Day one abstracts

Day one - 8 November 2011

Burden of meningitis, advances from research, prevention of pneumococcal disease

Session 1 - Counting the cost of meningitis and septicaemia; burden of illness

CHAIR

PROF GEORGE GRIFFIN
ST GEORGE'S, UNIVERSITY OF LONDON

Prof George Griffin George Griffin is currently Professor of Infectious Diseases and Medicine at St George's, University of London. He was Chair of Meningitis Research Foundation’s Scientific Advisory Panel for six years and then became a Trustee of MRF, a position which he still holds. Professor Griffin trained at King's College London, gaining an intercalated BSc in Pharmacology and Molecular Biology and a PhD in skeletal muscle biochemistry before completing his clinical training at St George's. Following a Harkness Fellowship at Harvard Medical School his postgraduate medical education was at the Royal Postgraduate Medical School and St George's as Lecturer in Medicine where he developed an interest in Infectious Diseases. This culminated in a Wellcome Senior Clinical Fellowship, during which he started to develop the Academic Unit at St George's, alongside the Clinical Infection Unit. His principal research interests centre around the host response to infection and vaccines at the cell, molecular and whole body level. He has built up an academic unit of international reputation with PI lead groups focussing on HIV, TB, malaria, cryptococcal disease, lymphocyte turnover and vaccines. Professor Griffin has been a member of many Wellcome and MRC research committees, was elected a Founder Member of the Academy of Medical Sciences and is currently Chairman of the Government Advisory Committee on Dangerous Pathogens.
SCOTTIE KERN
MEMBER OF MENINGITIS RESEARCH FOUNDATION

PATIENT EXPERIENCE OF MENINGITIS

Scottie Kern Scottie Kern is a clinical research professional of some 16 years experience. Originally from West London, he now lives with his family in Swindon, Wiltshire. Educated as a biologist at the University of Ulster, Scottie's career has included time with SmithKline Beecham (now GlaxoSmithKline), Yamanouchi (now Astellas), Wyeth and most recently Pfizer. He left Pfizer at the end of October 2011.

ABSTRACT

The story of Cailan Kern is one of the bitterest irony. Cailan's father Scottie joined the Wyeth Vaccines Research unit in 2004 to work in support of vaccine clinical development. That pipeline – now belonging to Pfizer – produced what became Prevenar 13, a vaccine which Scottie spent a substantial period of time working on as part of its clinical development team. Prevenar 13 was added to the Infant Immunisation Schedule for England and Wales in April 2010. Cailan had contracted pneumococcal meningitis just under 11 months earlier in May 2009.

This is the story of how a clinical researcher's family were faced with the reality of a disease that had dominated his recent professional life, and the ongoing impact of that experience.

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DR MARY RAMSAY
HPA COLINDALE, LONDON

CURRENT EPIDEMIOLOGY OF MENINGOCOCCAL DISEASE IN THE UK AND EUROPE, INCLUDING ISSUES FOR SURVEILLANCE RELATING TO A MENB VACCINE

Dr Mary Ramsay Dr Mary Ramsay obtained her medical degree at University College in London. Before joining the Health Protection Agency she held an academic post at St Mary’s Hospital Medical School in London. She became a Consultant Epidemiologist in 1994 with responsibility for the national surveillance of vaccine preventable diseases, blood-borne hepatitis and transfusion transmissible infections.

She regularly produces information to the Joint Committee on Vaccination and Immunisation to inform policy on vaccination and for a range of groups on the prevention and control of hepatitis. She is joint Chief Editor of Immunisation Against Infectious Diseases – the recognised national source of advice on vaccination, last published in 2006 and with subsequent updated chapters. She has also been involved in several national guidance documents on public health policy in her disease areas. In addition she provides expert clinical and public health advice in the field of vaccination and blood borne virus prevention. Her work has directly contributed to several major decisions on national vaccination policy, that, in turn has provided benefits for public health.

She often acts as a temporary advisor to WHO on vaccine preventable diseases and advises the European Centre for Disease Control on surveillance and epidemiology of vaccine preventable diseases.

Over the past two years she has been Head of the Immunisation, Hepatitis and Blood Safety Department. In this role she has continued to lead national surveillance and to demonstrate a track record in surveillance development, in managing acute investigations and in providing expert advice and support to a wide range of professionals and organisations who contribute to public health, both in England and overseas. Dr Ramsay’s research interests involve establishing the potential role for new vaccines.

ABSTRACT

Following the introduction of conjugate vaccination against serogroup C meningococcal disease in the UK, the number of cases of invasive meningococcal disease (IMD) due to serogroup C infection declined from 955 in 1998/9 to 13 in 2008/9. Cases due to serogroup B have also declined, but less dramatically, from 1401 to 786 over the same period. Despite this decline, the overall incidence of IMD in the UK remains high in comparison to other European countries. In 2009, the latest year for which Europe-wide data are available, 29 countries reported 4,637 cases of IMD, with an overall incidence of IMD of 0.92 per 100,000 population; the highest rates were reported from the Republic of Ireland (3.4/100,000) and the UK (2.0/100,000). Between 2006/7 and 2009/10 serogroup B (MenB) accounted for 88% (3,907/4,435) of cases in England and Wales. The highest incidence of MenB was observed among infants (38.2/100,000) and cases in those aged <1 year accounted for 27% of all IMD. After infancy, the number of IMD cases decline up to 12 years of age and then increase to reach a second peak at 18 years. Several European countries, including the UK, have recently reported an increase in invasive MenY disease, although MenY disease still only accounted for around 6% of infections in England and Wales in 2010.  

