkholderia pseudomallei (BP). The current estimation of melioidosis cases is 165,000 cases worldwide with 89,000 deaths. Mortality in severe melioidosis cases presenting with sepsis can reach 50% in Thailand. Diabetes is a major risk factor for melioidosis with a 12-fold increased susceptibility to the infection. Tuberculosis (TB) is a major global killer. In 2018, an estimated 10 million people were infected with Mycobacterium tuberculosis and over a million people died from TB. Moreover, DM confers a 3-fold increased susceptibility to TB. Tuberculosis and melioidosis share many key features including an overlap of clinical manifestations, immunopathology, and host immune responses. A previous study in Thailand demonstrated that transcriptomic profiles between tuberculosis and melioidosis were indistinguishable. Host-immune responses to the infections are dysregulated in people with diabetes including killing mechanisms, cell-cell communication, and migration. However, mechanisms involved in the increased susceptibility in DM to intracellular pathogens are to be elucidated. In this project we used RNA sequencing to study transcriptomics in melioidosis and tuberculosis patients in order to characterise the difference in host response to infection for those with and without DM. Differential gene expression analysis between melioidosis patients with (n = 49) and without DM (n = 32) identified two genes CD163L1 (scavenger-receptor cytokine-rich protein) and FAM1932 (a member of the CC chemokine family) were differentially expressed with a false discovery rate < 0.05. However, gene set enrichment analysis using hallmark gene sets showed distinctive profiles in several comparisons. A comparison between melioidosis cases with and without DM showed a number of enriched gene sets dominated by immune, proliferation, and signalling in the DM group only. We identified gene signatures in people with diabetes indicative of endoplasmic reticulum stress and are now confirming this finding in validation experiments in peripheral blood mononuclear cells. Further analysis comparing the impact of diabetes in acute melioidosis with tuberculosis revealed shared transcriptomic signatures of increased inflammatory responses, increased neutrophil degranulation and increased platelet degranulation. However, looking at the whole blood transcriptome we saw opposite effects of diabetes on interferon-gamma signalling, with an increase in acute melioidosis (which may represent non-specific neutrophil activation) and a decrease in tuberculosis. Using an additional sample set from a collaboration with Eoin West at University of Washington, USA, we compared patients who went on to survive melioidosis in Ubon Ratchathani (n = 80) with fatal cases (n = 84) and found dominance in fatal cases for non-specific pro-inflammatory pathways but down-regulation of T cell signalling pathways, especially in those with diabetes. Overall, our data shows that excessive pro-inflammatory immune responses with reduced T cell signalling are associated with poor clinical outcomes, and people with diabetes have an excessive non-specific pro-inflammatory response to both melioidosis and tuberculosis, with increased neutrophil and platelet activation. The massive neutrophil activation in sepsis from acute melioidosis is associated with increased interferon-gamma pathway activation, in contrast to tuberculosis where overall interferon-gamma activity is reduced in diabetes - most likely reflecting the less acute nature of disease from M. tuberculosis. Vaccines targeting T cells for these intracellular pathogens may be especially important to correct the increased susceptibility seen in diabetes.
Impact Collaborations: • This project allowed the building of a collaboration between S. Dunachie and J. Cliff, which we aim to be a foundation for further work. • Further collaborations that this project was a springboard for: 1. Paul Brett and Mary Burtnick, University of Nevada in Reno, USA - planning a Phase 1 vaccine trial of a public health melioidosis vaccine to target people with diabetes 2. Helen McShane and Elena Stylianou, U. Oxford, UK - establishing a mouse model of diabetes for vaccine testing 3. Claire Chewapreecha, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand - "Dissecting the genetic basis of melioidosis infection" 4. Eoin West, University of Washington, Seattle, USA (extension from previous collaboration on sepsis and Toll-like receptors) - transcriptomic signatures of melioidosis and sepsis 5. Chiranjay Mukhopadhyay, Manipal Academy of Higher Education, India - cellular immunity in TB and melioidosis (which has been awarded a subsequent VALIDATE pump-priming grant, P033) 6. Mohammad Ali, Dhaka Medical College, Bangladesh - metabolism, DM and TB 7. Vivek Jha, George Institute, New Delhi, India - diabetes and infection database research 8. Prof. Chang-Hwa Song, Chungman National University, South Korea - macrophage immunology in TB +/- DM As a result of the VALIDATE networking session in 2018, a team assembled with an interest in developing a diabetic mouse model for testing of immune response to disease and vaccination, and this was a successful pump-priming award from VALIDATE in early 2019 (PI Elena Stylianou, P022 - further details below). Papers: This project influenced the following manuscripts: • Dunachie, S. and P. Chamnan, The double burden of diabetes and global infection in low and middle-income countries. Trans R Soc Trop Med Hyg, 2019. 113(2): p. 56-64. https://doi.org/10.1093/trstmh/try124 • Kronsteiner, B., et al., Diabetes alters immune response patterns to acute melioidosis in humans. Eur J Immunol, 2019. 49(7): p. 1092-1106 https://doi.org/10.1002/eji.201848037 • Eckold, C. et al., Impact of intermediate hyperglycaemia as well as diabetes on immune dysfunction in tuberculosis. Clinical Infectious Diseases 2021 https://doi.org/10.1093/cid/ciaa751 • Eckold et al., Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity MedRxiv 2022 https://doi.org/10.1101/2022.02.07.22269422 • Tomás-Cortázar, J., Bossi, L., Quinn, C., Reynolds, C.J., Butler, D.K., Corcoran, N., . . . McClean, S. BpOmpW Antigen Stimulates the Necessary Protective T-Cell Responses Against Melioidosis. Front. Immunol. 12, 767359-767359 (2021). 10.3389/fimmu.2021.767359. https://pubmed.ncbi.nlm.nih.gov/34966388 • Chewapreecha, C., Pensar, J., Chattagul, S., Pesonen, M., Sangphukieo, A., Boonklang, P., . . . Corander, J. Co-evolutionary Signals Identify Burkholderia pseudomallei Survival Strategies in a Hostile Environment. Mol. Biol. Evol. 39, msab306 (2022). 10.1093/molbev/msab306. https://pubmed.ncbi.nlm.nih.gov/34662416 Two manuscripts are in preparation directly from this work: 1. Rongkard, P., Kronsteiner B., Hantrakunb, V., Teparrukkul, P., Wongsuvanb, G., Limmathurotsakul, D., Lovelace-Macon, L., Day, N.P., Klenerman, P., Chantratita, N., Gharib, S., Dunachie S., West, T.E. Transcriptomic signatures in fatal melioidosis. Manuscript in preparation 2. Rongkard, P., Hantrakunb, V., Teparrukkul, P., Wongsuvanb, G., Limmathurotsakul, D., Lovelace-Macon, L., Day, N.P., Gharib, S., West, T.E, Cliff, J., Klenerman, P., Kronsteiner B., Dunachie S. The impact of type 2 Diabetes on the immune response to melioidosis and tuberculosis. Manuscript in preparation Related funding: 1. 2021-2026 NIHR Professorship in Global Health "Developing a vaccine to prevent death from melioidosis in people with type 2 diabetes mellitus in low- and middle-income countries" (Dunachie PI), £1,951,296 2. 