Title: NIHR Global Health Research Unit on Mucosal Pathogens (MPRU), University College London
Funder: Department of Health and Social Care

Abstract: a) UCL STRATEGY: MPRU embodies UCL’s Global Health Grand Challenge, bringing together internationally leading investigators to find solutions to global health problems & policy change. UCL 2034 principal themes include academic leadership & excellence; cross-disciplinarity; impact through innovative international partnerships. Excellence in infection GHR has been targeted through Africa Health Research Institute (AHRI) & partnership with leading LMIC centres. b) UCL GHR INFRASTRUCTURE: Infection & Immunity Division houses world-class investigators with complementary expertise in pathogen biology (closely AHRI affiliated). Faculty of Population Health Sciences includes Institutes of Child Health (Vaccinology Research Group) & Global Health. Farr Health Informatics Research Institute uses big data to address population-sized questions (UCL, LSHTM, PHE). MRC Clinical Trials Unit is at forefront of innovative clinical trials in LMICs. UCL will provide MPRU with newly refurbished offices & labs; will commit Director/Co-Directors time; & additional administrative support c) EXISTING PARTNERSHIPS: MPRU will add value by bringing together multi-institutional expertise (>25 senior investigators), capitalising on LMIC partnerships with differing epidemiological, climactic & environmental environments (Malawi, Kenya, Mali, Gambia, South Africa); & UK partners from Edinburgh; Southampton, Oxford, Liverpool & UCL. Links with NIHR HPRU in Immunisation will bring strengths in modelling, programmatic evaluation & national policy making. Partnership with UK Public Health Rapid Support Team will bring internationally leading epidemiological, modelling & social science expertise in epidemic responsiveness. MRC, WT, Gates Foundation funded programmes will be leveraged to achieve greatest impact in LMICs, strengthening research capacity by investing in people (PhD studentships & post-doctoral funding). d) RESEARCH PROGRAMME (see figures) BACKGROUND: Mucosal pathogens e.g. S. pneumoniae, N. meningitidis & Group B Streptococcus (GBS) account for >2M deaths globally & substantial disability, predominately in LMICs. Vaccines have reduced under-5 mortality but more effective control of carriage & transmission is crucial to maintaining long-term effectiveness & limiting AMR emergence Knowledge from resource-rich settings often cannot be extrapolated to LMICs where populations are under complex pressures from co-infections (e.g. HIV, helminths & malaria); malnutrition, climate & environment. We have an incomplete understanding of how to measure herd protection & long term vaccine-induced immunity in LMICs, where carriage patterns differ from high-income countries. There is increasing realisation that conventional antibody-based correlates of protection have limited utility. There is uncertainty about how to effectively dose & schedule new/existing vaccines; & how other non-vaccine interventions e.g. commensal colonisation & population-based antimicrobial prophylaxis will impact on disease STRATEGY: Research will be led by UK-LMIC investigator partnerships, primarily in Africa, focusing in this first phase, on high disease burden URT pathogens & the neonatal pathogen GBS. MPRU team brings together the disciplines required for high quality, innovative, relevant research using cutting-edge laboratory facilities in UK & LMIC centres OVERALL AIM: To address the limitations in long-term effectiveness of current vaccines in LMICs, MPRU aims to reduce mucosal pathogen carriage & transmission to achieve herd protection against life-threatening endemic/ epidemic disease OBJECTIVES: 1) Define mucosal pathogen carriage & transmission biology in LMICs; evaluate impact of bacterial/viral co-infections; derive mathematical models predictive of protection (short-medium term) 2) Generate novel approaches to protective immunity assessment that overcome limitations of antibody correlates (short-medium term) 3) Optimise existing vaccine dosing & scheduling; test new vaccines & commensal colonisation approaches to interrupt pathogen carriage (medium-long term) 4) Strengthen GHR partnerships between UK & LMIC investigators to deliver disease reductions, epidemic response; two-way dialogue with public/ policymakers (medium-long term) PROJECTS Led by UK/ LMIC interdisciplinary partnerships, examples include: i. Assessing vaccine herd protection in LMICs (Yr 1-3) Can routinely collected disease data, carriage ascertainment & mathematical modelling be used to assess indirect pneumococcal vaccine effects? Ascertaining indirect vaccine effects is crucial for programmatic evaluation. Using ongoing pneumococcal carriage surveys, we will iteratively refine mathematical models with health record data /demographic surveillance to optimise herd protection Outputs: Estimation of vaccine effectiveness & assessment of programmatic schedule