MRF Conference 2019

Mike Davies - Meningitis Research Foundation Member

Mike became ill with meningococcal meningitis and septicaemia at Christmas 2017.

He was wrapping presents on the afternoon of Christmas Eve when he began to get colder and colder, getting into bed didn’t help.

Mike says: “I looked like a ghost with blue lips. My family insisted on the trip to The Royal Sussex County hospital where the fantastic NHS clicked in. On Christmas Day my family were told I was unlikely to survive, but after I spent ten weeks in Intensive Care I pulled through.

"During this time I began to look forward (yes, looking forward) to having my hands and feet amputated. Legs went one week - hands the next, and the hands took seven hours alone. Then I had weeks of recovery and wound healing. For a long time I had to have my blood detoxified three times a week at dialysis in hospital as my kidneys were so badly affected, but I could have died. One day I flatly refused to get out of bed to attend hospital for the necessary and life-saving dialysis I was having three days a week.

"The greatest thing to happen to me then was to be offered counselling through the hospital renal department. In my darkest moments I would think, how would I ever shower, toilet, eat breakfast, drink tea, go shopping, walk places, catch a bus? But overcoming each of these challenges was another little victory. "

I feel lucky to have had my meningitis journey and support in a country where good aftercare is available. I learned to accept my situation and be at peace with it. I feel in quite a positive place in my mind about the challenges I still have to overcome. Support from other people has been key. I am a lucky man. There needs to be better recognition of the after effects, that’s why I’m helping to raise awareness of the serious health outcomes, and how good aftercare can help."

Claire Wright, Meningitis Research Foundation

Claire Wright is Evidence and Policy Manager for Prevention at Meningitis Research Foundation.

Her responsibilities include maintaining and developing a range of information resources for the public and health professionals. These include paper and electronic publications, including presentation materials, fact sheets, statistics, articles for medical/nursing media, and web based information. She also liaises with health professionals on behalf of MRF members who wish to ask specific health related questions.

Claire has a degree in Biology from the University of Sheffield. She has published research on the lifelong costs of a severe case of meningitis and septicaemia in the UK, France and Spain.

More recently Claire has been working on collating and comparing global estimates on the burden of meningitis and neonatal sepsis globally and has worked with colleagues to bring a selection of the existing data together in an online visualisation tool, the Meningitis Progress Tracker.

Abstract

WHO recently launched the Defeating Meningitis by 2030 initiative. The scope includes organisms considered to be the leading causes of acute bacterial meningitis, and for which vaccines are either available or likely to become available in the next few years.

As a result of limitations in country-specific health data in many low and middle income countries, there is a heavy reliance on global health estimates to track progress in global health initiatives. We aimed to define the current global burden of meningitis caused by Neisseria meningitidis (Nm), Streptococcus pneumoniae (Spn), Haemophilus influenzae type b (Hib) using two major global modelling efforts so that progress can be monitored over time. Meningitis estimates from the Institute for Health Metrics and Evaluation GBD2017 and Maternal Child Epidemiology Estimation (MCEE)/ Johns Hopkins School of Public Health (JHSPH) Child Mortality estimates: syndromic and meningitis pathogen models were compared.

The comparison demonstrated that:

• There were considerable differences in under 5 meningitis/encephalitis mortality estimates between the different modelling efforts, with GBD 2017 and MCEE/JHSPS estimating around 190,000 and 142,000 deaths globally in 2015 respectively.
• GBD 2017 estimated higher global incidence of pathogen specific meningitis in 1-59 month olds in 2015 than MCEE/JHSPH. GBD2017 estimated an incidence of 34/100,000, 31/100,000 and 40/100,000 for meningococcal, Hib and pneumococcal meningitis respectively compared to MCEE/JHSPH’s estimate of 5/100,000 and 12/100,000 for Hib meningitis and pneumococcal meningitis respectively.
• Global mortality and proportions of meningitis deaths attributable to Spn and Hib in children aged 1-59 months also differed substantially between GBD2017 and MCEE/JHU estimates
• A high proportion of global child deaths (over 90% in one model) are based on verbal autopsy data leading to considerable uncertainty in these estimates Lack of alignment in the estimates has led to the recommendation that to measure progress towards the defeating meningitis by 2030 initiative, multiple estimates and surveillance sources should be tracked in parallel over time.

Meningitis Research Foundation have created the Meningitis Progress Tracker to allow estimates of global cases and deaths from meningitis to be tracked from multiple sources. The tracker has been aligned to the five pillars of the roadmap: Prevention, Surveillance, Diagnosis and Treatment, Support and Aftercare, and Advocacy. Users can interact with the site to create the visualisations most relevant to them and their work. Visualisations can be created which will show country, regional and globally specific estimates and trends over time.

Access the tracker

Presentation

Dr Maria Knoll, Johns Hopkins Bloomberg School of Public Health

Dr Maria Deloria Knoll is the Associate Director of Science at the International Vaccine Access Center (IVAC) and a Senior Scientist in the Department of International Health at the Johns Hopkins Bloomberg School of Public Health.

Her work focuses on research and synthesis of evidence that support the needs of vaccine policy decision making. Example projects include: estimating the global mortality and morbidity of pneumococcal, Hib and meningococcal disease; measuring the impact of pneumococcal conjugate vaccines (PCV) on pneumococcal disease, carriage, immunogenicity and serotype distribution; evaluating the evidence to inform decision making regarding PCV dosing schedule and product choice; estimating the etiology of severe pneumonia; evaluating novel diagnostic methods to improve sensitivity and specificity to identify the causes of pneumonia.

Abstract

Historically Hib and pneumococcus were the dominant pathogens responsible for endemic meningitis globally. Introduction of Hib and pneumococcal conjugate vaccines (PCV) have reduced meningitis cases and deaths due to these pathogens over the last decade in children <5 years of age. The recent introduction of meningococcal A conjugate vaccine in the African meningitis belt has virtually eliminated epidemic and endemic meningococcal A disease in that region. Recently, meningococcal meningitis global disease burden (cases and deaths) has been estimated for children 1-59 months of age from 2000-2015 using similar methods as for Hib and pneumococcal meningitis (Wahl B, et. al, Lancet 2018). Briefly, WHO and Maternal and Child Epidemiology Estimation (MCEE) meningitis mortality (Liu L, et. al, Lancet 2016) was apportioned using pathogen distribution in cases and pathogen-specific case fatality ratios. Estimates accounted for HIV prevalence, access to care, vaccine use and proportion vaccine-type serotype/serogroup. In 2015, for the first time, global endemic meningitis due to Hib (7,200 deaths and 31,400 cases) was estimated to be lower than for meningococcus (11,600 deaths and 38,400 cases). Pneumococcus was still the dominant pathogen causing endemic meningitis (37,900 deaths and 83,900 cases) but is continuing to fall as more children <5 years in high mortality countries have received PCV. On average over the 15-year time period, meningitis outbreaks (all causes combined) in the Africa meningitis belt region caused as many deaths as the global total estimated for endemic meningococcus meningitis. Global endemic meningococcal meningitis deaths fell 32.3% from 2010 to 2015 following introduction of MenA conjugate vaccine in the meningitis belt compared to 15.6% the previous 5 years (2005 to 2010). Hib, pneumococcus and meningococcus combined accounted for an estimated 51% of endemic meningitis deaths globally in 2015, with the remaining due to epidemic disease (14%, primarily due to non-A meningococcus and pneumococcus) and other (largely unknown) bacterial etiology (35%; excluding TB). The year 2015 was the first time other (unknown) bacterial etiology of endemic meningitis deaths exceeded that estimated for any of these three bacterial pathogens, making unknown etiology now the single largest group of meningitis deaths.

Dr Anna Seale, London School of Hygiene and Tropical Medicine

Dr Anna Seale trained in paediatrics, then epidemiology and public health.

Her research focus is on infectious diseases, particularly around birth, and on Group B Streptococcus (GBS).

She has led large epidemiological studies to determine the clinical and molecular epidemiology of GBS in East Africa, and estimated the burden of disease worldwide in pregnant women, children and stillbirths.

Anna currently holds a Wellcome Trust Career Development Fellowship, and through this is investigating the aetiology of maternal infection and its association with stillbirth in Ethiopia (Haramaya University) and Kenya (KEMRI-Wellcome Trust Research Programme). Her work in Ethiopia is based at a new Bill & Melinda Gates funded Child Health and Mortality Prevention Surveillance site, which she initiated for the London School of Hygiene & Tropical Medicine in 2017, in partnership with Haramaya University in Eastern Ethiopia. Based in London at present, she leads the research programme of the UK Public Health Rapid Support Team (UK-PHRST) as Deputy Director for Research.

This is a collaboration between LSHTM and Public Health England to support response to infectious disease outbreaks worldwide.

Abstract

Infections causing sepsis, meningitis, or pneumonia contribute directly to around 0·6 million neonatal deaths worldwide annually, and indirectly to many more through pathways leading to preterm birth and neonatal encephalopathy.

Despite this knowledge, understanding of the causes of neonatal infection, particularly in resourcepoor settings, is limited. Most studies of neonatal sepsis in sub-Saharan Africa have been facility based, often in referral hospitals where microbiological investigations are done. As such, data are biased towards the inclusion of neonates whose mothers’ deliver in hospital, or those who survive long enough to be brought and admitted to hospital. As microbiological investigations are often limited, findings can also be biased away from more fastidious organisms.

Treatment in many resource-poor settings in sub-Saharan Africa relies on sensitive but non-specific clinical diagnoses of possible serious bacterial infection, made by front-line health-care workers and defined according to set criteria. Of the almost 7 million neonates needing treatment worldwide each year based on this diagnosis, most are not tested for specific infectious causes and many are likely to have non-infectious conditions. Pragmatic clinical trials to improve access to treatment have reflected this reality, but in doing so have not investigated or confirmed neonatal sepsis cases within their participants, raising uncertainties about trial findings.

Improving the data on neonatal sepsis from sub-Saharan Africa is critical, and in doing this, we need to consider the neonates that, at present, even the most robust observational study cannot identify as they die at home. These are the neonates that as clinicians, we “don’t see”. Whilst this is challenging, new approaches, including investigations after death, and maternal vaccine probe studies, offer important new opportunities to better understand neonatal sepsis.

Presentation

Dr Marie-Pierre Preziosi, WHO

Marie-Pierre Preziosi MD PhD, is leading on Flagships at the Initiative for Vaccine Research, World Health Organization (WHO), a team currently concentrating on meningococcal, Ebola and malaria vaccines, as well as on the R&D Blueprint for action to prevent epidemics.

From 2012-2014, she was director of the Meningitis Vaccine Project, a partnership between WHO and PATH, established in 2001. The project mission was to eliminate epidemic meningitis as a public health problem in sub-Saharan Africa through the development, testing, introduction and widespread use of meningococcal conjugate vaccines.

A project member since 2003, Dr Preziosi previously served as the director of clinical development. While leading the strategy and implementation of the clinical research, she helped foster strong relationships between the partner organizations and contributed technical guidance to meningococcal vaccine introduction activities and research to define evidence-based policy for optimal vaccine use.

Prior to joining MVP, she was a visiting assistant professor at the Rollins School of Public Health at Emory University in Atlanta, where she conducted research on pertussis vaccination. As an epidemiologist at the Institute for Research and Development, she spent several years in Senegal conducting pertussis vaccine trials.