2020-2022 US Defense Threat Reduction Agency award "Optimization of lead melioidosis and glanders vaccine formulations" Prof Paul Brett University of Nevada, Reno PI with sub-contract award to Dunachie, Oxford PI, $733,976.61 USD (£524,269) to Dunachie lab. 3. 2022-2025 MRC Biomedical Catalyst Developmental Pathway Funding Scheme (DPFS) / US Defense Threat reduction Agency award, "Developing a vaccine for Burkholderia pseudomallei - a Phase I Clinical Trial" (Dunachie PI) £3,238,214. 4. 2019-2020 VALIDATE pump-priming project: "Characterising the cellular immunity and metabolic response to Mycobacterium tuberculosis and Burkholderia pseudomallei in Indian patients for vaccine design". (Mukhopadhyay, Manipal Academy of Higher Education, India PI, Dunachie Co-PI) £48,993 (£7,000 to Dunachie lab). 5. 2019-2020 Global Challenges Research Fund (GCRF) "Diabetes and Infection: Developing a network for using real-world datasets to evaluate the relationship between diabetes and infection in low and middle income countries?" (Dunachie PI) £?26,728.50. 6. 2019-2022 Bangladesh Prime Minister's PhD Scholarship for DPhil study at U. Oxford for "Metabolic changes in immune cells of diabetic patients and their impact on immune responses to tuberculosis"(Mohammad Ali, Dhaka Medical College, Bangladesh applicant, Dunachie supervisor) $258,823 USD (£184,874). 7. 2019-2020 MRC VALIDATE "Developing a mouse model of diabetes to evaluate vaccines for TB and melioidosis' (Stylianou PI, Dunachie Co-PI) £49,733.91 - £5,500 to Dunachie lab). In addition, S.Dunachie has been PI or Co-Investigator for grants totalling £5.7 million addressing the immune response to SARS-CoV-2 from infection and vaccination. The immunology expertise developed in her melioidosis work was rapidly applicable to SARS-CoV-2 due to similarity of vulnerable patient group (increased age, diabetes, immunocompromise). Capacity building: • This was Prof Susanna Dunachie's first formal funding to look at the relationship between diabetes and infection (although it was already an interest), and has sparked a whole programme of work (see collaborations and funding). She is now leading the world's first clinical trial of a vaccine for melioidosis. • Mr Patpong Rongkard, Mahidol-Oxford Tropical Medicine Research Unit (MORU), Bangkok - came to Oxford to undertake this project, and was able to register for a DPhil "Understanding how type II diabetes increases susceptibility to intracellular infections". This VALIDATE project has enabled him to receive extensive training in bioinformatics for analysis of RNAseq data, all using open-source software in R. He passed his DPhil viva in November 2022 and has now been awarded the DPhil. • Susanna Dunachie is supporting development of immunology research in India and Bangladesh, by supporting a new collaboration with Dr Mukhopadhyay at Manipal Academy of Higher Education, India, and supported the writing of a successful PhD scholarship application by Dr Ali of Dhaka Medical College, who is now undertaking a DPhil at U Oxford. • Dr Lee (LSHTM) was instrumental in writing her first grant application "Building investigator links for studies on the roles of complement C1q and endoplasmicreticulum (ER) stress in macrophage polarisation during Mycobacterium tuberculosis infection for a successfully funded MRC-KHIDI UK-Korea Partnering Award. • Secondments: Mr Rongkard was unable to undertake the planned secondment at U. Washington, Seattle, USA, in May 2020 due to the pandemic. However, using Microsoft Teams we have been able to build a close collaboration and he has used the skills acquired in this project to analyse the raw RNAseq data generated in an independent cohort of melioidosis patients as part of a sepsis study in the same region of Northeast Thailand as our study (see results). • Susanna organised the VALIDATE Melioidosis Vaccine Symposium: Moving from animal models to man on February 26th 2019, with support from the VALIDATE team (see separate section on this Symposium). Outreach: March 2022. Talk to local 6th form college about careers in tropical medicine. 2022 Dunachie S. Vaccines against melioidosis: How far are we? European Melioidosis Congress, Gratz, Austria, May 2022 2022 Rongkard P. T-cell dysfunction is associated with fatality in community-acquired melioidosis 2019 Dunachie S. Diabetes and melioidosis: What do we know, and what can we do? Invited plenary speaker at World Melioidosis Congress, Hanoi, October 2019 This project was presented at the 2018, 2019 and 2021 VALIDATE Annual Meetings. As a result of the VALIDATE networking session in 2018, a team assembled with an interest in developing a diabetic mouse model for testing of immune response to disease and vaccination, and this was a successful pump-priming award from VALIDATE in early 2019 (PI Elena Stylianou, P022). New datasets of RNAseq data in acute melioidosis have been generated from this project and will be available to VALIDATE members. Awards/Recognition: Susanna Dunachie: - Professor of Infectious Diseases - NIHR Global Research Professorship - Medical Fellow, Corpus Christi College, Oxford Product Development We organised a VALIDATE workshop on vaccines for melioidosis in February 2019, and as a result submitted a successful application to MRC's DPFS grant call to undertake the first human Phase I Vaccine Trial of a melioidosis vaccine, in Oxford using Paul Brett and Mary Burtnick's melioidosis vaccine candidate. The subunit vaccine has been developed at University of Nevada, Reno (UNR) and combines the bacterial capsule polysaccharide (CPS) conjugated to the immunogenic diphtheria toxin mutant CRM197, with recombinant B. pseudomallei Hcp1 protein in an Alhydrogel-CpG adjuvant. In a mouse model, the combined vaccine generated high levels of opsonising anti-CPS antibodies, alongside high T-cell responses to Hcp1, and protected 100% of mice against a robust lethal inhalational B. pseudomallei challenge. We plan to develop the vaccine as a public health vaccine for people with diabetes in low- and middle-income countries (LMICs). The group of investigators in UK (Dunachie, McShane, Kronsteiner), USA (Brett, Burtnick) and Thailand (Chantratita), brought together by the MRC VALIDATE Network, are planning a first-in-man study of 36 healthy human volunteer subjects in Oxford, UK, randomised to receive either the CPS-CRM197 alone, Hcp1 alone, or the CPS-CRM197 / Hcp1 combination. This will be followed by 12 subjects aged 40-60 years with Type II diabetes in Oxford receiving the CPS-CRM197 / Hcp1 combination. Endpoints will be safety and immunogenicity (antibody and T cell responses). The team seeks to define the key immune correlates of protection for monitoring vaccine efficacy in subsequent field trials, using functional growth inhibition assays and transcriptomics in the vaccinated population, existing melioidosis patient cohort studies, and animal models in collaboration with UNR. The vaccine is currently completing manufacture at Resilience Corp, Florida, USA (funded by US Defense Threat Reduction Agency) and we will commence the Phase 1 clinical trial in Oxford, UK in early 2023. Next we plan to undertake a Phase 1b study in Thailand (will require future funding). Ultimately we seek to accelerate production of a vaccine for the 280 million people with diabetes and the many with other risk factors for melioidosis including older age, chronic renal disease and immunosuppression who live in melioidosis-endemic regions in 83 countries across the globe.
Start Year 2018
 
