Meningitis and septicaemia in children and adults 2011

Tuesday 8 and Wednesday 9 November 2011 Royal Society of Medicine, London, UK Organised by Meningitis Research Foundation 12 CPD Credits (event 66478)

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Contents
Meningitis Research Foundation Conference 2011 Meningitis and Septicaemia in Children and Adults

Welcome

Dear delegate, Welcome Useful information Programme of events Day one morning sessions – biographies and abstracts Day one afternoon sessions – biographies and abstracts Pfizer satellite session Novartis Vaccines satellite breakfast session Day two morning sessions – biographies and abstracts Day two afternoon sessions – biographies and abstracts Poster abstracts Steering committee Sponsors and exhibitors page 3 page 4 pages 6-7 page 8 page 14 page 18 page 20 page 22 page 26 page 32 page 64 page 64
Christopher Head

I am delighted to welcome you to Meningitis Research Foundation’s 2011 conference – Meningitis and Septicaemia in Children and Adults. This is the eighth conference held by the charity and the event grows in stature every time. First of all I would like to thank the Steering Committee for putting together such a high-quality programme. We are excited to see how many delegates our programme has attracted from such a range of disciplines and from all over the world. I hope these two days will provide an opportunity for sharing state-of-the-art knowledge on topics of global interest, and for forging new collaborations.

It is my great pleasure to welcome our expert speakers from the UK and overseas. In addition to the invited programme of talks we have had an excellent response to our call for posters, with 58 submissions this year, and I encourage all of you to visit these posters, which represent a real showcase for talent. Over the two days we will be examining clinical management from the perspective of a number of different disciplines, and looking at current successes in vaccination and possibilities for the future. I hope the conference will provide you with the best of medicine and science in these fields, and that it will be a stimulating experience for all of us. At the charity we are working hard towards our vision of a world free from meningitis and septicaemia through research and education, as well as offering support to people affected. Meningitis Research Foundation was set up 22 years ago by a group of parents whose children had been affected by meningitis. Since then we have awarded 133 research grants at a cost of over £16.5m, all funded by public donation. Much of this funding continues to come from families and communities affected by these diseases, and I would like to pay tribute to them for turning their personal tragedies into a powerful force for change. This year the conference opens with remarks by one of our members, Scottie Kern, whose son Cailan died from pneumococcal meningitis in 2009. I hope you will also take the time to visit the exhibition stands during the breaks. We are grateful to our sponsors who have supported the event. They are represented here and I hope you will take the opportunity to talk to them. On the charity’s own stand you will find resources for health professionals together with public education materials. We are currently running a campaign Counting the Cost of Meningitis, and there is an associated petition to Government. You will find more information about both on our stand, and once you have had a look I hope you will want to support us by signing our petition. On behalf of the charity’s trustees I would like to thank the speakers, chairs and presenters of posters. I would also like to thank the charity’s staff for their hard work in organising the event. Finally I thank you, the delegates, for working to prevent and treat these deadly diseases as effectively as possible. I hope you find Meningitis Research Foundation’s 2011 conference both informative and enjoyable. Yours sincerely,

Meningitis Research Foundation
Meningitis Research Foundation has an international vision of a world free from meningitis and septicaemia. We work towards this by funding vital scientific research, promoting education and awareness and supporting people affected. Our research looks at all aspects of detection, treatment and prevention, not only in the UK and Ireland, but in the developing world. We raise awareness of the diseases with the public through talks, symptoms leaflets, our website and campaigns. Our Counting the Cost campaign sets out the life-long costs of surviving meningitis or septicaemia with severe sequelae, and highlights the importance of immunisation. We provide a range of resources for health professionals including protocols for best practice in diagnosis and treatment of patients, most recently in collaboration with NICE. We offer written and audio information in 22 languages, and all information is given freeof-charge We support people affected by meningitis and septicaemia through our 24-hour Freefone helpline. We operate an accredited befriending programme with over 145 trained befrienders. We run an interactive disability rights and benefits website, providing tailored personal information to people living with the after-effects of the diseases. MRF relies on the generosity of individual donors to fund its work. www.meningitis.org

Christopher Head Chief Executive

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Useful information

Queries
Please contact a member of Meningitis Research Foundation’s conference team (identifiable by red badges) if you require any assistance during the conference.

Bulletin Board
If you would like to leave a message for a delegate or participant, there is a message board on MRF’s exhibition stand in the Atrium.

CPD certification
Please enlist for your certificate of attendance at registration. Certificates will be available for collection from the registration desk at the end of the conference. For those delegates who are only attending Day One, your certificate will be available at the end of the day.

Business services
Basic business services, including photocopying (small charge per copy) and fax facilities (free of charge) are available in the Events Office on the lower ground floor.

Telephones
A public telephone is located in the cloakroom on the ground floor.

Mobile phones/pagers
Please switch off all mobile phones and pagers when you are in the lecture theatre.

Toilets
Toilets are situated downstairs through the Atrium and also by the RSM restaurant on the ground floor.

Questions during the conference
Questions will be taken at the discretion of the chairman. Wait until questions are invited and, if you would like to speak, raise your hand and wait to be called. When you are called, speak clearly into the microphone handset, giving your name and where you are from. The handset should be held like a mobile phone and the blue button pressed and held continuously while you speak.

Cloakroom facilities
The cloakroom is on the Ground Floor next to the main reception. Lockers take £1 coins, which are returnable.

Parking
There are no parking facilities available at One Wimpole Street to accommodate vehicles. There are limited street parking spaces available in the surrounding area, as well as numerous parking structures close by, including one in Cavendish Square, directly opposite the Society.

Programme and Oral Presentations
Meningitis and Septicaemia in Children and Adults
Tuesday 8 and Wednesday 9 November 2011

Conference evaluations
Please complete the conference evaluation form and hand it in at the registration desk before you leave. The form is included in your delegate pack.

Lunch and refreshments
Lunch and refreshments will be served in the Atrium and the EDR.

Disabled facilities and access
All floors are accessible (except the fifth) via two lifts. The lecture theatre is fully accessible and there are removable seats allowing space for wheelchairs. There is a personal delegate hearing system where each delegate wears an RSM receiver and earpiece. There are accessible toilets on the first mezzanine floor of the Library and on the ground floor.

Wine reception
The wine reception will take place in the Atrium and the EDR after the Pfizer satellite session finishes on Day 1.

Poster presentations
Please visit the posters during registration, morning and afternoon breaks, lunchtimes and the wine reception. Posters are displayed around the Atrium walls and in the EDR. Authors of posters will be on hand to discuss their work and can be identified by their green badges. The award for the best poster will be presented after lunch on Day Two so that delegates can view the winning poster during the final tea break that afternoon.

Smoking
Please note that smoking is not permitted in any part of the building.

Fire and evacuation procedure
If the fire alarm sounds: Proceed quickly and calmly to the nearest fire exit. Escape routes and emergency exits are clearly indicated by Fire Exit signs. Do not stop to collect personal possessions. Use the stairs – do not use lifts. Proceed to the assembly point in front of RSM in Henrietta Place.

The exhibition
The exhibition will be open for viewing during registration, morning and afternoon coffee, lunch on both days and during the wine reception on Day One. The exhibition stands are displayed around the Atrium and in the EDR.

First aid
There is a first aid room and many first aiders in the building. If an accident occurs, please contact reception on the ground floor.

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Programme – Tuesday 8 November 2011
Burden of meningitis, advances from research, prevention of pneumococcal disease
8:00 9:15 REGISTRATION AND COFFEE Welcome Chris Head, CEO, Meningitis Research Foundation, UK 8:00 8:20

Programme – Wednesday 9 November 2011
Treatment of meningitis and septicaemia, prevention of meningococcal disease
REGISTRATION AND COFFEE NOVARTIS SATELLITE BREAKFAST SESSION

Counting the cost of meningitis and septicaemia: burden of illness Chair: Prof George Griffin, St George’s University of London
9:25 9:40 Patient experience of pneumococcal disease Scottie Kern, Member of Meningitis Reasearch Foundation Current epidemiology of meningococcal disease in the UK and Europe, including issues for surveillance relating to a MenB vaccine Dr Mary Ramsay, HPA Colindale, London Neurological impact of meningitis Dr Peta Sharples, University of Bristol Counting the cost of meningitis Claire Wright, Meningitis Research Foundation COFFEE, EXHIBITION AND POSTERS

Tackling Meningitis in Africa Chair: Prof Robert Heyderman, Malawi-Liverpool-Wellcome Trust
9:20 9:50 10:20 10:50 Introduction of meningococcal serogroup A vaccine in the African meningitis belt Dr Marc LaForce, Meningitis Vaccine Project, PATH/WHO, Ferney-Voltaire, France Carriage and spread of meningococcus in the meningitis belt: the MenAfriCar project Dr Caroline Trotter, University of Bristol Bill & Melinda Gates Foundation activity to combat meningitis in Africa Prof Richard Adegbola, Bill & Melinda Gates Foundation COFFEE, EXHIBITION AND POSTERS

10:10 10:40 10:50

Current Issues in recognition and treatment Chair: Dr Simon Nadel, St Mary’s Hospital, Imperial College London
11:20 11:50 Pitfalls in recognition of meningitis and septicaemia in teenagers Dr Nelly Ninis, St Mary’s Hospital, Imperial College London Overview of evidence for managing children with sepsis, including fluid management of children in shock Dr Mark Peters, Institute of Child Health, University College London Current advances in sepsis management in adults Prof Mervyn Singer, University College London LUNCH, EXHIBITION AND POSTERS AWARD FOR THE BEST POSTER

Cost of illness, cost effectiveness analysis and decisions about introducing vaccines Chair: Dr Mary Ramsay
11:20 11:50 12:20 13:00 Modelling the potential impact of meningococcal B vaccines in England Dr Hannah Christensen, University of Bristol Meningococcal outcomes study in adolescents and in children Prof Russell Viner, Institute of Child Health, University of London Any questions: Meningococcal vaccines and objective policy and purchasing decisions Prof Adam Finn, University of Bristol – moderator LUNCH, EXHIBITION AND POSTERS

12:20 12:50 13:50

Advances from research: implications for prevention and treatment Chair: Prof Christoph Tang, University of Oxford
14:00 14:30 Reducing the very high mortality for adult meningitis in Africa Prof Robert Heyderman, Malawi-Liverpool-Wellcome Trust Genetic susceptibility to meningococcal disease – the role of Factor H and Factor H-related proteins Prof Michael Levin, St Mary’s Hospital, Imperial College London Bacterial meningitis in infants: the burden of disease and prospects for improving the outcome Prof Paul Heath, St George’s University of London COFFEE, EXHIBITION AND POSTERS

Prevention of meningococcal disease Chair: Prof Ray Borrow, Vaccine Evaluation Unit, Health Protection Agency, Manchester
14:00 Changes to UK immunisation programme, including prospects for a teenage meningococcal booster Prof Andrew Pollard, University of Oxford Dealing with a localised MenB epidemic – the Cumbrian situation Dr Paul Cleary, HPA Northwest, Liverpool COFFEE, EXHIBITION AND POSTERS

14:25 14:50

15:00 15:30

Prospects for prevention of meningococcal B disease Chair: Prof Ian Feavers, National Institute for Biological Standards and Control
15:10 15:40 16:10 16:50 Prospects for use of Novartis 4CMenB vaccine Dr Peter Dull, Novartis Vaccines and Diagnostics, Cambridge, MA, USA Pfizer strategy for prevention of meningococcal B disease Dr Kathrin U Jansen, Pfizer Inc, NY, USA Interactive session: Implementing a MenB vaccine Prof Andrew Pollard, University of Oxford –moderator CLOSE

Preventing pneumococcal disease Chair: Prof David Goldblatt, Institute of Child Health, University College London
16:00 16:30 17:00 18:00 Impact of pneumococcal conjugate vaccination in England Pauline Kaye, HPA Centre for Infections, London Need for and development of protein-based pneumococcal vaccine Dr William Hausdorff, GlaxoSmithKline Biologicals, Wavre, Belgium PFIZER SATELLITE SESSION WINE RECEPTION, EXHIBITION AND POSTERS

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Morning – Tuesday 8 November 2011 Burden of meningitis, advances from research, prevention of pneumococcal disease
9:15 Welcome Christopher Head, CEO, Meningitis Research Foundation, UK 9:40

Morning – Tuesday 8 November 2011
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 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.

Notes

Counting the cost of meningitis and septicaemia: burden of illness
Dr Mary Ramsay

Chair:
Notes

Professor George Griffin, St George’s, University of London
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 Prof George Griffin 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.

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.

9:25
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Scottie Kern, Member of Meningitis Research Foundation Patient experience of pneumococcal disease
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.

10:10
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Dr Peta Sharples, University of Bristol Neurological impact of meningitis
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 Dr Peta Sharples 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
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 Kern 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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Notes Notes

Morning – Tuesday 8 November 2011
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.

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.

10:50
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COFFEE, EXHIBITION AND POSTERS

Cost of illness, cost effectiveness analysis and decisions about introducing vaccines
Dr Mary Ramsay, HPA Colindale, London
Biography on page 8

Chair: 10:40
Notes

Claire Wright, Medical Information Officer, Meningitis Research Foundation, UK Counting the cost of meningitis
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.

11:20

Dr Hannah Christensen, University of Bristol Modelling the potential impact of meningococcal B vaccines in England
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.
Dr Hannah Christensen

Notes

Claire Wright

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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.

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
Professor Adam Finn is Head of the Academic Unit of Child Health at Bristol Medical School, School of Clinical Sciences 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.
Prof Adam Finn

Panel:
Notes

11:50
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Professor Russell Viner, Institute of Child Health, University College London Meningococcal outcomes study in adolescents and in children
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.

Dr Peter Dull, Novartis Vaccines and Diagnostics, Cambridge, MA, USA
Dr 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 Peter Dull

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.

Prof Russell Viner

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.

Professor John Edmunds, London School of Hygiene and Tropical Medicine, UK
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).
Prof John Edmunds

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Afternoon – Tuesday 8 November 2011
Notes

Afternoon – Tuesday 8 November 2011

Dr Dorian Kennedy, Department of Health, London, UK
Dorian 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.

14:00
Notes

Professor Robert Heyderman, Malawi-Liverpool-Wellcome Trust Reducing the very high mortality for adult meningitis in Africa
Rob Heyderman is Professor of Tropical Medicine and Director of the Malawi-LiverpoolWellcome 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.
Prof Robert Heyderman

Dr Dorian Kennedy

Abstract

Dr Caroline Trotter, University of Bristol, UK
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, costeffectiveness studies, analyses of large databases and seroprevalence studies. She is currently working on the MenAfriCar project (www.menafricar.org).

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.

Dr Caroline Trotter

14:30
Notes

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 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.

Professor Russell Viner, Institute of Child Health, University College London
Biography on page 12

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LUNCH, EXHIBITION AND POSTERS

Advances from research: implications for prevention and treatment
Chair:
Notes

Prof Michael Levin

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.

Professor Christoph Tang, University of Oxford
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.
Prof Christopher Tang

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Afternoon – Tuesday 8 November 2011
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Afternoon – Tuesday 8 November 2011
16:00 Pauline Kaye, HPA Centre for Infections, London Impact of pneumococcal conjugate vaccination in England
After graduating from Edinburgh University in 1982, Pauline Kaye (Waight) worked as a 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 Pauline Kaye 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.

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 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.

Notes

Prof Paul Heath

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.

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.

15:30

COFFEE, EXHIBITION AND POSTERS

Notes

Preventing pneumococcal disease
Professor David Goldblatt, Institute of Child Health, University College London
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.
Prof David Goldblatt

Chair:
Notes

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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Afternoon – Tuesday 8 November 2011
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Afternoon – Tuesday 8 November 2011
17:00 PFIZER SATELLITE SESSION Preventing pneumococcal disease: Where have we come from and what does the future hold? Dr John Porter BA (Hons) MBBS PhD
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.

Dr William Hausdorff, GlaxoSmithKline Biologicals, Wavre, Belgium Need for and development of protein-based pneumococcal vaccine
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.
Dr William Hausdorff

Chair:
Notes

Dr John Porter

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.

Speaker:
Notes

Dr Laura York, Senior Director, International Scientific & Clinical Affairs, Pfizer Vaccines
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.
Dr Laura York

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Breakfast – Wednesday 9 November 2011
18:00 8:00 8:20
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Breakfast – Wednesday 9 November 2011
Notes

WINE RECEPTION, EXHIBITION AND POSTERS REGISTRATION AND COFFEE

Dr Liam Dorris D.Clin.Psych BSc (Hons) AFBPsS, Consultant Paediatric Neuropsychologist & Honorary Senior Clinical Lecturer, Royal Hospital for Sick Children, Glasgow Societal impact: Psychosocial impacts of meningococcal disease
Dr Dorris has been a Consultant Paediatric Neuropsychologist at RHSC Glasgow since 2005, with prior appointments within NHS Greater Glasgow as a Clinical Psychologist in neurosciences, community child health and also as clinical lecturer at the Department of Psychological Medicine, University of Glasgow. He has published widely in several areas of child disability and neurological disorder and has active research interests in acquired brain injury, epilepsy and sleep disorders.

NOVARTIS SATELLITE BREAKFAST SESSION Real lives, real costs; the toll of meningococcal disease
This Novartis sponsored satellite symposium will be chaired by Dr Peter Dull of Novartis Vaccines and Diagnostics and will explore the wide-reaching impacts of meningococcal disease in the UK. The symposium will start with Mr Fergal Monsell, a consultant paediatric orthopaedic surgeon. Using his first-hand experience of working with meningitis survivors, he will discuss the reality of the disease as well as treatment and associated costs. Dr Liam Dorris, a consultant neuropsychologist, will then present data from a study currently in-press regarding long-term disability, quality of life and psychosocial consequences of paediatric meningitis. Finally, Dr Stuart Clarke, a reader in infectious disease epidemiology, will examine the public health impact of meningococcal disease by presenting his own case study of an outbreak situation, discussing the response as well as associated costs. The symposium will be concluded by the chairman who will summarise the key points discussed including reference to new vaccines in development to tackle this devastating disease.

Dr Liam Dorris

Chair:
Notes

Dr Peter Dull, Novartis Vaccines and Diagnostics, Cambridge, MA, USA
Biography on page 13

Notes

Dr Stuart C Clarke, Reader in Infectious Disease Epidemiology and Honorary Consultant in Health Protection, University of Southampton, UK Public Health impact: Meningococcal disease outbreaks
Dr Clarke is Reader in Infectious Disease Epidemiology and Honorary Consultant in Health Protection. He has a major interest in the epidemiology of infectious diseases, particularly in relation to vaccine development and the evaluation of new vaccines. Dr Clarke developed his independent research career when Director of the Scottish Meningococcus and Pneumococcus Reference Laboratory between 1998 and 2004. His research focuses on the molecular epidemiology of vaccine-preventable bacterial infections. He is also a member of the Biofilm and Microbial Communities group in Southampton where he provides an essential link between epidemiology and microbial communities. Dr Clarke was involved in the national meningococcal carriage study, led by Professors Martin Maiden and James Stuart, which was mainly funded by the Wellcome Trust. He is now involved in various pneumococcal and meningococcal carriage studies.

Mr Fergal Monsell, MSc PhD FRCS(Orth), Royal Hospital for Children, Bristol Immediate impact: Musculo-skeletal impacts of meningococcal disease
Mr Fergal Monsell has been a Consultant Paediatric Orthopaedic Surgeon at the Royal Hospital for Children, Bristol since 2005. He worked in the same capacity at The Hospital for Sick Children, Great Ormond Street and The Royal National Orthopaedic Hospital, Stanmore between 1997 and 2005. He completed his higher surgical training at the University of Manchester and fellowship training at the Royal Alexandra Hospital for Children, Sydney, Australia. He has a broad based practice with a special interest in limb reconstruction surgery using a spectrum of contemporary techniques. He has considerable experience in the management of patients with the skeletal consequences of septicaemia and contributes to a multi-disciplinary team specifically managing this patient group. He is active in all aspects of paediatric trauma and has published on this subject.
Dr Stuart Clarke

Mr Fergal Monsell

Dr Clarke has published more than 80 peer-reviewed papers mainly in the field of N. meningitidis and S. pneumoniae infection. In 2009, Dr Clarke won the Bupa Foundation's award of ‘best emerging medical researcher in the UK’ for his work on the molecular epidemiology of pneumococcal infection around the introduction of pneumococcal conjugate vaccines.

He has an active clinical and basic science research portfolio and received a Doctorate of Philosophy in 2010, defending a thesis that explored the effect of chemotherapy on regenerate bone formation in distraction osteogenesis.

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Morning – Wednesday 9 November 2011 Tackling meningitis in Africa
Chair: Professor Robert Heyderman, Malawi-Liverpool-Wellcome Trust
Biography on page 15
Notes

Morning – Wednesday 9 November 2011
and Niger, where MenAfriVac campaigns began at the end of 2010) in rural and urban sites were performed in the rainy season between September and December 2010. Detailed longitudinal studies were also performed in households where a carrier was identified to examine rates of acquisition and loss and describe patterns of transmission within households. Preliminary results from the first cross-sectional surveys will be presented, including risk factors for carriage. The prevalence of meningococcal carriage overall was low at around 4% and serogroup A carriers were only identified in Chad. The implications of these results for the design of the subsequent stages of the study will be discussed. Several methodological challenges were encountered, including difficulties with serogrouping using slide agglutination, and implementation of a new data management system. A brief update on the current activities in the second round of surveys will also be given.

9:20
Notes

Dr Marc LaForce, Meningitis Vaccine Project, PATH/WHO, Ferney-Voltaire, France Introduction of meningococcal serogroup A vaccine in the African meningitis belt
Dr Marc LaForce joined the Meningitis Vaccine Project as Director in August 2001. He has a long and distinguished career in disease prevention, vaccinology, and international health. The Meningitis Vaccine Project is a partnership between WHO and PATH aimed at developing, testing, licensing and introducing conjugate meningococcal vaccines in Sub-Saharan Africa. Dr LaForce earned his Doctor of Medicine degree from Seton Hall College of Medicine and Dentistry in Jersey City, NJ. He completed his internal medicine and infectious disease training on the Harvard Service at Boston City Hospital. After serving as an Epidemic Intelligence Service Officer in the Meningitis and Special Pathogen units at the Centers for Disease Control and Prevention he joined the faculty at the University of Colorado School of Medicine. He is board certified in internal medicine and infectious diseases and is a Fellow of the American College of Physicians and the Infectious Diseases Society of America. Before joining PATH he was Physician-in-Chief at the Genesee Hospital and Professor of Medicine at the University of Rochester School of Medicine and Dentistry in Rochester, NY.