For new vaccines that aim to provide direct protection against serogroup B IMD, vaccination would need to commence in early infancy to have a major impact on overall incidence. The potential role of indirect protection will require further evaluation. 

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DR PETA SHARPLES
UNIVERSITY OF BRISTOL

NEUROLOGICAL IMPACT OF MENINGITIS

Dr Peta Sharples Dr Sharples studied medicine at St Mary’s Hospital London. She trained in paediatric neurology in Great Ormond Street Hospital, Oxford and Newcastle where she was an Action Research Training Fellow and First Assistant in Paediatric Neuroscience. Her PhD, which described the relationship between clinical outcome and cerebral metabolism in children with severe traumatic brain injury, was awarded the Michael Blacow prize of the Royal College of Paediatrics and Child Health and the Ronnie McKeith Prize of the British Paediatric Neurology Association.   Dr Sharples is a Consultant Paediatric Neurologist at the Bristol Royal Hospital for Sick Children and a senior lecturer in the Institute of Child Health at Bristol. As well as leading the paediatric neuro-rehabilitation service at Frenchay Hospital, she heads a clinical and experimental program of research, funded by grants from national bodies including the Department of Health, the British Brain and Spine Foundation, the Royal College of Surgeons, and Cancer and Leukaemia in Childhood. She has developed the paediatric neurology department in Bristol   from a single handed unit to one of the largest regional units in the UK, with eight consultants.

ABSTRACT

Despite new antimicrobial agents and vaccine advances, bacterial meningitis remains an important cause of death and acquired disability in childhood. Half of all cases of non-traumatic encephalopathy admitted to the South West Regional PICU over a five year period were due to CNS infection. Improvements in paediatric intensive care have led to a fall in mortality rates from meningitis, leading to increased focus on quality of outcome in survivors. Various studies have suggested that, overall, 10-20% of survivors of meningitis are left with neurological disability. Data from Bristol suggests outcome in children with meningitis admitted to PICU is poor in 26% and that a further 15% have moderate or mild disability.   

Brain damage in meningitis results from activation of host inflammatory pathways, mediated by cytokines. Cytokine production activates a cascade of destructive molecular events, including generation of excitatory amino acids, generation of nitrous oxide and free radicals, and calcium influx into neurons. These processes result in cellular energy depletion, loss of cell membrane integrity, entry of fluid into cells, cellular lysis and neuronal death by necrosis. Inflammatory processes, including glutamate production, may also result in activation of enzymes responsible for programmed cell death, leading to apoptotic neuronal loss.   

In experimental models of meningitis, cerebral blood flow increases in the first 1-6 hours after infection and is associated with raised intracranial pressure and brain oedema formation. As infection progresses, cerebral blood flow decreases in associated with increasing intracranial pressure. Cerebral oxygen delivery becomes inadequate to meet the brain’s metabolic needs, leading to ischaemic brain damage.  

Inflammatory processes can also cause raised intracranial pressure by blocking normal drainage pathways for cerebrospinal fluid, causing ventriculomegaly with raised intracranial pressure (hydrocephalus). Bacterial meningitis is the single largest cause of non-tumoural hydrocephalus. Single hospital series suggest hydrocephalus complicates 1/7-2.8% of episodes of bacterial meningitis in children.   

The impact in any individual patient of an acquired brain injury such as meningitis, depends on the areas of the brain involved. Damage to the frontal lobes causes difficulties with attention, intellect, executive function and the inhibitory aspects of behaviour, and higher aspects of memory function, including working memory. Temporal lobe damage, for example, by uncal herniation, causes problems with fundamental memory functions such as encoding and retrieval, as well as language dysfunction and behavioural and emotional difficulties. Parietal lobe damage can cause problems with language and visuo-spatial functioning.   

Occipital lobe damage can cause visual problems, such as cortical blindness or visual field defects. Raised intracranial pressure can result in brain stem dysfunction, leading to problems with arousal or attention, cranial nerve palsies and motor dysfunction (spastic quadriparesis or ataxia).   

There is increasing recognition that neuronal plasticity does not necessarily result in children doing better than adults following acquired brain damage. Young children, in particular, may do worse. Early intensive neurorehabilitation is indicated in cases with significant disability, to optimise recovery. Cognitive and behavioural difficulties may not become apparent until some years after the acute illness, emphasising the need for long term monitoring, including of milder cases.      

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CLAIRE WRIGHT
MEDICAL INFORMATION OFFICER, MENINGITIS RESEARCH FOUNDATION

COUNTING THE COST OF MENINGITIS

Claire Wright Claire’s responsibilities at MRF include maintaining and developing a range of information resources for the public and health professionals. These include paper and electronic publications for health professionals and the public, 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 biology background and has spent much of the past year undertaking a project which aims to count the lifelong costs of a severe case of meningitis and septicaemia.  

ABSTRACT

Long-term sequelae resulting from meningococcal disease (MD) impose a considerable burden on healthcare  resources, however there is a lack of published information in the UK on costs associated with severe cases.

Economic evaluations such as cost effectiveness analyses (CEA) are becoming an increasingly important feature in decisions about whether immunisation programmes should be implemented. The conclusions reached by these analyses are dependent on the accuracy of the input data.   

AIM: To estimate lifelong rehabilitation costs associated with severe cases of MD and to present these costs in a format appropriate for use in a cost effectiveness analysis so that in future data input into such models can more accurately represent costs associated with severe outcome of MD.   