Description Representation of VALIDATE at Events, Meetings, Workshops or similar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact VALIDATE has been represented at various events to promote our network and encourage new membership, as well as to speak to funding bodies about our work:

30 Jul 2017, VALIDATE Management Team Prof Helen McShane (Director), Prof Helen Fletcher (Co-Director) and Samantha Vermaak (Network Manager) attended the MRC Vaccines Network meeting in London hosted by MRC.

23-24 Nov 2017, talk about VALIDATE given by Dr Iman Satti (VALIDATE Associate) at HIC-VAC 1st Annual Meeting.

5 Dec 2017, VALIDATE Network Manager Samantha Vermaak co-hosted a stand at the BSI Congress with the other GCRF MRC-funded Vaccine Networks, with a pull-up banner and leaflets about VALIDATE, speaking to the event delegates about our Network and the benefits of membership.

15 Jan 2018, VALIDATE Director Prof Helen McShane presented a slide about VALIDATE, and had leaflets at the event to promote VALIDATE.

18 Jan 2018, VALIDATE Director Prof Helen McShane mentioned VALIDATE in her talk at the UK Veterinary Vaccinology Network Conference, and had leaflets.

12 Feb 2018, VALIDATE Co-Director Prof Helen Fletcher had a slide about VALIDATE in her talk at the UCL-AHRI Symposium "Towards HIV and TB elimination in South Africa".

22 Feb 2018, VALIDATE leaflets and representation (Samantha Vermaak) at University of Oxford's 'Global Research Day: Tackling International Challenges" event.

26-27 Feb 2018, VALIDATE talk by Director Prof Helen McShane at Bactivac Annual Meeting (leaflets too).

20 Mar 2018, VALIDATE talk by Network Manager Samantha Vermaak at European Melioidosis Congress. Our Associate Dr Panjaporn Chaichana (MORU, Thailand) also presented her VALIDATE-funded research and thanked VALIDATE for our funding.

23 Mar 2018, VALIDATE Director Prof Helen McShane had VALIDATE slide at UCL/LSHTM/UCSF World TB Day Super-Symposium https://panopto.lshtm.ac.uk/Panopto/Pages/Viewer.aspx?id=5ddad554-12f4-42e3-bab8-8bdc83ecbfb2

26-27 Mar 2018, VALIDATE Network Management Board member Prof Paul Kaye mentioned VALIDATE in his talk at IVVN's 1st Annual Meeting (leaflets at meeting).

19 Apr 2018, VALIDATE Co-Director Prof Helen Fletcher gave a careers talk to 30+ PhD students from LSHTM/UCL, mentioning VALIDATE.

10 May 2018, VALIDATE Research Data Analyst Dr Deniz Cizmeci gave a talk about VALIDATE at an IDDO meeting.

5 Jul 2018, VALIDATE Network Manager Samantha Vermaak gave a talk about VALIDATE at the Acid Fast Club meeting.

30 Jul 2018, Prof Helen McShane and Samantha Vermaak attended the MRC GCRF Vaccine Network first year meeting.

19 Sep 2018, Network Manager Samantha Vermaak gave a talk about VALIDATE at the 9th EDCTP Forum.

25 Sep 2018, Network Manager Samantha Vermaak gave a talk about VALIDATE at the IMPRINT 2nd Annual Meeting (leaflets available too).