10:20
Notes

Prof Richard Adegbola, Bill & Melinda Gates Foundation Bill & Melinda Gates Foundation activity to combat meningitis in Africa
Dr Richard Adegbola joined the Bill & Melinda Gates Foundation in 2009 as Senior Program Officer and lead for Pneumonia Clinical Studies, coming from 19 years with the UK Medical Research Council (MRC) Unit in The Gambia. There he was Head of Bacterial Diseases Programme, with a focus on bacterial infections including pneumonia, meningitis and tuberculosis research. His work there included a Phase IV Hib vaccine effectiveness study, and the pneumococcal vaccine efficacy trial that demonstrated a 16% reduction in childhood mortality as a result of pneumococcal vaccination. Results from these studies have provided pivotal evidence for the large scale uptake of these new vaccines. His current interests include the bacteriology of large vaccine efficacy trials, herd effect of conjugate vaccines and maternal immunization as a strategy for prevention of microbial infection in young infants. Dr Adegbola received his undergraduate education in medical microbiology at the Lagos University Teaching Hospital in Nigeria and obtained his Ph.D. in Microbiology from University of Dundee, Scotland. He is a Fellow of the Royal College of Pathologists, London (in Medical Microbiology) and an Honorary Fellow of the Royal College of Physicians, London. The University of Leicester, UK appointed him an Honorary Visiting Professor on 1 May 2005. He has over 20 years research experience with over 167 journal publications and 5 book chapters in bacterial infections of the tropics particularly, pneumonia and meningitis, caused by Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis in young children.
Prof Richard Adegbola

Dr Marc LaForce

Dr LaForce has published over 170 papers and book chapters chiefly in the areas of pulmonary defence mechanisms, clinical infectious diseases, epidemiology and vaccinology.

Abstract
A new Group A meningococcal (Men A) conjugate vaccine, MenAfriVacTM, was prequalified by the World Health Organization (WHO) in June 2010. Because Burkina Faso has repeatedly suffered meningitis epidemics due to Group A Neisseria meningitidis special efforts were made to conduct a country-wide campaign with the new vaccine in late 2010 and before the January 2011 onset of the next epidemic meningococcal disease season. In the ensuing five months (July–November 2010) the following challenges were successfully managed: 1) doing a large safety study and registering the new vaccine in Burkina Faso; 2) developing a comprehensive communication plan; 3) strengthening the surveillance system with particular attention to improving the capacity for real-time polymerase chain reaction (PCR) testing of spinal fluid specimens; 4) improving cold chain capacity and waste disposal; 5) developing and funding a sound campaign strategy; and 6) ensuring effective collaboration across all partners. Each of these issues required specific strategies that were managed through a WHO-led consortium that included all major partners (Ministry of Health/Burkina Faso, Serum Institute of India Ltd., UNICEF, Global Alliance for Vaccines and Immunisation, Meningitis Vaccine Project, CDC/Atlanta, and the Norway Institute of Public Health/Oslo). The new meningococcal A conjugate vaccine was introduced on December 6, 2010, in a national ceremony led by His Excellency Blaise Compaore, the President of Burkina Faso. The ensuing 10-day national campaign was hugely successful, and over 11.4 million Burkinabes between the ages of 1 and 29 years (100% of target population) were vaccinated. African national immunization programs are capable of achieving very high coverage for a vaccine desired by the public, introduced in a well-organized campaign, and supported at the highest political level. The Burkina Faso success augurs well for further rollout of the Men A conjugate vaccine in meningitis belt countries.

At the Gates Foundation, Dr Adegbola’s role is taking pneumonia and meningitis research findings to policy, implementation and evaluation for impact. He is responsible for vaccine impact studies, including impact evaluations for pneumococcal and meningococcal conjugate vaccines and maternal immunization program and for studies of the microbial causes of pneumonia and meningitis in the developing world.

Abstract
For more than a century, meningococcal group A epidemics have swept across the African meningitis belt stretching from Senegal in the west to Ethiopia in the east with apparently unstoppable force. With each epidemic, the disease decimates communities, killing about 10% of affected people, leaving 25% of survivors with sequelae such as brain damage or deafness and rendering a struggling health care system completely overwhelmed. A population of 400 million is at risk of this disease and children as well as adults can be infected by meningitis epidemics. Polysaccharide vaccines against meningococcal serogroups A, C, Y and W135 have been available for over 20 years but the vaccines are used for re-active mass vaccination campaigns along with antimicrobial treatments for epidemic containment only. They neither provide long-lasting protection nor confer herd immunity, particularly in young children who are at highest risk for disease. A quadrivalent protein-polysaccharide conjugate vaccine containing meningococcal serogroups A, C, Y and W135 and monovalent group C conjugate vaccine with a more lasting protection against meningococcal disease have been introduced in developed countries but these vaccines are at a cost that is unaffordable at settings with a poor resource base. In 1996 there occurred a most devastating epidemic in the African meningitis belt with 200,000 cases and 20,000 deaths with as yet undisclosed number of survivors with sequelae. This generated a major concern among the public health officials of the affected communities to which they drew a global attention. Consequently the Meningitis Vaccine Project (MVP), a partnership between WHO and PATH, was formed with funding from the Gates Foundation in 2001 to address the prevention and ultimately the elimination of epidemic meningitis in Sub-Saharan Africa. The

9:50

Dr Caroline Trotter, University of Bristol Carriage and spread of meningococcus in the meningitis belt: the MenAfriCar project
Biography on page 14 Abstract
MenAfriCar (the African Meningococcal Carriage Consortium) is a global research effort to study how meningococci are spread in Africa, and to document the impact of a new meningitis vaccine (MenAfriVac) on reducing transmission. . Carriage and seroprevalence studies are being conducted in seven countries across the meningitis belt: Ethiopia, Chad, Niger, Nigeria, Mali, Ghana and Senegal, in collaboration with the London School of Hygiene and Tropical Medicine and 11 other international centres. The first cross sectional carriage surveys of 2,000 individuals per country (5,000 in Mali

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Morning – Wednesday 9 November 2011
Notes
vision was to: n Develop a meningococcal conjugate vaccine and evaluate it in Africa n Create a pathway for the licensure of vaccine to be used largely in Africa n Assure production in sufficient volume to meet projected needs n Monitor throughout to assure the effectiveness and safety of the intervention n Finance the procurement of vaccine through existing or new global programs n Introduce the vaccine through mass and routine immunization programs in synergy with other public health programs. The Goal was to eliminate epidemic meningitis in Africa as a public health problem through the development, testing, licensure and widespread use of conjugate meningococcal vaccines at a cost that is affordable in the affected countries in the meningitis belt. After 10 years of Research and Development including safety, immunogenicity and antibody persistence studies and a process of licensure in India and WHO pre-qualification in June 2010, MenAfriVac™ became the first vaccine developed specifically for a poor population at a cost of approximately $1 to purchase and deliver. In December 2010, people across Burkina Faso, Mali, and Niger became the first to receive the vaccine with highly promising effects. Preparations are underway for MenAfriVac™ introduction to the remaining countries and for studies aimed at collecting data required for licensure for infant indication.

Morning – Wednesday 9 November 2011
Notes

Abstract
There have been great improvements in the medical management of children with meningitis and septicaemia over the past 15 years. Paediatricians in the UK have become united in managing sepsis in a standardised way. Meningococcal disease is no longer accepted to be an invariably fatal condition, 20 years of research has resulted in evidence-based protocols and MRF has been particularly instrumental in ensuring that this work is disseminated widely. Similarly in the adult based world, the Surviving Sepsis Campaign has produced protocols for improving the outcome from sepsis in adults. But how about the grey area of late adolescence? It is known that older teenagers have increased rates of meningococcal disease and higher case fatality rates than younger children. It is also known that teenagers are undergoing a metamorphosis from childhood to adulthood with physical changes occuring both in their bodies and brains. Socially teenagers can be difficult and this may affect the way diseases are recognised in this age group. The impact of a major disease such as meningococcal disease in teenagers can be profound. Sequelae are not only physical but also emotional, educational and social. These outcomes are worse than for younger children. Follow up rates in teenagers are also poor. Are all these problems due to the teenagers themselves or do we as medics contribute to the poor outcomes? Who should manage a 16 and a half year old who is still in school? A paediatrician or an adult physician? Are they always taken seriously when they present. Do they present late to doctors as it is assumed they are hungover or just being wimps? Does the fact they are able to compensate well in sepsis make recognition of disease severity more difficult? I would like to propose that we set up an adolescents sepsis UK task force to set standards for the care of adolescents with sepsis and particularly meningococcal disease. We need to bring together experts in paediatric and adult intensive care and adolescent physcians to mount a campaign to raise the profile of young people with sepsis. As I am actually not an expert in any of these fields, I propose to take the minutes and make the coffee! I welcome your interest.

10:50

COFFEE, EXHIBITION AND POSTERS

Current issues in recognition and treatment
Chair:
Notes
Simon Nadel has been a Consultant in Paediatric Intensive Care since 1994. Prior to this he trained in paediatric infectious diseases. He has been involved in coordinating and running therapeutic trials in children with meningococcal and other septic shock, and has taken part in research studies into the pathophysiology, treatment and outcome of meningococcal disease in children. He has been involved in writing clinical guidelines for the management of children with septicaemia and meningitis.

Dr Simon Nadel, St Mary’s Hospital, Imperial College London 11:50
Notes
Dr Mark Peters is Senior Lecturer in Paediatric Intensive Care at the Institute of Child Health, UCL and Hon. Consultant at Great Ormond Street Hospital and The Children's Acute Transport Service. His research interests started in laboratory studies in innate immunity and cellular adhesion and have developed into clinical studies in children with critical illnesses including trauma, sepsis and respiratory failure. He chairs the Paediatric Intensive Care Society Study Group and the Medicines for Children Research Network Clinical Studies Group for Anaesthesia, Pain, Intensive Care and Cardiology.

Dr Mark Peters, Institute of Child Health, University College London Overview of evidence for managing children with sepsis, including fluid management of children in shock

Dr Simon Nadel

Abstract

11:20
Notes

Dr Nelly Ninis, St Mary’s Hospital, Imperial College London Pitfalls in recognition of meningitis and septicaemia in teenagers
Dr Nelly Ninis is currently a consultant in General Paediatrics at St Mary’s Hospital, Paddington. She has completed training in paediatric infectious diseases and immunology and has an Msc in tropical medicine. She worked for three years on the Paediatric Intensive Care Unit at St Mary’s when it was a specialist referral unit for meningococcal sepsis. She conducted the RCPCH study on healthcare delivery and the outcome of meningococcal disease in children, funded by Meningitis Research Foundation. From this study she has developed an interest in the way sepsis is diagnosed both in primary and secondary care. Dr Ninis is also a part of the National Institute for Health and Clinical Excellence (NICE) Guideline Development Group for Meningitis and Septicaemia.
Dr Nelly Ninis

Observational studies in septic shock associate improvements in outcome with early and rapid fluid resuscitation. Adoption of protocols recommending >40mls/kg volume expansion in the first hour of in-hospital resuscitation, prior to intensive care may be crucial. Human albumin solution may be preferable to saline – perhaps because of a greater degree of volume expansion per administered volume. Adult and paediatric randomised trial data support the use of objective summary measures of the adequacy of oxygen delivery (ScvO2 or lactate clearance) to guide resuscitation. These studies imply that traditional goals of heart rate, blood pressure and perfusion are inadequate and more fluid and more inotrope therapy may rescue more patients. The very early septic shock deaths seen in the UK may be improved by simple adherence to existing protocols.
Dr Mark Peters

This standard view of the critical role of fluid resuscitation has been challenged recently by trial data from resource-limited settings. There are numerous possible explanations why cost and benefit of fluid resuscitation might differ widely in different populations but these data remind us of the poor evidence base on which our current practice is based. We need high quality studies of fluid resuscitation in critically ill children.

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Afternoon – Wednesday 9 November 2011
12:20
Notes

Afternoon – Wednesday 9 November 2011
14:00
Notes
Andrew J Pollard, FRCPCH PhD, is Professor of Paediatric Infection and Immunity at the University of Oxford, Director of the Oxford Vaccine Group, James Martin Senior Fellow, Jenner Institute Investigator, Fellow of the Infectious Disease Society of America, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital, Oxford, UK. 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 Prof Andrew Pollard guidelines development group, and chairs the NICE topic expert group developing quality standards for management of meningitis and meningococcal septicaemia. He sits on the Department of Health committee that considers use of meningococcal vaccines. He runs one of the largest paediatric research groups in the UK with 70 staff. Current research activities include clinical trials of new and improved vaccines for children, surveillance of invasive bacterial diseases in children in Nepal, studies of cellular and humoral immune responses to glycoconjugate and typhoid vaccines, and development of a serogroup B meningococcal vaccine. His publications include over 200 manuscripts and books on various topics in paediatrics, infectious diseases, and high altitude medicine.

Professor Mervyn Singer, University College London Current advances in sepsis management in adults
Mervyn Singer is Professor of Intensive Care Medicine at University College London. He has a major research interest in sepsis and multi-organ failure and champions the key role of mitochondria in causing organ dysfunction. He is an NIHR Senior Investigator and his research is funded by the Wellcome Trust, MRC, EU and NIHR. He has had major involvement in a number of multi-centre trials related to sepsis such as CORTICUS, PAC-MAN and ProMISe.

Professor Andrew Pollard, University of Oxford Changes to UK immunisation programme, including prospects for a teenage meningococcal booster

Abstract
Outcomes continue to improve though this appears more related to enhancements in the general process of care rather than specific innovations. High-profile campaigns have promoted early identification of sepsis and generic management guidelines though, of note, the reduction in mortality rates seem to have occurred outwith. To my mind, this highlights a Prof Mervyn Singer dilemma of which we are becoming increasingly aware, namely that our drugs and technologies have considerable power to, if not save, then at least prolong life yet, by the same token, have a powerful ability to cause harm. The detrimental effects are, however, subtle and rarely apparent at 'the end of the bed'. Our current lack of sophistication in immune, hormonal and metabolic monitoring fails to detect these covert changes. This monitoring deficiency may also be responsible in large part for the repeated failure of high-profile and high-expense multi-centre trials attempting to modulate the immune process. Thus, Prof Mervyn Singer the frequent inability to deliver the right dose to the right patient at the right time and for the right duration may contribute to the overall neutral or even negative outcomes of these studies. The subsets who may have benefitted are diluted or cancelled out by those where it did not deliver a positive effect. There is a considerable push at present to develop novel biomarkers to identify infection, sepsis and organ dysfunction at an early stage, and to prognosticate. This will probably assist greatly in identifying appropriate patients for treatment. This will also be allied with a greater appreciation of the pathophysiology underlying sepsis, and recognition that many seemingly 'negative' consequences may actually represent intrinsic attempts at adaptation which should be perhaps supported rather than reversed by our management.

Abstract
Since the implementation of a serogroup C meningococcal (MenC) vaccine programme in the UK 12 years ago, there have been a number of changes to the immunisation schedule designed to improve individual and population protection against bacterial meningitis and meningococcal septicaemia. The introduction of boosters at 12 months of age for Haemophilus influenzae type b (Hib) and MenC in 2006 and a reduction in the number of priming doses for MenC were undertaken in attempt to defend and sustain protection through early childhood. Whilst this approach appears to have been especially successful for Hib, MenC antibody wanes rapidly after the booster. With the highest rates of Hib carriage being in childhood, high antibody levels in the first few years of life both protect the individual and provide herd immunity by blocking Hib transmission, with the result that Hib disease is once again at a very low incidence. However, meningococcal carriage peaks in adolescence and early adulthood, and so strategies to sustain immunity at this age are being evaluated on both sides of the Atlantic to protect the individual from disease and block transmission of this organism to other cohorts (both older and younger) who remain susceptible. Strategies using either MenC or MenACYW vaccines could be considered. Maintaining Hib, and MenC immunity amongst the segment of the population responsible for transmission of the organism is essential for public health in the long term.

12:50 13:50

LUNCH, EXHIBITION AND POSTERS AWARD FOR BEST POSTER
On behalf of the Steering Committee, Professor David Lalloo will announce the award for best poster. The prize has been kindly donated by Pfizer.

Prevention of meningococcal disease
Chair:
Notes
Prof Ray Borrow is Head of the Vaccine Evaluation Unit at the Health Protection Agency (HPA) North West, Manchester, UK, where he is responsible for the evaluation of serological responses to various bacterial and viral vaccines with a special interest in meningococcal and pneumococcal vaccines. He is also the Deputy Head of the HPA Meningococcal Reference Unit for England & Wales. He gained his PhD in 1994, his MRCPath in 2003, became an Honorary Professor of Vaccine Preventable Diseases at the University of Manchester in 2009 and Visiting Professor of the Manchester Metropolitan University in 2011. His scientific findings resulted in over 190 peer reviewed published papers. He serves as a member of the DoH Joint Committee on Vaccination and Immunisation (JCVI) and frequently advises WHO and companies on both meningococcal and pneumococcal vaccines. He sits on the medical-scientific advisory panels for Meningitis Research Foundation, Meningitis UK and Meningitis Trust.

14:25
Notes

Professor Ray Borrow, Vaccine Evaluation Unit, Health Protection Agency, Manchester

Dr Paul Cleary, HPA Northwest, Liverpool Dealing with a localised MenB epidemic – the Cumbrian situation
Paul is a medical epidemiologist who joined the HPA in 2009. After several years as a hospital physician and periods working in epidemiological research in the UK and abroad, he retrained in public health and epidemiology. Since becoming HPA NW regional epidemiologist he has led the epidemiological investigation of a number of regional and national infectious disease outbreaks. His current research projects relate to Clostridium difficile and influenza and he has an ongoing interest in the use of advanced statistical methods in epidemiology.

Abstract
Invasive group B meningococcal disease remains a cause of significant morbidity and mortality in the United Kingdom. Most disease occurs sporadically but localised outbreaks occur, and Dr Paul Cleary available public health interventions are limited. Dr Cleary will describe the investigation and public health response to a cluster of invasive meningococcal disease in West Cumbria in early 2011 against the background of the wider epidemiology of invasive group B meningococcal disease and describes a meningococcal carriage prevalence study undertaken in West Cumbria to attempt to better understand the transmission of disease in this setting.

Prof Ray Borrow

14:50

COFFEE, EXHIBITION AND POSTERS

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Afternoon – Wednesday 9 November 2011 Prospects for prevention of meningococcal B disease
Chair:
Notes
Ian Feavers, PhD, is Head of the Division of Bacteriology at the NIBSC, UK. He studied for his PhD at the University of Newcastle upon Tyne, eventually moving to NIBSC after periods of postdoctoral research at the University of Sheffield and the Friedrich Miescher Institut in Basel. During the late 1990s, when new conjugate vaccines were being introduced, he headed the laboratory responsible for the control and standardisation of meningococcal and pneumococcal vaccines. Ian continues to oversee an active research programme on the molecular genetics and immunology of meningococcal and pneumococcal antigens. Because of his broad experience of bacterial vaccines and molecular biology, he has been closely involved with a number of meningococcal vaccine developments. He regularly contributes to WHO and EU guidelines, serves as one of NIBSC’s representatives on the Vaccine Working Party of the EMA, and is a member of the JCVI subgroup on meningococcal vaccines. Ian teaches on a number of vaccine related courses in the University of London and is a Visiting Professor at Imperial College.

Afternoon – Wednesday 9 November 2011
Notes
Dr Jansen left Merck in October 2004 to join VaxGen as Chief Scientific Officer and Senior Vice President for Research and Development with responsibility for VaxGen’s anthrax and smallpox vaccine programs. In 2006 she joined Wyeth (now Pfizer) as a Senior Vice President to lead the vaccine research, early development and clinical testing groups. Dr Jansen was appointed an Adjunct Professor at the University of Pennsylvania School of Medicine in 2010. She brings a recognised series of accomplishments, as well as an established international reputation in vaccine discovery research and development.

Professor Ian Feavers, National Institute for Biological Standards and Control

Abstract
Pfizer is developing a bivalent factor H binding protein (fHBP/LP2086) vaccine to prevent Neisseria meningitidis serogroup B (MnB) disease. fHBP, an outer membrane lipoprotein, protects MnB from complement attack. More than 2,500 invasive MnB disease isolates in addition to carriage isolates have been studied. IMDB and carriage isolates all contain the fhbp gene. The fHBP protein sequences segregate into two immunologically distinct subfamilies, A and B. Preclinical studies identified the importance of including one lipidated protein from each subfamily into the vaccine to achieve robust serum bactericidal antibody responses and broad coverage of disease isolates. Vaccine coverage in the context of fHBP sequence diversity is an important consideration for licensure, and post-licensure surveillance with appropriate surveillance mechanisms. fHBP sequences, expression levels, patient age and epidemiological markers were analyzed for MnB invasive isolates. Breadth of vaccine coverage was evaluated by hSBA using bivalent, rLP2086 immune sera from phase 2 studies conducted in adolescents ages 11 – 18 and young adults. A method to bridge hSBA responses from a limited number of IMDB isolates to a wider panel of MnB isolates was developed. The bivalent, rLP2086 vaccine candidate induced robust hSBA responses against diverse MnB strains. Clinical data from phase I/II will be reviewed in the context of epidemiological studies. Bridging data to epidemiologically important IMDB isolates will also be presented. The bivalent, rLP2086 investigational vaccine confers broad seroprotection against diverse MnB invasive strains. Efficacy will be determined and monitored using hSBA responses (surrogate for protection) with invasive MnB strain expressing heterologous (compared to vaccine) fHBP sequences.

Prof Ian Feavers

15:10
Notes

Dr Peter Dull, Novartis Vaccines and Diagnostics, Cambridge, MA, USA Prospects for use of Novartis 4CMenB vaccine
Biography on page 13 Abstract
The variability of expression of serogroup B immunodominant surface proteins, coupled with the poor immunogenicity of the MenB capsule, have prevented the successful introduction of a broadly protective MenB vaccine. Vaccines tailormade to specific MenB strains have been developed to control epidemic outbreaks caused by specific MenB clones. In New Zealand, an outer membrane vesicle-based MenB vaccine (MeNZB) has proven effective in all age groups, including infants, after its introduction in 2004. As approaches using standard Pasteur principles to develop a universal MenB vaccine have so far been unsuccessful, utilising a novel ‘reverse vaccinology’ technique, Novartis Vaccines has identified multiple new vaccine targets and incorporated them into a multicomponent vaccine, 4CMenB (Bexsero™). Phase 3 clinical trials have been completed and an application for licensure was submitted in Europe in December 2010 which included data from over 5000 infants and 1500 adolescents. Recently available clinical data will be reviewed as well as updates provided on the regulatory status of the vaccine.