METHODS: Two severe scenarios of MD with major sequelae were developed; one which presented acutely as meningitis and the other as septicaemia. They were based on systematic reviews of literature describing the sequelae of MD, dialogue with MRF members who have experience of MD and discussions with paediatricians who have been responsible for managing children with MD over many years. The two scenarios were devised to represent cases typical of the severe end of the spectrum.   

To obtain a comprehensive list of the health, educational and other resources used by survivors during and since their acute illness, families of individuals with sequelae similar to those in each of our scenarios were interviewed. Relevant academics and professionals in health, social care and education were consulted in order to ensure that our scenarios accurately represented the treatment and support that individuals with such sequelae might realistically receive from the NHS, the local authority and personal social services (PSS).  

The majority of costs were derived from English Department of Health reference costs and unit costs of health and social care reflecting values for the financial year 2008-9. Costs were based on a life expectancy of 70 years in each scenario and are presented at a discount rate of 3.5% for the first 30 years and 3% thereafter as recommended by the UK treasury (non-discounted costs are also presented for comparison). Costs are presented from both an NHS/PSS perspective and a government perspective.   

RESULTS: This study has revealed that severe cases of disease which result in longterm sequelae can result in costs to the NHS/PSS of around £150,000-£190,000 in the first year alone. Over a lifetime of 70 years, discounted costs from an NHS/PSS perspective ranged from approximately £600,000 to £1,000,000 (£1,230,000 to £3,160,000 undiscounted) and discounted costs from a government perspective ranged from £1,300,000 to £1,700,000 (£2,980,000 to £4,280,000 undiscounted).   

CONCLUSION: This study fills a gap in UK literature and can potentially be input into CEA to better represent the cost of illness at the severe end of the spectrum. Costs from a government perspective highlight the wider impacts of this disease which is important for clinical decision makers, budgetary and service planners to be aware of when making decisions about the benefits of implementing health policy.
       

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Session 2 - Cost of illness, cost effectiveness analysis and decisions about introducing vaccines



CHAIR

DR MARY RAMSAY
HPA COLINDALE, LONDON

CURRENT EPIDEMIOLOGY OF MENINGOCOCCAL DISEASE IN THE UK AND EUROPE, INCLUDING ISSUES FOR SURVEILLANCE RELATING TO A MENB VACCINE

Dr Mary Ramsay Dr Mary Ramsay obtained her medical degree at University College in London. Before joining the Health Protection Agency she held an academic post at St Mary’s Hospital Medical School in London. She became a Consultant Epidemiologist in 1994 with responsibility for the national surveillance of vaccine preventable diseases, blood-borne hepatitis and transfusion transmissible infections.

She regularly produces information to the Joint Committee on Vaccination and Immunisation to inform policy on vaccination and for a range of groups on the prevention and control of hepatitis. She is joint Chief Editor of Immunisation Against Infectious Diseases – the recognised national source of advice on vaccination, last published in 2006 and with subsequent updated chapters. She has also been involved in several national guidance documents on public health policy in her disease areas. In addition she provides expert clinical and public health advice in the field of vaccination and blood borne virus prevention. Her work has directly contributed to several major decisions on national vaccination policy, that, in turn has provided benefits for public health.

She often acts as a temporary advisor to WHO on vaccine preventable diseases and advises the European Centre for Disease Control on surveillance and epidemiology of vaccine preventable diseases.

Over the past two years she has been Head of the Immunisation, Hepatitis and Blood Safety Department. In this role she has continued to lead national surveillance and to demonstrate a track record in surveillance development, in managing acute investigations and in providing expert advice and support to a wide range of professionals and organisations who contribute to public health, both in England and overseas. Dr Ramsay’s research interests involve establishing the potential role for new vaccines.
DR HANNAH CHRISTENSEN
UNIVERSITY OF BRISTOL

MODELLING THE POTENTIAL IMPACT OF MENINGOCOCCAL B VACCINES IN ENGLAND

Hannah Christensen Hannah Christensen is an epidemiologist with particular interests in infectious diseases, modelling and health economics. Having previously worked for the Health Protection Agency South West Regional Epidemiology Unit and the South West Public Health Observatory she has recently completed her PhD at the University of Bristol. Her thesis used infectious disease and economic models to predict the potential impact of introducing a new meningococcal vaccine into the UK schedule. Hannah is currently working at the University of Bristol on the TARGET study, an NIHR-funded Programme Grant aiming to improve the quality of care given to children presenting to primary care with respiratory tract infections (RTIs). Her research focuses on assessing the population impact of public health interventions aiming to reduce levels of infectious disease.   

ABSTRACT

Neisseria meningitidis remains an important cause of meningitis and septicaemia. The difficulty faced by both the public and clinicians is that the early signs and symptoms of meningococcal disease can be non-specific; however invasive disease can progress rapidly and be fatal within hours. The key to preventing disease, therefore, is vaccination. Serogroup B (MenB) is responsible for most meningococcal disease in the UK. There is currently no broadly effective vaccine against this group, but new ‘MenB’ vaccines are expected to go to licensure shortly. Our objective was to assess (using mathematical models) the potential epidemiological and economic impact of introducing a meningococcal vaccine, able to protect against MenB disease, into the vaccination schedule for England.

Two types of model, one allowing for direct protection only (cohort model) and another also allowing for herd immunity effects (transmission dynamic model) were developed following hypothetical birth cohorts over their lifetime (max 100 years). A number of contemporary data sources were used to estimate the epidemiological parameters and the costs of meningococcal disease and vaccination to the health service. Future costs and benefits were discounted back to 2008. Several routine and catch-up vaccination strategies were simulated.  