10 Oct 2018, Prof Helen McShane and Samantha Vermaak had a teleconference with Willem Hanekom and Anne Kasmar at the Gates Foundation re VALIDATE.

12 Nov 2018, Prof Helen McShane and Samantha Vermaak met with Prof Sarah Rowland-Jones, President of RSTMH, to discuss how our two networks could work together to mutual benefit.

9 Jan 2019, representation of VALIDATE by Network Director Prof Helen McShane and Network Management Board member Prof Paul Kaye at HIC-VAC Regulatory Workshop "Human challenge agents: scoping potential manufacturing guidelines".

29 Jan 2019, Director Prof Helen McShane gave a talk about VALIDATE at the TBVAC2020 Les Diablerets meeting, as part of the TBVI Symposium "TB Vaccines Global Collaboration and Recent Advances in the Field."

29 Jan 2019, Director Prof Helen McShane met with Ole Olesen at EDCTP to discuss VALIDATE.

18 March 2019, Fellow and NMB member Dr Rachel Tanner presented at the 3Rs Research Review Launch and 2018 Prize Presentation "An in vitro functional assay to replace virulent M.tb challenge for the testing of TB vaccine candidates".

20-21 March 2019, VALIDATE Manager Samantha Vermaak represented VALIDATE at Bactivac 2nd Annual Meeting in Birmingham.

29 April - 3 May 2019, VALIDATE Director Prof Helen Fletcher and member Prof Jayne Sutherland were speakers at the Vaccinology in Africa course.

16 May 2019, VALIDATE Director Prof Helen McShane spoke at the 20th ADVAC (Advanced course of vaccinology) in Annecy, France, and had VALIDATE leaflets.

1-7 July 2019, VALIDATE member Dr Amanda Gibson and the RVC TB research group had a stand at the Royal Society Summer exhibition, with VALIDATE logo to show they are supported by our Network.

24 Sept 2019, VALIDATE NMB member Prof Jo Prior had a VALIDATE poster and chatted to the MRC/UKRI team during their visit to dstl.

7 Nov 2019, VALIDATE Fellow and NMB member Dr Rachel Tanner won 'Woman of the Future award for Science'.

18 Nov 2019, VALIDATE Director Prof Helen McShane presented on why we need a human TB challenge model at HIC-VAC Annual Meeting.

18 Nov 2019, VALIDATE NMB member Prof Paul Kaye presented on progress with leishmaniasis challenge studies at HIV-VAC Annual Meeting.

31 Jan 2020, VALIDATE is a partner of the first World NTD Day (https://worldntdday.org/partners/).

In 2020 our representation at face-to-face meetings was curtailed by the COVID-19 pandemic, but we continued to talk via Skype/Zoom/Teams to funders about possibilities for VALIDATE and VALIDATE's members:

10 Mar 2020, Samantha Vermaak and Mirvat Surakhy (VALIDATE Bioinformatician) met IDDO staff to discuss data sharing opportunities.

Aug 2020 VALIDATE Director Prof Helen McShane was phone interviewed by Cristiana Vagnoni (Biological Sciences and Health Advisor at UK Parliamentary Office of Science and Technology [POST], an office of both Houses of Parliament) for research for a four-page briefing on advances in vaccine technologies and policy approaches to stimulate and fast-track vaccine research and development 'given VALIDATE Network's role in supporting the development of vaccines for complex neglected pathogens'. Publication 29.09.21 "Advances in vaccine technologies" UK Parliament POSTnote https://post.parliament.uk/research-briefings/post-pn-0657/

21 Oct 2020, Helen McShane and Samantha Vermaak talk to Hannu Laang (GTBVP).

11 Nov 2020, Helen McShane and Samantha Vermaak talk to Ann Ginsberg (BMGF).

13 Nov 2020, Helen McShane and Samantha Vermaak talk to Katrin Eichelberg (NIH).

Oct 2020, VALIDATE Fellow Dr Rachel Tanner presented her research project findings at the TBScience 2020 meeting (part of 51st Union World Conference on Lung Health). and was invited as a panellist to talk about her work and experience as a female scientist for the 2020 Women of the Future Awards and the 2021 Oxford Women in Engineering, Science and Technology (OxWEST) Annual Symposium.

30 Jan 2021, VALIDATE is a partner of World NTD Day (https://worldntdday.org/partners/).

9 Mar 2021, Helen McShane and Samantha Vermaak talk to Ann Ginsberg (BMGF) and Ksenia Koon (CTVD) [this talk eventually led to the BMGF follow-on funding VALIDATE received].

1 Oct 2021, Helen McShane gave CTVD (virtual) workshop talk re VALIDATE-CTVD partnership & VALIDATE progree to date and future plans (including VALIDATE-CTVD joint grant calls).

28 Oct 2021, Helen McShane and Samantha Vermaak present about VALIDATE to GTBVP.

Nov 2021, Prof Susie Dunachie gave a talk about her P033 India-UK pump-priming project, as well as an intro to VALIDATE at FIS conference.

8-9 Nov 2021, Prof Samantha Sampson (VALIDATE Co-Director) gave presentation about VALIDATE at Birmingham University BBSRC Chaperonins workshop.

10 Jan 2022, Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with Mike Whelan at CEPI re possibilities to work together and for VALIDATE funding.

31 Jan 2022, Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with BMGF NTD team about VALIDATE; invited to submit small grant proposal (awarded Oct 2022).

18 Feb 2022, Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with Indian British High Commission re possibilities.

18 Mar 2022, Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with Francesco Berlanda Scorza at GSK to discuss possibilities to work together.

4 Apr 2022, Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with Fleming Fund Manager at Mott MacDonald re possibilities to work together.

26 May 2022 Samantha Vermaak virtual meeting with Suzanna Francis at IAVI who are looking for potential MTBVAC trial sites (where they could build capacity). Agreed she will add VALIDATE to their grant proposal and will get back in touch if successful.