15:40
Notes

Dr Kathrin U Jansen, Pfizer Inc, NY, USA Pfizer strategy for prevention of meningococcal B disease
Kathrin U Jansen, PhD is a Senior Vice President at Pfizer’s Pearl River, NY campus. She has responsibility for the scientific management of vaccine research and early development including management responsibilities for all vaccines clinical testing. She received her doctoral degree in Microbiology, Biochemistry & Genetics from Phillips Universitat, Marburg, Germany, in 1984. Following completion of her formal training and postdoctoral work at the Institute for Mikrobiologie in Marburg, Dr Jansen continued her training with Professor GP Hess at Cornell University working on the expression of the acetylcholine receptor in yeast for structural and functional studies. She then joined the Glaxo Institute for Molecular Biology in Geneva, Switzerland where she focused on basic studies of a receptor believed to be a drug target to treat allergies. In 1992 Dr Jansen moved to the Merck Research Laboratories. During the following 12 years she directed a number of vaccine research efforts, including Merck’s novel bacterial vaccine programs. She initiated Merck’s vaccine program for the prevention of human papillomavirus infection (HPV). She played a central role in the vaccine’s design, the development of novel HPV clinical diagnostic assays, clinical trial designs, the study of the virus’ epidemiology, and the entry of the vaccine into definitive clinical trials. Her efforts led to the licensure of the world’s first cervical cancer vaccine (Gardasil®).
Dr Kathrin U Jansen

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Afternoon – Wednesday 9 November 2011
16:10
Notes

Afternoon – Wednesday 9 November 2011
Notes

Interactive session: Implementing a MenB vaccine Moderator: Professor Andrew Pollard, University of Oxford
Biography on page 27

Professor Michael Levin, St Mary’s Hospital, Imperial College London
Biography on page 15

This interactive session, involving a panel of experts in the fields of vaccine development, epidemiology, clinical management and research, will discuss the issues surrounding the introduction ofa MenB vaccine into the UK immunisation schedule. Questions on all aspects of MenB vaccine implementation are invited from the audience as part of this ‘Any Questions’ style session. Panel:
Notes

Dr Mary Ramsay, HPA Colindale, London
Biography on page 8

Dr Chris Worth, UK Medical Director, Novartis Vaccines Professor Ray Borrow, Vaccine Evaluation Unit, Health Protection Agency, Manchester
Biography on page 26
Dr Chris Worth MRCGP FFPM FFPH is UK and Northern Europe Medical Director for Novartis Vaccines and is based at the Frimley (UK) office. He graduated in medicine from Nottingham University Medical School. After working for some years in general practice in the Midlands, Chris became a successful Director of Public Health for a number of Health Authorities in West Yorkshire within the NHS during the 1990s. Chris was also Visiting Professor of Public Health at the University of Huddersfield during that period. He actively contributed to UK and local public health policy and wrote many scientific publications. Chris joined Janssen-Cilag Ltd in 2000 as Head of Medical Affairs, before moving to GSK as the UK Head of Vaccines in 2005. He has been with Novartis Vaccines since May 2007. Chris' current role is to lead a wide range of medical affairs activities in the UK, Ireland and Northern Europe across the whole vaccines portfolio, with special reference to meningococcal disease. In recent years, Chris has been Deputy Registrar of the Faculty of Pharmaceutical Medicine.

Professor Ian Feavers, National Institute for Biological Standards and Control
Biography on page 28

Dr Chris Worth

Professor Adam Finn, University of Bristol
Biography on page 13

16:50 Dr Nick Kitchin, Senior Director, Vaccine Clinical Research, Pfizer
Nick attended medical school in London where he obtained a BSc in Biochemistry with first class honours in 1988 before qualifying as a physician in 1991. His early clinical career was as an anaesthetist, probably the specialty in medicine where the clinical pharmacology of drugs can be most obviously observed. Seeking new challenges, Nick joined the pharmaceutical industry in 1994, initially working on the first clinical trials of new drugs in man – so-called Phase I trials. In 1995 he joined the Clinical Development department of Bayer Pharmaceuticals in the UK, working primarily on later stage (Phases II to IV) clinical trials of cardiovascular drugs, for example for the treatment of hypertension and hyperlipidaemia. In addition, Nick was the European project leader for a replacement treatment for patients with alpha-1 antitrypsin deficiency. Nick started specialising in the field of vaccines in 1998 when he joined Pasteur Mérieux MSD in the UK as Head of Clinical Affairs and Pharmacovigilance. He was integral to the licensure of, and subsequent national recommendation for, the company’s paediatric vaccines Pediacel®, Repevax®, and Revaxis®. Nick was also closely involved in the company’s response to the disproved allegations that MMR vaccine caused autism and bowel problems. After a spell as Medical Director for Baxter BioScience in the UK, Nick became Medical Director of Sanofi Pasteur MSD in the UK in 2004 where he was responsible for all activities of the medical department including Medical Affairs, Medical Information, Pharmacovigilance, Regulatory Affairs and Quality Assurance. Latterly he also took on responsibility for the company’s Health Economics and Market Access functions. In 2011 Nick joined Pfizer as a Senior Director in Vaccine Clinical Research where he is part of the global team working on the development of rLP2086, the company’s investigational vaccine against serogroup B meningococcal disease.
Dr Nick Kitchin

CLOSE

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Host-Pathogen Interactions
H1

Poster Presentations
Meningitis and Septicaemia in Children and Adults
Tuesday 8 and Wednesday 9 November 2011

Neisseria meningitidis serogroup B targets human dendritic cells to modify T helper cell responses in vitro
Alastair Copland1,2, Hannah E. Jones2, Mona Bajaj-Elliott2, Nigel J. Klein2, Garth L. J. Dixon2,3
1Division

of Infection and Immunity, University College London, London, UK Diseases and Microbiology Unit, UCL Institute of Child Health, London, UK of Microbiology, Great Ormond Street Hospital for Children NHS Trust, London, UK

2Infectious

3Department

Keywords: dendritic cells, interleukin-17, T helper cells, signal transduction, immune evasion Neisseria meningitidis serogroup B (Nm) is an important cause of meningitis and septicaemia. To date, no broadly-protective vaccine is yet available. Several recent studies have assessed the interaction between human dendritic cells (DCs) and Nm, as DCs are key mediators of adaptive immunity and vital for efficacious vaccine responses. We have previously reported that live and killed Nm differentially mature DCs, with live Nm inhibiting the full maturation of human DCs. Here we examine how Nm inhibits phenotypic DC maturation and also describe how this affects T helper (Th) cell responses. DCs were infected with live and killed Nm and analysed for surface maturation markers CD40 and CD80. Killed Nm increased the surface expression of these markers and induced full phenotypic maturation, while live Nm prevented the increase in expression (p=<0.05). Further experiments showed that live Nm was able to block the activity of potent TLR agonists including the viral mimetic poly(I:C) and peptidoglycan from Staphylococcus aureus, with DCs unable to increase the expression of maturation markers. We next sought to investigate whether signalling pathways necessary for DC maturation were being affected by live Nm. Detection of IκB-⍺ by Immunoblotting was used as a measure of NF-κB activity. At 2 hours, killed Nm induced IκB-⍺ degradation, whereas there was no apparent degradation of IκB-⍺ in DCs infected by live bacteria. This raises the possibility that live NMB may interfere with NF-κB signalling pathway, which is required for DC maturation. As an effective Th cell repertoire is critical for pathogen clearance, we wanted to know whether the modification of DC signalling affected Th polarisation. An in vitro DC-CD4 co-culture model was used to assess the development of Th1, Th2 and Th17 cells by DCs pulsed with live or killed Nm. Flow cytometry experiments showed that live Nm induced a stronger Th2 response than killed Nm, and also produced a lower percentage of Th1 cells. Furthermore, live Nm was found to inhibit the development of Th17 cells when compared to killed Nm and positive controls. Our data suggest that live Nm actively modifies DCs via a crucial signalling pathway and this modulates the resulting Th response. We speculate that this may be a novel form of meningococcal immune evasion by the DC-mediated inhibition of antibacterial T cells. Candidate immunological receptors and bacterial ligands responsible for this effect are currently under investigation.

Host-Pathogen Interactions H1-6

pages 33-35

Epidemiology and Surveillance E7-18

pages 36-41

Clinical Diagnosis, Treatment and Sequelae C19-29

pages 42-47

H2
Public Health Management PH30-32

Anti-inflammatory and cyto-protective properties of commensal Neisseriae
pages 47-49
Keith Page and Victoria Davenport Faculty of Life Sciences, University of the West of England, Bristol, UK Contact email: victoria.davenport@uwe.ac.uk

Vaccine Discovery and Vaccinology V33-58

Keywords: Nasopharyngeal, inflammation, cytotoxicity, invasion, commensal

pages 49-63

Objective of the study N. lactamica is a human tropic commensal of the nasopharynx that may convey protection against invasive and/or colonising N. meningitidis in the population. We have previously demonstrated that N. lactamica attenuates inflammation induced by N. meningitidis in nasopharyngeal derived epithelial cells, by suppressing NFκB activity in a PPARγ-dependent manner. This study aimed to determine whether Neisseria commensals commonly found in the upper respiratory tract of healthy adults, N. cinerea and N. polysacchareae, share N. lactamica’s ability to attenuate host cell innate inflammation induced by N. meningitidis. We further aimed to investigate the effects of commensal Neisseriae on host cell invasion and host cell death by N. meningitidis and the Gram positive pathogen S. pneumoniae. Methods used The human nasopharygeal epithelial cell line Detroit 562 (D562) was grown to confluence and challenged with N. meningitidis (strain MC58) in the presence or absence of commensal Neisseriae (N. cinerea, N. polysaccharea, N. lactamica). Cells were challenged for 3h with bacteria, washed and cultured for a further 21h in the presence of antibiotics to generate supernatants for the evaluation of IL-6 cytokine secretion by sandwich ELISA. Standard gentamicin protection assays were performed to determine the effect of commensals on N. meningitidis invasion but using a lux-transformed N. meningitidis (Lux-MC58) and light output which was monitored by luminometer. Fluorescent molecular probes, Yopro1 and propidium iodide, were used to determine pathogen-induced host cell death and levels of protection afforded by commensal Neisseriae against Streptococcus pneumonia (Sp14) and Neisseria meningitidis. Summary of results We demonstrate for the first time that N. lactamica (p<0.001) and N. cinerea (p<0.01) but not N. polysacchareae were able to significantly attenuate host IL-6 cytokine secretion induced by N. meningitidis. Nasopharyngeal cell invasion by N. meningitidis was also inhibited by both N. lactamica and N. cinerea (p<0.0001) but not N. polysaccharea. Both necrotic and apoptotic host cell death was induced in nasopharyngeal cells challenged with N. meningitidis. Whilst both N. lactamica (p<0.001) and N. polysacchareae (p<0.0001) were able to attenuate necrotic cell death, only N. lactamica was able to suppress induction of apoptotic cell death induced by N. meningitidis (p<0.001). In contrast both N. lactamica (p<0.01) and N. cinerea (p<0.001) were able to suppress the induction of apoptosis by S. pneumoniae.

Please visit the poster presentations during breaks, lunchtimes and the wine reception. The posters are displayed around the atrium walls and in the EDR. Presenters will be on hand to discuss their work. The prize for the best poster will be awarded after lunch on Wednesday 9th November.

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Conclusions Commensal Neisseriae which colonise the nasopharynx of children and adults afford host cell protection against related Gram-negative and unrelated Gram-positive pathogenic bacteria that naturally colonise the same niche.

Acute and convalescent CFH levels were not found to be statistically different in each of the genotypes for the SNPs rs1065489 or rs11582939. Conclusion CFH polymorphisms increase susceptibility to MD. Both CFH genotype and protein levels are associated with clinical sepsis parameters, but the mechanism needs to be elucidated. In the presence of infection, there is depletion of the serum CFH, which may increase complement activation. Excessive complement action, may in part be responsible for the multisystem failures seen in sepsis, as suggested by the correlation between poorer coagulation and cardiac function as well as outcome measures with lower CFH levels in the acute setting. Further study of CFH protein concentration and function in relation to genotype are required to define the mechanisms.
References: 1. Davila S, Wright VJ et al., Nat Genet. 2010 Sep;42(9):772-6. 2. Agbeko RS et al., Pediatr Crit Care Med. 2010 Sep;11(5):561-7 3. Haralambous E et al., Scand J Infect Dis. 2006;38(9):764-71

H3 Role of factor H binding protein (fHbp) in intracellular survival of Neisseria meningitidis after phagocytosis by human macrophages
Pike A1, Keats S1, Green L1, Serruto D2, Read RC1
1Dept

of Infection & Immunity, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK degli Studi di Siena, Siena Italy

2Universita

Keywords: Meningococcus, Factor H binding protein, Innate immunity, Phagocytosis, Macrophage Project Rationale & Hypothesis Factor H binding protein (fHbp) is a surface antigen of N. meningitidis which inhibits complement deposition on the bacterial surface and may also be protective against endogenous defensins. fHbp is a major component of new generation meningococcal vaccines. Objectives To determine whether fHbp influences meningococcal phagocytosis by primary human monocyte-derived macrophages (MDMs), and if fHbp enhances intracellular survival of N. meningitidis after phagocytosis by MDMs. Methodology N. meningitidis was coincubated with 14 day-old MDMs at a range of multiplicities of infections, under opsonic and non-opsonic conditions. Bacterial association to the macrophage surface and internalisation were quantified by immunofluorescence. Intracellular survival of bacteria over 2 hours after phagocytosis was measured using a standard gentamicin protection assay. Uptake and survival of wild type organisms were compared with fHbp null mutants and a complemented strain. Findings fHbp significantly reduced internalisation of meningococci by MDMs opsonised by complement C6 deficient serum, but not under nonopsonic conditions. No difference was observed in intracellular survival of non-opsonised bacterial strains even when the MDMs were activated with Interferon-γ. We conclude that meningococcal fHbp inhibits opsonic uptake of N. meningitidis by macrophages, but has no effect on resistance to intracellular microbicidal mechanisms.

H5 Gene Expression in relation to severity of Meningococcal Disease
V. Wright1, N. Yang2, L. Ling2, C. Hemingway1, N. Pathan1, H. Betts1, D. Inwald1, S. Nadel1, M.L Hibberd2, M. Levin1
1Paediatrics, 2Infectious

Imperial College London, UK;

Disease, Genome Institute of Singapore, Singapore

Keywords: RNA expression profiling Background and aims Meningococcal sepsis and meningitis remains one of the most devastating infections affecting young children and adolescents worldwide. Considerable progress has been made in understanding the pathophysiology and immunopathogenesis of the disorder, but mechanisms underlying shock and multi-organ failure still remain poorly understood. We aimed to understand the host response to meningococcal infection using whole-genome RNA expression profiling, both in acute disease and after recovery. Methods We used the Illumina Sentrix BeadChip array to examine patterns of gene expression in peripheral blood from 39 Caucasian paediatric patients with meningococcal meningitis or meningococcal sepsis. We compared gene expression in the acute phase to 21 Caucasian controls, as well as comparing expression levels between different clinical forms and different phases of the disease. Results We identified distinct subsets of genes differentially expressed by >2-fold between cases and controls, acute and convalescence, and meningococcal sepsis and meningococcal meningitis. Multiple biological pathways were found to be activated in the acute samples, including those mainly involved with the inflammatory response and in cell-to-cell signaling and interaction. Conclusions RNA expression analysis provides a way of studying the complex inflammatory and metabolic processes in critically ill children. Our analysis identifies inflammatory genes and pathways involved in meningococcal sepsis and meningitis, and provides a comprehensive insight into the complexity of the host response to meningococcal infection.

H4 Complement factor H genotype and protein levels associated with the clinical sepsis phenotype in children with meningococcal disease
Rodrigues CMC1, Wright VJ1, Inwald D1, Khor CC2, Davila S2, Hibberd ML2, Levin M1
1Department 2Infectious

of Paediatric Infectious Diseases, 2nd Floor Wright-Fleming Institute, St Mary’s Campus, Imperial College London, UK

diseases, Genome Institute of Singapore, Singapore

Contact email: c.rodrigues@imperial.ac.uk Keywords: Complement factor H, meningococcal disease, sepsis, genotype, clinical markers Introduction Sepsis secondary to Neisseria meningitidis infection is a feared presentation for parents and professionals alike, due to the potentially rapid and devastating decline in these patients. The disease process and subsequent morbidity can be profound producing cardiovascular, coagulation, renal and limb impairment. A recent genome wide association study (GWAS)[1] has identified variants in the complement factor H (CFH) gene and associated regions, which predispose to meningococcal disease (MD) susceptibility. CFH polymorphisms and MD associations have also been noted in 2 other UK based studies[2],[3]. Aim We aimed to establish if serum CFH protein level and sepsis phenotype are associated with CFH genotype, thereby affecting risk of MD. Method A retrospective analysis using CFH data from the GWAS[1] of 475 paediatric patients with MD and 4073 population controls was undertaken. Genotypes, serum CFH levels (measured on an initial cohort of 60 patients) and several parameters of the sepsis phenotype, including clinical and biochemical markers, were investigated. Results Mean serum CFH levels were higher in the convalescent samples compared to the matched acute samples (p=0.0005). There was a trend for higher mean CFH levels in convalescent samples when compared to adult controls (p=0.0583). When acute CFH levels were compared to the sepsis parameters, there was significant positive correlation with: ICU free days (p=0.0499), white cell count (p=0.0001), CRP (p=0.0087) and negative correlation with: Rotterdam score (p=0.0332), GMSPS (p=0.0070), PRISM (p=0.0135), INR (p=0.0235), APTT (p=0.0037). Mean acute serum CFH levels were lower in the group requiring inotropes (p=0.0327). Only CRP level (p=0.0032) and platelet count (p=0.0095) were significantly different by genotype for the 2 most significant SNPs identified in GWAS[1] (rs1065489 and rs11582939).

H6 Meningococcal surface protein mutations that disrupt human serum protein binding - a strategy for enhanced immunogen design
Lan Zhang1, Arthur Fridman2, Irene Pak2, Jing Lin1, Hui Xu1, Xin-Min Wang1, Zhiyun Wen1, Bob Lucas1, Eberhard Durr1, Chris Mensch1, Thomas Rosahl3, Ansu Bagchi2, Jan ter Meulen1, Craig Przysiecki1
1Vaccine

Research, Merck, West Point, PA, USA IT, Merck Global Service, Rahway, NJ, USA

2Informatics 3ETS,

Capability Del. In Vivo, Merck, Rahway, NJ, USA

Contact email: lan_zhang2@merck.com Keywords: meningococcal B vaccine, pathogen-host interaction, transgenic mice Many bacterial human pathogen surface proteins bind specifically to human sera components or cell surface proteins with high affinity. These interactions are important for bacterial virulence during infection or in the maintenance of the carriage state. By altering host ligand binding sites on these bacterial surface proteins, it may be possible to increase the titers and breadth of specific humoral immune responses by potentially increasing the number of accessible epitopes. Meningococcal factor H binding protein (fHbp) binds human factor H (fH), a serum intrinsic complement pathway inhibitor. fHbp has been identified as an important vaccine target and is included in several vaccines currently in clinical trials to prevent serogroup B meningococcal infection. We have designed fHbp analogs with potentially reduced binding to fH as vaccine candidates, by disruption of salt bridges and hydrogen bonds based on known protein structures. These analog proteins were expressed recombinantly in E. coli and purified. The overall folding of these mutants was analyzed by their CD spectra and their ability to bind anti-fHbp monoclonal antibodies. fH binding ability of these analogs was also evaluated using ELISA. Based on these in vitro screening experiments, selected fHbp analogs are injected into human fH transgenic mice (as well as wildtype mice) to evaluate the effect of the mutations on eliciting a functional immune response, antibodies with serum bactericidal activity. To identify additional human sera binding partners of bacterial surface proteins, a qualitative Ni-NTA resin pull-down assay was developed using recombinant HIS-tagged bacterial surface proteins with in-gel proteomics analysis. We have obtained proof-of-concept data using recombinant HIS-tagged fHbp to pull-down human fH from normal human serum.
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Epidemiology and Surveillance
E7 2011 - Invasive Bacterial Diseases caused by N.meningitidis, H.influenzae, S. pneumoniae and L.monocytogenes at University Hospital for Infectious Diseases “Dr Fran Mihaljević” Zagreb, Croatia
Suzana Bukovski University Hospital for Infectious Diseases “Dr Fran Mihaljević” Zagreb, Croatia Contact email: sloukovski@bfm.hr; suzana.bukovski@mefos.hr Keywords: IBD, sepsis, meningitis, S.pneumoniae, N.meningitidis Introduction Since 2005 at University Hospital for Infectious Diseases “Dr Fran Mihaljević” invasive bacterial disease (IBD) caused by N.meningitidis, H.influenzae, S. pneumoniae and L.monocytogenes was diagnosed using simultaneously traditional cultivation method and molecular method, in house real time polymerase chain reaction (PCR). The cultivation, as a “gold standard”, gives us important information about the antibiotic susceptibility pattern of IBD causing microorganisms. Materials and methods Data about patients treated at our hospital from January till mid September 2011 with positive blood or/and cerebrospinal fluid (CSF) samples for N.meningitidis, H.influenzae, S. pneumoniae and L.monocytogenes were included. Two methods for the detection of etiological agent are used, cultivation with antibiotic susceptibility testing and in house real-time PCR detection based on specific primers. Results During the analysed period 74 patients with IBD treated at our hospital had positive blood or/and CSF. There were 23 children and 51 adults. S.pneumoniae was the predominant etiological agent and it caused 49/74 IBD mainly in adults (35/49) while N. meningitidis caused 18/74 IBD, in 9 adults and 9 children. L.monocytogenes caused IBD in 5 adults and H.influenzae was the cause of 2 adults IBD cases. It was recorded that sepsis was the dominant presentation of IBD in children (21/23) and it was caused by S.pneumoniae in 13/21 children while in 8/21 children N.meningitidis caused sepsis. Group B N.meningitidis predominated (7/8 isolates) and 1 isolate was N.meningitidis group C. One N.meningitidis isolate was recorded as penicillin intermediate (0.094 µg/mL) and 1 was recorded as penicillin resistant (0.5 µg/mL). All isolates were susceptible to ciprofloxacin, rifampicin and ceftriaxone. Sepsis was the predominant presentation of IBD in adults too (27/51). Among S.pneumoniae cases meningitis was the predominant clinical presentation in adults (18/20). L.monocytogenes caused meningitis in three adults and sepsis and meningitis in two adults. H.influenzae non b type caused sepsis in one adult and sepsis and meningitis in one adult. Conclusion Once again the main cause of IBD at our hospital was S.pneumoniae. It was the main cause of sepsis in adults and in children. H.influenzae cases were recorded in adults and all were non-vaccinable type. N.meningitidis causes mainly sepsis in children and N.meningitidis group B was the predominant isolate. Therefore our focus could be on a meningococcal vaccine against N.meningitidis group B.

Abstract conclusions This study represents the first comprehensive report outlining the national baseline serotype distribution of PM in Niger before the introduction of conjugated vaccine against pneumococci. All years during the study period, serotype 1 was the most common and accounted from 34 to 53% of CSF investigated. This is a similar finding to that of the study carried out in Burkina Faso (2) and to a lesser extent to Malawi (3). This report shows the importance of a sustained and efficient microbiological surveillance of PM complemented by an accurate analytical methodology for determining pneumococci serotypes.
References 1. Pai R, Gertz RE, Beall B. Sequential multiplex PCR approach for determining capsular serotypes of Streptococcus pneumoniae isolates.