In the current model, assuming the vaccine could provide direct protection only, predictions indicate that routine infant vaccination (vaccination at 2,3,4+12 months of age, 75% effective vaccine coverage, 36 months average protection following booster) could prevent 20% of meningococcal disease cases annually. However, this strategy may only be cost effective if the vaccine were to cost £7 per dose. Catch-up campaigns (=17 years) are unlikely to be cost-effective if the vaccine does not affect carriage. If the vaccine does have a reasonable (60%) effect on reducing carriage, the annual number of cases could be reduced by 71% after 10 years by introducing routine infant immunisation plus a catch-up campaign. These results are sensitive to assumptions about: disease incidence and case fatality; sequelae rates; the profile of the vaccine; carriage prevalence; population mixing patterns; and discount rates.  

Introducing a new meningococcal vaccine, with the capacity to protect against MenB could reduce disease levels, with substantial reductions predicted when the vaccine can prevent carriage as well as disease. Such a vaccination programme could be cost-effective if the vaccine were to be competitively priced.

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PROFESSOR RUSSELL VINER
UNIVERSITY COLLEGE LONDON

MENINGOCOCCAL OUTCOMES IN ADOLESCENTS AND IN CHILDREN

Russell Viner Russell Viner is an academic paediatrician and Professor of Adolescent Health at the UCL Institute of Child Health in London. He has a major interest in follow-up studies, and has collaborated with paediatric infectious diseases colleagues to undertake a series of follow-up studies of invasive meningococcal and pneumococcal disease in children and adolescents, funded by Meningitis Research Foundation. Most recently he was commissioned by the Meningitis Trust to undertake the MOSAIC study (Meningococcal outcome study in adolescents and in children), the largest study to date of the outcomes of serogroup B meningococcal disease.   
ABSTRACT

The MOSAIC study was a nationally representative case-control study of the outcomes and costs associated with surviving invasive meningococcal serogroup B disease (MenB). It was commissioned by the Meningitis Trust to inform cost-effectiveness decisions regarding MenB vaccines and to improve aftercare for survivors.   

Survivors (cases) 3-16y were identified through a national database and healthy controls via case GPs. Consenting subjects underwent a standardised assessment. We recruited 573 subjects (245 cases and 328 controls), of whom 221 were well-matched case-control pairs.   

We found that MenB disease is associated with a marked series of deficits in survivors, including reduced quality of life, psychological disorders, IQ and memory impairment as well as hearing loss, limb amputations and scarring. Economic analyses showed significantly increased medical and social costs and significant QALY loss in cases compared with controls.   

This is the largest outcome study of MenB disease in children and adolescents. Economic evaluation of these deficits will inform vaccine development and implementation decisions and improved aftercare for survivors.      

ANY QUESTIONS: MENINGOCOCCAL VACCINES AND OBJECTIVE POLICY AND PURCHASING DECISIONS

TOPICAL DISCUSSION IN WHICH A PANEL OF EXPERTS FROM THE WORLDS OF EPIDEMIOLOGY, COST-BENEFIT ANALYSIS, PUBLIC HEALTH POLICY AND VACCINE PRODUCTION ARE POSED QUESTIONS BY THE AUDIENCE

MODERATOR

PROFESSOR ADAM FINN
UNIVERSITY OF BRISTOL


Prof Adam Finn Professor Adam Finn is Head of the Academic Unit of Child Health at Bristol Medical School, Dept of Clinical Science South Bristol and an honorary consultant in paediatric infectious diseases and immunology at Bristol Royal Hospital for Children. He is director of the South West Medicines for Children Research Network and heads the Bristol Children's Vaccine Centre. He trained in Infectious Diseases at the Children's Hospital of Philadelphia and in Immunology at the Institute of Child Health in London where he obtained his PhD.

He worked in Sheffield between 1992 and 2001 where he was involved in several trials of meningococcal group C and other vaccines. His current main research interest is the mucosal immune response to respiratory bacteria including pneumococcus and meningococcus.

PANEL:

DR PETER DULL
NOVARTIS VACCINES AND DIAGNOSTICS, CAMBRIDGE, MA, USA

Peter DullDr Peter Dull is Head, Meningitis Cluster, at Novartis Vaccines and Diagnostics, where he leads clinical development activities for the Menveo® (MenACWY-CRM), Menjugate®, and a candidate meningococcal B, vaccine programmes.   

Dr Dull attended medical school at the University of Wisconsin-Madison and completed his internal medicine training at Oregon Health Sciences University in Portland, Oregon. After training as an Epidemic Intelligence Officer in the Meningitis and Special Pathogens Branch at the Centers for Disease Control and Prevention in Atlanta, Georgia, he completed subspecialty training in infectious diseases at Emory University in Atlanta. He joined Chiron Vaccines (now Novartis Vaccines and Diagnostics) in 2004.   

Dr Dull’s research areas have included meningococcal meningitis outbreak investigations and vaccination implementation strategies in the United States and Africa, oropharyngeal carriage of Neisseria meningitidis associated with the Hajj, and molecular diagnostics of bacterial meningitis.