17 Aug 2022 Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with Afrigen CEO Prof Petro Terblanche about possibilities of working together (Afrigen subsequently joined VALIDATE and participated in a joint grant proposal).

17 Sept 2022 Helen McShane, Samantha Sampson & Samantha Vermaak virtual meeting with SA MRC. Samantha Sampson invited to give talk re VALIDATE at MRC's Funders Forum 20-22 November 2022 (bringing together local and global funders in the SADC region).
Year(s) Of Engagement Activity 2017,2018,2019,2020,2021,2023
 
Description VALIDATE 2nd Annual Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact On 6-7th November 2018, we held our 2nd Annual Meeting in York, UK. The meeting contained updates about VALIDATE, Prof Heidi Larson (LSHTM) talking about vaccine hesitancy, our pump-priming funded projects each giving an update about their research, as well as some animated and engaged networking to get our members meeting each other and sparking collaboration ideas. We had an ECR showcase, where our network's ECRs hosted posters outlining their current research and future career and research ambitions to facilitate and spark new collaborative relationships amongst our members and to network them with both their peers and senior scientists and PIs in VALIDATE. We also had an industry showcase where our industry members had posters highlighting their research experience and expertise, again to network them in with other members.

On day 2 we held a facilitated 'Ideas Laboratory' aiming to help our delegates think big to tackle vaccine development for our focus pathogens - what breakthroughs need to be achieved, what challenges need to be overcome, what do we need to start/stop/continue doing to achieve success? The room buzzed with energy as people exchanged ideas, gradually building up to concrete research project concepts that everyone worked collaboratively on to develop further, and some of which have been submitted as pump-priming grants in our subsequent round of funding.

62 delegates from 13 countries (Brazil, Cameroon, Ireland, Italy, Mexico, Mozambique, Nepal, Nigeria, South Africa, Thailand, Uganda, UK, USA) attended, as well as two members of our SAB. We awarded 9 travel scholarships to LMIC members to encourage and facilitate their attendance (7 to female scientists), 7 or which were to ECRs.

The meeting had excellent feedback from our members. We also used the meeting to produce three short videos, showcasing VALIDATE to encourage further new members to join and to highlight the benefits of VALIDATE membership (viewable at https://www.youtube.com/channel/UC4jnwrHLkvK-xJjYJYpnYog).

Outputs include:
- (from the 2nd AM and the VALIDATE melioidosis 2019 workshop) a new collaboration between Prof Susanna Dunachie (PI - Oxford), Assoc Prof Paul Brett (Nevada), Assoc Prof Mary Burtnick (Nevada), Prof Helen McShane (Oxford) and Prof Narisara Chantratita (Mahidol) applied for and were awarded an MRC Biomedical Catalyst DPFS / US Defense Threat Reduction Agency grant, "Developing a vaccine for Burkholderia pseudomallei - a Phase I Clinical Trial" of £3,238,214 in 2020 (to 2023). This will be the first ever human clinical trial of a melioidosis vaccine.
This new collaboration have also been awarded a Defense Threat Reduction Agency (DTRA) Subaward "Developing a vaccine for Burkholderia pseudomallei - a Phase I Clinical Trial" (Brett PI, Dunachie Oxford subcontracting PI to value of $733,976.61(£524,269) to Dunachie lab) for 2020-2021, and a US Defense Threat Reduction Agency 2020-2021 award "Optimization of lead melioidosis and glanders vaccine formulations" Prof Paul Brett University of Nevada, Reno PI with sub-contract award to Dunachie, Oxford PI, (awarded in principle, awaiting contract) $733,976.61 USD (£524,269).
- During the 2nd Annual Meeting Facilitated 'Ideas Laboratory', Dr Barbara Kronsteiner-Dobramysl (University of Oxford ECR) was approached by Prof Javier Sanchez (IPN, Mexico) who also had an interest in immunometabolism and they formed a new collaboration, being successfully awarded a VALIDATE pump-priming grant in 2019.
- A new collaboration was formed between Dr Julen Tomas Cortazar and Dr Siobhan McClean (UCD), Dr Louise Gourlay (University of Milan) and Prof Susanna Dunachie (University of Oxford), which resulted in a successful pump-priming grant application in 2019.
Year(s) Of Engagement Activity 2018
URL https://www.validate-network.org/article/validate-2nd-annual-meeting-report
 
Description VALIDATE LinkedIn 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact We have set up a closed LinkedIn VALIDATE group with three aims:
1. To make it easier for our members to connect to each other.
2. To create a further social media forum on a different platform for dissemination of relevant and interesting news as well as VALIDATE outputs, to reach members who may not be using Twitter.
3. To add a way to keep up to date with outputs and news from our members e.g. job vacancies are often posted to LinkedIn, that we can then share and also publicise on our website and Twitter accounts.

Currently 329 of our members have connected and are now following our account.
Year(s) Of Engagement Activity 2018,2019,2020,2021,2022,2023
URL https://www.linkedin.com/in/validate-network/
 
Description VALIDATE Seminars 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact VALIDATE aims to host regular seminars by our members about their research to inform members and the general public, and to spark new research ideas and collaborations. These are live-streamed online to enable all our members and the general public, no matter where they are based in the world, to join and benefit from the information, ideas, and findings being disseminated.

Our first talk was held on 6 Dec 2017, by Assoc Prof Helen Fletcher and Dr Andrea Zelmer at LSHTM, entitled "Correlates of risk of TB disease and their back-translation into animal models", and was viewed by c.43 people.

Our second talk was held on 15 Feb 2019, by Prof Helen McShane and Dr Rachel Tanner at University of Oxford, entitled "Developing a better vaccine against TB" and was viewed by 52 unique viewers.

Our 2020 Summer Seminar Series involved:
30 June 2020 'Developing a vaccine for Melioidosis: Probing the protective immune response'
By Prof Siobhán McClean and Dr Julen Tomás Cortázar (UCD, Ireland). 52 people from 16 countries registered for the event (India, Nigeria, Bangladesh, USA, UK, UCD, Ghana, Brazil, Italy, Hungary, Pakistan, Camaroon, Algeria, Thailand, Vietnam, Indonesia).