Her interest in vaccines started with Hib vaccine studies at Pasteur Merieux. Marie-Pierre Preziosi earned her medical degree from Lyon University and her PhD in epidemiology from Bordeaux University (France). She trained in tropical medicine at the Institute of Tropical Medicine in Antwerp (Belgium) and in field epidemiology at the Centers for Disease Control and Prevention in Atlanta (USA).

Abstract

In 2017, representatives from governments, public health organizations, academia, the private sector and civil society called for a global vision to defeat meningitis. Representatives from all countries of the African meningitis belt amplified this call, highlighting the need for equitable and sustainable access to meningitis vaccines. WHO took up the call to action and, together with its global partners and experts involved in meningitis prevention and control, developed a roadmap to defeat meningitis by 2030. Broad public and expert consultations took place through 2019.

This first global roadmap on meningitis sets a path to tackle the main causes of acute bacterial meningitis (meningococcus, pneumococcus, Haemophilus influenzae and group B streptococcus). The three visionary goals are to (i) eliminate bacterial meningitis epidemics, (ii) reduce cases and deaths from vaccine-preventable bacterial meningitis and (iii) reduce disability and improve quality of life after meningitis due to any cause. To achieve these, strategic goals, key activities and milestones are set out in five interconnected pillars: Prevention and epidemic control, Diagnosis and treatment, Disease surveillance, Support and care for people affected by meningitis, Advocacy and engagement. For prevention and epidemic control, the drive for action is expanding coverage of existing vaccines, development of new vaccines, improved prevention strategies and response to epidemics. For diagnosis and treatment, the focused is on the rapid confirmation of meningitis and optimal care. Improved global surveillance based on effective national surveillance systems is needed to guide meningitis prevention and control measures, document the impact of vaccines and improve estimation of disease burden including aftereffects. For care and support of those affected by meningitis, the focus is on early recognition and improved management of after-effects, on availability of support and access to care. For advocacy and engagement, the drive is to ensure that the roadmap is integrated into country plans, that there is high population awareness of meningitis and its impact, of the right to meningitis prevention and care, with increased demand for vaccines and after-care services.

In September 2019, over 110 representatives, from ministries of health, government agencies, pharmaceutical companies, non-governmental and civil society organizations, academia, funding agencies, UNICEF and WHO, met to finalize the shared strategy. Participants, from 29 countries and all regions of the world, called for urgent global action against meningitis, emphasised the timeliness of setting a global agenda and pledged their commitment to the success of the roadmap. In October 2019, the WHO Strategic Advisory Group of Experts on Immunization confirmed their support to the approach and that the meningitis strategy will transform their recommendations into reality.

The meningitis roadmap is an essential component of achieving Universal Health Coverage and a powerful lever, integrated with other initiatives, to drive progress to strengthen Primary Health Care, immunization programmes, antimicrobial resistance; improve control of infectious diseases, global health security and access to disability support. Member States voiced their intent to submit a resolution on meningitis to the World Health Assembly for endorsement by its 194 member states. Regional Implementation Frameworks will translate the strategy into concrete steps.

Presentation

Dr Marc LaForce, Serum Institute of India

Dr Marc LaForce has served as Director of Technical Services at the Serum Institute of India in Pune since 2012.

Between 2001 and 2012, Marc directed the Meningitis Vaccine Project, a Gates Foundation funded partnership between PATH, WHO and the Serum Institute of India which led to the development and introduction of an affordable Group A meningococcal conjugate vaccine in Sub-Saharan Africa.

From 1994 to 2001, he chaired the Steering Committee on Epidemiology and Field Research for the World Health Organization’s (WHO) vaccine cluster, and from 1998 to 2001, served as President of the US Armed Forces Epidemiological Board.

Marc completed his internal medicine and infectious disease training on the Harvard Service at Boston City Hospital. He has since held research, clinical and senior administrative positions at the University of Colorado and the University of Rochester Schools of Medicine. He has also served on immunisation advisory committees for the US Centers for Disease Control and Prevention (CDC) and the American College of Physicians.

Abstract

The public health impact that has followed the introduction of the Men A conjugate vaccine in SubSaharan Africa continues to be robust. During the last two years no confirmed case of Group A meningitidis meningitis has been reported from meningitis belt countries. African meningitis surveillance data over the last 10 years have shown a major decrease in “suspected meningitis” cases and bacteriologic studies have clearly shown the potential for Group C, W and X meningococci to cause epidemics.

Suspected cases of meningitis and pathogens identified since the introduction of the Men A conjugate vaccine (15 meningitis belt countries; WHO Meningitis Weekly Bulletin)

 

 *Not confirmed by PCR

To meet the challenge of nonA meningococcal disease, a pentavalent meningococcal (ACYWX) vaccine has been developed and is now in Phase 3 clinical trials in India and Africa. Results of a Phase 2 study conducted at the Center for Vaccine Development in Bamako demonstrated that the vaccine is safe when given to 12-23 month olds and that high titers of bactericidal antibodies against all 5 serogroups are detected one month after inoculation. There was no enhancement in antibody response when an aluminum phosphate adjuvant was added.

Phase 3 studies in 2-29 year olds have commenced in The Gambia and Mali to test the safety and immunogenicity of the ACYWX conjugate vaccine when compared to a licensed quadrivalent (ACYW) meningococcal conjugate vaccine. A Phase 3 study in adults will begin later this year at 13 Indian sites where the safety and immunogenicity of the ACYWX conjugate vaccine will be compared to a licensed polyvalent meningococcal vaccine. Funds are currently being solicited to support an infant study to support an EPI indication.

Three Africa-specific cost effectiveness studies on the use of polyvalent meningococcal conjugate vaccines have been published. All three studies concluded that the expanded use of polyvalent meningococcal conjugate vaccines in the EPI as well as in reactive or preventive campaigns would be cost effective. Furthermore, if a new polyvalent meningococcal conjugate vaccine induces herd protection against all vaccine serogroups there is the real possibility that epidemic meningococcal disease could be eliminated in Africa.

Presentation

Dr Mark Alderson, PATH

Dr Mark Alderson is the Bacterial Vaccine Initiative Leader with PATH’s Center for Vaccine Innovation and Access, playing a lead role in the Pneumococcal Vaccine Project (PVP), Group B Streptococcal (GBS) Vaccine Project and Meningococcal Vaccine Project, Polyvalent (MVPP).

These projects seek to accelerate the development and licensure of promising pneumococcal, GBS and meningococcal vaccines and ensure their availability and use in developing countries.

Dr. Alderson has more than 30 years of experience in medical research, biotechnology, pharmaceuticals and vaccine development. He joined PATH in August, 2006, serving initially as PVP Scientific Director until his appointment as PVP Director in July, 2007. He was appointed MVPP director in 2012 and GBS Vaccine Project Director in 2016.

Prior to joining PATH, Dr. Alderson was Director of Immunology at GlaxoSmithKline Biologicals, Seattle, where he led preclinical work on synthetic adjuvants for a variety of vaccine targets.

Prior to GSK, he was Senior Director of Immunology at Corixa Corporation where he was responsible for the preclinical discovery and evaluation of adjuvants and vaccines for tuberculosis, Chlamydia and HSV. Dr. Alderson has extensive experience in vaccine development and has published over 80 manuscripts in peer reviewed journals. He served as an Affiliate Associate Professor, Department of Pathobiology at the University of Washington from 2002 until 2006.

Dr. Alderson earned his PhD in immunology at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia and his MBA at Seattle University.

Abstract

Pneumococcal disease remains a major cause of morbidity and mortality in young children, particularly in low- and middle-income countries (LMICs). Vaccines are a critical strategy for protecting children from pneumococcal disease and licensed pneumococcal conjugate vaccines (PCVs) are having a significant impact on reducing invasive pneumococcal disease and pneumonia throughout the world. Currently available PCVs do not, however, cover all pneumococcal serotypes and are complicated and relatively expensive to manufacture, driving prices up. New PCV development is focused on either higher valency or more inherent affordability for LMICs. One of the latter vaccines is Serum Institute of India Pvt. Ltd.’s PCV-10 (PNEUMOSIL®). A Phase 3 trial with SIIPL-PCV10 was recently completed in The Gambia and the data demonstrated lot-to-lot consistency, immunological non-inferiority compared to the licensed PCV10 Synflorix®, and non-interference with co-administered Expanded Program on Immunization vaccines. Lower cost PCVs, like PNEUMOSIL®, manufactured by vaccine manufacturers from emerging economies have the potential to play an important role for freeing up Gavi, the Vaccine Alliance and country funds for other public health priorities; enabling PCV access for middle-income countries ineligible for Gavi pricing; and sustaining access for countries transitioning from Gavi eligibility. Higher valency (15+ valent) PCVs are in various stages of development, some of which incorporate novel conjugation technologies designed to simplify manufacturing processes or reduce the phenomenon of carrier suppression seen with high-valency vaccines.

Since PCVs do not protect against all 90+ pneumococcal serotypes (even with added strain coverage) efforts are ongoing to develop common protein-based pneumococcal vaccines with the potential to broadly protect across the full spectrum of pneumococcal serotypes and avoid serotype replacement. Preclinical studies have demonstrated that protein vaccine candidates can protect against both nasopharyngeal carriage (NPC) and invasive disease—protection mediated by distinct immunological mechanisms (antibody and cell-mediated immunity). Protein vaccines, either alone or used in combination with PCVs, have advanced into Phase 1 and 2 clinical trials and have been demonstrated to be safe and immunogenic. The potential for these vaccines to impact NPC and otitis media is being explored in proof-of-concept studies in children. Demonstrating impact on invasive disease and pneumonia will, however, likely be required for product licensure. Despite their potential, pneumococcal protein vaccines face considerable challenges before they can become licensed and widely distributed.

Presentation

Dr Matt Coldiron, Epicentre, Médecins Sans Frontières

Dr Matt Coldiron has worked as a medical epidemiologist at Epicentre / Médecins Sans Frontières since 2011.

After completing an AB at Princeton, he received MD and MPH degrees from Emory University, and completed residency training in Internal Medicine at NYU-Bellevue Hospital in New York.

His major areas of interest are meningitis and malaria in the African Sahel, the treatment of snakebite in resource-limited settings, emerging infectious diseases, and conducting research in humanitarian emergencies.

Abstract

Antibiotic prophylaxis for contacts of cases of meningococcal meningitis is standard in high-income settings but has not been recommended during epidemics in sub-Saharan Africa. This is because there is little evidence for or against its use, and because of a desire to maintain focus on case management and implementing reactive vaccination campaigns.

During an epidemic in rural Niger in 2017, we performed a cluster-randomized trial of single-dose oral ciprofloxacin prophylaxis as an epidemic response. Limiting prophylaxis to household members of cases did not decrease overall attack rates during the epidemic, but village-wide distributions of ciprofloxacin reduced attack rates by 60%. A nested sub-study found no changes in antibiotic resistance patterns of enteric organisms before and after the trial.

Epidemic location and duration are unpredictable, so repeating the trial has not yet been possible. We have therefore explored the potential utility of antibiotic prophylaxis in modeling studies.

We used data from a 2015 outbreak in two districts of rural Niger where there was information about distribution of cases both among households and villages. During the epidemic, there was not significant clustering at household level, but there was at village-level. Up to one-third of cases could have been prevented using a village-wide prophylaxis strategy. Compared to reactive vaccination campaigns, reactive antibiotic prophylaxis is much more efficient. At current epidemic thresholds, over 4200 persons would need to be vaccinated to prevent one case, while only 1012 persons would need to receive a dose of ciprofloxacin to prevent one case.