changes. ii. Immune correlates of pneumococcal carriage (Yr 1-3) Where there are high rates of multiple serotype carriage, what are the immune correlates of pneumococcal carriage acquisition? Preventing pneumococcal carriage acquisition/ onward transmission is key to herd immunity & long-term protection. Ongoing human challenge (Liverpool) & pneumococcal carriage studies (LMICs) will be used to generate novel correlates of protection against acquisition (antibody, transcriptomic) & determine what constitutes long term protection. DNA microarray serotyping & bacterial whole genome sequencing (WGS) will be used to relate multiple serotype carriage/bacterial population structure to immune profiles Outputs: Predictive mathematical models, vaccine scheduling evaluation, vaccine clinical trials & vaccine escape assessment iii. Impact of viral/ bacterial co-infections on pneumococcal & meningococcal carriage (Yr 2-4) How does viral co-infection & upper respiratory tract microbiome influence the onset of pneumococcal & meningococcal carriage? Mucosal pathogens inhabit complex microbiological niches influenced by host & environmental factors. Impact of viral co-infection & URT microbiome on pneumococcal & meningococcal carriage/ transmission in high burden populations is poorly defined. We will assess relationship between mucosal pathogen carriage, seasonality, viral co-infection & upper respiratory tract microbiome Outputs: Mathematical models predicting how changes in viral/ bacterial co-infections influence pneumococcal/ meningococcal carriage dynamics, emerging epidemics & N. lactamica challenge studies iv. Intranasal challenge with N. lactamica to reduce meningococcal carriage (Yr 2-4) Can N. lactamica be used to prevent or interrupt meningococcal carriage? Studies in UK students have shown intranasal inoculation of N.lactamica reduces N.meningitidis acquisition. As this offers a rapid method to control meningococcal carriage during outbreaks, we will seek to reproduce these findings in Africa. Outputs: Development of modified live N. lactamica strains & preliminary studies with lyophilised preparations, leading to modified N. meningitidis whole cell & sub-component vaccines v. Molecular epidemiology of GBS carriage & immune correlates (Yr 1-3) What is the population structure of GBS carriage & what are the immune correlates? GBS causes stillbirth, neonatal death & disability in LMICs but is under-researched. Vaccine trials with disease endpoints require very large sample sizes. Carriage has thus been proposed as an endpoint but GBS population structure & multiple serotype carriage have not been defined. These will be assessed by novel DNA microarray, supported by WGS. Immune correlates of carriage will then be validated across populations using serological markers, exploiting existing strain /serum collections from Africa & prospectively sampled mother-infant pairs Output: Predictive mathematical models, evaluation of GBS vaccine impact on carriage & assessment of vaccine escape vi. Impact of GBS conjugate vaccine on carriage (Yr 3-4) What is the impact of GBS conjugate vaccine on maternal & neonatal GBS carriage? We have led the first trials of GBS conjugate vaccine in Africa. How they influence maternal & neonatal carriage is unknown. We will assess impact of maternal vaccination on maternal & neonatal GBS carriage, alongside vaccine-induced immunity & assess long-term protection. Outputs: vaccine trials assessing carriage endpoints; mathematical models evaluating vaccine scheduling, relative importance of carriage reduction & transplacental antibody transfer e) COMMISSIONED RESEARCH (Specific project tools): 1) Microarrays for S. pneumoniae detect multiple serotype carriage have been adopted in vaccine impact studies worldwide. BµG@S bioscience will validate a GBS microarray for molecular serotyping (£100k; project v). 2) Generation & preliminary experimental human challenge studies of lyophilised N. lactamica in Southampton (£100k; project iv). f) RESPONSIVE CAPACITY: 10% budget for response capacity will be reserved within each theme (partnership with the UK Public Health Rapid Support Team). g) ENGAGEMENT STRATEGY (Yr 1-4): MPRU investigators have considerable engagement experience, encouraging two-way dialogue & public input into our strategy. The Strategy Group with HPRU in Immunisation input will support national/ international policymaking through mathematical model development & research briefs. Through MPRU partnerships (incl. MRF & AMP), public engagement will be through community engagement groups, patient advocates, a website, newsletters, radio & social media; events will bring together policymakers, interest groups, schools & industry. h) SUSTAINABILITY: MPRU will focus on strengthening existing government & research centre infrastructure in LMICs, & building LMIC investigator capacity through training & mentorship. Using MPRU outputs we will leverage further funding for surveillance & interventional studies.