23 July 2020 'Melioidosis and Glanders' by Prof Mary Burtnick (University of Nevada, Reno School of Medicine, USA). 35 people registered to attend from 15 countries (Vietnam, India, Hungary, Ireland, UK, Sri Lanka, USA, Nigeria, Cameroon, Ghana, China, Pakistan, Bangladesh, Thailand, Malaysia).

29 July 2020 'Nonspecific factors in the immunopathogenesis of leishmaniasis' by Assoc Prof Hiro Goto and Dr Eduardo Milton Ramos Sanchez (Universidade de Sao Paulo, Brazil). 12 people attended from 6 countries (UK, India, Sri Lanka, Hungary, Pakistan, Brazil).

01 September 2020 'Efforts to understand the immunology of bovine TB' by Prof Bernardo Villarreal-Ramos (University of Aberystwyth and APHA) and Dr Amanda Gibson (Aberystwyth University). This seminar was pre-recorded, with 57 people registering to watch the recording from 12 countries (Brazil, Mexico, Argentina, UK, India, Uganda, Algeria, Nigeria, South Africa, Tanzania, Ghana, Ethiopia).

Our 2020 Winter seminar series included:
24 November 2020 'Mtb in the host Persisters and PE&PPE Proteins' by Prof Samantha Sampson and Dr Jomien Mouton (Stellenbosch University, South Africa). 60 people joined the seminar from 18 countries (Hungary, Brazil, UK, Argentina, India, Mexico, South Korea, India, Ghana, Uganda, Italy, South Africa, Malaysia, Germany, Australia, Sri Lanka, USA, Lithuania). 111 views on YouTube.

3 December 2020 'Computational approaches in structural vaccinology - Structural biology for antigen-based therapeutics & diagnostics' by Prof Giorgio Colombo (University of Pavia, Italy) and Asst Prof Louise Gourlay (University of Milan, Italy). There were 31 attendees from 20 countries (UK, Brazil, Bangladesh, Vietnam, Mexico, Burkina Faso, UK, USA, Ghana, Kenya, India, Uganda, Tanzania, Nigeria, Pakistan, Italy, Malaysia, Ireland, Cameroon, Sri Lanka). 118 views on YouTube.

15 December 2020 'Immune profiles of healing in cutaneous leishmaniasis, what to target and when?' by Dr Maria Adelaida Gomez (CIDEIM, Colombia). 39 people attended from 15 countries (Nigeria, USA, India, Colombia, Sri Lanka, Morocco, Vietnam, Belgium, UK, Uganda, Algeria, Pakistan, Spain, Brazil, Cameroon, Ghana, Lithuania). 108 views on YouTube.

2021 Industry Seminar Series:
11 March 2021 'Capturing and recreating recombinant polycloncal antibodies for passive immunization to treat difficult to treat infections' by Dr Sheila Keating of GigaGen. 18 people attended from 9 countries joined (Uganda, UK, Ghana, India, USA, Colombia, Nigeria, South Africa, and Thailand). 83 views on YouTube.

27 April 2021 'Addressing pathogen and human diversity' by Graham Clarke, Chair and former CEO of ImmBio. ~30 attended with 60 registered from 25 countries (Austria, Brazil, Burkina Faso, China, Croatia, Ethiopia, Gambia, Germany, Ghana, India, Indonesia, Ireland, Mexico, Nigeria, Nigeria , Pakistan, Paraguay, South Africa, Tanzania, Thailand, The Gambia, Uganda, United Kingdom, United States and Venezuela). 25 views on YouTube.

15 Jul 2021 'Tuberculosis Infection and T cell-Mediated Immunity' by Dr Yupei Xiao, Medical Science Liaison, Oxford Immunotec. This was the last in our series of Industry Seminars. 64 attended with people registering from Argentina, Bangladesh, Belgium, Brazil, Bulgaria, China, Colombia, Ethiopia, France, Germany, Ghana, Hungary, India, Indonesia, Ireland, Japan, México , Nigeria, Pakistan, South Africa, South Korea, Sri Lanka, Sweden, Switzerland, Tanzania, Thailand, The Gambia, Uganda, United Kingdom, United States, Venezuela and Zambia. 302 views on YouTube.

30 November 2021 - seminar by Dr Yumi Maeda (Leprosy Research Center, NIID, Japan) 'Vaccine development and sero-diagnosis of leprosy'. 23 people attended from 14 countries (Japan, Peru, United Kingdom, Ghana, Sri Lanka, Nigeria, Portugal, Albania, India, South Africa, Senegal, Japan, Burkina Faso).

6 Apr 2022 "A vaccine for leishmaniasis?" by Prof Mitali Chatterjee (IPGMER, India) and Dr Mohamed Osman (University of York, UK) provided members with an overview and update on the current state of research into vaccines for leishmaniasis. 55 online attendees from 21 countries (14 LMIC). 137 views on YouTube.

18 May 2022 "A vaccine for melioidosis?" by Prof Chiranjay Mukhopadhyay and Dr Somasish Ghosh Dastidar (MAHE, India) discussed the prospects for a melioidosis vaccine. 38 online attendees from 16 countries (13 LMIC). 96 views on YouTube.

22 June 2022 - ECR Summer Showcase 1 online seminars - Dr Nguyen Ho Lam (University of Medicine & Pharmacy, Vietnam), Dr Nidhi Gupta (CURAJ, India) and Dr Rachel Tanner (University of Oxford, UK) gave short talks on their research. 36 online attendees from 16 countries (11 LMIC).

28 June 2022 "A vaccine for leprosy?" - Dr Khushboo Slater (University of Surrey, UK) and Dr Chyntia Diaz Acosta (IICS, Paraguay) discussed the prospects for a leprosy vaccine. 40 online attendees from 24 countries (14 LMIC). 110 views on YouTube.