J Clin Microbiol. 2006;44:124-31. 2. Njanpop-Lafourcade B, Sanou O, van der Linden M, Levina N, Karanfil M, Yaro S, Tamekloe TA, Mueller JE. Serotyping of pneumococcal meningitis cases in the meningitis belt by use of multiplex PCR with cerebrospinal fluid. J Clin. Microbiol. 2010; 48:612-4. 3. Cornick JE, Everett DB, Broughton C, Denis BB, Banda DL, Carrol ED, Parry CM. Invasive Streptococcus pneumoniae in children, Malawi, 2004-2006. Emerg Infect Dis 2011; 17:1107-9.

E9 Epidemiology of Serogroup B Invasive Meningococcal Disease in Ontario, Canada, 2000-2010
Vica Dang1,3, Frances Jamieson1,3, Sarah Wilson1,2, Prasad Rawte1, Natasha S Crowcroft1,2, Karen Johnson1, and Shelley L Deeks1,2
1Public 2Dalla

Health Ontario, Toronto, Canada, of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada

Lana School of Public Health, University of Toronto, Toronto, Canada,

3Department

Keywords: Invasive Meningococcal Disease, Neisseria meningitidis, serogroup B, epidemiology, Ontario (Canada) Objectives The introduction of a meningococcal quadrivalent (serogroups A, C, Y and W-135) vaccine into Ontario’s publicly-funded immunization program has left serogroup B as the only invasive meningococcal disease (IMD) serogroup that is not yet vaccine preventable. Vaccines targeting this serogroup are close to being approved, which prompted an assessment of the epidemiology of serogroup B disease in Ontario, Canada. This is important to assess the potential impact of vaccines, as well as to provide baseline data prior to vaccine availability. Methods Information on confirmed IMD cases was retrieved from Ontario’s integrated Public Health Information System and linked to IMD laboratory records from Public Health Ontario’s Laboratory via probabilistic linkage. The surveillance period was from January 1, 2000 to December 31, 2010. Capture re-capture method was used to estimate sensitivity of the linked IMD data. Rates were calculated with denominator data obtained from Statistics Canada. Results A total of 713 IMD cases were identified over the 11-year period in either data source, of which 77.3% (551/713) were successfully linked. The sensitivity of linked IMD data was estimated to be 98.9% (713/721). Over the surveillance period serogroup B was the most common IMD serogroup (259/713, 36.3%); incidence ranged from 0.11 to 0.27 per 100,000 per year, and fluctuated over time. There was a male predominance (55.1%) and cases ranged in age from 13 days to 101 years, with a median age of 17 years. Age distribution was positively skewed; 21.4% (55/257) of cases occurred in infants (< 1 year), of which 70.9% were < 6 months of age. The highest incidence occurred in infants (3.70 per 100,000; 95% CI, 2.72 to 4.67), followed by children 1-4 years (0.66 per 100,000; 95% CI, 0.46 to 0.87). There was geographic variation in rates, with the incidence in Toronto (0.11 per 100,000; 95% CI, 0.07 to 0.15) significantly lower than both Central West regions (0.22 per 100,000; 95% CI, 0.17 to 0.28) and Eastern (0.22 per 100,000; 95% CI, 0.16 to 0.29). The case-fatality ratio (CFR) was 10.7% overall; individuals ≥ 65 years had the highest CFR (21.1%), followed by infants (13.5%). The most common antigenic variant was B:14:P1.14 (10.4%; 22/242). Conclusions Between 2000 and 2010, serogroup B was the most common cause of IMD in Ontario and infants had the highest risk of disease. These findings can aid in decision-making regarding serogroup B vaccination programs in Ontario, including considerations of target age.

E8 Determination of Pneumococcal Serotypes in Meningitis Cases in Niger, 2003 – 2011
Abdel-Kader Alio Sanda, Jean-François Jusot, Bassira Alkassoum, and Jean-Marc Collard Centre de Recherche Médicale et Sanitaire (CERMES), Niamey, Niger Contact email: jmcollard@cermes.org Keywords: pneumococcal meningitis, microbiological surveillance, sequential multiplex PCR, pneumococcal conjugate vaccine. Abstract background Invasive pneumococcal disease and particularly pneumococcal meningitis (PM) causes an enormous burden in sub-Saharan Africa. Little is known about the circulating serotypes of Streptococcus pneumoniae responsible for meningitis cases in Niger. Since 2003, a total of 1016 cerebrospinal fluids (CSF) have been detected positive for PM based on a lytA PCR assay but only a limited number of strains (about 10% of the collected CSF) were isolated on culture and were serotypable. In order to characterise the circulating pneumococcal serotypes responsible for meningitis cases in Niger prior to the introduction of a potential pneumococcal conjugate vaccine, we formulated a new multiplex PCR algorithm for serotyping pneumococci directly on refrigerated/frozen CSF. Abstract methods Serotyping was performed using the sequential multiplex PCR method (SM-PCR) described by Pai et al. (1) with a national algorithm in which 32 different serotypes were grouped into eight PCRs. All PCRs included four primer pairs for different serotypes. The national algorithm was adapted according to the distribution of 86 pneumococcal strains isolated between 2003 and 2008 and serotyped by the use of the Quellung reaction (Hamidou AA, unpublished data). Abstract results Between 2003 and June 2011, the serotype of S. pneumoniae present in 740 CSF was determined (83 were non-recoverable, 68 were cpsA negative and 127 were non-typeable with the SM-PCR). In total, 26 different serotypes were identified. Serotype 1 (n=388) was the most prevalent and accounted for 44.8% of infections (non-typeable included), followed by serotypes 12F/(12A/44/46) (6.5%), 6/(6A/6B/6C) (5.2%), 14 (5.1%), 5 (4.6%), 23F (4.0%), 45 (3.6%), 2 (3.0%) and 18/(18A/18B/18C/18F) (2.8%).

E10 The Epidemiology and Surveillance of Meningococcal Disease in England and Wales
Gray SJ1, Campbell H2, Marsh WJ3, Carr AD1, Newbold LS1, Mallard RH1, Guiver M1, Borrow R1, Ramsay M2 and Kaczmarski EB1.
1Health 2

Protection Agency (HPA) Meningococcal Reference Unit (MRU), NW Regional HPA Laboratory, Manchester Royal Infirmary, Manchester M13 9WL, UK Immunisation Department, Centre for Infections, HPA, Colindale, London, UK Department, Manchester Medical Microbiology Partnership, Manchester Royal Infirmary, Manchester, UK

3Virology-Molecular

Email: steve.gray@hpa.org.uk Keywords: meningococcal disease, epidemiology, surveillance, serogroups, age groups Background and Aims: The HPA performs surveillance of invasive meningococcal disease for England and Wales to ascertain case numbers and characterise strains.

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Materials and Methods: Clinicians notify suspected cases of meningococcal meningitis/septicaemia to the Office for National Statistics. Microbiology laboratories submit isolates for phenotypic characterisation and since, October 2007, by porA sequencing. MICs of penicillin, cefotaxime, rifampicin and ciprofloxacin are determined. Clinical samples are submitted for non-culture detection and serogroup confirmation by PCR. Results and Conclusions: The increase in serogroup C cases from 1995-9 resulted in the introduction (November 1999) of serogroup C conjugate (MenC) vaccine into the UK population. Laboratory confirmed cases rose from 1,448 in 1995 to peak at 2,804 in 1999 falling to 917 in 2010. During 2010, 489 cases (53%) of invasive meningococcal disease were confirmed by PCR alone (comprising 16,607 samples representing 11,418 patients investigated by PCR). Serogroup B accounted for 88% of all confirmed cases (2010), 7% were serogroup Y (more than doubling from 28 cases in 2004 to 68 in 2010) whereas only 2% (20 cases) were confirmed as serogroup C and 3% serogroup W135. Phenotypic and genotypic shifts have been observed, specifically the relative contribution of clonal complexes ST-41/44, ST-269, ST-32, ST-213 and ST-11 to meningococcal epidemiology. Surveillance has demonstrated a sustained reduction in serogroup C infections since 1999 to 2005 remaining at <20 cases per year, a direct consequence of the MenC programme and resultant herd immunity. A small but detectable increase in serogroup Y cases is now being closely monitored.

Results From 2005-2010 the incidence of invasive pneumococcal disease (IPD) increased from 1.57 to 3.87 cases / 100,000 population (2005: 1.57, 2006: 2.03, 2007: 4.22, 2008: 2.99, 2009: 3.54, 2010: 3.87). The cases with the clinical manifestation meningitis decreased from 23.3% in 2005 to 15.1% in 2010. After low case fatality rates in the years 2005, 2006 and 2007 (2.4%, 3.9%, 3.6%), an abrupt rise was seen in 2008 (14.07%) and 2009 (17.9%). In 2010 the case fatality rate declined to 7.9%.The age specific incidence shows in all years the typical international pattern with the highest incidence rates in the under one year and 80+ age groups. The lowest incidence was observed in the age group 10-14 years. Serotype data was available for 1168 invasive isolates. A total of 47 different serotypes were identified. The five most frequent serotypes were 3 (15.6%), 14 (10.1%), 1 (8.7%), 7F (7.0%) and 4 (5.6%). All other serotypes were under 5%. The PCV/7 covered serotypes decreased from 46% (50/108) in 2005 to 16% in 2010 (48/291). The additional serotypes in PCV10, PCV13 and PPV23 showed only minimal fluctuations. The non-vaccine serotypes increased from 7% (8/108) in 2005 to 15% (48/291) in 2010. Conclusions After introduction of PCV/7 an abrupt reduction of the incidence of IPD in the age group 0-5 years in 2006-2007 was registered. This was followed by a subsequent return to almost prevaccine levels in 2009-2010. In the 0-5 age group a steady rise in non-PCV7 serotypes from 2005 to 2010 and also a subtle recurrence of the PCV7 serotypes 2007-2010 is seen. These results must be interpreted with caution because the completeness of the serotype data and the sensitivity of laboratory surveillance varied in the years 2005-2010.

E11 Modifications to a Published ctrA PCR Assay for the Improved Non-Culture Confirmation of Meningococcal Disease in England and Wales
Guiver M1, Corless CE2, WJ Marsh3, Gray SJ1, Newbold LS1, Borrow R1 and Kaczmarski EB1
1Health

E13 Approaches to modelling serogroup A meningococcal disease in Africa
Tom Irving1,2,3,*, Caroline Colijn4, Konstantin Blyuss5, Caroline Trotter2
1 2 3 4 5

Bristol Centre For Complexity Sciences, University of Bristol School of Social and Community Medicine, University of Bristol Department of Engineering Mathematics, University of Bristol Department of Mathematics, Imperial College London Department of Mathematics, University of Sussex

Protection Agency (HPA) Meningococcal Reference Unit (MRU), NW Regional HPA Laboratory, Manchester Royal Infirmary, Manchester M13 9WL, UK. of Microbiology, 7th Floor Duncan Building, Royal Liverpool University Hospital, Liverpool. L7 8XP, UK. 3Virology-Molecular Department, Manchester Medical Microbiology Partnership, Manchester Royal Infirmary, Manchester, M13 9WL, UK.

2Department

Contact email: malcolm.guiver@hpa.org.uk Keywords: meningococcal disease, PCR, ctrA, non-culture, modified primers Background and Aims: The HPA MRU has used a realtime Taqman™ ctrA PCR to detect capsulated Neisseria meningitidis in clinical samples (non-culture confirmation) since 1997. In 2003 it was observed that a small number of culture proven cases were matched with clinical samples negative with the screening ctrA assay (Corless et al., 2001). It is with interest we note recent publications from other groups reporting the same phenomenon (Cavrini et al., 2010 and Jaton et al., 2010). Methods and Results: Nucleotide sequencing was performed on a 142bp region spanning the ctrA real-time PCR assay primer binding regions on 7 cultured isolates that were ctrA assay negative. The isolates were B:NT:P1.9 (4) B:NT:P1.5,2 (2) and B:NT:P1.7 (1) but all MLST CC ST-269. The nucleotide sequence data identified 4 nucleotide substitutions in the reverse primer sequence (A702G, T705G, A708C and A717G) and a single substitution in the probe binding region (G606A) based on the full length ctrA gene sequence (AF520903). A modification of the published assay (Corless et al., 2001) to incorporate an additional reverse primer (5’-TTGCCGCGGATTGGCCACCA-3’) has been made to enable detection of this variant strain. Results and Conclusions: Since March 2003 approximately 80,000 samples have been screened with the modified ctrA assay and there have been no obvious culture proven only cases where appropriately matched clinical samples have been ctrA negative. This is an illustration of the potential for the emergence of variants that may present problems in PCR based assays and highlights the need for continued surveillance of isolates.

* Canynge Hall, 53 Whatley Road, Bristol, BS8 2PS. Email tom.irving@bristol.ac.uk Keywords: Africa, meningococcal disease, modelling, meningitis belt, epidemics The causes of the frequent but unpredictable large epidemics of meningococcal disease that affect the African meningitis belt are poorly understood, but are likely to be a combination of climatic effects and waning population immunity. With the ongoing introduction of the serogroup A vaccine in sub-Saharan Africa, it is important to be able to gain insights into the pattern of these epidemics and to investigate how they might change. Mathematical modelling has been widely used to gain insights into infectious diseases and to help formulate vaccination policy. We outline our past and future modelling approaches. Deterministic models suggest that population immunity is more important than climatic factors in causing epidemics. Properly parameterised stochastic models will be used to further investigate these findings.

E14 Epidemiology of Invasive Meningococcal Disease in Moscow, 2005-2010
T.A. Maxina1, I.S. Koroleva1 I.M. Zakroeva1, G.V. Beloshitsky1, I.N. Lytkina2, and A.P. Pyaeva2
1Federal

Center for Surveillance on Bacterial Meningitis, Central Research Institute of Epidemiology, Moscow, Russia of Federal Service on Surveillance for Consumer Rights Protection and Human Well-Being for Moscow, Russia

2Directorate

Contact email: irina-korol@yandex.ru Keywords: surveillance, morbidity, mortality, meningococci, serogroup Invasive meningococcal disease (IMD) remains a significant problem for public health in Moscow. Twice during the last 15 years, (in 1996 and 2003) a significant increase in IMD morbidity was observed in the city with respective incidence 3.8 and 3.6 per 100,000 population. Official records on IMD cases in Moscow were retrospectively analyzed for the period 2005-2010. From 2005 to 2010, 1348 cases of IMD were identified (with an incidence of 2.1 per 100,000 people in 2005, 2.5 in 2006, 2.3 in 2007, 2.8 in 2008, 1.9 in 2009, 1.3 in 2010). Mortality from IMD was characterized by the absence of down and up trends. In the studied period 114 deaths due to IMD were registered (case-fatality ratio: 7.2% in 2005, 11.7% in 2006, 11.1% in 2007, 4.4% in 2008, 6.5% in 2009, 11.1% in 2010). A seasonal rise of IMD incidence was observed with the peak during winter-spring period. The proportion of laboratory-confirmed IMD cases in Moscow from 2005 to 2010 was in the range of 52 to 67%. One of the important parameters of epidemiologic surveillance for IMD is serogroup distribution. During the studied period mainly meningococci of serogroups A, B, and C were identified in laboratoryconfirmed IMD with predominance of serogroup A (except 2009), although meningococci of serogroups Y, Z, W-135 were also detected in some cases. Unlike other years, in 2009 IMD incidence caused by meningococci of serogroups A and C was nearly equal. IMD incidence among children ≤14 years of age in Moscow (7.5 per 100,000) was five times higher than in persons over 15 years of age (1.5 per 100,000). Average annual incidence of IMD in males exceeded those in females (1.3 and 0,9 per 100,000, respectively). Comparison of morbidity between children not attending day care centers (not organized), attending day care centers (organized), and schoolchildren showed that during the studied period IMD incidence in not organized children was 5.3-fold higher than in the organised children (0.63 and 0.12 per 100,000 of the cohort, respectively) and 2.3-fold than in schoolchildren (0.27 per 100,000 of the cohort). Introduction of mass vaccination with meningococcal conjugated vaccines (MCV) in the USA and Europe led to a dramatic reduction in IMD incidence. There is a rationale for use of multivalent MCVs in Russia due to substantial proportion of children below 2 years of age in the total number of IMD cases as well as the dominance of A and C and presence of W-135 and Y serogroups in the structure of laboratoryconfirmed cases.

E12 Austria 2005-2010, Epidemiology of Invasive Pneumococcal Disease
S. Heuberger1, A. Kormann-Klement1, U. Orendi1 , Y-L. Liu2 und D. Schmid2,
1National

Reference Centre for Meningococci, Pneumococci and H.influenzae, Austrian Agency for Health and Food Safety, Graz, Austria Centre for Infectious Diseases Epidemiology, Vienna, Austria

2Competence

Contact email: sigrid.heuberger@ages.at Keywords: Pneumococci, Epidemiology, Incidence, Disease Background The National Reference Centre for Pneumococci (NRCM) was founded by the Ministry of Health in 2004. The NRCM collects data on cases of invasive pneumococcal disease (IPD) for annual analysis. The heptavalent pneumococcal vaccine (PCV/7) was introduced 2004 and is offered free of charge to children in high-risk groups. The 23-valent polysaccharide vaccine (PPV23) is recommended for persons aged ≥ 65 years and older. Methods The IPD case definition is consistent with 2008/426/EG. The isolates referred to the NRCM are routinely serotyped by serum-agglutination. The statistical analysis of seasonal and long term trends by the yearly incidence of invasive pneumococcal disease in Austria was done with regression analysis.

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E15 The epidemiology of invasive meningococcal disease in Scotland 1999-2010
Eisin McDonald1, Barbara Denham2, Alison Smith-Palmer1, Giles Edwards2, Claire Cameron1
1Health 2The

E17 Continuing increase in 19A and 6C serotype carriage in children after the introduction of PCV-7 in the Netherlands
S.M.P.J. Prevaes1,2, N. Y. Rots3, J. Spijkerman1,2, E.J.M. van Gils1,2, R.H. Veenhoven2, A.J.Wijmenga-Monsuur3, D. Bogaert1, J.P. Bruin4, E.P. IJzerman4, G.P.J.M. van den Dobbelsteen3, E.A.M. Sanders1
1Department 2Research 3National 4Regional

Protection Scotland, Meridian Court, 5 Cadogan Street, Glasgow, G2 6QE

Scottish Haemophilus Legionella Meningococcus and Pneumococcus Reference Laboratory (SHLMPRL), Stobhill Hospital, 133 Balornock Road, Glasgow, G21 3UW

of Pediatric Immunology and Infectious Diseases, Wilhelmina Children Hospital, University Medical Center, Utrecht,

Contact email: eisin.shakir@nhs.net Keywords: Epidemiology, Meningococcal disease, Serogroup B, Clinical presentation, Case fatality ratio Meningococcal disease is a notifiable disease caused by infection with the bacterium Neisseria meningitidis. It is a significant cause of morbidity and mortality, particularly in children and young people. Meningococcal Invasive Disease Augmented Surveillance (MIDAS) was introduced in Scotland in 1999 to monitor the impact of the meningococcal C vaccine. This poster presents the epidemiology of invasive meningococcal disease in Scotland from 1999-2010 and discusses the potential implications for meningococcal B vaccine introduction. There has been an average of 190 cases of meningococcal disease (3.4 cases per 100,000 population) reported each year in Scotland, including both clinical and laboratory confirmed cases. This has decreased steadily from 350 cases (6.8 cases per 100,000 population) in 1999 to 99 cases (1.9 cases per 100,000) in 2010. Approximately half of all cases reported are in children under five years of age (1083/2286; 47.4%) and the highest incidence is observed in children under one year of age with an average 82.8 cases per 100,000 population. Laboratory confirmed cases of invasive meningococcal disease submitted to the Scottish Haemophilus, Legionella, Pneumococcal and Meningococcal Reference Laboratory (SHLMPRL) are routinely serogrouped. Serogroup B has been the most commonly detected serogroup in Scotland (903 cases), followed by C (208 cases), Y (42 cases) and W135 (34 cases). The most commonly reported clinical presentation for cases was meningitis (799 cases; 35%), followed by septicaemia (641 cases; 28%) and both meningitis and septicaemia (387 cases; 17%). There were 136 deaths reported in the time period equating to an overall case fatality ratio (CFR) of 5.9%. However, CFR was found to vary by age and meningococcal serogroup. In summary, meningococcal disease has declined in recent years in Scotland but remains a significant source of morbidity and mortality, especially among young children. As group B disease accounts for around three quarters of laboratory confirmed cases, any ability to prevent these infections could have a substantial impact on overall incidence of disease.

Center Linnaeus Institute, Institute of Public Health and the Environment, Bilthoven, Laboratory of Public Health, Haarlem The Netherlands

Keywords: pneumococcal vaccine, carriage, The Netherlands, subtypes, 19A Background Pneumococcal conjugate vaccine (PCV-7) was implemented in the Dutch NIP in 2006. We studied the ongoing effect of PCV-7 introduction on nasopharyngeal pneumococcal carriage over time. Methods In follow-up of a randomized controlled trial (RCT) (NCT00189020), we performed two cross-sectional studies in 2009 and 2010 collecting nasopharyngeal swabs at 11 and 24 months of age from PCV-7 vaccinated children and from one of the parents of the latter group (n ~ 330 = per group). Swabs were cultured for S. pneumoniae and serotyped by Quellung. Results In 11-month-olds PCV-7 carriage rates were 38%, 8% and 3% in 2005, 2009 and 2010, respectively, whereas in 24-month-olds vaccine serotype carriage was 36%, 3% and 3% (p<0.001 for all comparisons vs. 2005). Carriage of non-PCV-7 serotypes increased in 11-montholds from 29% in 2005 to 39% and 50% in 2009 and 2010, respectively (p<0.01 for all comparisons vs. 2005) and from 30% to 45% and 61% in 24-month-old children (p<0.001: vs. 2005). A significant increase in carriage of 19A was found in 11 and 24-month-old children over time (11 months: 2%, 10% and 12%, 24 months: 3%, 6% and 14%, respectively). Moreover, the latter serotype also became the most dominant serotype. Besides, 6C carriage increased as well as other non-vaccine serotypes over time. In parents a similar shift of serotypes was seen. Conclusions Within 4.5 years after introduction of PCV-7, vaccine serotypes are virtually eliminated in children and their parents. However, non-PCV-7 serotypes, in particular 19A, have emerged. Pneumococcal disease surveillance remains important.