Ongoing work is using case-based surveillance data from three countries which participated in the MenAfriNet project to explore different settings and possible differences between epidemic and nonepidemic periods.

Our work suggests that single-dose ciprofloxacin prophylaxis is more effective and efficient than reactive vaccination campaigns during meningococcal meningitis epidemics in the African meningitis belt.

Presentation

Abstract

WHO has recently recommended that either a 3+0 or 2+1 schedule should be used for vaccination against S. pneumoniae.

We will debate the following motion:

“This house believes that a 2+1 PCV schedule is preferable to a 3+0 PCV schedule in LMICs.”

Prof Adam Finn, University of Bristol, UK

Prof Adam Finn is Professor of Paediatrics at the University of Bristol, UK.

He studied Medical Sciences at Cambridge University and then moved to University of Oxford Medical School to complete his clinical degree in 1983. After qualifying he did training jobs in paediatrics in Sheffield, Bristol and Guy’s Hospital London before taking up a fellowship in Infectious Diseases at the Children’s Hospital of Philadelphia in 1987.

He completed his academic training as Lecturer in Immunology at the Institute of Child Health, Great Ormond St, London where he wrote his PhD.

In 1992, he took up a senior lecturer position at the University of Sheffield, UK. Over the following 9 years he established both clinical and laboratory research groups there, focussing on mucosal immune responses to paediatric conjugate vaccines and the pathogenesis of upper and lower respiratory tract pneumococcal infection. In 2001, he moved to Bristol where he is now Theme Leader for Infection & Immunity, University of Bristol and Clinical Research Lead - Children, Dermatology, Genetics, Haematology, Infectious Diseases and Microbiology, Reproductive Health and Childbirth for the NIHR Clinical Research Network: West of England. He is also a senior clinician in the paediatric immunology and infectious diseases clinical service for at Bristol Royal Hospital for Children and the South West region and heads the Bristol Children's Vaccine Centre. In addition, he became Chairman of the WHO European Technical Advisory Group of Experts (ETAGE) on Immunization in December 2011 and ex officio member of the WHO Strategic Advisory Group of Experts, Member of the UK Department of Health Joint Committee on Vaccination and Immunisation (JCVI) since October 2014. He was President of the European Society for Paediatric Infectious Diseases (ESPID) from 2015 to 2019.

His research interests are elucidation of the nature of naturally acquired mucosal immunity to pneumococcus, meningococcus and other respiratory bacteria, the determinants of bacterial transmission and vaccine indirect effects and development of tools to assess human immune responses to candidate vaccine antigens. He also leads and supports numerous clinical trials of drugs and medicines in children.

Presentations

Prof Andrew Pollard, University of Oxford

Prof Andy Pollard is Professor of Paediatric Infection and Immunity at the University of Oxford, Honorary Consultant Paediatrician at Oxford Children’s Hospital and Vice Master of St Cross College, Oxford.

He is the clinical lead for a number of national vaccine preventable infections, including Haemophilus influenzae type b (Hib), Streptococcus pneumoniae and Neisseria meningitidis, which are all major causes of childhood bacterial meningitis.

He obtained his medical degree at St Bartholomew’s Hospital Medical School, University of London in 1989 and trained in Paediatrics at Birmingham Children’s Hospital, UK, specialising in Paediatric Infectious Diseases at St Mary’s Hospital, London, UK and at British Columbia Children’s Hospital, Vancouver, Canada.

He obtained his PhD at St Mary’s Hospital, London, UK in 1999 studying immunity to Neisseria meningitidis in children and proceeded to work on anti-bacterial innate immune responses in children in Canada before returning to his current position at the University of Oxford, UK in 2001.

He chaired the UK’s NICE meningitis guidelines development group, the NICE topic expert group developing quality standards for management of meningitis and meningococcal septicaemia. His research includes the design, development and clinical evaluation of vaccines including those for meningococcal disease and enteric fever and leads studies using a human challenge model of (para)typhoid. He runs surveillance for invasive bacterial diseases and studies the impact of pneumococcal vaccines in children in Nepal and leads a project on burden and transmission of typhoid in Nepal, Bangladesh and Malawi, and co-leads typhoid vaccine impact studies at these sites. He has supervised 37 PhD students and his publications includes over 500 manuscripts and books on various topics in paediatrics and infectious diseases.

He chairs the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation and the European Medicines Agency scientific advisory group on vaccines and is a member of WHO’s SAGE. He received the Bill Marshall award of the European Society for Paediatric Infectious Disease (ESPID) in 2013 and the ESPID Distinguished Award for Education & Communication in 2015. He was elected to the Academy of Medical Sciences in 2016 and is an NIHR Senior Investigator. He made the first British ascent of Jaonli (6632m) in 1988 and Chamlang (7309m) and was the Deputy leader of the successful 1994 British Medical Everest Expedition.

Presentation

Dr Shamez Ladhani, Public Health England

Dr Shamez Ladhani is a paediatric infectious diseases consultant at St. George’s Hospital, senior lecturer at St. George’s University of London and consultant epidemiologist at Public Health England.

He is the clinical lead for a number of national vaccine preventable infections, including Haemophilus influenzae type b (Hib), Streptococcus pneumoniae and Neisseria meningitidis, which are all major causes of childhood bacterial meningitis.

He completed his medical training at Guy’s and St. Thomas’s Hospitals, London, and then worked in a children’s hospital in rural Kenya. Upon returning to London, he obtained his PhD in genetic epidemiology and vaccine failure in children and completed his specialist paediatric infectious diseases training at St. George’s and Great Ormond Street Hospitals, London.

He is currently responsible for the national evaluation of the meningococcal group B vaccine, Bexsero®, in the national infant immunisation programme and the meningococcal ACWY conjugate vaccination programme for teenagers. His main research interests include vaccine-preventable infectious diseases and he has published extensively in this fields.

Abstract

In September 2015, the United Kingdom became the first country to introduce the novel, multicomponent protein-based meningococcal B (MenB) vaccine, 4CMenB, into the national infant immunisation programme. Infants received the vaccine at 8 and 12 weeks of age with a booster on their first birthday. Within 10 months of the programme, there were rapid reductions in MenB disease in vaccine-eligible infants. Three years on, large declines in MenB disease continue in all cohorts eligible for the vaccine, with significant reductions observed in infants, one year-olds and two yearolds, with more than 60% of cases prevented during the first three years of the progamme. The vaccine is associated with an increased risk of fever when administered with other routine infant immunisations. This risk can be reduced significantly with administration of paracetamol prophylaxis, with the first dose given around the time of infant vaccination. So far, more than 5 million doses of 4CMenB have been administered, with no major safety concerns identified.

At the same time as the 4CMenB infant programme, the UK also implemented an emergency adolescent meningococcal ACWY conjugate vaccine programme for teenagers in order to combat a national increase in group W meningococcal (MenW) disease due to a hypervirulent strain belonging to clonal complex 11 since 2009. The vaccine was offered to 13-18 year-olds over three years, along with replacement of the MenC vaccine with the MenACWY conjugate vaccine for 13-14 year-olds in the routine immunisation programme and for new university entrants. Four years on, large and significant declines were observed for both menW and group Y meningococcal (MenY) disease across all age groups because of the direct and indirect (herd) protection offered by the emergency immunisation programme. So far, more than 3 million doses have been given, with no safety concerns identified; MenACWY conjugate vaccine failure is extremely rare.

The recent implementation of two meningococcal vaccines into the UK immunisation programme has played a major part in reducing the burden of meningococcal disease in the UK. Continued use of both vaccines in the targeted age groups will further reduce disease incidence in the coming years. Important questions that require additional study include host and pathogen characteristics of children who develop meningococcal disease despite appropriate vaccination and the protection offered by 4CMenB against other meningococcal serogroups.

Dr Kate Walker, University of Nottingham

Kate Walker is a Clinical Assistant Professor in Obstetrics and Gynaecology at the University of Nottingham, UK.

She divides her time equally between clinical work and research.

She completed her PhD in 2016 and during her PhD conducted a randomised controlled trial of induction of labour at 39 weeks versus expectant management for women over 35 years of age – the “35/39 trial”, published in the NEJM in 2016.

Her research work focuses on randomised controlled trials in obstetrics and neonatology.

She is the Clinical Chief Investigator for an NIHR HTA funded cluster randomised trial to determine the clinical and cost-effectiveness of testing for Group B Streptococcus (GBS) in late pregnancy (the “GBS3 trial”). This is the first RCT of routine GBS screening in the world.

Abstract

Group B Streptococcus is carried by one in four pregnant women in the gut and genital tract. GBS rarely causes symptoms in adults but around a third of colonised women will transmit the bacteria to her child. Of those babies who are colonised, the vast majority will remain asymptomatic but 3% will develop early-onset GBS (EOGBS) infection. EOGBS infection affects 1 per 1750 births in the UK (517 babies per year) and tends to be associated with pneumonia and sepsis. GBS is the most common proven cause of early-onset infection (accounting for 40% of all isolates in culture positive cases) in the UK. One study has estimated that in the UK EOGBS infection causes more than 10 neonatal deaths and around 30-54 cases of long-term disability every year. Mortality is around 5-10% but higher among preterm babies (23%).

Epidemiological studies have suggested that various factors present at the time of birth are associated with the baby having an increased risk of developing GBS disease, presenting as either an early or late onset infection. UK practice since 2003 has been to offer antibiotics to the mother in labour when the baby is at higher risk of developing the infection. Giving intravenous antibiotic prophylaxis (IAP) to mothers who are known to be colonised with GBS has been shown to substantially reduce the risk of babies developing EOGBS infection.

This approach is imperfect: some babies are missed and many women with risk factors do not carry GBS but receive antibiotics unnecessarily. Antibiotics may cause short term complications for the mother (anaphylaxis, medicalisation of labour) or baby, although data on the incidence of adverse events from IAP is limited.

The current strategy recommended by the RCOG and adopted locally across the UK involves identifying maternal risk factors for their baby developing GBS disease, and offering those ‘higher risk groups’ IAP.

Universal testing for GBS is undertaken in most developed countries and has been attributed to the reduction in EOGBS disease in those countries. In the UK the incidence of EOGBS disease is rising. The UK National Screening Committee (NSC) recommends “not to screen for maternal GBS carriage in the general population” due to the absence of randomised data on either its effectiveness or costeffectiveness.

The GBS3 trial is a two arm, cluster randomised trial to determine the clinical and cost-effectiveness of testing for Group B Streptococcus in late pregnancy in the UK. It will involve 320,000 women from up to 80 maternity units in England, Scotland and Wales. Recruitment will take 2 years and will start in spring 2020. The study is sponsored by the University of Nottingham and funded by the NIHR HTA programme.

The GBS3 trial will be the first randomised trial of routine GBS testing in late pregnancy ever done and will guide UK practice.

Dr Kirsty Le Doare, St George’s University of London and Mulago Hospital, Uganda

Kirsty Le Doare is a Reader in Paediatric Infection and Immunity at St George’s.

She was recently awarded a UKRI Future Leaders Fellowship for a project she is setting up in Uganda and the UK. She is working to set up a mother and baby study in Uganda, with the aim of understanding what it is that makes babies sick. Then she wants to understand whether there are things in the mothers’ immune systems that can be transferred, whether via blood or breast milk,that might stop babies getting those infections.

The idea is to investigate whether developing vaccines for women when they are pregnant, against Group B streptococcus and pertussis (whooping cough), could boost that natural immunity and result in babies that aren’t infected with these diseases any more.