PROFESSOR JOHN EDMUNDS
LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE
  

John Edmunds Prof. John Edmunds' research concentrates on the design of cost-effective intervention programmes against infectious diseases. He has a Chair in Modelling Infectious Diseases at the London School of Hygiene and Tropical Medicine. Before that he was the head of the Modelling and Economics Unit at the Health Protection Agency. He has co-authored over 100 peer-review articles, and acted as an advisor on national and international committees on many occasions on topics ranging from HPV vaccination to pandemic influenza. He has been a member of the WHO HPV Expert Advisory Group, and is now a member of the committee that advises WHO on modelling and economic evaluation for vaccination programmes (QUIVER).   

DR DORIAN KENNEDY
DEPARTMENT OF HEALTH, LONDON, UK

Dorian KennedyDorian Kennedy is a career Civil Servant who worked in the Food Standards Agency on a range of food safety, quality and nutrition issues before joining the Department of Health in 2002 to work on Immunisation. He has been heavily involved in HPV and pneumococcal vaccines being added to the routine immunisation programmes in the UK. In addition to immunisation, he was responsible for co-ordinating the pandemic flu preparedness work in the Department from 2004 – 2006. Since 2007, he has been Head of Immunisation Branch in the Department of Health.   

DR CAROLINE TROTTER
UNIVERSITY OF BRISTOL

Caroline Trotter Dr Caroline Trotter is a Senior Research Fellow in the School of Social and Community Medicine at the University of Bristol. She is an infectious disease epidemiologist, with an MSc and PhD from the London School of Hygiene and Tropical Medicine. Her research focuses on assessing the population impact of vaccination against meningococcal and pneumococcal disease, using a range of research methods including mathematical modelling, cost- effectiveness studies, analyses of large databases and seroprevalence studies. She is currently working on the MenAfriCar project (www.menafricar.org).

Session 3 - Advance from research: implications for prevention and treatment



CHAIR

PROFESSOR CHRISTOPH TANG
UNIVERSITY OF OXFORD

Christoph Tang Professor Christoph Tang is currently Professor of Cellular Pathology at the Sir William Dunn School of Pathology at the University of Oxford, having recently moved from the Centre for Molecular Microbiology and Infection at Imperial College London. His group studies the pathogenesis and prevention of disease caused by Neisseria meningitidis and Shigella flexneri, particularly during interactions with the host innate immune system. He was previously an MRC Clinician Scientist at the University of Oxford, and completed his PhD at the Royal Postgraduate Medical School on the identification of virulence factors in the fungal pathogen, Aspergillus fumigates. Christoph originally trained in medicine at the University of Liverpool and spent two years working in The Gambia, West Africa.   

PROFESSOR ROBERT HEYDERMAN
MALAWI-LIVERPOOL-WELLCOME TRUST

REDUCING THE VERY HIGH MORTALITY FOR ADULT MENINGITIS IN AFRICA

Robert Heyderman Rob Heyderman is Professor of Tropical Medicine and Director of the Malawi-Liverpool-Wellcome Trust Clinical Research Programme. He trained in London and Zimbabwe. His current research interests comprise the endothelial biology, coagulopathy and immunology of severe infection; the development of naturally acquired immunity to Neisseria meningitidis and Streptococcus pneumoniae; regulation of the host inflammatory response; and the clinical diagnosis and management of meningitis and septicaemia. Current initiatives include new approaches to mucosal vaccination to prevent pneumonia and meningitis both in the UK and in the tropics; management of meningitis and severe sepsis in resource-poor settings; and microbial genetic diversity in the contact of HIV infection.  

ABSTRACT

Meningitis in adults is a common reason for hospital admission in sub-Saharan Africa and is associated with an HIV seroprevelence exceeding 80%. The disease is also associated with an unacceptably high rate of death and disability. Studies conducted in Malawi, funded by MRF, have found no benefit from either adjunctive corticosteroids or oral glycerol in these populations. The cause of this high mortality remains uncertain but late presentation and delayed door-to-needle times, marked fluid, acid-base and electrolyte derangement on admission, impaired sterilisation of the cerebrospinal fluid (CSF), and viral co-infection of the central nervous system may all contribute. The studies that have attempted to address these issues will be summarised.   

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PROFESSOR MICHAEL LEVIN
ST MARY'S HOSPITAL, IMPERIAL COLLEGE LONDON

GENETIC SUSCEPTIBILITY TO MENINGOCOCCAL DISEASE - THE ROLE OF FACTOR H AND FACTOR H-RELATED PROTEINS

Michael Levin Michael Levin is Professor of Paediatrics and International Child Health, and Director of the Wellcome Centre for Tropical Clinical Medicine at Imperial College London. He trained in medicine in South Africa and in paediatrics in the UK before specialising in infectious diseases. His research has focused on life threatening infections of childhood. He currently heads an international EU-funded consortium studying novel diagnostic methods for tuberculosis in Africa working with colleagues in Malawi and South Africa. He recently led an ESPID funded consortium studying the genetic basis of meningococcal disease, and is a co-investigator on the MRC funded Phase III trial of fluids as supportive treatment for critical illness in African children (‘FEAST’), the results of which are recently published in the New England Journal of Medicine. He is the co-ordinator of a recently funded European Commission FP7 award studying the genetic basis of meningococcal and other life threatening bacterial infections of childhood, working with a consortium of colleagues from Europe, Africa and Singapore.   