13 July 2022 - ECR Summer Showcase 2 online seminars - Asst Prof Nargis Khan (University of Calgary, Canada), Dr Laura Sibley (UKHSA, UK) and Dr Cristian Segura-Cerda (CIATEJ, Mexico) gave short talks about their research. 31 online attendees from 25 countries (20 LMIC).

16 Nov 2022 "A flexible and efficient platform to develop a nanovaccine against Burkholderia pseudomallei" by Prof Alfredo G Torres (UTMB, USA). 31 online attendees from 13 countries (8 LMIC). 83 views on YouTube.

14 Dec 2022 "Targeting Immunometabolism in Host Defense Against Mycobacterium Tuberculosis" by Dr Luciana Balboa (CONICET, Argentina). 53 online attendees from 26 countries (16 LMIC). 70 views on YouTube.

27 Jan 2023 Prof Makram Essafi "Targeting FOXO3 transcription factor as a host-directed approach to enhance the efficacy of BCG against Mtb" & Prof Dhafer Laouini "Vaccine against human leishmaniasis: Institut Pasteur de Tunis contribution". 31 online attendees from 16 countries (9 LMIC). 30 views on YouTube.

Nearly all the talks were recorded and these recordings are available to VALIDATE members via the VALIDATE Hub; open-access talk recordings are also shared on the VALIDATE YouTube Channel.

In addition, in 2020, Dr Julen Tomas Cortazar (UCD, Ireland) made three videos talking about his research on T-cell inducing vaccines, in English, Spanish and Basque respectively. These have 512 YouTube views in total.

One of our ECRs, Wilfred Aniagyei (KNUST/KCCR) said 'VALIDATE online seminar gave me insight into other research methodologies that helped with my current research' while Christine Petersen (University of Iowa) commented 'VALIDATE has provided some wonderful seminars and other platforms for scientific discourse during this year [2020] of limited ability to otherwise interact with our scientific peers. This has been very helpful to maintain productivity and connection.'

Prof Samantha Sampson's seminar led to an invitation to speak at University of Surrey, which has led to several follow-on conversations about possible collaborations (with Suzie Hingley-Wilson, VALIDATE member). One of her PhD students has been assisting one of Prof Sampson's MSc students with protocol development.
Year(s) Of Engagement Activity 2017,2018,2019,2020,2021,2022,2023
URL https://www.validate-network.org/seminars
 
Description VALIDATE Twitter account 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact On 28 July 2017 we launched our VALIDATE Twitter account @NetworkVALIDATE. We post regularly about news, opinions and activities relevant to our Network members, including grant calls, training opportunities, events, journal articles, opinion pieces, tips/advice, and disease statistics from VALIDATE and relevant external organisations, to promote both our activities and items that could help our members advance their research and careers - or inform general public followers about our research, vaccine development, vaccine hesitancy etc. We highlight papers authored by our members, raising their profile and potential citations, as well as papers relevant to our members' research, making keeping up to date with new research in the field easier for our members. We also have social media engagement activities for World Leprosy Day, World NTD Day, International Day of Women & Girls in Science, World TB Day, Immunization Week and others. To date we have 1,140 followers, which we hope will continue to increase, forming an engaged community.
Year(s) Of Engagement Activity 2017,2018,2019,2020,2021,2022,2023
URL https://twitter.com/NetworkValidate
 
Description VALIDATE YouTube Channel 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact On 4 Dec 2018 VALIDATE launched its You Tube Channel, with videos of our members talking about VALIDATE and the benefits of membership, to promote our network in another format and to hopefully encourage new members to join VALIDATE. https://www.youtube.com/channel/UC4jnwrHLkvK-xJjYJYpnYog.

We added 7 further videos of member interviews taken during our 3rd Annual Meeting and ECR workshop (2019) e.g. 'How VALIDATE is accelerating vaccine development', 'How VALIDATE is capacity building' as well as overview videos of our Annual Meetings and the benefits of being a VALIDATE member.

In 2020/2021 we expanded our Channel aims to include educating the general public about VALIDATE's focus pathogens and research, and encouraging teenagers towards careers in STEM. We added an interview with Prof Helen McShane for World TB Day, three videos (English, Spanish, Basque) by Dr Julen Tomas Cortazar explaining his research, a recording of our first VALIDATE for Schools talk by Prof Helen McShane and Dr Rachel Tanner (attended live by >200 school kids), three open-access scientific seminars by VALIDATE members based in South Africa, Italy and Colombia, and a video by Dr Hua Wang about leprosy for World Leprosy Day 2021. The latter is our most successful video, with 6.3k views.

In 2021/2022 we added recordings of our two BCG100 public talks, 3 industry open-access seminars, a further VALIDATE for Schools recorded talk, two trailers for our BCG Adventure computer games, and an original video 'A few things you might not know about Leishmaniasis' (as part of World NTD Day 2022), as well as further member scientific open-access seminars.
Year(s) Of Engagement Activity 2018,2019,2020,2021,2022,2023
URL https://www.youtube.com/channel/UC4jnwrHLkvK-xJjYJYpnYog
 
Description VALIDATE in the spotlight - in writing 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact In 2020, VALIDATE Fellow Dr Rachel Tanner took part in BSI's 'a day in the life of a vaccine researcher' blog. She was also interviewed for a 500WomenScientists article, and contacted by school student in California who interviewed her for a presentation on 'scientists that don't fit the conventional mold'

12 May 2020, '10 minutes with Prof Helen McShane' in BMJ Leader bmjleader.bmj.com/content/early/2020/05/10/leader-2020-000268

29 Apr 2020, VALIDATE highlighted in BSI's 'protecting the world' report on UK vaccinology www.immunology.org/sites/default/files/BSI_Celebrate_vaccines_report_2020_FINAL_0.pdf 29.04.20

Apr 2020, World Immunization Week, VALIDATE is part of BSI's Instagram campaign www.immunology.org/news/world-immunisation-week-2020