E16 Bacterial meningitis in babies 0-90 days of age: a UK and Republic of Ireland prospective study
I.O. Okike¹, K. Henderson², R. Blackburn², B.Muller-Peabody², A. Johnson², P.T. Heath¹
¹Child ²HCAI

E18 Seroprevalence of serum bactericidal antibodies against group W135 and Y meningococci in England in 2009
Caroline Trotter1, Helen Findlow2, Helen Chadha2, Kelly Townsend2, Dani Thompson2, Lesley Mabey2, Stephanie Slater2, Stephen Clark2, Kate Nolan2, Ray Borrow2
1School

Health and Vaccine Institute, St George’s, University of London & AMR Department, Health Protection Services Colindale, HPA

Keywords: bacteria, meningitis, neonates, burden, management Background and aims Meningitis in the first 3 months of life is associated with significant mortality and morbidity. Previous UK studies were conducted in the 1980s and 1990s. It is important to define the current burden of disease and how they are being managed and identify any opportunities for improvements in diagnosis and management in order to prioritise treatment and prevention strategies and establish an evidence based management guideline. Methods Cases are identified prospectively by active surveillance through the British Paediatric Surveillance Unit (BPSU), routine microbiological surveillance through the Health Protection Agency, and via parents of cases through meningitis and Group B streptococcus (GBS) support charities. The surveillance period is July 2010 – July 2011 (burden of disease study) and September 2011- March 2012 (healthcare delivery study-HCD). Only cases notified outside the standard BPSU methodology in England are used for the healthcare delivery study. This study is based on a detailed medical notes review and parent-completed questionnaire. With parental consent, recruited babies will also be contacted at two years of age for a neurodevelopmental assessment. Results Over the first 10 months of the study 213 cases meeting the case definition of bacterial meningitis were reported; 189 (88.7 %) and 9 (4.2%) from England and Wales respectively. 130 (61%) were male and the median age of disease was 14 days (range 0-88). 123 isolates were obtained from the cerebrospinal fluid; GBS (63, 51.2%) was the most common bacterium followed by Streptococcus pneumoniae (12, 9.8%), Neisseria meningitidis (9, 7.3%), Escherichia coli (9, 7.3%) and other Gram positives (12, 9.8%). 35 (16.4%) had CSF pleocytosis, a negative CSF culture but a positive blood culture, while 58 (27.2%) had clinical signs, CSF pleocytosis (≥20 or ≥10 cells/mm3 for babies ≤28 days or 29-90 days respectively), but no organism identified. Conclusions There remains a significant burden of meningitis in the first 3 months of life which has not changed over the last 3 decades. New strategies for prevention are required. The HCD study will provide data on the timing of events (symptoms/ signs) leading up to the diagnosis of bacterial meningitis in babies 090 days old in England. Both studies will contribute to new guidelines on the management of neonatal meningitis. Funded by Meningitis Research Foundation.

of Social and Community Medicine, University of Bristol, Bristol, UK Evaluation Unit, Health Protection Agency North West, Manchester, UK

2Vaccine

Keywords: seroprevalence, serum bactericidal antibody activity, N meningitidis group Y, N meningitidis group W135, UK Background and aims Serological surveillance has been used in the United Kingdom to inform vaccine policy for several infections, including group C meningococci. Quadrivalent meningococcal conjugate vaccines, containing groups A, C, W135 and Y, are now available. The aim of this study is to establish a baseline for immunity for groups W135 and Y in England. Methods Serum samples collected in 2009 from individuals across all ages (N=1191) were obtained from the Health Protection Agency Seroepidemiology Unit, which collects residual sera from participating laboratories across the country. Serum bactericidal activity (SBA) against serogroup Y (strain M03 241125) and W135 (strain M01 240070) was determined using a standardized complement-mediated SBA assay, with complement derived from baby rabbits. The age-specific geometric mean titres (GMTs) and percentage of individuals with SBA ≥8 (the putative protective level) were calculated, together with 95% confidence intervals. Results and conclusions Antibody prevalence varied according to age and serogroup. In general, titres were low in younger children with 7% and 13% of children under 5 years achieving titres ≥8 against group W135 and Y respectively. GMTs peaked in 20-24year olds for group W135 (GMT= 7.1 95% CI 4.7, 10.9) and in 30-44 year olds for group Y (GMT=8.6, 95% CI 5.9, 12.7). Unlike seroprevalence against group B meningococci, there was not an obvious peak in titres in teenagers. Natural immunity against group W135 and Y meningococci in England is low.

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Clinical Diagnosis, Treatment and Sequelae
C19 Oculomotor nerve palsy secondary to childhood bacterial meningitis: a systematic literature review of outcome and management effectiveness
Archer, J1 and Brown, R2
1Foundation 2Consultant

C21 Distal tibial growth arrest following meningococcal septicaemia; management and outcome in a series of seven ankles
F Monsell, J Barnes, A McBride, R Kirubanandan Bristol Royal Hospital for Sick Children, Bristol, UK Keywords: Meningococcal Septicaemia, deformity, external fixator, growth arrest, Limb alignment Survivors of infantile meningococcal septicaemia often develop progressive skeletal deformity as a consequence of physeal damage at multiple sites, particularly in the lower limb. Distal tibial physeal arrest typically occurs with sparing of the distal fibular physis leading to a rapidly progressive varus deformity. Isolated case reports include this deformity, but to our knowledge there is no previous literature that specifically reports the development of this deformity and potential treatment options. We report our experience of 6 patients (7 ankles) with this deformity, managed with corrective osteotomy using a programmable circular fixator.

Year Two, Paediatrics, Peterborough City Hospital, UK Paediatrician, Peterborough City Hospital, UK

Keywords: Bacterial meningitis, oculomotor nerve palsy, neurological sequelae, paediatric, amblyopia Background Oculomotor nerve palsy is a recognised sequela of meningitis reported in 3% (123/4102) of cases. We were struck by the lack of literature available to guide best practice management and inform parents regarding prognosis. Reviews of oculomotor palsies and of sequelae post bacterial meningitis use categories such as ‘post-infectious’ aetiologies or ‘neurological sequlae’. Potentially valuable information is lost. Objectives To evaluate: 1) In patients ≤ 16 years what is the course and outcome of oculomotor nerve palsy secondary to bacterial meningitis? 2) To what extent can different management strategies influence the above? Method A review was conducted of English language reports which included information of oculomotor palsies secondary to bacterial meningitis for subjects ≤16 years at diagnosis. Studies of encephalitis and aseptic meningitis were excluded. Papers were identified from an electronic database (OvidMEDLINE(R) 1950 to June 2011) and reference lists. The inclusion of descriptive studies was necessary. Due to heterogeneity of studies, calculating a summary estimate of effect was not possible. Results and Conclusions 8 reports (9 cases) were reviewed. Data from our unpublished case report was included. In all but two cases (6/8) the oculomotor palsy completely resolved. Time to resolution was a median 46 days (range 5 days to 1 year). This suggests it is largely a short-lived resolving sequela. The time to onset of the oculomotor palsy post symptoms’ onset was a median 4 days (range 2 to 11 days). Five cases proceeded to CT head of which four were initially normal. Palsies were all unilateral. 5/7 were partial. Pupillary involvement was inconsistent. Non-reactive mydriasis may be a sign of impending tentorial herniation, suggesting the need for a low threshold for ICP management. Some cases did not show other signs of raised ICP, supporting suggestions that nerve encasement by subarachnoid space exudate and vasculitis are also causes to target treatment. Cranial nerve palsies and pupillary involvement are significantly associated with death and sequelae at follow-up suggesting that oculomotor palsy should prompt management escalation. Amblyopia is common in oculomotor palsy. Cases respond to part-time patching. This highlights the need to remember the risk of amblyopia in the susceptible age-group. Post bacterial meningitis, while results are inconsistent a meta-analysis suggests adjuvant dexamethasone may reduce long-term neurological deficits and a double-blind placebo-controlled trial suggests oral glycerol may reduce neurological sequelae. The small sample size limits conclusions, suggesting the need for further study including contacting authors for unpublished data.

C22 Development of a tmRNA based NASBA Assay for the detection of Neisseria meningitidis
Eoin Clancy1,2,3, Helena Coughlan1,2,3, Terry Smith2,3 and Thomas Barry1,2,3
1Microbiology, 2Molecular

School of Natural science, National University of Ireland, Galway, Ireland

Diagnostics Research Group, National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Diagnostics Institute Programme, National Centre for Biomedical Engineering Science, National University of Ireland, Galway,

Ireland
3Biomedical

Ireland Keywords: Bacterial meningitis; Molecular diagnostics; tmRNA; NASBA; µTAS Failure to promptly diagnose and treat bacterial meningitis can result in significant morbidity and mortality. Bacterial meningitis is most commonly caused by one of three bacteria; Haemophilus influenzae type b (Hib), Neisseria meningitidis, and Streptococcus pneumoniae. A culture-independent means of rapid, low-cost multiplexed nucleic acid sequence-specific detection of these three bacteria would have a major impact, ultimately saving many lives and potentially reducing the use of broad spectrum antimicrobial agents to treat this disease. We have recently demonstrated the potential of the ssrA gene and its corresponding RNA transcript, tmRNA, as a molecular based target for the specific detection of a number of bacterial pathogens[1-3]. We are currently developing a suite of tmRNA isothermal in vitro amplification assays capable of detecting and differentiating the three main causative bacteria associated with bacterial meningitis. Once validated, these assays will be integrated onto a micro- Total Analysis System (µTAS) that will separate, capture, and detect the bacterial meningitis-specific targets from whole blood samples in less than one hour. In this poster, we demonstrate the development and use of a tmRNA based isothermal NASBA in vitro diagnostics assay for the sensitive and specific detection of N. meningitidis.
1. O'Grady, J., et al., tmRNA - a novel high-copy-number RNA diagnostic target - its application for Staphylococcus aureus detection using real-time NASBA. Fems Microbiology Letters, 2009. 301(2): p. 218-223. 2. McGuinness, S., et al., Development and validation of a rapid real-time PCR based method for the specific detection of Salmonella on fresh meat. Meat Science, 2009. 83(3): p. 555-562. 3. Wernecke, M., et al., Evaluation of a novel real-time PCR test based on the ssrA gene for the identification of group B streptococci in vaginal swabs. BMC Infectious Diseases,

C20 Angular deformity of the ankle with distal fibula sparing following meningococcal septicaemia
F Monsell, A McBride, J Barnes, R Kirubanandan Bristol Royal Hospital for Sick Children, Bristol, UK Keywords: Meningococcal Septicaemia, deformity, ankle, physis, varus deformity Progressive angular deformity of an extremity due to differential physeal arrest is the most common late orthopaedic sequelae following meningococcal septicaemia in childhood. 10 patients (14 ankles) with distal physeal arrest as a sequelae of meningococcal septicaemia have been reviewed. Radiographic analysis of their ankles has demonstrated a distinct pattern of deformity. In 13 out of 14 cases we have found that the distal fibula physis is completely unaffected and that continued distal fibula growth contributed to a varus deformity. We recommend that planning of surgical management should take in to account of this consistent finding during correction of these deformities.

2009. 9: p. 148-156.

C23 Meeting the health, social and educational needs of children who have survived meningitis and septicaemia: the parents perspective
Laura Clark1,2, Linda Glennie2, Suzanne Audrey1, Caroline Trotter1
1School

of Social and Community Medicine, University of Bristol Research Foundation, Bristol

2Meningitis

Contact email: laura.J.Clark@hotmail.co.uk Keywords: children, aftercare, needs, meningitis, parent There is little published research on the needs and provision of aftercare for children surviving meningitis and septicaemia. To investigate this further we used a mixed methods study design, employing a survey and in-depth follow-up interviews of a sample of survey participants. Participants were recruited from Meningitis Research Foundation’s member database and social media sites. Eligible participants were parents of children who survived meningitis or septicaemia between January 2000 and May 2010, living in the UK or Ireland. In stage one, participants completed a multiple choice questionnaire, either online or by post. In stage two, twenty participants were invited to take part in a follow-up interview, based on their answer to the survey question, ‘overall, to what extent does / did the aftercare and support received

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meet your child's needs?’ Interviews were designed to explore the factors affecting parents’ opinions of whether their child’s needs for aftercare had been met. Here we report on findings from follow-up interviews with 18 parents. We identified three main themes from interviews; accessing services, communication, and relevance or appropriateness of services. Our findings lend support to the NICE guideline recommending a follow-up appointment with a paediatrician 4-6 weeks after discharge and go further in identifying a need for parental support to cope with an often uncertain long term prognosis for their child. Difficulty navigating services emerged as an important issue and an understanding of the link between meningitis and cognitive and psychosocial problems amongst educationalists remains inadequate, so improvements in these areas would contribute to meeting the needs of parents and children.

A total of 159 were diagnosed with BM. Twenty seven percent (n=43) received dexamethasone. Of those patients without dexamethasone, only 13.9% (n=16) had received antibiotics before admission. In comparison, the mortality was non-significantly increased for those treated with dexamethasone (16.3% (n=7)) compared with patients without dexamethasone treatment (14.6% (n=17)). In addition, a nonsignificant increase was found in the risk of complications, intensive care treatment and sequelae. Detailed data analysis are pending. Conclusion We found no substantial benefit of adjunctive dexamethasone treatment in adults with BM. Empirical use of dexamethasone in this setting appears controversial. In addition, a limited amount of adults had received dexamethasone. Funded by Aarhus University Research Fund.

C24 Recognition and action to tackle acute bacterial meningitis in urban Blantyre, Malawi
N Desmond1, 2, D Nyirenda1, E Molyneux3, M Mallewa1,2,3, D Lalloo2, R Heyderman1
1Malawi-Liverpool-Wellcome 2Liverpool 3Queen

C26 How sick is this child? Predicting serious infections using four vital signs
Susannah Fleming1, Matthew Thompson1,2, Lionel Tarassenko3
1Department 2Department 3Institute

Trust Clinical Research Programme, Blantyre, Malawi

of Primary Health Care, University of Oxford, Oxford, UK of Family Medicine, Oregon Health and Sciences University, Portland, USA

School of Tropical Medicine, UK

Elizabeth Central Hospital, Blantyre, Malawi

of Biomedical Engineering, University of Oxford, Oxford, UK

Contact email: ndesmond@liverpool.ac.uk; nic.desmond@gmail.com Keywords: Acute bacterial meningitis, qualitative, recognition, action, Malawi Background More than one million cases of acute bacterial meningitis occur annually in sub-Saharan Africa including Malawi. Late presentation has been identified as a major contributor to high case fatality rates since prompt treatment is vital to effective management. We present findings from a Meningitis Research Foundation (MRF) funded cross-sectional study to explore treatment seeking pathways and reasons for late presentation in adults and young children at Queen Elizabeth Central Hospital (QECH) in urban Blantyre, Malawi. Methods We conducted 16 in-depth case history interviews (IDI) with carers and patients of adults and children purposively sampled by outcome. We held four focus group discussions (FGDs) with communities in QECH catchment areas. Following interim analysis we conducted 20 semistructured interviews with randomly selected Health Care Workers (HCW) stratified proportionally by cadre. Results Recognition Meningitis was commonly misdiagnosed at household level, often as malaria leading to prolonged periods of self-treatment or common indigenous illness requiring traditional medicine. Misdiagnoses at primary care level meant discharge with inappropriate treatment and deterioration of health status prior to re-presentation and subsequent delayed referral. Barriers to prompt action Treatment seeking decisions were embedded in social norms. Childhood illness was recognised earlier and men were slowest to acknowledge treatment need. Treatment seeking was delayed by economic constraints, perceptions of accessibility, long waiting times, erratic medical supplies and mistreatment by health providers. Treatment with chloramphenicol and referral followed later stage, emergency diagnosis. Policy priorities to reduce maternal mortality have had severe negative repercussions on other emergency referrals. Conclusion The prevention of meningitis is dependent on reactive, secondary prevention through prompt treatment seeking. There is need to develop and evaluate public health campaigns to address meningitis in Malawi, drawing on these findings and successful approaches implemented elsewhere.

Contact email: susannah.fleming@phc.ox.ac.uk Keywords: Vital signs, prediction, infection, data fusion Introduction Vital signs are known to be predictive of serious illness in children, but measuring them accurately and interpreting their values poses considerable challenges in primary and emergency care. Combining vital signs in a simple score may be a more useful and practical way of identifying children with serious illness. Method An existing dataset containing heart rate, temperature, respiratory rate and oxygen saturation measurements from 568 children admitted to a paediatric assessment unit with a suspected infection. The outcome measure used was the diagnosis of a serious infection, which was likely to be life-threatening if untreated, or which had a high chance of life-threatening complications or sequelae. Classification was carried out using the heart rate, temperature, respiratory rate and oxygen saturation elements of an existing paediatric scoring system (PAWS), designed for use in secondary care. In addition, a variety of data fusion models, including regression and distribution modelling, were developed using the same four vital signs. Jack-knifing was used to obtain accurate estimates of model quality. Results The existing scoring system had a potential range of 0-12 points, and showed best separation of the data when a score ≥2 was used to identify serious infection. This gave a sensitivity of 73.1%, and specificity of 49.5%. The area under the ROC curve was 0.64, which was below the 10th percentile for area under the ROC curve in the four best-performing data fusion models. The best-performing model produced a median area under the ROC curve of 0.69 (10th-90th percentile 0.66-0.72), with an optimal sensitivity of 64.6% (60.6-68.2) and specificity of 65.7% (61.6-69.7). This method fitted a four-dimensional Gaussian distribution to the vital signs data from each group, allowing the probability of membership into each class to be calculated for each child. Conclusion Data fusion of four vital signs (heart rate, temperature, respiratory rate, and oxygen saturation) provides moderate accuracy for predicting serious illness in children, and outperforms existing scoring systems. Although this type of score cannot easily be calculated by hand, it could be incorporated into commonly-available handheld phone applications, or into an integrated device incorporating a thermometer and pulse oximeter. Such a device would require a means of entering the patients age, as the technique uses evidence-based curves to allow for the normal variation of heart rate during childhood, and would also require entry of manually-measured respiratory rate.

C25 C27 Bacterial Meningitis In Adults And Dexamethasone: A 10 Year Review From Aarhus, Denmark
Schou K, Damsgaard J, Soegaard O, Oestergaard L, Leutscher P, Laursen AL, Deutch S Department of Infectious Diseases Q, Aarhus University Hospital, Skejby, 8200 Aarhus N Keywords: Bacterial meningitis, dexamethasone, outcome, treatment, adults Introduction including objectives Patients suffering from bacterial meningitis have a substantial risk of sequelae and death. Since 2002, treatment with adjunctive intravenous dexathasone has proven beneficial for the outcome of bacterial meningitis in adults. The aim of the study was to assess adjunctive intravenous dexamethasone in adult community-acquired bacterial meningitis (BM) in daily practice. Furthermore, to compare the outcome of these patients (dexamethasone vs no dexamethasone) regarding the causative agents, clinical manifestations, neurological status, and the course of the disease. Materials and methods We reviewed the reports of all adults with BM admitted to Aarhus University Hospital from January 1999 to December 2008. Sociodemographic and clinical data were extracted from the patients’ medical files for further in-depth analysis. In particular, we assessed the risk of complications, mortality and use of antibiotics and dexamethasone. Results

Purpura Fulminans in Childhood Meningococcal Septicaemia
Robert Fuller, Sian Falder University of Liverpool, Liverpool, UK L69 3BX Dept of Plastic Surgery, Alder Hey Children’s NHS Foundation Trust, Eaton Road, Liverpool L12 2AP Keywords: Septicaemia, Purpura Fulminans, APTT, Amputations, Audit Introduction Acute infectious purpura fulminans (PF) occurs in severe acute sepsis and is most commonly associated with gram negative bacteria, particularly Neisseria meningitidis. It is characterised by progressive and patchy cutaneous haemorrhage leading to tissue death as a result of vascular necrosis and disseminated intravascular coagulation. PF has been associated with higher mortality, cosmetic deformities and multiple amputations. t-PA has been shown to reduce incidence of amputations but has high rate of intra-cerebral haemorrhage. There is controversy over the use of fasciotomies. Aims (1) To audit all cases of meningococcal septicaemia and PF in Alder Hey since 2007 (2) To ascertain whether there are any factors or early signs that may assist in early diagnosis of purpura fulminans or predict its development (3) To compare our surgical management and outcomes of purpura fulminans to those of published literature. Methods

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This is a retrospective study of all patients admitted with suspected meningococcal septicaemia from 1st January 2007 to 31st May 2011. Electronic patient care records and laboratory data were retrieved to identify those patients who developed PF. Blood test results from days 1-7, medical and surgical interventions and outcome were reviewed. Results 125 patients were treated as suspected meningococcal sepsis. The mean age was 3 years 4 months (range was 1 month 24 days to 17 years; median 2 years 1 month). The number of admissions per year with meningococcal septicaemia decreased from 32 cases in 2007 to 23 cases in 2010, with 9 cases in the first 5 months of 2011. Mortality for meningococcal septicaemia was 4/125 (3.2%). Sixteen patients of the 125 developed PF (12.8%). Of these 16, 7 had surgical amputations (43.8%). None of these patients died. No patients underwent fasciotomy. The causative organism was N. meningitidis group B in 10 patients, and was unknown in the remaining 6. The study found that patients admitted who went on to develop PF had a significantly higher mean APTT on day one (95.6) compared to patients who did not develop PF (38.6). Conclusions (1) The number of cases of meningococcal septicaemia admitted to Alder Hey is decreasing (2) Both the mortality and amputation rates at Alder Hey Hospital compare favourably with published rates (3) Day one APTT may be useful in identifying patients who are at risk of developing PF and who may respond to an early intervention or be a suitable group for future prospective study into PF.

In young children with suspected meningitis, lumbar puncture (LP) forms an important component of the diagnostic and therapeutic process However, pre-request for CT scan can cause undesirable delay in effective treatment. Aim To find out if doing CT scan before lumbar puncture affects the clinical decisions in cases of suspected meningitis including the initiation of treatment. Methodology We retrospectively reviewed charts of children who were admitted with a diagnosis of meningitis between the age of 18 months and 14 years over a two year period in our tertiary hospital. A neuroradiologist subsequently reviewed all scans. Results A total of 116 cases were included, 79 (68.1%) were boys and 37 (31.9%) girls. 55.2% were in the age group 5 – 9 years, 25% were under 5. Mean age was 6.3±2.7 year. The majority (68.1%) were from the Middle East and 110 (94.8%) cases had LP done. CSF studies showed that 104 (92.8) cases were aseptic meningitis, 10 were bacterial and 2 were due to mycoplasma infection. Only 6 scans showed abnormalities. 2 scans showed diffuse brain oedema; one suggested possible uncal herniation and one showed dilatation of the ventricular system. One scan showed mild brain oedema and one mild ventricular dilatation and in both cases LP was done. No specific symptom or sign could predict the scan result with fever and vomiting occurring in all 6 cases. On average LP was done 8.9 hours after presentation (CI 7.7 – 10.1). CT scans were done 7.7 hours after presentation (CI 5.5 – 9.9). Antibiotics were started 6.3 hours after presentation (CI 5.3 – 7.3). No serious complication related to LP was reported in any of the cases. Conclusion CT scan is widely used in cases of children with suspected meningitis to decide on the safety of performing LP. The yield of the scans in these cases is very low. Performing the scans has resulted in significant delays in performing the LP and most importantly in initiating antibiotic therapy, a practice which can have serious consequences to the outcome of these cases.