Group B Streptococcus is the major cause of death and illness in babies under the age of 3 months and is usually passed from mother to baby at birth. Vaccinating the mother could prevent the disease as the mother would pass antibodies via the placenta to her infant.

She then spent a very long time developing the project. They received money from the Gates Foundation to set up a pilot and we’ve now received further funding from EDCTP to do part of the study. Now obviously the Fellowship money has come along to fund the setting up of the cohort.

Abstract

Despite over 50 years of research, there is still no vaccine against Group B Streptococcal disease (GBS) and GBS remains the leading cause of meningitis in neonates and early infancy.

Several vaccine manufacturers have progressed maternal vaccines against different targets as far as Phase II clinical trials. However, GBS disease incidence means that a classical phase III efficacy trial would be extremely large and therefore costly. Thus, it is widely accepted that developing serocorrelates of protection against the main GBS disease-causing serotypes might be a useful tool to progress a vaccine to licensure. Such a serocorrelate would be predicted in natural immunity studies, comparing antibodies in infants with GBS disease to healthy controls. It is important to consider that any antibodies measured in both GBS disease cases and healthy controls must have been generated following exposure of the pregnant (or pre-pregnancy) woman and passed to the infant via the placenta. Thus, the protective mechanism is predominantly from IgG, as this is the only immunoglobulin that crosses the placenta. This makes the protection conferred from a maternal GBS vaccine different to that of vaccines designed for the infant vaccine schedule, where immunity is conferred by both IgG and IgM. It is therefore likely that a serocorrelate would be based on quantitative IgG concentrations correlated to in vitro function. Several issues remain unresolved before such a serocorrelate can be finalised. Firstly, any seroepidemiology study will still be large, because of the need to prospectively collect cord blood from large numbers of women in anticipation of an infant going on to develop disease. Investigating whether maternal, cord and infant serum antibodies are comparable is critical to logistical and cost planning of such studies. Secondly, there remains a need to understand whether antibody-mediated protection is similar in countries with high burdens of malaria, HIV and syphilis in pregnancy. These factors, and potentially others such as maternal under-nutrition in pregnancy, are vital in understanding if protection via maternal vaccination will be effective in low and middle income countries. Finally, we need to explore whether antibodies generated following exposure to GBS via colonisation in the pregnant woman function in the same way as vaccine-induced antibodies. All these steps need to be explored as a matter of urgency if we are ever to see a maternal GBS vaccine licensed and available for those countries with the highest burden of disease.

Presentation

Dr Andrea Collins, Liverpool School of Tropical Medicine

Dr Andrea Collins graduated from Bristol University in 2002 and moved to the North-west in 2007.

She is now an NHS Respiratory consultant and Senior Clinical Lecturer in Respiratory Medicine in Liverpool. She was the Early Career Investigator Award Winner from the British Lung Foundation's British Thoracic Society Conference in London, 2014 for one of the studies in my PhD and my group was awarded the best research team/site of the year in the NWC Research and Innovation awards in 2019.

Her current research involves both patients and healthy volunteers and is currently focused mainly on our globally unique Experimental Human Pneumococcal Challenge (MRC, Pfizer and Unilever funded) Model, and research bronchoscopy techniques (MRC and industry partner projects).

Her clinical and research interests are in pneumonia, bronchiectasis and respiratory infection and vaccination.

Abstract

Pneumococcal carriage is the pre-requisite to pneumococcal disease, and pneumococcus is the commonest cause of pneumonia. Approximately 1 in 10 of us will have it in our noses right now. So…. Is carriage good or bad for you?

Can controlled exposure help us to test vaccines selecting the best ones to take forward to expensive later stage clinical studies?

Can controlled exposure to pneumococcus help us to understand transmission dynamics more?

The Experimental Human Pneumococcal Challenge model (EHPC) was set up in 2009 in Liverpool; we have now exposed our 1600th participant and started our 30th study and attracted over £7M in funding in the last 5 yrs alone. We have investigated normal healthy volunteers, at risk groups such as asthma, elderly, COPD and smokers), and various different pneumococcal serotypes including a GMO. Our current research investigates PCV-13’s lack of ‘coverage’ of serotype 3 and also direct pneumococcal shedding in asymptomatic adult carriers which was previously not thought to be important in transmission and therefore herd protection.

Prof Rob Read, University of Southampton

Prof Rob Read is Professor of Infectious Diseases at the University of Southampton, and Honorary Consultant Physician in Infectious Diseases at University Hospital Southampton.

An NIHR Senior Investigator, he is Director (2017-2022) of the NIHR Southampton Biomedical Research Centre (BRC), and leads the Microbial Science cross cutting theme of the BRC. Read has studied the mechanisms of bacterial colonisation of the upper respiratory tract, including the use of controlled human infection models of Neisseria lactamica and Bordetella pertussis colonisation in human volunteers.

Recent activity includes an MRC-funded programme to manufacture and utilise genetically modified strains of N.lactamica to conduct early phase studies of microbiome-modification of the nasopharynx.

Read has an international profile in Infectious Diseases research, translation and policy, which is reflected by his role as Chair of the European Society for Clinical Microbiology and Infectious Disease (ESCMID) Executive Council (2005-2012). The Infectious Disease Society of America nominated him to deliver the 2016 IDSA Max Finland Award Lecture, the first non-American to receive this honour. Translating research into policy, he has co-authored 4 pan-Meningitis and Septicaemia 2019 European Clinical Practice Guidelines including the European Respiratory Society (ERS) Lower Respiratory Tract Infection Guidelines (2010), the ERS Hospital Acquired Pneumonia Guidelines (2018) and the ESGIB/ESCMID Bacterial Meningitis Guidelines (2016).

Nationally, he has contributed to the NIHR research portfolio by chairing the national Infectious Disease and Microbiology Specialty Group for the NIHR Clinical Research Network (2010-2015). He was a founding member of the 2009 Department of Health (DoH) Influenza Clinical Infection Network (Flu-CIN), which coordinated a national research response to the 2009 Influenza pandemic. His experience in meningococcal, influenza and pneumococcal disease research, and clinical trials expertise have led to membership of the UK Joint Committee for Vaccination and Immunisation (JCVI) (since 2013), and expert advisory groups of the European Medicines Agency (2011-2016) and the Commission on Human Medicines (2008-2014).

Abstract

At a population level, carriage of Neisseria lactamica has an inverse relationship with meningococcal disease, suggesting that N.lactamica carriage is associated with natural protection. Intranasal inoculation of adult volunteers with Neisseria lactamica results in stable colonisation for at least 6 months in most colonised individuals. This event leads to an expansion of antigen-specific B cells together with a serological response to N.lactamica. We previously showed that induction of N.lactamica carriage in University students reduces acquisition of N.meningitidis over the course of the University term, and also displaces existing N.meningitidis carriage. Inoculation of N.lactamica does not induce serum bactericidal antibody responses against N.meningitidis but recent work has used B cell ELLISPOT to demonstrate expansion of peripheral blood B cells cross reactive with N.meningitidis. Genome sequencing reveals that during colonization of the human nasopharynx, the N.lactamica genome is very stable but adapts ad hominem mainly via the mechanism of phase variation. We have recently genetically modified N.lactamica to express the meningococcal antigen NadA, and shown that volunteers can be inoculated safely with this GMO. For future use of N.lactamica, either as an experimental tool, or as a potential `bacteria medicine`, lyophilisation provides a means to conveniently prepare and distribute inocula. We have shown that reconstituted lyophilised N.lactamica elicits colonisation kinetics that are equivalent to frozen stock. This will be an important step toward future studies in the field.

Dr Olivier Ronveaux, WHO

Dr Olivier Ronveaux, from Belgium, is a medical doctor specialized in Public Health and trained in field epidemiology (Epiet programme).

He joined WHO in 2001, initially in vaccine preventable diseases control and now as the meningitis focal person for the Health Emergency Programme.

Between 2005 and 2008, he was based in Bolivia, then in Burkina Faso from 2010 to 2013. His current work essentially consists of supporting sub Saharan countries in their fight against epidemic meningitis.

He is actively engaged in the building of the 2030 defeating meningitis global strategy.

Abstract

The next generation meningitis Rapid Diagnostic Tests (RDTs) should provide a diagnostic option for all facilities, including those lacking infrastructure for laboratory testing, to diagnose suspected meningitis cases and permit medical staff to rapidly initiate appropriate treatment. The global roadmap to defeat meningitis by 2030 includes in its strategic goals the development and usage of RDTs for meningitis diagnosis and surveillance, for three major purposes:

1. to impact the clinical management of patients with suspected meningitis at first contact with the patient. The provision of a result by a biomarker RDT that does not attribute meningitis symptoms to a bacterial etiology could prompt clinicians to assess the patient for other etiologies. While standard antibiotic treatment for meningitis may be initiated and continued until a causative pathogen is identified, the clinician can incorporate other treatment options as a result of the non-bacterial RDT result and broadened patient evaluation, which could substantially reduce disease morbidity and decrease antibiotic use. An ideal biomarker has yet to be identified however, in particular for a detection in non-cerebrospinal fluid samples.

2. to identify the causative meningitis pathogen, thus providing clinicians with the assurance needed to initiate an appropriate treatment. For this purpose, established or innovative multiplex technologies need to be promoted. A specific target product profile (TPP) is being finalized targeting the district or decentralized hospital level.

3. to monitor and detect outbreaks. In the African meningitis belt, integrating next generation RDTs into meningitis surveillance systems at the point of care level can lead to the early identification of outbreaks and the prompt activation of mass vaccination campaigns. A new lateral flow option (immunochromatography) targeting the main circulating Nm serogroups is currently under evaluation.

WHO, in coordination with international partners is moving this agenda forward. All stakeholders including manufacturers are invited to contribute.

Presentation

Dr Senjuti Saha, Child Health Research Foundation and Dhaka Shishu (Children) Hospital, Bangladesh

Dr Senjuti Saha is a Bangladeshi-Canadian microbiologist working at the intersection of Clinical Microbiology and Global Health as a Scientist at the Child Health Research Foundation in Bangladesh.

She is also an Associate Faculty at the Johns Hopkins Bloomberg School of Public Health, USA.

After completing her Ph.D. in Molecular Genetics in Canada, she moved to back to Bangladesh to pursue a career that brings together basic science and public health.

Her work is also grounded in advancing the cause of health and research equity - she believes that everyone across the world should have equal access to the practice and benefits of science. Her focus is on paediatric preventable infectious diseases, with the goals (i) of using state-of-the art technology like on-site metagenomics to identify etiologies of meningitis that elude standard laboratory testing in LMICs and (ii) of understanding the indirect impacts of interventions like vaccines on the overall health system.

She advocates for equal access to scholarly literature and science education.

As a team, their mission is to break free of the vicious cycle of limited resources that lead to lack of data required for evidence-based policy decisions, which lead back to limited resources; instead we are committed to building virtuous cycles of data-generation, that are sustainable and cost-effective.

Abstract

Background

The burden of meningitis in low-and-middle-income countries remains significant despite the introductions of Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCV). The infectious causes of these remaining cases of meningitis are largely unknown, and there has been little development in evidence-based diagnostics for implementation in LMICs. This lack of data on etiology of meningitis impede institution of evidence-based treatment and prevention decisions. We conducted a validation and application study of unbiased metagenomic next-generation sequencing (mNGS) study to elucidate etiologies of pediatric meningitis in Bangladesh.