ABSTRACT


There is clear evidence that genetic factors are important determinants of meningococcal disease susceptibility and severity, and have also been implicated in other forms of meningitis. A number of studies of genetic associations with meningococcal disease have been published, but many of the reported genetic associations have not been validated in subsequent studies. Numerous methodological flaws in early studies have made interpretation of the findings difficult. In order to conduct a definitive study of the genetic basis of meningococcal disease, an international study was established, with support from ESPID and MRF. This study aimed to establish a large enough cohort of patients with meningococcal disease and controls to allow Genome Wide study (GWAS) of over 500,000 genetic variants. The combined cohort of patients from UK, Holland, Austria and Spain included over 1,500 cases. An Initial GWAS was conducted in the UK cohort, with validation in the central and southern European cohorts. This study has definitively identified genetic variation in the Factor H gene and FH related genes as controlling meningococcal disease susceptibility. Further analysis of the cohorts to identify severity genes and those controlling outcome is underway, and the significance of the findings to date will be discussed in this talk. Michael Levin on behalf of the International meningococcal disease consortium.

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PROFESSOR PAUL HEATH
ST GEORGE'S UNIVERSITY OF LONDON

BACTERIAL MENINGITIS IN INFANTS: THE BURDEN OF DISEASE AND PROSPECTS FOR IMPROVING THE OUTCOME

Paul Heath Paul Heath is a Professor/Honorary Consultant in Paediatric Infectious Diseases at St George’s, University of London and Vaccine Institute in London. His training in paediatrics and infectious diseases was at the Royal Children’s Hospital, Melbourne, the John Radcliffe Hospital, Oxford and St George’s Hospital, London. His particular research interests are in the epidemiology of vaccine preventable diseases, in clinical vaccine trials, particularly in at-risk groups, and in perinatal infections. He coordinates a national neonatal infection surveillance network (neonIN) and currently a national study on neonatal meningitis. He sits on national committees concerned with meningitis, Group B streptococcus prevention, pneumococcal and Hib infections, neonatal infections and on immunisation policies in children. He is a Fellow of the Royal Australasian College of Physicians, a Fellow of the Royal College of Paediatrics and Child Health, a member of the committee for Scientific Affairs and Awards of the European Society of Paediatric Infectious Diseases and a member of the steering committee of the international Brighton Collaboration on vaccine safety.

ABSTRACT

The outcome of neonatal meningitis remains unacceptable. Despite declines in mortality over the last 2 decades, the most recent data on neurodevelopmental outcome suggest little change with up to 50% of infants having some form of disability at 5 years of age. Strategies for prevention are relatively few but should be prioritised and vaccination, especially with an effective Group B Streptococcal vaccine holds much promise. Using recent developments in the management of meningococcal disease as a model, it seems likely that a number of aspects of the current management of neonatal meningitis could be improved with potential for better outcomes. These might include earlier recognition of signs and symptoms by parents and healthcare workers, earlier identification of the causative pathogen, earlier initiation of antimicrobial therapy, improvements in supportive care, better antimicrobial agents and effective adjunctive therapies. More data are needed to quantify these issues, formulate new strategies of intervention and ultimately demonstrate their efficacy

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Session 4 - Preventing pneumococcal disease



CHAIR

PROFESSOR DAVID GOLDBLATT
INSTITUTE OF CHILD HEALTH, UNIVERSITY COLLEGE LONDON

David Goldblatt David Goldblatt obtained his medical degree from the University of Cape Town, South Africa, his paediatric qualifications from the Royal College of Physicians (London) and a PhD in Immunology from the University of London, UK. He is currently Professor of Vaccinology and Immunology and Head of the Immunobiology Unit at the Institute of Child Health, University College London (UCL) as well as a Consultant Paediatric Immunologist at the Great Ormond Street Hospital for Children NHS Trust. He is the Director of Clinical R&D for the joint Institution where he is also Director of the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre. In 2009 he was appointed as Program Director of the Child Health theme for the UCL Partners Academic Health Science Centre.

He has a long-standing interest in the immune response to vaccines and infectious diseases in childhood and has an active research programme studying natural and vaccine induced immunity to infectious diseases. He is a regular advisor to the World Health Organization (WHO) on vaccines and is Director of the WHO Reference Laboratory for Pneumococcal Serology based at the UCL Institute of Child Health in London. He served as a member of the UK Department of Health Joint Committee on Vaccines and Immunisation (JCVI) for 10 years (1997-2007) and contuinues to contribute to UK policy via membership of JCVI subcommittees. He has been a member of the MRC Infection and Immunity Panel, co-chaired the Wellcome Trust Immunology and Infectious Disease Funding Committee until its close in 2011 and continues as a member of the Wellcome Trust’s ‘Immune System in Health and Disease’ Expert Review Group.
PAULINE KAYE
HPA CENTRE FOR INFECTIONS, LONDON

IMPACT OF PNEUMOCOCCAL CONJGATE VACCINATION IN ENGLAND

Pauline Kaye After graduating from Edinburgh University in 1982, Pauline Kaye (Waight) worked as a Notes scientist for 18 years in the Immunisation Department of the PHLS on a wide variety of surveillance activities for vaccine preventable diseases and HIV, research projects and Dept of Health sponsored clinical trials of vaccines including the Meningococcal C conjugate vaccine trials prior to their introduction into the UK vaccination schedule. She left Britain in 2001 to work for the Medical Research Council in The Gambia where she continued to be involved in clinical trial work, this time for new malaria vaccines, on long term hepatitis B vaccination surveillance, research and surveillance work involving congenital CMV infection, and on HIV surveillance in Guinea Bissau. She returned to the UK in 2005 to the HPA which had now replaced the PHLS to work in the Department of Health Care Associated Infections and Antimicrobial Resistance for 18 months before returning to Immunisation to help implement and manage the enhanced surveillance system for invasive pneumococcal disease following the introduction of PCV7 in the UK. She also continues to work on the clinical trials which continue within the Immunisation Department as part of the National Vaccine Evaluation Consortium. As with many other HPA staff she was heavily involved in the HPA response to swine flu in 2009.