C28 Risk Evaluation and Plan to Prevent Meningococcal Infections in Eculizumab-treated Individuals
Lucia Lee1, Therese Cvetkovich2, Robert Kane2
1Center 2Center

for Biologics Evaluation and Research, for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA

Keywords: eculizumab, safety, meningococcal, vaccine, post-marketing Background Eculizumab is a monoclonal antibody that inhibits complement component C5. Eculizumab-treated individuals are at increased risk of developing invasive meningococcal disease due to drug-induced terminal complement deficiency. In 2007, eculizumab was approved by EMA and FDA for treatment of paroxysmal nocturnal hemoglobinura (PNH), and is being reviewed for treatment of atypical hemolytic uremic syndrome (aHUS). Objective To review the current post-marketing safety requirements for meningococcal disease prevention in eculizumab-treated individuals, and describe characteristics of identified disease cases. Method Published articles and product approval summaries were reviewed for meningococcal disease cases in clinical trials. Post-marketing reports of cases through the year 2010 were identified from the FDA Adverse Event Reporting System. Results As part of the risk management strategy for preventing invasive meningococcal infections, all patients treated with eculizumab must be vaccinated with an age appropriate meningococcal vaccine beginning at least 2 weeks before initiating eculizumab, and patients are to be revaccinated according to country-specific recommendations for individuals with late complement component deficiencies. Eculizumabtreated patients are provided a Patient Safety Card that describes possible signs and symptoms of invasive meningococcal infection for which the patient should seek immediate medical attention. Of nineteen identified pre-licensure trial/post-marketing cases of meningococcal disease, the median age was 24 years (range 15–54). All but one individual had received a meningococcal vaccine as follows: tetravalent conjugate (n=4) or polysaccharide (PS, n=6), bivalent/monovalent PS or conjugate (combined n=8), and in n=3 the type of vaccine was not identified. The median time from first eculizumab dose to event onset was 5 months. Of 13 cases with known serogroup, seven were due to serogroup B. In 37 aHUS patients, no meningococcal infections occurred during the 26 weeks of eculizumab treatment. No cases of recurrent invasive meningococcal infection among eculizumab treated patients have been identified to date. Conclusions If approved, increased use of eculizumab for the treatment of aHUS would include greater numbers of pediatric patients. Invasive meningococcal infections can be anticipated among eculizumab-treated patients due to drug-induced complement deficiency, vaccine failure, and the lack of safe and effective licensed meningococcal serogroup B vaccines. The availability of multivalent infant meningococcal PS conjugate vaccines and serogroup B vaccines would optimize current strategies for meningococcal disease prevention.

Public Health Management
PH30 Meningitis in the Facebook generation: Public health out of hours management of a complex meningitis case in a teenager
Charlotte Ashton and Barry Walsh (joint presenting authors) South West London Health Protection Unit, Health Protection Agency, London, England Keywords: Public Health; out of hours; contact tracing; anxiety; teenager The Health Protection Agency provides 24/7 public health management of cases of infectious diseases including meningitis. Two of the salient actions following a probable or confirmed case of bacterial meningitis is to identify close ‘household’ contacts and arrange chemoprophylaxis for these individuals. The second is to manage concerns of contacts of the case who do not need antibiotics but are worried about becoming unwell. The aim of this piece of work is to share the response and lessons learnt by SW London HPU (SWLHPU) from the management of a meningococcal meningitis case with multiple close contacts over a weekend. SWLHPU received a call from a microbiologist on a Saturday lunchtime during the summer of 2011, notifying a case of probable bacterial meningitis in a teenager who had been admitted to ITU. As well as a number of close family contacts requiring prophylaxis we were informed that the case had recently returned from a holiday sharing an apartment with an extended group friends – all of whom required prophylaxis. There was a high level of anxiety particularly as several of the close contacts had meningitis like symptoms. Sadly the teenager’s condition deteriorated and they died. This escalated anxiety within the friend network. There was considerable concern from friends who had had minimal contact with the case in the previous week and were presenting at a range of out of hours GP practices and A&E units across South London and Surrey and who wanted prophylaxis. The case resulted in an extremely large workload over the weekend and a number of lessons can be shared with others around managing public health actions out-of-hours including: effective approaches to providing prophylaxis in a systematic manner to multiple close contacts through liaising closely with out of hours GPs; limiting anxiety and misinformation within the ‘Facebook generation’ who have access to a range of instantaneous routes of communication and through which rumours can spread rapidly; ensuring a consistent approach to provision of prophylaxis based on evidence based guidelines and effective communication of risk. Following the case a number of local resources are being developed to support management of cases in the future including increasing awareness of management of close contacts amongst clinicians; working with the MRF to develop supporting material for the worried well and primary care; local processes for transferring information to hospitals out of hours and local factsheets to support management of risk communication.

C29 In suspected cases of meningitis, do we need a CT scan before doing a lumbar puncture?
Wail Seleem1, Khalid Ibrahim1, Ahmed Sotouhi1, Hoda Badran1, Farooq Abdul-Aziz2, Nahla Sharf1
1Hamad 2Aspetar

Medical Corporation, Doha, Qatar Medical Center, Doha, Qatar

Keywords: meningitis, CSF, lumbar puncture, CT head

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PH32 Investigation of the uptake of chemoprophylaxis by contacts of cases of meningococcal disease in the North East of England
Anne Halewood, Health Protection Nurse1, Tom Inns, Epidemiology and Surveillance Scientist2, Dr Naweed Sattar, Specialist Registrar in Rehabilitation Medicine3, Dr Tricia Cresswell, Consultant in Health Protection1
1North 2North

Vaccine Discovery and Vaccinology
V33 Correlation of a high-throughput flow cytometric antibody-mediated membrane attack complex assay with the serum bactericidal assay
L.Allen, C.Brookes, S. Taylor, A.Gorringe Microbiological Services Porton, Health Protection Agency, Porton Down, Salisbury, UK Keywords: Neisseria meningitidis, complement, correlation, SBA, flow cytometry Serum bactericidal activity (SBA) has long been established as a correlate of protection for meningococcal vaccines with SBA titres of ≥1:4 measured using human complement established as providing a protective response. Thus potential vaccine efficacy is widely assessed by the measurement of serum bactericidal antibodies and this method is currently a requirement for vaccine licensure. However, the serum bactericidal assay requires large volumes of sera and can be laborious to perform. Development of high-throughput assays which require very low sera volumes is important in order to enable the assessment of bactericidal responses against large strain panels. We have developed a high-throughput flow cytometric assay measuring antibody mediated complement deposition. The assay uses fixed meningococci, IgG-depleted human plasma as the complement source and fluorescent anti C3c and C5b-9 antibodies to measure deposition of C3b/iC3b and C5b-9 (membrane attack complex) on the surface of bacteria. We have previously demonstrated good correlation between the deposition of C5b-9 and bactericidal titres using meningococcal strain M01-240149 (R=0.87, p<0.01). We have analysed antibody-mediated complement deposition and SBA with a panel of 40 human sera and a number of diverse meningococcal strains. We have confirmed the correlation between antibody-mediated C5b-9 deposition and bactericidal response. This data will be used to establish a cut-off value for C5b-9 deposition that will predict SBA.

East Health Protection Unit, HPA, Newcastle upon Tyne, England East Health Regional Epidemiology Unit, HPA, Newcastle upon Tyne, England Park Hospital, Newcastle upon Tyne, England

3Walkergate

Contact email: anne.halewood@hpa.org.uk Keywords: chemoprophylaxis; meningococcal disease; compliance; audit Objectives n To investigate the uptake of antibiotic chemoprophylaxis by contacts of cases of meningococcal disease, including timeliness of receipt of prescription, ease of access to prescription and medication, compliance with advice. n To make recommendations to improve uptake. Methods An audit was undertaken retrospectively involving the cohort of contacts of cases of meningococcal disease which occurred from 1 January to 31 March 2011. Contacts of cases who had died were excluded. A questionnaire was designed based on current North East Health Protection Unit (HPU) and national guidelines. The questions were tick box or scales with minimal free text except for a final open ended question. Cases and contacts were identified from the case management database. The questionnaire was administered by telephone to contacts by an experienced health protection nurse (AH). Epidata was used for data entry and STATA 11.2 for analysis Results There were 130 contacts of 28 cases with an average number of 4.6 contacts per case. Analysis of factors impacting on compliance was not possible as compliance was 99.23%. Key findings were: n 100% of contacts received advice, 75% within 24 hours n 34% received written information n 100% reported advice as “clear” n 48% of contacts were issued antibiotics on the hospital ward n Of the 52% issued with a prescription, 75% received this from a GP and 23% from a hospital doctor n Of those given a prescription, 28% had to go to more than one pharmacy and 22% reported obtaining the antibiotic from a pharmacy as “difficult”. Review of the responses to the open ended question suggested high levels of overall satisfaction with the advice given but difficulty in obtaining antibiotics from community pharmacies. Further analysis of the open ended question will be provided in the poster. Conclusions The national guidance on chemoprophylaxis changed in March 2011, recommending a single dose of ciprofloxacin in preference to a two day course of rifampicin. This may resolve a number of the problems identified in obtaining the chemoprophylaxis (which was usually rifampicin) in this study. Compliance was unexpectedly high in this audit but access to antibiotics was reported as easier when these were directly issued on the ward rather than by prescription. Efforts will be made by the HPU to improve the provision of written materials and there will be further dialogue with clinicians in relation to directly providing chemoprophylaxis to family contacts whenever feasible.

V34 Evaluation of the Impact of fHBP Vaccines on IMBD and N. meningitidis Carriage Isolates
Annaliesa S. Anderson1, Shannon Harris1, Ellen Murphy1, Neil Oldfield2, Dlawer Ala’Aldeen2 and Kathrin U. Jansen1
1Pfizer

Vaccine Research, Pearl River New York, USA for Biomolecular Sciences, University of Nottingham, Nottingham, UK

2Centre

Neisseria meningitidis serogroup B (MnB) is the last of the invasive disease causing N. meningitidis serogroups for which no broadly effective vaccine is licensed. Current vaccines in late stage development for the prevention of invasive meningococcal serogroup B disease (IMBD) include meningococcal factor H binding protein (fHBP) as the most important antigen to generate serum bactericidal antibodies. fHBPs are common to all N. meningitidis serogroups and can be categorized into two distinct subfamilies (A and B) on the basis of sequence diversity and serological response. The distribution of subfamily A and subfamily B is 30% and 70% respectively from subjects with IMBD. The vaccines in clinical development have differing degrees of cross-reactivity across fHBP variants. N. meningitidis polysaccharide conjugate vaccines for other serogroups are effective both at preventing invasive disease and interrupting oral-pharyngeal carriage, the primary mechanism for disease transmission. It is expected that a vaccine that targets IMBD isolates should also be effective at interrupting carriage. We evaluated the fHBPs of common carriage isolates, which are also associated with disease, to assess whether fHBP based vaccines have the potential to be effective against carriage-associated fHBP variants. Analysis of fHBP variants associated with carriage in the UK and US reveals that there is a higher proportion of subfamily A variants associated with carriage than with IMBD, increasing to 50% (UK) and 73% (US). The majority of carriage isolate variants are associated with IMBD, 95% (UK) and 85% (US), and are responsible for 84% to 92% of IMBD in these regions. The Pfizer bivalent fHBP vaccine was evaluated for its ability to generate serum bactericidal antibodies to kill IMBD isolates with fHBP variants associated with carriage. Isolates with variants that represented over 75% of fHBP carriage variants were tested. Carriage associated variants could be killed by the human bivalent fHBP immune serum. The coverage for IMBD isolates associated with carriage translated to >81% (US) and >85% (UK). Testing of additional variants is ongoing. These studies demonstrate that a bivalent lipidated vaccine has the potential to be effective against most fHBP variants that are associated with IMBD and meningococcal carriage isolates.

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V35 Examination of two meningococcal surface proteins as potential vaccine targets
F. Bidmos1*, H. Chan2, E. Kaczmarski3, I. Feavers2 and C. D. Bayliss1
1Department 2National

Results/Conclusion Using MATS, we estimated that 78% of the strains (95% confidence interval 66-91%) would be covered by 4CMenB. Half of the total strains (64% of the covered strains) potentially could be targeted by bactericidal antibodies against more than one antigen. Coverage estimates varied by country and ranged from 73% to 87%. 4CMenB has the potential to protect against a significant proportion of the MenB strains that have caused invasive disease recently in Europe.

of Genetics, University of Leicester, LE1 7RH, UK Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK

Institute of Biological Standards and Control, Blanche Lane, Potters Bar, EN6 3QG, UK

V37 The application of Structural Vaccinology in the development of a meningococcal antigen inducing broad protective immunity
MJ Bottomley1, M Scarselli1, B Aricò1, B Brunelli1, S Savino1, F Di Marcello1, E Palumbo1, D Veggi1, L Ciucchi1, E Cartocci1, E Malito1, P Lo Surdo1, M Comanducci1, MM Giuliani1, F Cantini2, S Dragonetti2, A Colaprico1, F Doro1, P Giannetti1, M Pallaoro1, B Brogioni1, M Tontini1, M Hilleringmann1, V Nardi-Dei1, L Banci2, M Pizza1 & R Rappuoli1
1Novartis 2CERM

3Manchester

* Corresponding author. Email: fab5@le.ac.uk; Keywords: menB, phase variation, haemoglobin receptors, antibodies, vaccine Recombinant protein preparations are currently being employed as alternatives to capsular polysaccharide conjugates in the production of effective vaccines against meningitis due to menB strains. While one of these vaccines (Bexsero® by Novartis), due for licensing later this year, has a strain coverage of about 80%1, there is a need for vaccines against other OMP targets that will provide broader protection. In this study, two phase-variable haemoglobin receptors that are believed to be crucial to the survival of the meningococcus in the blood, HpuAB and HmbR, are being considered as targets for the production of bactericidal antibodies. Previous studies in our lab have shown that one or both receptors are present and expressed in >95% of disease isolates tested2, indicative of the importance of the expression (phase variation ON-state) of these receptors during infection. A total of 5 variants of genes encoding these proteins were cloned from 1 carriage and 2 disease isolates and expressed in the E. coli expression strain BL21. HpuA was purified by binding to a nickel affinity column before elution with 120 mM or 150 mM imidazole. Inclusion bodies of HpuB and HmbR were solubilised in 6 M guanidine hydrochloride and refolded in the presence of 50 M hemin. Refolded proteins were subsequently purified using an ion exchange column. Mice were immunized subcutaneously with 20 g of each protein at weeks 0, 3 and 5. Terminal bleeds and spleens were taken at week 7. Sera were tested for reactivity with the relevant immunogens and also for cross-reactivity with antigenic variants and unrelated proteins in ELISAs and western blots. ⍺-HpuA antibodies reacted against antigenic variants of HpuA but not HpuB or HmbR. A degree of cross-reactivity was observed between ⍺-HmbR antibodies and the HpuB protein. Similarly, ⍺-HpuB antibodies reacted with HmbR. Epitopes shared between both proteins could be responsible for this cross-reactivity. Ongoing and future work includes the construction of deletion and complementation mutants, which will be used in whole blood assays to investigate the ability of meningococci lacking HpuAB and HmbR to grow in blood. Immunodetection assays to probe for antibodies against these receptors in carrier sera will be performed in addition to serum bactericidal assays to ascertain the ability of ⍺-HpuA, ⍺-HpuB and ⍺-HmbR antibodies to kill meningococci.
References 1. Donnelly, J., Medini, D., Boccadifuoco, G., Biolchi, A., Ward, J., Frasch, C., Moxon, E. R., Stella, M., Comanducci, M., Bambini, S., Muzzi, A., Andrews, W., Chen, J., Santos, G., Santini, L., Boucher, P., Serruto, D., Pizza, M., Rappuoli, R. and Giuliani, M. M. 2010. Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proceedings of the National Academy of Science. 107 (45), 19490-19495. 2. Tauseef, I., Harrison, O. B., Wooldridge, K. G., Feavers, I. M., Neal, K. R., Gray, S. J., Kriz, P., Turner, D. P., Ala'Aldeen, D. A., Maiden, M. C., Bayliss, C. D. 2011. Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence. Microbiology. 157, 1446-1456.

Vaccines & Diagnostics, Via Fiorentina 1, 53100 Siena, Italy.

Magnetic resonance Center, University of Florence, 50019 Sesto Fiorentino, Italy

Contact email: matthew.bottomley@novartis.com Keywords: vaccine, antigenic variability, structure, fHBP, MenB The development of vaccines against many pathogens is hampered by the sequence variability of their protective antigens. Where antigenic variability is limited (e.g. S. pneumoniae), vaccines have been developed by including several antigenic variants in a single vaccine. However, when antigenic variability is very high, as for Neisseria meningitidis serogroup B (MenB), the development of a successful vaccine has been problematic. To solve this problem, we have developed a Structural Vaccinology approach, to design a single antigen capable of inducing broad protective immunity against all natural variants of MenB. The factor H binding protein (fHBP) has been identified as a protective antigen of MenB. However, >300 variants of fHBP have been described, making it difficult to select a single variant to be included in a vaccine. Therefore, we analyzed all known fHBP variant sequences and were able to classify them into three groups (variant groups 1, 2 and 3). Using the NMR structure of variant 1 fHBP as a scaffold, we designed 54 different chimeric variant 1 proteins, each engineered to display a portion of a variant 2 or 3 protein on its surface. The structural integrity of each lead candidate eliciting bactericidal antibodies was verified by several biophysical techniques. Ultimately, by ‘transplanting’ patches of residues from variant 2 and 3 proteins onto the variant 1 scaffold, we created a single fHBP protein (named ‘G1’) bearing characteristics of variants 1, 2 and 3, which, when combined with novel adjuvants (see poster by M Pallaoro et al.) was able to induce antibodies able to kill all strains of MenB tested. We determined the crystal structure of the efficacious G1 protein, revealing at atomic resolution how the multiple immuno-dominant epitopes have been successfully grafted onto a single molecule§. We believe that the Structural Vaccinology approach may be suitable to develop antigens against other pathogens which, like MenB, show a high degree of antigenic variation. § Reference: M Scarselli et al., Science Translational Medicine (July 2011), vol 3 issue 91.

V36 Estimating the Potential Strain Coverage in Europe of a Multicomponent Vaccine Targeting Serogroup B Meningococci
Giuseppe Boccadifuoco1, John Donnelly1, Duccio Medini1, Marzia Giuliani1, Maria Stella1, Giacomo Frosi1, Maurizio Comanducci1, Stefania Bambini1, Alessandro Muzzi1, Mariagrazia Pizza1, Rino Rappuoli1, Jamie Findlow2, Ray Borrow2, Stefanie Gilchrist2, Danielle Thompson2, Morgan Ledroit3, Eva Hong3, Muhamed-Kheir Taha3, Raquel Abad4, Julio Vazquez4, Paola Mastrantonio5, Paola Stefanelli5, Cecilia Fazio5, Anna Carannante5, Jan Oksnes6, Dominique A. Caugant6, Heike Claus7, Ulrich Vogel7
1Novartis 2Health 3Institut

V38 Potential strain coverage of a multi-component meningococcus B vaccine in Germany and the Czech Republic
Heike Claus1, Pavla Krizova2, Martin Musilek2, Giuseppe Boccadifuoco3, Maria Stella3, Giacomo Frosi3, Duccio Medini3, Maurizio Comanducci3, Mariagrazia Pizza3, John Donnelly3 and Ulrich Vogel1
1University

of Würzburg, Institute for Hygiene and Microbiology and German Reference Laboratory for Meningococci, Würzburg,

Vaccines and Diagnostics, Siena, Italy;

Germany;
2National 3Novartis

Protection Agency, Manchester, UK; Pasteur, Paris, France; de Salud Carlos III, Madrid, Spain; Institute of Public Health, Oslo, Norway; of Wurzburg, Wurzburg, Germany Superiore di Sanita, Rome, Italy;

Reference Laboratory for Meningococcal Infections, National Institute of Public Health, Prague, Czech Republic; Vaccines and Diagnostics, Siena, Italy

4Instituto 5Istituto

Contact email: hclaus@hygiene.uni-wuerzburg.de Keywords: meningococcus, serogroup B, vaccine, antigen expression, strain coverage Object of the study The multi-component vaccine 4CMenB has been developed to target the antigenically variable population of serogroup B meningococci. The immune-dominant components of the vaccine are: FHbp (factor H binding protein), NHBA (Neisserial heparin binding antigen), NadA (Neisserial adhesion A), and outer membrane vesicles. Aim of the study was to estimate the strain coverage of 4CMenB in serogroup B meningococci in Germany and the Czech Republic. Material and methods Measurement of the relative antigen potencies of FHbp, NHBA, and NadA by the MATS ELISA (Donnelly et al. PNAS 2010) as well as antigen sequence typing of the variable region 2 of porin A (PorA) and multi-locus sequence typing were performed on 222 German serogroup B strains isolated 2007/2008 and 108 Czech serogroup B strains isolated 2007-2010. Results and conclusions The strain population differed with regard to the ST-41/44 clonal complex, which was more prevalent in Germany, and the ST-18 and ST35 clonal complexes which were more prevalent in the Czech Republic. Relative potencies above the positive bactericidal threshold were observed for FHbp in 69% of the German and 67% of the Czech isolates, for NHBA in 63% of the German and 42% of the Czech isolates and for NadA in 3% of the German and 4% of the Czech isolates. Antigen sequence typing revealed the presence of PorA P1.4 in 21% of the German and 1% of the Czech isolates. In total, the strain coverage of 4CMenB was estimated to be 81% (95% confidence interval 7193%) for the German and 74% (95% CI 59-87%) for the Czech isolates.

6Norway

7University

Keywords: Serogroup B, multicomponent, vaccine, coverage, Europe Background A multicomponent vaccine (4CMenB) is proposed for prevention of invasive serogroup B (MenB) meningococcal disease. Because MenB clinical isolates are diverse, it is necessary to assess the potential public health impact of 4CMenB. We defined a target population of MenB strains in Europe to estimate strain coverage by 4CMenB. Methods To evaluate strain coverage by 4CMenB we used the Meningococcal Antigen Typing System (MATS), which predicts the potential for bactericidal activity of sera from immunized 13-month-olds, based on quantity and crossreactivity with the vaccine-induced immune response of three antigens (factor H binding protein, Neisserial Heparin Binding Antigen, and Neisserial Adhesin A), and the genotype of a fourth antigen, PorA. As a recent and representative target strain population, we evaluated invasive MenB strains isolated mainly in a single epidemiologic year (July 2007-June 2008) by the national reference laboratories of England and Wales, France, Germany, Norway, and Italy, a total of 1052 strains. Valid MATS results were obtained for 1011/1052 strains and were used to estimate coverage, and were linked to MLST and antigen sequence data.