11 Feb 2020, VALIDATE blog post for International Day of Women and Girls in Science, chatting to five of our female members about their research, inspiration, and advice/tips they would give to girls wanting to aim for a career in scientific research: www.validate-network.org/article/international-day-of-women-and-girls-in-science-2020

31 Jan 2020, VALIDATE First World NTD Day blog post, discussing NTDs and new NMB member Dr Alvaro Acosta-Serrano's research on leishmaniasis: www.validate-network.org/article/world-ntd-day-2020

27 Jan 2020, VALIDATE World Leprosy Day blog post, flagging the news and views for this day from around the world: www.validate-network.org/article/world-leprosy-day-2020

22 Mar 2019, VALIDATE Director Prof Helen McShane spoke to Phys.org ahead of World TB Day https://phys.org/wire-news/314702574/a-new-tb-vaccine-is-within-reach-prof-helen-mcshane.html

8 Mar 2019, VALIDATE blog post for International Women's Day 2019 interviewing 5 of our female scientists https://www.validate-network.org/article/international-womens-day-2019

27 Jan 2019, VALIDATE World Leprosy Day blog post, talking to two ECR researchers working on leprosy vaccine development: www.validate-network.org/article/world-leprosy-day-2019

26 Nov 2018, VALIDATE featured in RSTMH newsletter

18 Jun 2018, VALIDATE Director Helen McShane spoke to www.openaccessgovernment.org about "The current status of tuberculosis vaccine development" https://www.openaccessgovernment.org/current-status-tuberculosis-vaccine-development/46726/

30 Apr 2018, VALIDATE blog post for World Immunization week https://www.validate-network.org/article/vaccineswork-world-immunization-week-vaccines-validate

5 Dec 2017, VALIDATE featured in a blog post "Building international partnerships to tackle disease" on the University of Oxford Science blog, which has an extensive worldwide reach. http://www.ox.ac.uk/news/science-blog/building-international-partnerships-tackle-disease

22 Nov 2017, VALIDATE featured in article on GCRF Networks by Martin Broadstock for BSI Immunology News magazine https://www.immunology.org/news/the-network-effect-promoting-collaborative-research?utm_content=buffer15fca&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer

24 Oct 2017, VALIDATE launch featured on TBVI website 'news' https://www.tbvi.eu/new-international-vaccine-rd-network-validate/
Year(s) Of Engagement Activity 2017,2018,2019,2020,2021
 
Description VALIDATE in the spotlight - media 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact 24 Mar 2018, VALIDATE Director Prof Helen McShane gave an interview for World TB Day at BBCOxford Radio https://www.bbc.co.uk/programmes/p060zj9g 1:02:30 for the headline; 1:09:05 for the interview.

29 Apr 2020, VALIDATE Director Prof Helen McShane featured in The Guardian podcast 'What has the BCG vaccine got to do with COVID-19' www.theguardian.com/science/audio/2020/apr/30/covid-19-what-has-the-bcg-vaccine-got-to-do-with-it-podcast.

2020, VALIDATE Fellow, Dr Rachel Tanner was filmed in the lab for the YouTube 'Life in a Day' movie directed by Ridley Scott and Kevin McDonald which premiered at Sundance Film Festival (her submission was featured as part of the press release).

11 Dec 2020, VALIDATE Director Prof Helen McShane interviewed on Sky News re vaccine hesitancy studies (relating to COVID): https://twitter.com/SkyNews/status/1337320456211361794

In 2020 VALIDATE Fellow Dr Rachel Tanner took part in 'I'm a Scientist, Stay at Home!' to help school pupils stay connected with STEM during the lockdown. Rachel was invited as a panellist to talk about her work and experience as a female scientist for the 2020 Women of the Future Awards and the 2021 Oxford Women in Engineering, Science and Technology (OxWEST) Annual Symposium.
Year(s) Of Engagement Activity 2018,2020
 
Description VALIDATE website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact On 28 July 2017 we launched the VALIDATE Network website www.validate-network.org. The website publicises our network, our members (including a searchable members' directory to facilitate new collaborations), our funding opportunities, events, our mentoring scheme, projects and grants we have funded, seminars and workshops provided, external funding and training/job opportunities relevant to our members, and a weekly round-up of new grant calls/jobs/training/events and news. According to Google Analytics, to date the website has been viewed by 149k users from 215 countries/territories, with around 4,000 users per month in 2023.

Our aim is to make our website a central 'go to' hub for all relevant information for researchers working in our field (from academia, industry, government and non-profits), and for it to act as a hub of reliable information about vaccine research and our focus diseases for the general public and other interested parties. In 2018 we had 3 LMIC ECR members feedback outputs from our website information - one saw the Newton Travel Award listed in our external grants list and applied for and was awarded a grant; a second ECR member (from Uganda) applied for the "Data Management for Early Career Researchers" workshop in Nairobi that we listed in our training opportunities and was given a place and has now attended this course; while a 3rd ECR member from Cameroon applied for the Oxford University summer internship 2019 programme, having seen it advertised on the VALIDATE website. A further UK PhD (medical) student, when asked about any impact on career/research commented 'Easy notification of funding and training opportunities via validate website'.

In 2020 we also added a VALIDATE Microsoft Teams 'Hub' where members can more easily contact each other via several channels (including an ECR channel for ECR peer networking and support, and a collaborators channel for people looking for collaborators), and can access shared documents (including seminar recordings, Annual Meeting presentation slides, shared standardised SOPs and protocols).
Year(s) Of Engagement Activity 2017,2018,2019,2020,2021,2022,2023
URL http://www.validate-network.org
 
Description VALIDATE work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact In February 2019 a Six Form student from a school in Surrey attended two days' work experience/shadowing at the Jenner Institute, visiting the laboratories and the clinical trial clinics and talking to staff about their research and careers in science, after contacting VALIDATE with a request to visit. This hopefully helped Zack with choosing his degree and future career plans.
Year(s) Of Engagement Activity 2017,2019