Methods
This RNA mNGS study was performed on cerebrospinal fluid (CSF) specimens from patients admitted in the largest pediatric hospital, a World Health Organization sentinel site, with known neurologic infections (n=36), idiopathic meningitis (n=25), and with no infection (n=30), and six environmental samples, collected between 2012-2018. The conventional laboratory tests used to select samples for this mNGS study included culture, antigen tests and qPCR. The results of the mNGS data were analysed using the open-access bioinformatics pipeline IDseq and machine learning that distinguished potentially pathogenic microbes from environmental and commensal flora. The results were confirmed through qPCR and Sanger sequencing and cases were followed-up through phone/home-visits. A direct-PCR method was optimized to test additional CSF samples for the presence of Chikungunya virus.

Results
In samples with known etiology and without infections, there was 83% concordance between mNGS and conventional testing. In idiopathic cases, mNGS identified a potential bacterial or viral etiology in 40%. There were three instances of neuroinvasive Chikungunya virus (CHIKV), whose genomes were >99% Meningitis and Septicaemia 2019 November 5-6, 2019, British Museum, London. identical to each other and to a Bangladeshi strain previously shown to cause febrile illness in 2017. CHIKVspecific qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 (n=472) revealed 17 additional CHIKV meningitis cases exposing an unrecognized meningitis outbreak. Orthogonal molecular confirmation, case-based clinical data, and patient follow-up substantiated the findings.

Conclusions
Unbiased metagenomic studies, guided by careful selection of positive and negative controls, can facilitate attribution of etiology to meningitis cases where traditional techniques have failed. Inclusion of machine learning techniques facilitate analysis of metagenomic data, and complement methods independent of nucleic acid, such as direct antigen testing, or serology. While we do not foresee administration of metagenomics for everyday diagnosis in LMICs in the near future, or it as a replacement of all techniques, it can act as a complementary tool that can be used in established surveillance platforms in endemic regions, in both outbreak and non-outbreak situations. In this study, CHIKV RNA was detected using metagenomics and the outbreak of CHIKV meningitis was subsequently revealed by a low-cost qPCR technique guided by the findings of metagenomics. Ultimately, unbiased pathogen identification methods like mNGS can complement traditional surveillance methods to facilitate identification of etiologies that eludes standard laboratory testing. These improved patient and population-level data can inform better health policy decisions, including but not limited to vaccine deployment, antibiotic stewardship, vector control and pandemic preparedness.

Presentation

Prof Martin Antonio, MRC Unit the Gambia at LSHTM

Originally from Ghana, Martin trained in molecular microbiology in the UK and set up the molecular microbiology research group in 2005, when he was first appointed at Medical Research Council Unit The Gambia in 2005.

Martin is currently Professor of Molecular Microbiology & Global Health at the Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine (https://www.lshtm.ac.uk/aboutus/people/antonio.martin). He is also MRC (UK) Principal Investigator and the founding Director of the WHO Collaborating Centre for New Vaccines Surveillance.

Martin obtained his PhD from Queen Mary and Westfield College, University of London. He is Honorary Professor at Warwick Medical School, University of Warwick, Coventry, UK, Honorary Fellow of the Royal College of Physicians (London, UK), and Fellow of the Royal College of Pathologist, (London, UK).

Martin’s research deals with clinical, epidemiological and laboratory science leading to large-scale intervention clinical trials in The Gambia and West Africa.

Martin’s group has gained a global reputation for responding to meningitis outbreaks in West Africa. In May 2017, his team responded to the biggest meningococcal group C meningitis outbreak in Northern Nigeria involving 14,898 cases and 1,162 deaths.

His team in collaboration with WHO, Nigeria CDC and the Federal Ministry of health was instrumental in setting up case management, surveillance, lab diagnosis, data management at the epicentre of the outbreak in Zamfara State and identified the etiological agent leading to reactive vaccination. Similarly, in 2016 his team responded to a pneumococcal meningitis outbreak in Ghana.

Abstract

Background

Bacterial meningitis is a major cause of morbidity and mortality in sub-Saharan Africa. We analyzed data from the World Health Organization’s (WHO) Invasive Bacterial Vaccine-preventable Diseases Surveillance Network (2011–2016) to describe the epidemiology of laboratory-confirmed Streptococcus pneumoniae (Spn), Neisseria meningitidis, and Haemophilus influenzae meningitis within the WHO African Region. We also evaluated declines in vaccine-type pneumococcal meningitis following pneumococcal conjugate vaccine (PCV) introduction.

Methods

Reports of meningitis in children <5 years old from sentinel surveillance hospitals in 26 countries were classified as suspected, probable, or confirmed. Confirmed meningitis cases were analyzed by age group and subregion (South-East and West-Central). We described case fatality ratios (CFRs), pathogen distribution, and annual changes in serotype and serogroup, including changes in vaccinetype Spn meningitis following PCV introduction.

Results

Among 49 844 reported meningitis cases, 1670 (3.3%) were laboratory-confirmed. Spn (1007/1670 [60.3%]) was the most commonly detected pathogen; vaccine-type Spn meningitis cases declined over time. CFR was the highest for Spn meningitis: 12.9% (46/357) in the South-East subregion and 30.9% (89/288) in the West-Central subregion. Meningitis caused by N. meningitidis was more common in West-Central than South-East Africa (321/954 [33.6%] vs 110/716 [15.4%]; P < .0001). Haemophilus influenzae (232/1670 [13.9%]) was the least prevalent organism.

Conclusions

Spn was the most common cause of pediatric bacterial meningitis in the African region even after reported cases declined following PCV introduction. Sustaining robust surveillance is essential to monitor changes in pathogen distribution and to inform and guide vaccination policies.

Presentation

Dr Brenda Kwambana-Adams, University College London and Medical Research Council/London School of Hygiene and Tropical Medicine Gambia

Dr Brenda Kwambana-Adams is a Research Associate in Bacterial Pathogenesis and Genomics at the NIHR Global Health Research Unit on Mucosal Pathogens (MPRU), in the Division of Infection and Immunity at University College London.

Brenda’s primary goal is to develop and evaluate innovative diagnostic tools for meningitis and sepsis in low-resource settings.

She is the principal investigator of the BloTIMA study which sets out to determine whether and by how much, blood testing using molecular tools improves case ascertainment in the African meningitis belt.

Up until September 2018, Brenda served as the Deputy Head of the WHO Collaborating Center for New Vaccines Surveillance (WHO CC-NVS) hosted at the Medical Research Council Unit The Gambia. She supported surveillance of meningitis across Africa.

Brenda led WHO missions to provide technical support during meningitis outbreaks and to strengthen laboratory surveillance of meningitis across Africa. One of Brenda’s most notable achievements was leading the WHO Technical Mission team which supported Ghana to identify a novel strain of Streptococcus pneumoniae serotype 1 as the main cause of the deadly 2016 meningitis outbreak.

Brenda sits on several committees and panel including, 1) the Steering Committee of the 12th Meningitis Research Foundation (MRF) 2019 Conference, 2) the Scientific Advisory Panel for the “International Pathogenic Neisseria Conference” 2020 and part of the Diagnosis and Treatment Working Group for Defeat meningitis 2030 – developing a global roadmap.

Abstract

Background

Despite the implementation of effective conjugate vaccines against the three main bacterial pathogens that cause meningitis, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroup A., the burden of meningitis in West Africa remains high. The relative importance of other bacterial, viral and parasitic pathogens in central nervous system infections is less clear.

Methods

Cerebrospinal fluid (CSF) specimens were collected from children under five years with suspected meningitis presenting at pediatric teaching hospitals across West Africa in 5 countries that are part of the Paediatric Bacterial Meningitis (PBM) surveillance; Senegal, Ghana, Togo, Nigeria and Niger. CSF specimens were initially tested using a real time PCR assay used in routine meningitis surveillance targeting N. meningitidis, S. pneumoniae and H. influenzae. A custom meningitis TaqMan Array Card (TAC) assay was later used to detect 35 pathogens including 15 bacteria, 17 viruses, 1 fungus and 2 protozoans.

Results

Among 711 CSF specimens tested, the pathogen positivity rates were 2% and 20% by standard PCR (3 pathogens) and TAC (35 pathogens), respectively. TAC detected 10 bacterial pathogens, 8 viral pathogens, and Plasmodium. Overall, E. coli was the most prevalent (4.8%), followed by S. pneumoniae (3.5%) and Plasmodium (3.5%). Multiple pathogens were detected in 4.4% of the specimens. Detection of HIV and Plasmodium were associated with mortality. Among 220 neonates, 17% had at least one pathogen detected, dominated by the Gram-negative bacteria.

Conclusions

The meningitis TAC enhanced detection of pathogens in children with meningitis and may be useful for case-based meningitis surveillance.

Presenations

Prof Mike Levin, Imperial College London

Prof Mike Levin is Professor of Paediatrics and International Child Health, at Imperial College London.

He works as a paediatric infectious diseases consultant and has led research focused on the diagnosis and treatment of a range of childhood infections including meningococcal disease, tuberculosis, bacterial sepsis and Kawasaki disease.

He currently leads the EU funded PERFORM study investigating the application of RNA transcriptomics to improve diagnosis of childhood infection. He has recently received NIH funding to study Validation of Biomarkers of Pediatric TB and further development for use in diagnosis of childhood TB.

Abstract

There are numerous national and international guidance documents on the recognition and management of Sepsis and Meningitis, including specific guidance on Meningococcal disease. Many of the recommendations made in these documents are based on consensus clinical opinion and current practice, rather than on results of randomised controlled trials. This talk will discuss the changing definitions of Sepsis, in adults and children, and clinical features used in diagnosis.

The recommendations for initial management of Sepsis with broad spectrum antibiotics, rapid fluid volume expansion, inotropes and early ventilation will be discussed in the light of physiology and recent published studies. Adjunctive treatments using anti-inflammatory agents and anti -coagulation will be reviewed.

The aim of the talk will be to critically evaluate current recommendations and discuss future directions for improving the evidence base for treatment of sepsis and meningitis.

Prof Joe Jarvis, LSHTM/Botswana

Prof Joe Jarvis is a Professor at the London School of Hygiene and Tropical Medicine, and Research Associate at the Botswana Harvard AIDS Institute Partnership, based full time in Gaborone, Botswana.

His main research interests are advanced HIV disease, opportunistic infections, in particular central nervous system (CNS) infections, and strategies to rapidly and safely initiate ART in individuals with low CD4 counts.

He is the Chief Investigator for the Ambition Study, a multi-centre phase 3 trial investigating novel treatments for HIV-associated cryptococcal meningitis in Africa, and currently hold an NIHR research professorship based around translational research to reduce mortality from CNS infections in Africa.

He has served as Research Director for the CDC Implementation Protocol of the Botswana Combination Prevention Project (BCPP), a member of the external review group for the WHO Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy, and a guidelines development group member for WHO guidelines on preventing, diagnosing, and managing cryptococcal disease in HIV infected adults, adolescents and children.

He also works as a consultant in infectious diseases and tropical medicine, providing clinical care at Princess Marina Hospital, Gaborone, Botswana, and the Hospital for Tropical Diseases, UCLH, London.