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V39 Antigen diversity of the 4CMenB vaccine components in serogroup B meningococcal patient isolates from five European countries
S. Bambini1, J. Findlow2, H. Klaus3, M.K. Taha4, P. Stefanelli5, D.A. Caugant6, J. Lucidarme2, S. Gilchrist2, R. Borrow2, U. Vogel3, P. Mastrantonio5, R. Rappuoli1, J. Donnelly1, M. Pizza1, A. Muzzi1, M. Comanducci1
1Novartis 2Health

(p = 0.01).Cohort analysis showed significant reductions in IMD among both those eligible for the MCC program (born since 1992) and ineligible (born up to 1991); however, the decrease was more marked in the eligible group. Of cases that occurred in program-eligible persons, 80% (n=8) occurred in children too young to have been vaccinated (age < 1 or age < 12) and were therefore not directly preventable by the province’s vaccination program. Serotype and serosubtype were available for 91% (n=128) of PHOL records; of these, 44% (n= 56) were C:2a:P1.2. Of 114 isolates with ET, 77% (n=81) were ET-15, though its rate decreased significantly over time (p<0.01). There were 4 not ET-15, not ET-37 isolates since 2005 but none prior. Conclusions Rates of serogroup C IMD are low in the post-MCC vaccine era and clonal groups have changed. Cohort analysis suggests direct and indirect (herd) MCC program effects but those who have not reached program age remain at continuing, albeit reduced, risk. Future analyses with a longer time horizon and including the effect of Ontario’s new quadrivalent meningococcal conjugate vaccine program will be valuable.

Vaccines and Diagnostics, Siena, Italy of Wurzburg, Germany

Protection Agency, Manchester, UK Pasteur, Paris, France Superiore di Sanità, Rome, Italy Institute of Public Health, Oslo, Norway

3University 4Institut 5Istituto

V41 Immunogenicity of an Investigational Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine in Healthy Adolescents Following 1, 2 or 3 Doses
Peter M Dull, MD1, Marie Elena Santolaya2, Miguel O’Ryan3, Maria Teresa Valenzuela4, Valeria Prado3, Rodrigo Vergara5, Huajung Wang1, Alan Kimura1 for the V72P10 Meningococcal B Adolescent Vaccine Study group
1Novartis

6Norwegian

Keywords: MenB, 4CMenB, NadA, fHbp, NHBA Background To evaluate presence and degree of conservation of the main antigens of 4CMenB vaccine in the epidemiological background of some European countries, we analysed molecular diversity of the vaccine components in patient isolates. Molecular data were used with Meningococcal Antigen Typing System (MATS) results, for an estimation of 4CMenB coverage. Methods A total of 1052 invasive MenB strains, isolated in five European countries mainly in a single epidemiologic year were analysed by MultiLocus Sequence Typing (MLST) and tested for PorA genotypes. Presence and diversity of the vaccine components NadA, fHbp and NHBA were assessed. Results The clonal complex (cc) 41/44 was prevalent in 4 of the 5 countries considered. In those countries, cc32 was the second most represented cluster. The exception to this trend was the UK, where cc269 was predominant, and exceeded cc41/44 by 1.5%. The association between vaccine antigen variability and clonal complexes was confirmed. As a consequence, subvariants associated with cc41/44 (fHbp-1.14, 1.4 and NHBA-2) were predominant. fHbp-1.1, that is associated with cc32 only, accounted for more than 20% in France, and for 19, 12 and 9 % in Germany, Norway and Italy, respectively. The occurrence of NadA reflected those of the NadA (+) clonal complexes, namely cc32, 8 and 213. Conclusions The distribution and the vaccine antigen repertoire of each clonal complex differed among European countries. For compiling coverage estimates, genetic data are to be linked with expression and bactericidal data. This is accomplished by MATS.

Vaccines & Diagnostics, Cambridge, MA, USA de Pediatría, Hospital Dr Luis Calvo Mackena, Facultad de Medicina, Universidad de Chile, Santiago, Chile de Salud Pública y Epidemiología, Universidad de Los Andes, Santiago, Chile de Microbiología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile

2Departamento 3Programa

4Departamento 5Escuela

de Medicina Universidad de Valparaíso, Valparaíso, Chile

Contact email: peter.dull@novartis.com Keywords: serogroup B; adolescents; vaccine; booster; immunity Background Despite the success of meningococcal serogroup C vaccination programmes, there is still a heavy burden of meningococcal disease in adolescents due to serogroup B. We assessed immunogenicity and reactogenicity of an investigational, multicomponent meningococcal serogroup B vaccine (4CMenB) administered in different schedules to adolescents. Methods Healthy adolescents (11-17 years) were given 0, 1, 2 or 3 doses of 4CMenB or placebo, at least 1 month apart, over a 6 month period in different schedules. Immunogenicity was assessed 1 month after each vaccination and at 7 months, as protective serum bactericidal titers (≥4) with human complement (hSBA) against reference strains specific for vaccine antigen components: factor H binding protein (fHbp), Neisserial adhesin A (NadA), and outer membrane vesicles from New Zealand outbreak strain (NZOMV). Responses to the Neisseria Heparin Binding Antigen (NHBA) component were assessed by ELISA. Reactogenicity was monitored for seven days after each vaccination for solicited reactions, and throughout the study for adverse events. Results Overall, 1631 adolescents (13.8 ± 1.9 years) received 4CMenB or placebo. After two or three doses over two months 99–100% of 4CMenB recipients had hSBA titres ≥ 4 against test strains, compared with 92–97% after one dose (p < 0.02) and 29–50% after placebo. Antibody titres waned two months after the first dose, and continued to decline to six months in those who did not receive a second dose, when 91–100% of subjects who received two or three doses still had titres ≥ 4 for each strain, compared with only 73–76% after one dose. Following administration of a second or third dose at 6 months, rates reached 99–100% for each strain. ELISA results for NHBA displayed a similar pattern of responses. Local and systemic reaction rates were similar after each 4CMenB injection, did not increase with subsequent doses, but remained higher than placebo. The majority were described as mild to moderate in severity and resolved within 3 days of vaccination. No vaccine-related SAEs were reported and no significant safety signals were observed. Discussion One or two doses of 4CMenB induced protective immune responses in almost all subjects, which were boosted with a further dose at six months. Two doses have similar immunogenicity when given 1, 2 or 6 months apart, with similar reactogenicity for each dose.

V40 Serogroup C invasive meningococcal disease (IMD) in Ontario, Canada, 2000-2010: vaccine impact assessment
Anne Wormsbecker1,2,3, Vica Dang1,2, Frances Jamieson1,4, Sarah Wilson1,2, Prasad Rawte1, Natasha S Crowcroft1,2, Karen Johnson1, Shelley L Deeks1,2
1Public 2Dalla

Health Ontario, Toronto, Canada of Paediatric Medicine, Hospital for Sick Children, Toronto, Canada of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada

Lana School of Public Health, University of Toronto, Toronto, Canada

3Division

4Department

Keywords: Invasive meningococcal disease, Serogroup C, cohort analysis, Meningococcal C conjugate vaccine, Immunisation programs Objectives Meningococcal C conjugate (MCC) vaccination programs were introduced in the province of Ontario at age 1 and for grade 7 students in 2004/5. We sought to assess the impact of MCC vaccine on serogroup C invasive meningococcal disease (IMD) through descriptive epidemiologic and cohort analyses. Methods The period under surveillance was 2000 to 2010; a comprehensive province-wide dataset was created through probabilistic record linkage of data from the integrated Public Health Information System and Public Health Ontario Laboratories (PHOL). For most isolates, serotype and serosubtype were ascertained by indirect whole-cell enzyme-linked immunosorbent assay and electrophoretic type (ET) was determined by multilocus enzyme electrophoresis. Analysis was primarily descriptive and cohorts reflected vaccine program eligibility. Incidence rates were calculated using demographic data from Statistics Canada. Results Of 713 cases of IMD identified over the 11 year period, 155 were serogroup C and 141 had PHOL records. Median age was 26 years (range 17 weeks to 95 years) and case-fatality ratio was 17%. Yearly rates varied from 0.30 to 0.02/100 000. Age-specific rates were highest among 20-24, 15-19, and < 1 year olds (0.23, 0.21 and 0.20/100 000, respectively). While median age was stable throughout (p>0.05), age-specific rates for those 12-18 years (i.e. group in which all members in 2010 were eligible for grade 7 program) significantly decreased

V42 Evaluation of antibody persistence and response to a MenACWY-CRM conjugate vaccine (Menveo®) booster in adolescents five years after receiving MenACWY-CRM or a quadrivalent meningococcal polysaccharide vaccine (Menomune®) assessed by serum bactericidal assays using rabbit complement (rSBA)
Tatjana Odrljin, MD; Allen Izu, MS; and Peter M Dull, MD Novartis Vaccines and Diagnostics, Cambridge, MA Contact email: peter.dull@novartis.com Keywords: meningococcal disease, conjugate vaccine, persistence, anamnestic response, immunogenicity.

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Background A randomized phase II study demonstrated that Menveo®, a CRM-197 meningococcal conjugate vaccine against Neisseria meningitidis serogroups A, C, W-135, and Y (MenACWY-CRM) was well tolerated and immunogenic in adolescents, compared with Menomune®, a quadrivalent (A, C, W-135 and Y) meningococcal polysaccharide vaccine (MPSV4). Methods This open-label extension study was conducted to assess long-term persistence of bactericidal antibodies after vaccination with MenACWYCRM (n = 50) or MPSV4 (n = 51), and response to a MenACWY-CRM booster given 5 years post-primary immunization in all subjects. Booster results were compared with a control group of 54 age-matched naive subjects. Immunogenicity was assessed by serum bactericidal activity assay using human complement (hSBA) and rabbit complement (rSBA). Here, we present the results of the rSBA analysis. Immunogenicity was assessed as the percentage of subjects with rSBA titers ≥8 and ≥128, and by rSBA geometric mean titers (GMTs). Results Over 75% of subjects vaccinated 5 years previously with MenACWY-CRM maintained rSBA titers ≥8 against serogroups A (98%), W-135 (89%) and Y (78%); 56% maintained rSBA titers ≥8 against serogroup C. In contrast, 84%, 36%, 60% and 34% of MPSV4 vaccinated subjects maintained rSBA titers ≥8 against serogroups A, C, W-135 and Y, respectively, 5 years later. Using a more stringent measure, over 75% of Menveo pre-vaccinated subjects had rSBA titers ≥128 against serogroups A (96%), W-135 (85%), Y (76%), with 40% of MenACWY-CRM pre-vaccinated subjects maintaining rSBA titers ≥128 against serogroup C. A MenACWY-CRM booster administered 5 years post-prime elicited an anamnestic booster response that peaked at 1 week post-booster in Menveo pre-vaccinated subjects (GMT range, 5368–31002), but responses in MPSV4 pre-vaccinated subjects peaked at 1 month post-booster and were similar in magnitude to the response of subjects not previously vaccinated (GMT range: Menomune, 363–5366; previously Naive, 906–8670). Conclusions MenACWY-CRM provided persistence of bactericidal antibodies against all vaccine antigens for at least 5 years after vaccination, and immune memory as evidenced by an anamnestic response to a MenACWY-CRM booster in MenACWY-CRM pre-vaccinated subjects. Responses in MPSV4 pre-vaccinated subjects resembled a primary immune response, but the booster dose of MenACWY-CRM elicited a robust antibody response, regardless of vaccine history. These results confirm previously reported conclusions based on hSBA data.

V44 Immunogenicity of Meningococcal Quadrivalent (MenACWY-CRM197) Conjugate and Measles-Mumps-Rubella-Varicella (MMRV) Vaccines when Administered Concomitantly in 12 Month-Old Toddlers
Nicola P.Klein, MD, PhD1; Julie S. Shepard, MD2; Matthew Hohenboken, MD3; Christopher Gill, MD3; Peter M. Dull, MD3
1Kaiser 2Ohio

Permanente Vaccine Study Center, Oakland, CA; Vaccines & Diagnostics, Cambridge, MA.

Pediatric Research Association, Huber Heights, OH;

3Novartis

Contact email: peter.dull@novartis.com Keywords: Meningococcal disease, conjugate vaccine, immunogenicity, safety, infants Background A quadrivalent polysaccharide-protein conjugate vaccine (MenACWY-CRM197, Menveo®) is currently licensed in the USA for use from 2 years of age. To assess immune responses during the first year of life, we gave two doses of MenACWY at 7–9 and 12 months of age, with the second dose being given separately or concomitantly with measles, mumps, rubella, varicella (MMRV, ProQuad®) vaccine. Methods This phase 3, open-label, randomized, multi-center study enrolled and randomized 1630 healthy toddlers to three groups: Group A (n = 504) received MenACWY at 7– 9 months and MenACWY+MMRV at 12 months; Group B (n = 510) MenACWY at 7–9 and 12 months and MMRV at 13.5 months; Group C (n = 616) MMRV only at 12 months. Sera drawn 6 weeks later were tested for serum bactericidal activity with human complement (hSBA) against serogroups A, C, W and Y, expressed as geometric mean titers (GMT) and % with titers ≥ 8. Antibodies to MMRV were measured by standard ELISA methods. Results One month after a first MenACWY dose at 7-9 months, percentages of infants with hSBA ≥ 1:8 were 50% (45-56), 88% (83-92), 37% (30-44) and 31% (24-38) for serogroups A, C, W and Y, respectively. Six weeks after a second dose of MenACWY, regardless of concomitant MMRV, there were robust responses against all meningococcal serogroups expressed as proportions with hSBA titers ≥ 1:8 (Table), or as GMTs (not shown). Similarly, concomitant Menveo did not affect rates of seroconversion to MMRV components (Table), or as GMTs (not shown).

V43 Pivotal Safety and Immunogenicity of an Investigational Quadrivalent Meningococcal Conjugate Vaccine (MenACWY-CRM; Menveo®) in Infants in the United States and Latin America
Nicola P. Klein, MD, PhD1; Miguel W. Tregnaghi, MD2; Maria-Gabriela Graña, MD3; Lisa Bedell, MA3; Tatjana Odrlijn, MD3; Peter M Dull, MD3
1Kaiser

Permanente, Oakland, CA; Córdoba, Argentina; % hSBA ≥ 8 (95% CI) Group A Vaccine(s) Serogroup A C W Y MenACWY + MMRV N = 384/~203* 88% (84-91) 100% (98-100) 100% (97-100) 98% (95-99) Group B MenACWY N = 379/~199* 88% (84-91) 100% (98-100) 98% (96-100) 96% (93-99) Antigen Measles Mumps Rubella Varicella Seroconversion rate (95% CI) Group A MenACWY + MMRV N = 337–370 98% (96-99) 98% (96-99) 95% (93-97) 99% (97-100) Group C MMRV N = 459–515 99% (98-100) 96% (94-98) 97% (95-98) 99% (98-100) Vaccines and Diagnostics, Cambridge, MA.

2CEDEPAP, 3Novartis

Contact email: peter.dull@novartis.com Keywords: Meningococcal disease, conjugate vaccine, immunogenicity, safety, infants Background Infants are the group at highest risk of invasive meningococcal disease. MenACWY-CRM, a quadrivalent conjugate meningococcal vaccine, elicited robust immunologic responses in an earlier small-scale study in young infants. Methods In this Phase III study performed in the United States (US) and Latin America (LA), 4545 healthy infants were randomized 2:1 to receive routine vaccines along with MenACWY-CRM administered in a 3 or 4-dose schedule [2, 6, and 12 months (LA); or 2, 4, 6 and 12 or 16 months (US)], or routine vaccines alone followed by 1 or 2 MenACWY-CRM toddler doses in the second year of life. All subjects were monitored for local and systemic reactions and adverse events after each dose. Immunogenicity was assessed in subsets of subjects by serum bactericidal assay using human complement (hSBA). Results In both US and LA subjects, after 2 or 3 doses during the first year of life, 94-99% of subjects achieved an hSBA titer ≥ 8 for serogroups C, W-135 and Y and 67-89% for serogroup A (n = 182 to 274). After a 4-dose series, the % of subjects with hSBA titers ≥8 against the 4 serogroups was 94–100% in US subjects (n ~ 85). The percentage with hSBA titers ≥ 8 was 95–100% against all 4 serogroups after the final toddler dose of the 3-dose (n ~ 100) and 4-dose (n~115) series in LA subjects. In MenACWY-CRM naive toddlers, administration of 1 versus 2 toddler doses of MenACWY-CRM (n ~ 74, n ~ 99, respectively) the % of subjects with hSBA titers ≥ 8 was 72–91% and 97–100%, respectively. Responses to concomitant routine vaccines were non-inferior to routine vaccinations alone, except for slightly reduced responses to pertactin and PnC serotype 6B in US subjects. Safety profiles were similar in those who received routine vaccinations with and without MenACWY-CRM, with comparable rates of solicited local and systemic reactions typical of routine infant vaccines, and no evidence of any increase in unsolicited or vaccine-related adverse events. Conclusion MenACWY-CRM was shown to be highly immunogenic and well tolerated when administered as a four dose series with no evidence of clinically significant interference when co-administered with routine vaccines. Conclusion

* N = 384 & 379 for Serogroup A, 201-205 & 198-199 for C, W, Y, in Groups A & B, respectively.

Co-administration of a second dose of Menveo with MMRV did not affect immune responses elicited against either vaccine. Two doses of Menveo generated protective immune responses against all four serogroups in the majority of toddlers.

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V45 Potential Coverage of English and Welsh Capsular Group B Isolates by an Investigational Meningococcal Group B Vaccine (4CMenB)
J. Findlow1, S. Gilchrist1, D. Thompson1, M. Stella2, G. Frosi2, R. Borrow1
1Vaccine 2Novartis

2Bristol 3St

Children’s Vaccine Centre, University of Bristol, Bristol, UK

Georges Vaccine Institute, St George’s, University of London, London, UK Exeter and Devon Hospital, University of Exeter, Exeter, UK Maggiore della Carità - Clinica Pediatrica Boni, Novara, Italy IRCCS dell'Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena di Milano, Milano, Italy

4Royal

5Ospedale

6Fondazione 7Novartis

Evaluation Unit, Health Protection Agency, Manchester Royal Infirmary, Manchester, UK; Vaccines, Siena, Italy

Vaccines and Diagnostics Cambridge, MA and Siena, Italy

Contact email: nicoletta.gossger@paediatrics.ox.ac.uk Keywords: Meningococcus serogroup B, vaccine, clinical trial, reactognicity, routine infant vaccines Background An investigational serogroup B meningococcal vaccine containing 3 recombinant-proteins plus outer-membrane-vesicles (4CMenB) is in latestage development. We studied the reactogenicity of this vaccine when administered at 2, 4 and 6 months of age (concomitantly with and separately from routine-vaccines) and at 2, 3 and 4 months of age (concomitantly with routine-vaccines). Methods An open-label, parallel-group, multi-centre study was conducted with randomisation of 1885 participants 2:2:1:1 to receive i) 4CMenB at age 2, 4 and 6 months concomitantly with routine-vaccines (7-valent pneumococcal-vaccine and a combined DTaP/HepB/IPV/Hib-vaccine) ii) 4CMenB at 2, 4 and 6 months administered separately from routine-vaccines (given at 3, 5 and 7 months) iii) 4CMenB with routinevaccines at 2, 3 and 4 months or iv) routine-vaccines alone. Local and systemic reactions were recorded for 7 days after each vaccination. Results Fever (≥38°C) was found in 44%-61% of participants after each dose of 4CMenB given concomitantly with routine-vaccines, in 26%-41% receiving 4CMenB alone and in 23%-36% with routine-vaccines alone. A similar pattern was seen for the percentage of participants with irritability (66%-79% 4CMenB and routine-vaccines, 53%-63% 4CMenB alone, 44%-57% routine-vaccines only). Local reactogenicity was similar between all groups. Four seizures (none febrile) were reported within 48 hours after vaccination; one after 4CMenB and routine vaccines, one after 4CMenB alone and two after routine-vaccines alone. Conclusion 4CMenB when administered alone had a reactogenicity profile which was comparable to that produced by routine-vaccines, but systemic reactogenicity was increased when the study-vaccine was combined with routine-vaccination. No major safety concerns were raised.

*Corresponding author - Vaccine Evaluation Unit, Health Protection Agency North West, 2nd Floor CSB II, Manchester Royal Infirmary, Manchester, M13 9WZ, UK. E:mail: jamie.findlow@hpa.org.uk Keywords: Meningococcal, group B, vaccine, coverage, England & Wales An investigational multicomponent meningococcal group B vaccine (4CMenB) has proven safe and immunogenic in Phase I to III trials. The vaccine contains three recombinant proteins; factor H binding protein (fHBP), Neisserial Heparin Binding Antigen (NHBA) and Neisserial adhesin A (NadA) formulated with Outer Membrane Vesicles containing the immunodominant PorA protein. Protection afforded by 4CMenB will depend upon antigen expression and cross-reactivity of induced antibody to antigen variants. To address this issue, a meningococcal antigen typing system (MATS) was developed to predict whether 4CMenB covers individual isolates. As group B currently accounts for approximately 90% of meningococcal disease in England and Wales, we investigated the potential coverage of 4CMenB using MATS. All 535 capsular group B isolates all from cases of invasive disease received at the Health Protection Agency Meningococcal Reference Unit from the epidemiological year 2007/2008 were characterised genetically for PorA and by MATS for recombinant antigens. Of the isolates, 63.3%, 54.7% and 0.6% had positive MATS phenotype for fHBP, NHBA and NadA, respectively. Additionally, 20.3% harboured the homologous PorA (P1.4). Coverage (determined as >1 antigen with positive phenotype/homologous PorA genotype) was estimated at 72.9%. Among covered strains, 69% were positive for more than one antigen. To conclude, 4CMenB has the potential to protect against a significant proportion of MenB disease in England and Wales.