ABSTRACT

Invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae is a leading cause of morbidity and mortality in children causing septicaemia, meningitis and pneumonia. In England and Wales, prior to the introduction of the pneumococcal conjugate vaccine (PCV) around 5,000-6,000 cases of (IPD) were reported annually by laboratories to the Health Protection Agency (HPA). The highest incidence of IPD is found in children aged less than one year and in adults aged over 65 years. Around 20 to 25% of children with IPD aged less than five years will have meningitis of whom around 13% die.

Although around 90 different serotypes of S.pnuemoniae exist, when the new seven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the UK schedule in September 2006, it covered around 70% of the serotypes infecting children under the age of five years. PCV13 replaced PCV7 in April 2010 and contained a further six serotypes. Two of these (19A and 7F) had emerged as major causes of disease after the introduction of PCV7 as a result of serotype replacement.

Since 1996, enhanced national surveillance by the HPA in England and Wales has provided a baseline against which to evaluate the impact of PCV7 and PCV13 on vaccine type and non-vaccine type invasive pneumococcal disease in vaccinated cohorts.

The clear impact of the vaccine on the incidence of IPD in different age groups is apparent when incidence rate ratios are calculated using incidence rates from time periods before and after the introduction of the vaccine. Having accounted for changes in the sensitivity of the surveillance systems over time, these ratios show a 98% reduction of PCV7 vaccine type IPD in children aged less than two years with lesser reductions occurring in older age groups due to herd immunity. In children aged under five years with IPD and meningitis, a 95% reduction in disease caused by PCV7 serotypes has been estimated, although for both groups (with and without meningitis), these reductions are countered by increases in incidence of disease caused by non PCV7 serotypes. However the overall reduction in meningitis caused by all types of IPD in children aged less than five years has been estimated at around 44%.

Using HPA data it has been possible to estimate that around 500 IPD cases a year in children less than five years of age and 25-30 deaths a year in the same age group have been prevented by the PCV7 programme.

The impact of the PCV programme on serotype distribution in England and Wales can be shown graphically by plotting the total annual cumulative weekly number of isolates referred for serotyping. The reduction in cases after the introduction of PCV7 can be clearly seen for vaccine type serotypes in graphs showing either all cases of IPD or meningitis only cases.

Eighteen months after the replacement of PCV7 by PCV13, invasive disease and meningitis caused by the additional six serotypes in PCV13 is declining in PCV13 eligible age groups although the potential of further serotype replacement occurring following the introduction of PCV13 needs careful monitoring.

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DR WILLIAM HAUSDORFF
GLAXOSMITHKILINE BIOLOGICALS, WAVRE, BELGIUM

NEED FOR AND DEVELOPMENT OF PROTEIN-BASED PNEUMOCOCCAL VACCINE

William Hausdorf Bill Hausdorff joined GSK Biologicals in 2003, and is currently Vice President and Vaccine Development Leader for Pneumococcal Vaccines, based in Wavre, Belgium. Prior to that position he served as VP and as Director of Epidemiology and Scientific Strategy at GSK.

His academic background includes a PhD in Biology from Johns Hopkins University/the US National Institutes of Health, and a post-doctoral fellowship in molecular pharmacology at Duke University in the US. Subsequently he served as a Technical Advisor with the US Centers for Disease Control and Prevention, based at the US Agency for International Development in Washington DC and Cairo, Egypt. There he worked to expedite introduction of new vaccines into developing country immunisation programs. In 1995 he joined Wyeth Vaccines in the Scientific Affairs and Research Strategy group, where he participated in the development of pneumococcal conjugate vaccines. His major focus at GSK Biologicals is on the development and introduction of vaccines to prevent diseases caused by the pneumococcus, Haemophilus influenzae, meningococcus, rotavirus, and pathogens respresented in DTP-combination vaccines. He is the author of numerous scientific articles and book chapters, including extensive publications on the epidemiology of S. pneumoniae disease.

ABSTRACT

Pneumococcal polysaccharide conjugate vaccines (PCV) have proven to be extremely effective in preventing invasive diseaase (IPD), both in the infant target population and in older, unvaccinated age groups through herd protection. Nonetheless, with more than 40 antigenically distinct serogroups (comprising more than 90 serotypes) of pneumococcus, it was expected that the overall effectiveness of these vaccines against IPD in children would be limited to prevention of the 80-90% of IPD caused by the 10-11 serogroups represented in current vaccine formulations. In addition, it has been well documented that following introduction of the heptavalent PCV there has been near complete replacement of the vaccine serotypes colonizing the nasopharynx with non-vaccine types. Therefore, some replacement disease was also anticipated and this has been borne out by post-marketing surveillance. Considering the dynamics of pneumococcal serotype epidemiology, multi-factorial in origin, large uncertainty exists as to what proportion of this IPD increase is actually attributable to heptavalent PCV use, whether replacement in IPD also erodes vaccine effectiveness against other disease manifestations such as pneumonia and acute otitis media, and how serotype and disease epidemiology may evolve in the future.