Abstract

HIV-associated cryptococcal meningitis (CM) is now the commonest form of adult meningitis in southern, east, and central Africa, and a major contributor to HIV-associated morbidity and mortality, causing an estimated 181,000 deaths worldwide each year accounting for approximately 15% of all HIV-related mortality. Despite widespread roll-out of antiretroviral therapy (ART), the number of cases of CM has remained relatively stable in many African countries as an increasing population of patients discontinuing or failing ART offsets any decline in the number of patients with advanced HIV at first presentation. Current treatments for CM are inadequate. Ten-week mortality is approximately 60% with fluconazole treatment, the current standard-of-care in most of Africa. Conventional amphotericin B induction is more effective, but not widely available outside South Africa; use is limited by serious toxicity and the need for intensive nursing care and laboratory monitoring. New treatments are urgently needed. Recent data suggest highly effective and much safer therapy for HIV-associated CM is possible with a novelshort-course of high-dose liposomal amphotericin (L-AmB, Ambisome), a newer formulation of amphotericin B. Results from our recently completed phase-II study show that a single high (10mg/kg) dose of liposomal amphotericin B is safe, and leads to rapid clearance of infection. We are currently undertaking a multi-centre phase-III randomised noninferiority trial to determine whether short-course high-dose liposomal amphotericin B is as effective as standard amphotericin B-based therapy in averting all-cause mortality in HIVassociated CM. I will discuss the rationale for and design of the ongoing treatment trial, and discuss other recent approaches to improving outcomes in patients with CM. I will also present data from our studies in Botswana and South Africa validating novel diagnostic tests for cryptococcal infection, and exploring screening strategies to prevent patients with advanced HIV disease from developing CM.

Presentation

Abstract

In high-income countries, based on available trial and observational data, national and international guidelines generally recommend adjunctive corticosteroid therapy for children and adults with community acquired bacterial meningitis. There is less evidence of benefit in low- and middle-income countries, and antibiotic regimens used in trials in LMICs were more variable. Supportive care during and after meningitis is often less well-resourced in LMICs. Additionally, no trials of adjunctive corticosteroid therapy have been performed in the African meningitis belt.

Based on the current evidence, corticosteroid adjunctive therapy is currently not recommended as empiric treatment for bacterial meningitis in many African countries. Given recent changes in meningitis epidemiology, greater standardization of treatment regimens, and an increased focus on prevention of sequelae, the question arises whether we should reconsider steroids as adjunctive therapy in LMICs, particularly in the African meningitis belt. That is the question – with audience participation, this lively debate will answer it.

Dr Matt Coldiron, Epicentre, Médecins Sans Frontières

Dr Matt Coldiron has worked as a medical epidemiologist at Epicentre / Médecins Sans Frontières since 2011.

After completing an AB at Princeton, he received MD and MPH degrees from Emory University, and completed residency training in Internal Medicine at NYU-Bellevue Hospital in New York.

His major areas of interest are meningitis and malaria in the African Sahel, the treatment of snakebite in resource-limited settings, emerging infectious diseases, and conducting research in humanitarian emergencies.

Presentation

Prof Robert Heyderman, University College London

Prof Rob Heyderman is a clinician scientist with skills and experience that bridge clinical practice, disease prevention and the fundamental understanding of the mechanisms of infectious disease

He directed the highly successful Malawi-Liverpool-Wellcome Trust Programme (MLW) for over 8 years, transforming the Programme into a centre of excellence led by Malawian & international scientists, pursuing internationally-leading science, research training & improving the health of people in sub-Saharan Africa.

Since joining UCL, he has established a Mucosal Pathogens Research Group which pursues epidemiological, clinical and basic laboratory research in UK and Africa to address the microbial and immunological basis of severe infection caused by mucosal pathogens and their prevention through vaccination; the regulation of inflammation; and the diagnosis & management of meningitis and sepsis. He has recently launched the NIHR Global Health Research Unit on Mucosal Pathogens (MPRU), which is an interdisciplinary translational programme that brings together internationally recognised UK and African investigators to tackle limitations in the long-term effectiveness of existing vaccines to prevent meningitis, pneumonia and sepsis though new approaches to interrupting mucosal pathogen carriage/transmission.

Presentation

Background:

Cryptococcal antigen (CrAg) screening and treatment with pre-emptive fluconazole reduces the incidence of clinically-evident cryptococcal meningitis in individuals with advanced HIV-disease. However, mortality remains higher in CrAg-positive than in CrAg-negative patients with similar CD4+ Tlymphocyte counts. Causes of death among CrAg-positive patients are unclear.

Methods:

We conducted a cohort study to investigate causes of morbidity and mortality during six-months following routine CrAg screening, among asymptomatic CrAg-positive and CrAg–negative HIV-infected patients with CD4 counts <100 cells/µL (ratio of 1:2), attending two hospitals in Johannesburg, South Africa. CrAg-positive patients were offered lumbar punctures (LPs), and pre-emptive fluconazole (800 mg daily for two weeks, 400 mg for two months, 200 mg pending immune reconstitution and for at least one year) if subclinical cryptococcal meningitis was excluded. Causes of death were attributed by an expert panel using clinical information, interviews with family members, and the results of minimallyinvasive autopsies (MIA), when possible.

Results:

Sixty-seven CrAg-positive and 134 CrAg-negative patients were enrolled in the study. At baseline 17/67 (25%) asymptomatic CrAg-positive patients were found to have subclinical cryptococcal meningitis (n=11), cryptocccaemia (n=11) or pulmonary cryptococcosis (n=2). Although recommended antifungal (62/67 (93%)) and antiretroviral therapy (53/63 (84%)) was commenced for CrAg-positive patients, ART initiation was delayed for 36 days (compared to 17 days for CrAg-negative patients (p160 vs. ≤160) was predictive of subclinical cryptococcal disease at the time of screening (OR 17.6 (95% CI 4.6-67.7)), and of death within 6 months (HR 3.5, 95% CI 1.4–9.2, p=0.009).

Conclusions:

Cryptococcal disease remained an important cause of morbidity and mortality among asymptomatic CrAg-positive patients despite routine LPs to identify and treat those with subclinical cryptococcal meningitis, and pre-emptive treatment with fluconazole. Patients with higher blood CrAg titres were at greater risk of subclinical cryptococcal disease and death. Thorough investigation for cryptococcal disease, prompt initiation of antiretroviral treatment and more intensive antifungal treatment may reduce mortality among asymptomatic CrAg-positive patients identified through screening.

Introduction:

To describe the epidemiology of IMD in England,Public Health England (PHE) performs surveillance of invasive meningococcal disease (IMD) to ascertain case numbers, characterise strains and inform vaccine policy: in August 2015, conjugate ACWY vaccine was introduced for teenagers and in September 2015 4CMenB (Bexsero®) was introduced into the national infant schedule.

Methods:

Clinicians notify suspected cases of meningococcal meningitis/septicaemia to local Health Protection Teams. Hospital microbiology laboratories in England submit invasive meningococcal isolates to PHE for phenotypic characterisation and, since October 2007, porA sequencing. MICs of penicillin, cefotaxime, rifampicin and ciprofloxacinare determined. Since July 2010 all case isolates have undergone whole genome sequencing (WGS) * . Clinical samples are submitted by hospital laboratories for non-culture detection and capsular group confirmation by PCR.

Results:

Laboratory confirmed cases rose from the mid-1990s to peak at 2,595 (in 1999/00) then fell to 636 in 2013/14 since increasing to between 724 and 811 cases annually (755 in 2017/18). During 2017/2018, 295 cases (39%) were confirmed by PCR alone. Since November 1999 the major decrease in serogroup C was due to the MenC conjugate vaccine programme. From 2005/06 to 2014/15, there have only been 13-33 serogroup C cases annually in England but 42 were confirmed in 2015/16 and 64 in 2017/18.

There has been an overall decrease in serogroup B cases from 1,424 (2001/02) to 397 (2016/17). In 2017/18 serogroup B accounted for 54% (404 cases) of all confirmed cases; Where the UK national infant 4CMenB vaccination programme has resulted in reduced disease in targeted cohorts 1 . Serogroup Y accounted for 12% (88 cases) of IMD in 2017/18, and total serogroup Y cases have been relatively stable since peaking at 103 cases in 2015/16. Serogroup W represented 26% (193) of cases in 2017/18, reduced from 225 cases in 2016/17. The cases are predominantly phenotype W:2a:P1.5,2 and confirmed as cc11 by WGS 2 . The observed outbreak stimulated the introduction of the ACWY conjugate vaccine programme for UK teenagers which replaced the previous MenC dose in teenagers.

Conclusion:

The continued accurate surveillance and characterisation of meningococcal cases is essential to monitor the recent UK vaccine interventions and schedule modifications.

*Meningitis Research Foundation Meningococcus Genome Library

Presentation

Dr Steve Gray @ MRF's Meningitis and Septicaemia 2019 from Meningitis Research Foundation

Positively influencing the outcome of the host-pathogen interaction in pneumococcal meningitis is likely to improve clinical outcome from pneumococcal meningitis (PM). However, the clinical contribution of S.pneumoniae on outcome is poorly understood in-vivo.

Objectives

We describe the first report on the S.pneumoniae transcriptome in CSF during PM, validated against an in-vitro transcriptomic model. We investigated the role of highly expressed, poorly annotated genes from the transcriptome in a human CSF neutrophil-killing model of meningitis

Methods

CSF from adults with PM was collected prior to antibiotics and stored at -80ºC in PAXgene®. Total RNA was isolated and sequenced after ribodepletion on the Illumina Nextseq platform. Transcripts were mapped against multiple S.pneumoniae genomes, normalised and quantified. The clinical transcriptome was analysed against infection-relevant conditions in the in-vitro D39 transcription model PneumoExpress. Gene-deleted mutant bacteria were generated from highly expressed, poorly annotated virulence genes. Effects on growth and neutrophil-mediated killing in a human CSF model of meningitis were tested between wild-type and mutant bacteria.

Results

CSF transcriptomes were available for 11 Adults with PM (median age 32 years, 60% male, 70% HIV-1 co-infected, 10/11 non-survivors, median bacterial load 1.6x10 7 copies/ml CSF (IQR 4.1x10 6 – 7.0x10 7 ), predominant serotypes 1/23F/12F). Mapping was optimal against Serotype 1 strains (gamPN10373, P1031), 23F (D141, D122, D219), 3 (A66) and 19A (Hu15, Hu17). The top quartile of expressed genes by transcript copies/million reads was dominated by genes annotated in avoidance of opsonophagocytic killing and meningitis pathogenesis (including BgA, PsaA, PspC, CiaRH, NanA, ply, pepO, Pbp1A, CbpA) and genes with unknown function. Highly upregulated genes were co-correlated into clusters and tested against D39 expression in in-vitro conditions using pneumoexpress. The closest association was in the host-pathogen interaction model between S. penumoniae D39 and A349 epithelial cells.

We investigated further the role of highly upregulated genes with no known function in meningitis pathogenesis. We created gene deleted mutants of betagalactosidase (BgaA) and the operon SP_1800-5, and phenotyped the role of these genes in human CSF models of meningitis. Data on differential growth in human CSF and neutrophil-mediated killing of these gene-deleted mutants will be presented.

Conclusions

The pathogen transcriptome in PM represents unique insights into interactions with the host. S.pneumoniae prioritises expression of genes that avoid oposonophagocytic killing and resist oxidative stress during meningitis. The transcriptome revealed activity of genes with no known function in meningitis currently under investigation. The role of these genes in pathogenesis may reveal new adjunctive targets for intervention to reduce mortality from pneumococcal meningitis.

Background

Bacterial meningitis has significant mortality but frontline doctors will see it infrequently. Therefore, UK guidance on meningitis in adults, with auditable standards, was revised in 2016. We undertook a national audit to assess adherence to the guidelines.