Lay abstract: Mucosal pathogens causing pneumonia, meningitis & sepsis in young children account for >2 million deaths & substantial disability annually, with the greatest burden in LMICs. Vaccines have led to reductions in childhood deaths but if we are to achieve further disease reductions & make sure that these vaccines work in the long-term, more effective control carriage & transmission of mucosal pathogens is crucial. Knowledge from resource-rich countries often cannot be used to determine best approach in LMICs where populations are under complex pressures from co-infections (HIV & malaria), malnutrition, climate & environment. Mucosal Pathogens Research Unit (MPRU) at UCL is a world-leading UK (UCL, LSHTM, Edinburgh, Oxford, Liverpool, Southampton) & LMIC (Malawi, Kenya, Mali, Gambia, South Africa) research partnership bringing together >25 senior investigators with very strong ongoing research portfolios. Linking many of the best in the field, MPRU will take a transformative approach to the prevention of life-threatening disease caused by mucosal pathogens that could not be achieved by individual investigators/ institutions. Capabilities in disease monitoring, modelling, vaccinology, trial design, epidemic responsiveness & social science will be enhanced through strong links with the NIHR Health protection Unit (HPRU) in Immunisation & the UK Public Health Rapid Support Team. There will be partnerships with the new MRC Networks in Vaccinology. Led by UK & LMIC investigators, the overall aim of the MPRU is to optimise the control of mucosal pathogens through prevention of person to person spread, particularly in Africa, where population growth, urbanisation, climate change, poverty & periodic epidemics amplify disease burden & pressure on health systems. MPRU will exploit cutting-edge research teams & laboratory facilities in UK & LMICs to address the following research objectives, that will translate into large-scale interventions: 1) IMPROVED DISEASE INTELLIGENCE: targeted surveillance of mucosal pathogens incorporating new molecular epidemiology, mathematical modelling & diagnostic tools to support vaccine evaluation, uptake & safety monitoring. 2) NEW MEASURES OF IMMUNITY: novel approaches to measuring protective immunity to determine how best to use new & existing vaccines; & determine how other non-vaccine interventions, such as harmless “commensal bacteria” will impact on disease. 3) TESTING INTERVENTIONS: as a prelude to large-scale trials, develop novel trial designs & feasibility studies of vaccine & other interventions. 4) PUBLIC ENGAGEMENT: encourage a two-way dialogue with public & policymaker input into our thinking, ensuring that MPRU research is grounded in experience & needs of the public/policymakers. In collaboration with the HPRU in Immunisation, MPRU will support national/international policymaking through model development & research briefs. Public engagement will use websites, newsletters & social media; events involving policymakers, interest groups, schools & industry. MPRU will thus lead to improvements in LMIC human health & to reductions in disability through prevention of pneumonia, meningitis, & sepsis in young children. We will focus on strengthening government/research centre capability in LMICs, building LMIC investigator capacity through research training (PhD studentships, modelling short courses, post-doctoral funding) & mentorship. We will use MPRU outputs to leverage further funding for surveillance & interventions.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);3.4 VACCINES
Health categories: INFECTION