There has long been interest in a protein-based vaccine that could provide broad protection against all pneumococci. The ideal candidate would be expressed by all strains regardless of serotype, be antigenically highly conserved, and represent a virulence or growth factor. Unfortunately, many potential candidates fail in one or more of these areas. In addition, to enhance the likelihood of effective protection and avoiding immune evasion, multiple antigens may be desirable. An important hurdle to development has been the absence, to date, of a clinical demonstration in humans that such protein-based vaccines can indeed prevent disease. Vaccine developers have been reluctant to make major investments in the needed studies without recognized immune correlates of clinical protection against IPD or well validated pre-clinical disease models. In addition, clinical study design is complicated by the widespread implementation of highly effective multivalent conjugate vaccines.

There are a number of interesting protein candidates currently being explored, including choline binding protein A (CbpA), pneumococcal surface protein A (PspA), pneumococcal surface adhesion A (PsaA), detoxified pneumolysin (dPly) and pneumococcal histidine triad (Pht) proteins. Regarding the latter two, pneumolysin is produced by virtually all pneumococcal strains and is an important virulence factor, exerting cytotoxic effects on epithelial cells through its membrane pore-forming activity. Four members of the Pht protein family have been described, and found to be well conserved across the pneumococcal species. Recent data suggest that Pht proteins are involved in the regulation of Zn or Mn homeostasis, which are important for the growth of the bacteria. Immunisation with Pht, in particular PhtD, has been shown to elicit protection against several S. pneumoniae serotypes in various mouse models. Immunisation with a combined dPly and PhtD formulation was shown to protect monkeys from pneumococcal pneumonia. Overall, results indicate dPly and PhtD are promising candidates for development of a protein based pneumococcal vaccine.

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PFIZER SATELLITE SESSION
PREVENTING PENUMOCOCCAL DISEASE: WHERE HAVE WE COME FROM AND WHAT DOES THE FUTURE HOLD?

CHAIR

DR JOHN PORTER

John Porter Dr John Porter trained in Oxford and Newcastle medical schools, qualifying in 1995 before specialising in paediatrics. He then further specialised in paediatric diabetes and endocrinology at Birmingham Children’s Hospital. Dr Porter’s PhD was in the genetics of childhood diabetes. He joined Pfizer from the NHS in 2008, and was appointed as a medical team leader for Pfizer in 2009. His current role is as medical team lead managing the medical teams responsible for Pfizer’s anti-infectives, vaccines and endocrinology portfolios. He continues to practice clinical medicine with regular clinics in paediatrics.


SPEAKER

DR LAURA YORK
SENIOR DIRECTOR, INTERNATIONAL SCIENTIFIC AND CLINICAL AFFAIRS, PFIZER VACCINES

Laura York Dr York is Senior Director of International Scientific & Clinical Affairs, Pfizer Vaccines, and is currently based in Paris, France. She has worked in the vaccine field for over 20 years, gaining extensive experience in all phases of vaccine development. She first led a research group evaluating early vaccine candidates and novel adjuvants. Transitioning to Scientific Affairs in 1999, she focuses on licensure of late stage candidates and inclusion of newly licensed vaccines, such as Prevenar 13, into national immunization programs. Dr York did her post-graduate training in Canada, receiving her PhD (Microbiology) from the University of Saskatchewan after completing a MSc (Immunology) at Memorial University.

ABSTRACT

Pfizer Vaccines has a strong heritage in conjugate vaccines for the prevention of bacterial infections, including meningitis, developing HiBtiter, Meningitec, and Prevenar/Prevenar 13 for the prevention of Haemophilus influenzae type B, meningococcal serogroup C and pneumococcal infections, respectively. Though it was well known that antibodies directed to the polysaccharide capsule surrounding these bacteria were protective, vaccines made of purified polysaccharide were unable to generate protective responses in young children. This limitation was finally addressed by conjugation, the chemical linking of the polysaccharide to a protein carrier, and the implementation of conjugate vaccines has led to significant reductions in Hib, meningococcal C and pneumococcal infections. The rationale for the development of Prevenar, and subsequently Prevenar 13, was prevention of pneumococcal disease through the use of effective vaccines. Prevenar was licensed at the beginning of the century and has been used globally in national immunisation programs. Prevenar has been seen to be highly effective in preventing pneumococcal disease, including pneumonia, in vaccinated children, and in providing protection indirectly by reducing nasopharyngeal carriage in vaccinees and subsequent transmission to unvaccinated individuals. Prevenar 13, licensed since 2009, was developed to provide the broadest global coverage with the inclusion of six additional pneumococcal serotypes. Prevenar 13 is licensed in >80 countries around the world and is included in the national immunisation programmes of 28 countries. With the transition to PCV13, IPD due to the six additional serotypes has been shown to have declined while the significant impact on IPD due to the original Prevenar types remains unchanged. Pneumococcal serotypes seen in pediatric disease also cause disease in adults. The clinical development programme and recent licensure of Prevenar 13 for use in adults aged 50 years and above has now offered the potential benefits of conjugate vaccine technology towards addressing the burden of pneumococcal disease in adults. The clinical studies performed in adults for the licensure of Prevenar 13 involved over 6000 subjects providing robust safety and immunogenicity data. The data demonstrated that Prevenar 13 is immunogenic, as demonstrated by the induction of opsonophagocytic (killing) antibody, in individuals naïve to pneumococcal vaccine as well as in those who have been previously immunized with a plain polysaccharide vaccine. Data from longer term studies have also illustrated the ability to re-vaccinate healthy individuals who had received one dose of Prevenar 13 previously. Considerations on prevention of pneumococcal disease in adults should now include the potential use of Prevenar 13.


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