Methods

Patients with community acquired meningitis were identified through coding or laboratory data. Audit standards, including immediate management, diagnostics and treatment, were evaluated by notes review.

Results

Notes from 1472 patients with meningitis were reviewed – 309/1472 (21%) had bacterial aetiology, 615/1472 (42%) viral, 548/1472 (37%) unidentified aetiology. Only 50% of patients had blood cultures taken within one hour of admission and just 2% had a lumbar puncture (LP) within the first hour. 27% received antibiotics within one hour. Most patients received ceftriaxone or cefotaxime but only 37% of over-60s received empirical anti-listeria antibiotics. 26% of patients who had antibiotics were given adjunctive steroids. Half had CSF microscopy within two hours of LP. Less than a third had pneumococcal and/or meningococcal PCR on cerebrospinal fluid. Only 44% had an HIV test. 62% had unnecessary neuroimaging before LP. Overall mortality was 3% - 16% in pneumococcal disease and 8% in meningococcal meningitis. There was a trend toward improved survival in patients with pneumococcal meningitis who received dexamethasone [85/96 (88%)] compared to those who did not [57/73 (78%)] (p=0.066).

Conclusions

Adherence to the meningitis guidelines is inadequate, potentially compromising patient safety. Improvements in guideline dissemination, novel educational resources and clinician and patient engagement are required if we are to increase guideline adherence and improve outcome.

Presentation

Group B streptococcus (GBS; Streptococcus agalactiae) is an important cause of invasive disease in young infants. Early studies have demonstrated a correlation between low GBS specific IgG antibody levels in mothers and susceptibility to GBS disease in infants. There are 10 capsular polysaccharide serotypes of GBS. We conducted an extensive global surveillance study to confirm the appropriate vaccine serotype composition which resulted in the design of a six-valent capsular polysaccharide conjugate vaccine (GBS6) which covers the majority of infant GBS disease. GBS6 is being developed for immunization of pregnant women to protect their infants against invasive GBS disease via placental transfer of vaccine induced antibodies.

Prior to initiating clinical studies, preclinical animal trials demonstrated that GBS6 was well tolerated without evidence of systemic toxicity and resulted in a strong functional antibody response to each of the 6 serotypes in the formulations. GBS6 formulations with 5 µg, 10 µg, or 20 µg with and without aluminum phosphate were then tested in a Phase 1/2 randomized clinical dose escalation trial in nonpregnant adults. The vaccine was well-tolerated with a safety profile consisting primarily of mildmoderate pain at the injection site. GBS6 IgG geometric mean concentrations (GMCs) increased rapidly at 1-week post vaccination and peaked by 2-week for all 6 dose/formulations evaluated. IgG GMCs remained elevated through 6 months. There were no apparent differences observed by dose/formulation. Based on the safety and tolerability data observed, a Phase 1/2 study in nonpregnant and pregnant women in South Africa was initiated in January 2019.

Data from pregnant women in our ongoing Phase 1/2 clinical trial will provide the opportunity to confirm that GBS6 elicits a robust immune response beyond what is observed from natural exposure and that those antibodies are transferred to infants of vaccinated mothers. These data will inform ongoing work to identify a protective antibody threshold in pregnant women and infants against GBS disease.

Dr Suzanne Anderson, Evelina Children’s Community Services and UCL MRC clinical trials unit

Suzanne is a community child health paediatrician with a long-standing interest in tropical child health.

From 2007 to 2016 she was working in sub-Saharan Africa, latterly running the clinical services department at the MRC Unit Gambia for five years.

She now works as a paediatrician with Evelina Children’s Community Services and UCL MRC clinical trials unit on a multi-centre treatment trial of TB meningitis.

Abstract

In those who survive meningitis the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment which may have significant effect on their ability to lead their lives as they did prior to their diagnosis. In children who survive, severe illness may have occurred at a crucial time point in development leading to functional impairments, behavioural and cognitive delay. In low income countries (LICs) the extent and nature of this impairment is poorly understood. This is in large part due to limited laboratory resources for identifying causative pathogens, a lack of observational studies and inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. For the majority of children surviving meningitis in LICs follow-up post hospital discharge is limited, with a lack of culturally appropriate neurodevelopmental assessment tools and limited resources to provide effective therapy where needed.

Presentation

Prof Joy Lawn, London School of Hygiene and Tropical Medicine

Prof Joy Lawn is an African-born, British-trained paediatrician and perinatal epidemiologist with ~30 years of experience including clinical care, epidemiological burden estimates, and design/evaluation of maternal, newborn and child care services at scale, especially in sub-Saharan Africa.

Her medical degree and paediatric training were in the UK, followed by teaching, implementation and research, mainly living in Africa, including a decade for Save the Children. Her MPH was at Emory, Atlanta, USA, whilst at CDC, and her PhD at Institute of Child Health, London.

Her main contribution has been in developing the evidence-base to measure and reduce the global burden of 2.5 million neonatal deaths, 2.6 million third trimester stillbirths, and 15 million preterm births, as well as coordinating the first estimates of the burden of Group B Streptococcus. She has published >250 peer reviewed papers including several Lancet series.

She is currently Professor of Epidemiology, at the London School of Hygiene & Tropical Medicine and Director of Maternal, Adolescent, Reproductive & Child Health (MARCH) centre including several hundred academics from multiple disciplines organised around three research themes: Adolescents, Births, and Child health and development. She leads a research team working on newborn health, stillbirths and child development around the world, including being part of the ambitious NEST360 hospital newborn care scale up across four African countries.

She is the School’s Aurora Women’s Leadership Champion, and committed to gender quality and diversity, with a focus on next generation leadership, especially in Africa. @joylawn

Abstract

Meeting Sustainable Development Goal (SDG) 3.2 for child survival is increasingly dependent on neonatal deaths, which now account for 47% of under-five mortality worldwide. Survivors of neonatal infections, especially meningitis, are at high risk of neurodevelopmental impairment (NDI), yet there has been limited attention to this burden. The “Defeating Meningitis Roadmap” has four pillars, one of which is identification and care for meningitis survivors.

We have previously estimated 2.2 million (uncertainty range: 1.1-2.4 million) cases of neonatal sepsis/pneumonia, and 200,000 (21,000-350,000) cases of neonatal meningitis annually in Low and middle income countries (LMIC). Our systematic review found that amongst neonatal meningitis survivors 23% (95% CI: 19-26% (2,700-35,000)) had moderate to severe NDI, by 18-32 months of age. This estimate was based on 8 studies from High income countries (HIC). For comparison the survivors of neonatal tetanus had an NDI risk of16% (6-27%). No meta-analyses were possible for NDI amongst non-preterm survivors of neonatal sepsis. Regarding aetiology-specific estimates, our recent reviews for Group B Streptococcus (GBS) identified 18 studies following up survivors of GBS meningitis, but only to 18 months and all from HIC. There was a 32% (95% CI, 25%-38%) prevalence of any NDI, including 18% (95% CI, 13%-22%) with moderate to severe NDI.

Whilst data are limited, there is a consistently high risk after neonatal meningitis with at least 1 in 4 severely affected, such as with cerebral palsy and/or cognitive impairment. However, there were major data gaps. Firstly geographically, with no data from LMIC which carry the majority of the burden. Secondly longer term follow-up is required to more accurately identify hearing or visual deficits and subtler developmental delays, behavioural conditions and educational consequences. Identifying modifiable co-morbidities (e.g. epilepsy, under-nutrition) is also important. Finally, data regarding NDI amongst survivors of neonatal sepsis is a black hole, and given the high incidence of this exposure, even minor NDI would be of major public health importance.

To help close this data gap, we are now undertaking five GBS cohort re-enrolment studies (Argentina, India, Kenya, Mozambique, South Africa) and two national e-Cohorts (Denmark, Netherlands). Longer term follow-up and measuring the consequences for families, including economic impact, are crucial to inform full value case proposition analyses for GBS vaccines being undertaken by LSHTM and WHO.

The care gap is even greater than the data gap. Improved case management, and support for children with NDI, as well as their families, are all important strategies, yet currently receive limited investment. Primary prevention would be the most effective strategy to reduce burden and also the major life-long consequences for families.

Presentation

Prof Martin Maiden, PUniversity of Oxford

Prof Martin Maiden is a Professor of Molecular Epidemiology in the Department of Zoology at the University of Oxford.

He holds Fellowships at the Royal College of Pathologists, The Royal Sciety of Biology, The Academy of Medical Sciences, UK, and The American Academy of Microbiology. He has a visiting Professorship in the Department of Biosciences at the University of Cardiff.

After an initial training in microbiology, during which he developed an enduring interest in infectious disease and public health, Martin Maiden’s graduate studies used molecular, genetic, and biochemical techniques to study sugar transport proteins in Escherichia coli. He became interested in multi-disciplinary and evolutionary approaches to investigating biological problems. After a two-year MRC Training Fellowship, he joined the National Institute for Biological Standards and Control, including a year at the Max-Planck-Institut für molekulare Genetik, Berlin. In this period, he worked mainly on the biology Neisseria meningitidis and its implications for vaccination. In 1997, he secured a Wellcome Trust Senior Fellowship in Oxford to expand the scope of his research activities. He retains a strong commitment to developing public health applications.

Martin Maiden’s research team has, for more than 20 years, concentrated on the investigation of the phenotypic consequences of bacterial pathogen diversity, principally using nucleotide sequence-based analyses. Currently he is developing population genomics approaches to these questions, establishing links between genetic traits identified by means of next generation sequencing technology with defined bacterial phenotypes. He has published more than 270 articles in peer-reviewed international journals and around 60 book chapters and Meningitis and Septicaemia 2019 other publications, spanning a range of microbial pathogens, with the majority concerning the pathogenic Neisseria and Campylobacter. He played a principal role in establishing the MLST paradigm generally and developing and exploiting this approach in both of these organisms specifically which he has recently extended to whole genome approaches.

Abstract

More than ever, the control of infectious diseases is a global concern, requiring disease surveillance and public health responses to be international. The effective sharing of data is crucial to this enterprise, notwithstanding the fact that public health remains principally a responsibility of nation states. A fundamental requirement is unified nomenclatures that enable infectious agents to be accurately described and compared. Over the last 30 years the advent and development of nucleotide sequencing technologies has greatly facilitated this, by means of sequence-based typing, which is now possible up to the level of whole genome sequences (WGSs). Nucleotide sequences are definitive, reproducible, and widely comparable. As they are strings of letters, they are easily stored, transported, and manipulated with a wealth of analysis algorithms; however, as they are so large, with over two million letters for each meningococcus for example, they require interpretation to be useful and understandable, even by experts.

The open-access availability of these data has lagged behind their production for a variety of reasons. Barriers to effective sharing include imperatives of public health and privacy legislation (real and perceived) and concerns about commercial and research priorities (patents and publications). Large amounts of data are generated within local, reference, or research laboratories but are all-too-often ineffectively shared, even after publication. Frequently data are: (i) deposited in closed databases, which are only available to certain users, or (ii) placed open access in resources such as GenBank and the European Nucleotide Archive (ENA), but with little contextual or interpretative information, which limits their use. Those data collections that are available open-access are often contingent and not representative of global disease.

The Global Meningitis Genome Library (GMGL) Initiative aims to support the WHO global road map for defeating meningitis by 2030 by to addressing the issues of sequence data sharing for the four meningitis-associated pathogens: meningococcus; pneumococcus; group B streptococcus; and Haemophilus influenzae. It is inspired by, and builds on the on the success of, the Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL), which was founded by a collaboration among the Maiden and Tang Laboratories at the University of Oxford, Public Health England, and the Wellcome Trust Sanger Institute [1]. The MRF-MGL is hosted within the https://PubMLST.org databases, which was founded in 1998 for dissemination of sequence typing data. The GMGL will not be as a one-size-fits-all centralised database, but a collaborative initiative for data sharing, which will also act as a stimulus for the harmonisation of data collection, methodologies, nomenclature, and effective automated data sharing. It will also provide a single user interface that enables assess to a wide range of resources, including those hosted within https://PubMLST.org itself and other resources such as https://pubmed.gov, https://pathogen.watch/, https://microreact.org/ and many others. Active data curation and sophisticated data upload and sharing protocols will ensure data quality and enable the maintenance of confidentiality where this is essential.

1. Hill, D.M.C., J. Lucidarme, S.J. Gray, L.S. Newbold, R. Ure, C. Brehony, O.B. Harrison, J.E. Bray, K.A. Jolley, H.B. Bratcher, J. Parkhill, C.M. Tang, R. Borrow, and M.C.J. Maiden, Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study. Lancet Infect Dis, 2015. 15(12): p. 1420-8.

Presentation

Dr Jay Lucidarme, Public Health England, London

Jay Lucidarme is a Senior Scientist based at the Public Health England Meningococcal Reference Unit in Manchester.

He obtained his degree in Microbiology at the University of Sheffield before going on to complete a Masters in Medical and Molecular Microbiology at the University of Manchester.

He joined the Public Health England Vaccine Evaluation Unit in 2007 where he undertook a PhD in Genomic Epidemiology assessing the potential coverage of the meningococcal B vaccine, Bexsero, in England, Wales and Northern Ireland.

He has since contributed to various projects including the Meningitis Research Foundation Meningococcus Genome Library, and investigations into the vaccine candidacy of meningococcal haemoglobin receptors, the population biology of serogroup W meningococci, and the in vivo microevolution of meningococci during progression from being a harmless commensal to an invasive pathogen.

He currently contributes to the enhanced surveillance of invasive meningococcal disease in England, Wales and Northern Ireland following the introduction of meningococcal B and meningococcal ACWY vaccines into the routine vaccine schedule.

Abstract

The pathogenic Neisseria, N. meningitidis (the meningococcus) and N. gonorrhoea (the gonococcus), are genetically very closely related but differ considerably in many other ways. The meningococcus is a leading cause of meningitis and septicaemia, yet harmlessly inhabits the nasopharynx of approximately ten percent of the population. The gonococcus is a sexually transmitted obligate human pathogen that causes gonorrhoea and associated genitourinary diseases. Antibiotic resistance is prevalent among gonococci but relatively rare, thus far, in meningococci. Pathogenic meningococci typically possess an outer capsule, gonococci are acapsulate. Several effective vaccines exist against invasive meningococcal disease, for gonorrhoea there are none. Despite these and many other differences, gonococci occasionally cause invasive disease whilst meningococci have, over many decades, been documented as an occasional cause of genitourinary disease. The meningococci responsible, however, were notably diverse. Since the early 2000s, a particular serogroup C-associated strain of the ST-11 clonal complex (lineage 11.2/ET-15) has caused numerous outbreaks among men who have sex with men (MSM) in several Western countries. Early suggestions of possible adaptation to the genitourinary niche were supported by the discovery that corresponding isolates expressed nitrite reductase enabling growth in the anaerobic conditions of the GU tract. In 2015 a distinct lineage 11.2 strain was reported to be causing urethritis among mainly heterosexual males. This strain had independently acquired an efficient gonococcal nitrite reductase whilst also dispensing with the ability to express a capsule. Despite the lack of a capsule, a gonococcus-like trait proposed to enhance adhesion within the GU tract, this strain was reported to have caused several cases of IMD in the USA. Further concerns arising from this situation include the heightened potential for the acquisition of antibiotic resistance by GU tract-associated lineage 11.2 strains from gonococci. Along with the potential lack of a vaccine against the acapsulate urethritis-associated strain, or even yet-to-emerge GU-associated serogroup B strains, this may pose a particular threat to complement-deficient individuals taking long term antibiotic prophylaxis. Efficient transfer of resistance from GU-associated meningococci to the wider population of invasive meningococci is another worry, as is the potential emergence of novel GU-associated lineages with enhanced virulence/pathogenicity.

Presentation

Dr Muhamed-Kehir Taha, Institut Pasteur

Dr Muhamed-Kheir Taha has worked at the Institut Pasteur in Paris France since 1985.

He obtained his MD in 1983 Damascus University, PhD in1990 from the University Diderot in Paris, France and Habilitation in 1997 from University Descartes in Paris, France.

His research focuses on molecular pathogenesis and epidemiology of invasive bacterial Infections. His current position is Associate Professor at the Institut Pasteur, Paris, France, Head of the Unit Invasive bacterial infections.

He is responsible for the French National Reference Centre for Meningococci and Haemophilus influenzae.

He is responsible for the WHO collaborating centre for meningitis, is a Member of the French advisory board on immunisation (2007-2017).

He is President of the European Meningococcal and Haemophilus Disease Society (EMGM) since May 2019 and has published over 230 papers in peer-reviewed journals, >40 invited lectures, 4 international patents - Hisch h index: 40

Abstract

The complement system is a key actor of innate immunity that plays a central role in tissue homeostasis and in defence against infection. It is composed of several components (C) that are activated in cascade through different pathways (alternative, classical or lectin pathway). The activation and the control of complement occur around the key component, C3. Subsequently, the formation of the Membrane Attack Complex (MAC), a structure formed by the late components (C5b, C6, C7, C8 and C9), on cell surface disrupts the cell membrane leading to cell lysis. The complement is under a tight control through several negative regulators (CD35, CD46, CD55, CD59, Factor I, Factor H C4BP) to protect host cells from self-complement activation.

Deficiencies in complement negative regulators enhances complement activation on the surface of host cells such as erythrocytes with subsequent hemolysis. This uncontrolled complement activation is a hallmark in the pathogenesis of several devastating disorders such as paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD). Activation of complement via the alternative pathway on foreign cells contributes to hyperacute rejection of xenografts. The outcome of these diseases may benefit from drugs (such as monoclonal antibodies, Mab, against complement components) that inhibit complement activation. Mab against factor D can prolong the survival of xenografts. Eculizumab, the first licensed anti-C5 Mab (licensed in 2007), has provided a major advance in the treatment of PNH by reducing the amount of MAC but it does not completely prevent haemolysis due to C3-mediated extravascular haemolysis. Improvement of these anti-complement strategies is need. New inhibitors can be against the terminal complement pathway and/or against the key component, the C3.

At the opposite, complement activation eliminates pathogens, dying host cells and abnormal molecular structures. The complement system and in particular the components C5 to C9 that constitute the terminal complement pathway, plays a major role in defences against invasive meningococcal disease (IMD). Patients with terminal pathway deficiencies (TPD) are highly predisposed to invasive, often recurrent meningococcal infections that are provoked by isolates belonging to several serogroups and particularly serogroup Y. Deficiencies in components of the alternative pathway of complement (properdin and factor D) also predispose to IMD. Inhibition of terminal pathway increases therefore the risk of IMD in patients treated with anti-C5. New inhibitors can also increase IMD risk to a variable extent.

Anti-meningococcal vaccination is already recommended in subjects receiving eculizumab in some countries (e.g., UK and France). The protection should be wide as isolates belong to several serogroups (against ACWY and B serogroups). Vaccination scheme (number of doses) needs to be adapted as immunogenicity of these vaccines may be less optimal in these subjects. Boosters may be also required in addition to, antibiotic treatment (penicillin V). However, resistance to penicillin may jeopardise this use. Vaccination can also target household and close contacts of subjects with inherited or acquired complement deficiencies (cocooning strategy).

Presentation

Dr Madeleine Thomson, Wellcome Trust

Madeleine Thomson is the Senior Science Lead – Climate Change and Health in the Our Planet Our Health programme of the Wellcome Trust.

She leads Wellcome’s work to understand the connections between climate change and people’s health, and to find and implement solutions at scale.

She is a visiting Professor at Lancaster University.

She previously held senior research positions at the International Research Institute for Climate and Society (IRI) and the Mailman School of Public Health at Columbia University, New York.

She also served as director of the IRI/PAHO-WHO Collaborating Centre on Early Warning Systems for Malaria and Other Climate-Sensitive Diseases (including meningococcal meningitis and ZikaV). Madeleine originally trained as a field entomologist. She spent much of her early career doing operational research to support large-scale health interventions in Africa. She was educated at the University of Sheffield (BSc), Imperial College London (MSc) and the University of Liverpool (PhD).

Abstract

The successful roll-out of the group A meningococcal conjugate vaccine (MenAfriVac) has dramatically changed the epidemiology of meningococcal meningitis (caused by Neisseria meningitidis (Nm)) in the Sahel. However, although enormous progress has been made, problems remain. For example, despite substantial reductions in numbers of cases in Burkina Faso since 2010, when the MenAfriVac vaccine was first introduced, the burden of disease remains unacceptably high. Not only has NmA transmission persisted in the face of the vaccination campaigns but other meningococcal groups and the pneumococcus continue to ravage the region. In addition there are particular concerns regarding the emergence of N. meningitidis group C (NmC) strain in Nigeria 2013 and its implications for the region.

As has been historically the case, there remains considerable year-to-year variation in meningitis incidence with case numbers commonly varying by ten-fold on an annual basis. This variation, which challenges current prevention and response strategies for non NmA strains, is likely significantly related to variations in environmental drivers, namely high dust, temperatures and low humidity that dominate the Sahelian dry season. Prior work has indicated that between 25-40% of variations in cases can be attributed to climatic and environmental factors. The Meningitis Environmental Technologies (MERIT) Project sought to use the emerging evidence in the development of NmA early warning systems in the region and some initial trials were undertaken with limited success. These trials highlighted the fact that early warning is not only dependent on the identification of significant relationships between environmental drivers and health outcomes but also requires institutional mechanisms and capacities that can translate those relationships into practical operational tools that can inform real-time decision-making.

The climate of the Sahel has been intensively studied since the devastating persistent droughts of 1968-73 and 1982-84. These droughts led to widespread food insecurity, loss of livelihoods, high levels of morbidity and mortality as well as outward migration. This climatic shift in rainfall patterns from the wet 1950s and 1960s to persistent dry conditions in the 1970s and 1980s is, in magnitude and spatial extent, unparalleled globally in the meteorological record. Early studies suggested that a positive feedback loop, created from overgrazing and deforestation on marginal land, was responsible for atmospheric changes but this was later refuted when evidence emerged at the turn of the century of the significant correlation between decadal variations in Sahelian rainfall and sea surface temperatures in different regions. In addition, aerosols from coal-fired power plants in Europe were shown to have contributed to the drought and that the current wetting in the Sahel can be in part attributed to the cleaning up of Europe’s air. Thus the persistent Sahelien droughts of the 1970’s and 1980’s were likely the result of anthropogenic forcing connected to both global climate change and pollution from Europe.

Given the significance of environmental drivers of meningococcal meningitis incidence, new scientific understanding of the drivers of climate change in the Sahel and knowledge of the institutional gaps connecting environmental information to health decision-making - what is the likely impact of climate change on the environmental suitability for meningitis in the Sahel and what are the opportunities for the development of meningococcal meningitis early warning systems going forward?