V46 The Neisseria meningitidis-macrophage infectivity potentiator (MIP) protein induces cross-strain serum bactericidal activity and is a potential serogroup B vaccine candidate
Miao-Chiu Hung, Omar Salim, Jeannette N. Williams, John E. Heckels, and Myron Christodoulides Molecular Microbiology, Division of Infection, Inflammation and Immunity, Sir Henry Wellcome Laboratories, University of Southampton Faculty of Medicine, Southampton, UK Keywords: Neisseria meningitides, macrophage infectivity potentiator; meningococcal vaccine; liposome, monophosphoryl lipid A Objective Abundance of a ~29kDa protein - Macrophage Infectivity Potentiator (MIP) was observed in prior proteomic analysis of the meningococcal outer membrane (OM). Our objective was to investigate the potential of MIP as a vaccine candidate by preparing a recombinant protein and testing its ability to induce functional bactericidal antibodies. Materials and Methods The mip gene from MC58 was cloned into pRSETA system, propagated in E.coli DH5⍺ and expressed in E.coli BL21(DE3)pLysS. Recombinant MIP (rMIP) protein was purified by nickel column chromatography under native conditions to high yield and purity. Several preparations containing rMIP protein were used for animal immunization. Serological studies were performed to investigate the functional immunogenicity of rMIP. Results ELISA showed high antibody titres against rMIP and OM of MC58 (homologous strain). The surface location of MIP protein was demonstrated by Immunofluorescence. Several strains isolated either from patients or carriers were sequenced to survey the conservation of mip gene. Only 3 amino acid sequence types (type I, II and III) were identified with 98-100% similarity. Western blot showed the similar expression levels of MIP protein amongst all the surveyed strains. Serum bactericidal assay (SBA) showed that antisera raised against rMIP (type I) elicited antibodies with high bactericidal titres (up to 1/1,024) against MC58 (type I). Antisera were then tested against heterologous sequence type II and III strains and showed cross protection with high killing titres (1/256). Conclusion Meningococcal MIP protein is highly conserved amongst meningococci, surface-located, and functionally immunogenic. Therefore, it can be considered as a novel vaccine candidate against meningococcal B infection.

V48 Using lipooligosaccharide modified natural outer membrane vesicles to target meningococcal antigens to human dendritic cells
Hannah Jones1, Hendrik-Jan Hamstra3, Alastair Copland1, Jeremy Brown2, Nigel Klein1, Peter van der Ley3, Garth Dixon1.
1Infectious 2Centre 3Unit

Diseases and Microbiology Unit, Institute of Child Health, UCL, London, UK

for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, Rayne Institute, UK.

Vaccinology, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands

Keywords: dendritic cells, lipooligosaccharide, natural outer membrane vesicles, DC-SIGN, vaccine Neisseria meningitidis (Nm) is a major cause of meningitis and septicaemia worldwide. Effective vaccines have been developed against several serogroups but no broad coverage vaccine is currently licensed against serogroup B. Several minor outer membrane proteins (OMP) have been identified as potential vaccine targets and these are currently being explored. One way of presenting these minor OMPs in a vaccine is to use natural outer membrane vesicles (NOMV). Here we describe structure modification of lipooligosaccharide (LOS) to reduce toxicity and target NOMV to dendritic cells (DC), which have been widely considered to play a key role in the induction of protective immunity. We engineered an unencapsulated strain of Nm that expresses pentacylated lipid A (lpxL1), conferring reduced toxicity, and lgtB oligosaccharide structure that targets meningococcal OMV to DC via DC-SIGN (lgtB/lpxL1). Single deletion mutations lpxL1 and lgtB, were used as comparators. Human DC were stimulated with NOMV and DC responses were assessed using the following parameters 1) cytokine production, 2) antigen uptake, 3) DC maturation and 4) T cell stimulatory capacity. All NOMV induced DC maturation and production of TNFα, IL-1β, IL-6, IL-23 and IL-10, although those expressing lpxL1 were less potent stimulators than NOMV expressing wild type lipid A. NOMV with the lgtB/lpxL1 structure were significantly more potent stimulators of DC maturation and IL-23 and IL-10 production than NOMV with lpxL1 lipid A and wild type oligosaccharide. DC phagocytosed NOMV expressing lgtB/lpxL1, but not the single mutant lpxL1, and this was shown to be exclusively through DC-SIGN. All NOMV induced T helper (Th) 1, 2 and 17 responses in an in vitro DC-T cell co-culture model. The subtle differences in the magnitude of the T cell response induced by different NOMV may be explained by the differences in DC maturation and cytokines profiles. NOMV with the lgtB/lpxL1 structure were significantly more potent stimulators of DC than NOMV with lpxL1 and wild type oligosaccharide, suggesting that the lgtB modification enhances the stimulatory capacity of pentacylated lipid A. lgtB/lpxL1 NOMVs were shown to target the NOMV to DC but did not induce a pronounced proinflammatory cytokine response as observed with NOMV expressing wild type LOS. The lpxL1/lgtB NOMV shows potential for use as a meningococcal vaccine vector that could be further modified to over express OMP important for induction of cross-protective immunity.

V47 Reactogenicity and Safety of Multicomponent Meningococcal Serogroup B Vaccine (4CMenB) Administered with or without Routine Infant Vaccinations in Different Schedules
Nicoletta Gossger1, Ina Beeretz1, Matthew Snape1, Adam Finn2, Paul Heath3, Andrew Collinson4, Gianni Bona5, Susanna Esposito6, Peter Dull7, Ellen Ypma7, Daniela Toneatto7, Alan Kimura7, Clarissa Oeser3, Maggie West2 , Tessa John1, Andrew J Pollard1 and the European Men B Vaccine Study Group.
1Oxford

Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK

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V49 Preclinical safety and immunogenicity evaluation of a new generation nonavalent PorA OMV vaccine against serogroup B meningococcus
Patricia Kaaijk1, Ineke van Straaten2, Elmieke Boot2, Harry van Dijken1, Germie van den Dobbelsteen1
1National

tetanus-toxoid, inactivated-polio, acellular-pertussis, hepatitis B and Haemophilus influenzae type b-vaccine) ii) 4CMenB at 2, 4 and 6 months separately from routine-vaccines (given at 3, 5 and 7 months) iii) 4CMenB and routine-vaccines at 2, 3 and 4 months iv) routine-vaccines alone. The proportion of participants with human-complement serum bactericidal antibody (hSBA) titre ≥1:5 (serological correlate of protection) was calculated. Results At least 99% of participants receiving 4CMenB at 2, 4, 6 months (concomitantly or without routine-vaccines) or at 2, 3, 4 months (with routine-vaccines) developed hSBA titres ≥1:5 against strains 44/76 and 5/99. For NZ98/254 the correlate was reached or exceeded in 79% (2, 4, 6 months with routine-vaccines), 87% (2, 4, 6 months without routine-vaccines) and 81% (2, 3, 4 months with routine-vaccines). Percentages of participants responding to routine-vaccines given concomitantly with 4CMenB were non-inferior to routine-vaccines alone for all antigens except pneumococcal-serotype 6B. Conclusion 4CMenB is immunogenic against reference strains when administered concomitantly with routine-vaccines at 2, 4, 6 or 2, 3, 4 months.

Institute for Public Health and the Environment (RIVM), CIb/Vaccinology, Bilthoven, The Netherlands; Vaccine Institute, Quality Control Department, Bilthoven, The Netherlands

2Netherlands

Keywords: meningococcus serogroup B; vaccine; lpxL-1; preclinical; SBA Background Until now, only MenB vaccines based on outer membrane vesicles (OMV) have been proven successful in controlling MenB epidemics. The use of vaccine strains with inactivated lpxL1 gene, i.e. less toxic LPS while maintaining its adjuvant activity, enabled the use of a simple detergent-free process to obtain high yields of native OMVs with good batch-to-batch consistency. Consequently, an improved nonavalent PorA OMV vaccine (Nonamen) prepared from genetically engineered strains with attenuated endotoxin (lpxL1 LPS) was developed. In the present study, safety and immunogenicity of this new generation Nonamen was evaluated following repeated vaccination in rabbits and mice. Methods A formal GLP repeated-dose toxicology study including local tolerance was performed in New Zealand white rabbits. Rabbits were immunised (i.m.) five times with either adjuvanted placebo, plain (7.5 μg/PorA type or 15 μg/PorA type per dose of 0.5 mL) or aluminiumphosphate adjuvanted Nonamen (15 μ­ /PorA type per dose of 0.5 mL). Serum bactericidal antibody (SBA) titers against bacteria expressing g one of the 9 PorAs were determined in blood samples from New Zealand white rabbits and NIH mice taken after four immunisations with the three vaccine formulations. Results No toxicologically relevant findings in local and clinical signs were noted in the rabbits after vaccination. Slight increases in rectal temperature (0.1°C–0.9°C) were found compared to placebo control at 4 hours after dosing, while at 24 hours after treatment no difference in body temperature was observed in any animal. Inflammations at the injection sites were comparable to placebo control, except for the group receiving adjuvanted vaccine where more often granulomatous inflammation areas were observed. In rabbits, Nonamen induced high SBA titers against all MenB strains expressing the 9 PorAs, i.e., P1.7,16; P1.5-1,2-2; P1.19,15-1; P1.52,10; P1.12-1,13; P1.7-2,4; P1.22,14; P1.7-1,1 and P1.18-1,3,6, present in the vaccine. In mice, also good SBA titers were observed, although SBA titers varied more between the different PorA types. No statistically significant potentiating effect of aluminium phosphate adjuvant was observed, with the exception of a slightly higher SBA response against P1.5-1,2-2 in rabbits. Conclusions Nonamen is shown to have an acceptable toxicity safety profile in rabbits. In addition, Nonamen induced high SBA titers in both rabbits and mice against various MenB strains expressing PorA proteins that are present in the vaccine. These preclinical results support the start of the first clinical studies with this new generation Nonamen with lpxL-1 LPS.

V51 Impact of a New Serogroup A Meningococcal Conjugate Vaccine, MenAfriVac TM, on Carriage of Serogroup A Neisseria meningitidis: Preliminary results from Burkina Faso
Paul A. Kristiansen1, Fabien Diomandé2,3, Lassana Sangaré4,5, Rasmata Ouédraogo5,6, Idrissa Sanou5,7, Abdoul Salam Ouédraogo7, Ba Ki Absatou8, Denis Kandolo3, Pascal Kaboré9, Musa Hassan-King10, Jennifer D. Thomas2, Thomas Clark2, Nancy Messonnier2, Marie-Pierre Préziosi11, Marc LaForce10 and Dominique A. Caugant1,12
1Norwegian 2Centers 3WHO 4CHU

Institute of Public Health (NIPH), Oslo, Norway

for Disease Control and Prevention, Atlanta, USA

Inter Country Support Team, Ouagadougou, Burkina Faso of Ouagadougou, Burkina Faso

Yalgado, Ouagadougou, Burkina Faso Charles de Gaulle, Ouagadougou, Burkina Faso National de Santé Publique, Ouagadougou, Burkina Faso Vaccine Project, Ferney, France

5University 6CHUP 7CHU

Souro Sanou, Bobo-Dioulasso, Burkina Faso de la lutte contre la maladie, Ministry of Health, Burkina Faso

8Laboratoire 9Direction

10Meningitis 11WHO

Initiative for Vaccine Research, Geneva, Switzerland of Medicine, University of Oslo, Norway

12Faculty

Keywords: MenAfriVac, serogroup A carriage, Burkina Faso, herd immunity Objective To investigate the potential herd immunity effect of MenAfriVac™, a new conjugate vaccine against serogroup A Neisseria meningitidis (NmA), by assessing its ability to reduce NmA carriage prevalence. Methods Study design: A multicentre repeated cross-sectional study of meningococcal carriage prevalence in the 1- to 29-year-old population in Burkina Faso, before and after mass vaccination. Oropharyngeal swabs were obtained from a representative portion of the target population. Standard laboratory analysis was conducted in Burkina Faso. Meningococcal isolates were confirmed at NIPH/Oslo and further characterized using molecular methods. Baseline meningococcal carriage prevalence was determined from four sampling campaigns performed every 3 months during the year 2009, yielding a total of 20 326 samples. In September 2010 MenAfriVacTM was introduced as part of a pharmacovigilance study in Kaya, one of the three study sites, while the rest of the country was vaccinated in December 2010. A carriage study campaign was conducted in October-November 2010, representing the first post-vaccination carriage assessment for the district of Kaya, and the last pre-vaccination campaign for the districts of Bogodogo and Dandé. Post-vaccination sampling campaigns are continuing every three months in 2011, in the same way as before vaccination. Results Overall baseline meningococcal carriage was 3.98% while NmA prevalence was 0.39%. NmA carriage varied by season and district with higher prevalence in the dry season and in rural areas. The highest prevalence was found in the rural district of Kaya (0.93%). The campaign in October-November 2010 showed no NmA carriage in the vaccinated district of Kaya, while it was still present in the nonvaccinated district Dandé, at the same level as in 2009. Two additional sampling campaigns in 2011 showed that NmA was still absent in Kaya, 8 months after vaccination, and was undetected in Bogodogo and Dandé, 6 months after vaccination. Conclusion MenAfriVac vaccination induced a 100% reduction of NmA carriage prevalence (statistically significant, p<0.001, Chi-square test), 6 to 8 months after mass vaccination. The dramatic impact of MenAfriVac on NmA carriage is a first strong indication of its ability to confer herd immunity by preventing colonisation and transmission of NmA.

V50 Immunogenicity of an Investigational Multicomponent Meningococcal Serogroup B Vaccine (4CMenB) Administered with or without Routine Infant Vaccinations in Different Schedules
Nicoletta Gossger1, Matthew Snape1, Adam Finn2, Paul Heath3, Andrew Collinson4, Gianni Bona5, Susanna Esposito6, Peter Dull7, Ellen Ypma7, Daniela Toneatto7, Alan Kimura7, Sandra Dymond2, Su Wilkins4, Tessa John1, Sarah Kelly1, Andrew J Pollard1 and the European Men B Vaccine Study Group.
1Oxford 2Bristol 3St

Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK

Children’s Vaccine Centre, University of Bristol, Bristol, UK

Georges Vaccine Institute, St George’s, University of London, London, UK Exeter and Devon Hospital, University of Exeter, Exeter, UK Maggiore della Carità - Clinica Pediatrica Boni, Novara, Italy IRCCS dell'Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena di Milano, Milano, Italy

4Royal

5Ospedale

6Fondazione 7Novartis

Vaccines and Diagnostics Cambridge, MA and Siena, Italy

Contact email: nicoletta.gossger@paediatrics.ox.ac.uk Keywords: Meningococcus serogroup B, vaccine, clinical trial, immunogenicity, routine infant vaccines Background When administered at 2, 4 and 6 months of age an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) elicits bactericidal antibodies against reference MenB strains containing the vaccine-antigens. We studied the immunogenicity of 4CMenB when administered concomitantly or without routine-vaccines and in a 2, 3 and 4 month schedule. Methods An open-label, parallel-group, multi-centre study was conducted with randomisation of participants 2:2:1:1 to receive i) 4CMenB at age 2, 4 and 6 months concomitantly with routine-vaccines (7-valent pneumococcal glyco-conjugate-vaccine and a combined diphtheria-toxoid,

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V52 Meningococcal Antigen Typing System (MATS) was a conservative estimate of killing when confirmed in a serum bactericidal assay using human complement (hSBA)
A. Biolchi1*, G. Frosi1*,S. Gilchrist2, M. Stella1, B. Brunelli1, M. Comanducci1, S. Bambini1, S. Comandi1, F. Rigat1, J. J. Donnelly1, M. Pizza1, J. Findlow2, R. Borrow2, M. Giuliani1, D.Medini1
1Novartis

V54 Development of a Multiplex Bead Based Meningococcal Antigen Typing System (BMATS)
Gowrisankar Rajam1, Ellie Kim1, Marzia Giuliani2, John Donnelly2, George Carlone1
1Division 2Novartis

of Bacterial Diseases, CDC, Atlanta, GA 30333, USA Vaccines, Siena, Italy

Vaccines & Diagnostics, Via Fiorentina 1, Siena, Italy Agency, Manchester RoyalInfirmary, Manchester, UK

2HealthProtection

Keywords: Neisseria meningitidis, MenB, MenB vaccine, immune-phenotype, MATS, BMATS. Background Meningococcal Antigen Typing System (MATS) is an ELISA based immune-phenotyping technique used for Neisseria meningitidis B (MenB) strains. Novartis MenB vaccine, 4CMenB, has 4 major antigens. MATS is used to detect 3 of these antigens in MenB bacterial lysate. To test a single strain, 3 individual MATS ELISAs have to be performed. We have developed a multiplexed bead based meningococcal antigen typing system, BMATS that offers the capacity to measure three or more antigens simultaneously. Materials and methods A multiplex IgG capture assay was developed to quantify anti-4CMenB IgG. BMATS detects the homologous competition between the surface expressed/exposed antigens in the bacterial lysate and antigen conjugated fluorescent beads for antigen specific antibody (IgG) in the capture assay. Using xMAP technology, fluorescent beads are screened for captured antigen specific IgG and expressed as median fluorescence index (MFI). A strain with high density and/or cross-reactivity of antigen results in specific reduction in MFI. This inverse relationship establishes the MenB antigen phenotype. Eighteen MenB strains were tested by both methods. Results and conclusions Assay sensitivity, specificity, reproducibility and robustness are presented. BMATS successfully detected antigens on all MenB strains tested. Reference strains for fHbp and NHBA yielded 100% reduction in MFI, and NadA yielded 70% reduction. BMATS was in agreement with MATS ELISA for all 18 strains tested. Validation of BMATS with additional MenB strains and development of data reduction software to calculate antigen specific relative potency for each isolate is in progress.

*These authors contributed equally to the work duccio.medini@novartis.com Keywords: MATS, representative strain panel, hSBA, 4CMenB, vaccine strain coverage Background The meningococcal antigen typing system (MATS) predicts the strain coverage of a multicomponent meningococcal serogroup B vaccine (4CMenB) based on quantity of and cross reactivity with vaccine-induced immune responses of factor H binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA), and Neisserial Adhesin A (NadA), and on the genotype of PorA. MATS estimated that 4CMenB would cover 78% (95%CI: 66-91%) of 1052 isolates collected in five European countries (73-87% by country) during a specified time period. We compared MATS predictions with actual hSBA results for an unbiased representative set of isolated selected from the previously presented panel. Methods All 528 serogroup B strains isolated between July 2007-June 2008 by the Health Protection Agency had been evaluated by MLST and MATS, and genotyped for fHbp, NadA, and NHBA. A panel of 40 isolates was selected using stratified proportional sampling to account for coverage distribution and epidemiologically relevant strains by controlling for MATS scores and relevant genetic characteristics: MLST type and genotype of vaccine antigens. The 40 strains were then tested in hSBA using pooled post vaccination sera from infants or adolescents. Results were compared with MATS data. Results/Conclusion The panel selected for hSBA testing provided an unbiased sample of strains proportionally representative of 98% of the MATS phenotypes and >80% of MLST and vaccine antigen genotypes. MATS predicted 73% (95%CI: 58-87%) killing in the hSBA. The current analysis revealed that 85% (95%CI: 70-93%) of strains were killed by pooled infant sera as were 86% (95%CI: 70-94%) of strains by adolescent sera. These results confirm that MATS is a conservative measure of killing in the hSBA.

V55 AFCo1 provides nasal adjuvant activity against capsular polysaccharides of Neisseria meningitidis serogroup C and Salmonella Typhi
Belkis Romeu, Elizabeth González, Maribel Cuello, Osmir Cabrera, Julio Balboa, Miriam Lastre and Oliver Pérez Immunology Department, Vice-presidency of Research and Development, Finlay Institute, P.O. Box 16017, Havana, Cuba Contact email: bromeu@finlay.edu.cu Keywords: adjuvant, cochleate, mucosal response, polysaccharide antigen Increasing emphasis is being placed on the mucosal administration of vaccines in order to stimulate mucosal as well as systemic responses. Findings from our group suggest that proteoliposome-derived cochleate (AFCo1) acts as a potent mucosal adjuvant. As an alternative to chemical conjugation, the current study is aimed at determining the benefit of using AFCo1 to improve mucosal and systemic immune responses to capsular polysaccharides from Neisseria meningitidis serogroup C (PsC) and Salmonella Typhi (PsVi). Therefore, intranasal (i.n) immunisations of three doses one week apart with AFCo1 plus PsC or PsVi in adult mice were conducted. High specific anti PsC IgA responses were obtained at site of entry and distant sites such as the vagina. Higher IgG responses after i.n application of PsC or PsVi coadministered with AFCo1 were induced. Our results demonstrate a shift in the isotype pattern elicited in response to PsC and PsVi. Also, the avidities of PsVi antibodies elicited by AFCo1 were higher than those elicited by the polysaccharide alone. In summary, AFCo1 as a nasal adjuvant demonstrated the capability to elicit mucosal and systemic specific responses against thymus independent antigens.

V53 Inducing cross protection within fHBP variants
Michele Pallaoro1, Maria Scarselli1, Beatrice Aricò1, Brunella Brunelli1, Silvana Savino1, Federica Di Marcello1, Emmanuelle Palumbo1, Daniele Veggi1, Laura Ciucchi1, Elena Cartocci1, Matthew James Bottomley1, Enrico Malito2, Paola Lo Surdo1, Maurizio Comanducci1, Marzia Monica Giuliani1, Francesca Cantini3, Sara Dragonetti3, Annalisa Colaprico1, Francesco Doro1, Patrizia Giannetti1, Barbara Brogioni1, Marta Tontini1, Markus Hilleringmann1, Vincenzo Nardi-Dei1, Lucia Banci3, Derek O’Hagan1, Mariagrazia Pizza1, Rino Rappuoli1
1Novartis

Vaccines and Diagnostics S.r.l., Via Fiorentina 1, 53100 Siena, Italy Institute of Novartis Research Foundation, 10672 John Jay Hopkins Drive, San Diego, CA 92121, USA Resonance Center (CERM) and Department of Chemistry, University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy

2Genomics 3Magnetic

Keywords: fHBP, formulation, adjuvants Sequence variability of protective antigens is a major challenge to the development of vaccines; the factor H binding protein (fHBP) antigen present in different Neisseria meningitidis (MenB) vaccines under development is not different. The antigen is effective and provides excellent immune response in humans, however is extremely heterogeneous and more than 300 variants have been described to date. These variants can be classified into three distinct groups of antigenic variants that do not induce cross-protective immunity. With this limitation in mind we set out to test different strategies to overcome the problem. If on one side it is possible to follow a rational design approach based on structure information to improve the antigen from a structural point of view (see Bottomley MJ et el.), on the other side it is possible to improve the immune response with more potent adjuvants to enlarge the spectrum of coverage by enhancing immunogenicity and/or antigen presentation and processing. Here we describe a new adjuvant combination containing a Toll Like Receptor 9 agonist (IC31) in the presence of Aluminum hydroxide and the protection elicited by several different fHBP chimeras and show that this new adjuvant combination in the presence of the final selected chimeras is able to induce significant cross protection over more distantly related variants. Our data provide a solid rationale for the use of this formulation in a vaccine that recognizes all fHBP antigenic variants and should provide efficacious and broad protection against infection with MenB.

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V56 From Neisseria meningitidis serogroup B vaccine to Potent Adjuvants
Oliver Pérez*, Miriam Lastre, Osmir Cabrera, Caridad Zayas, Maribel Cuello, Elizabeth González, Belkis Romeu, Julio Balboa and Daniel Cardoso Immunology Department, Research Vice-presidency, Finlay Institute, Havana, Cuba Contact author: oliverp@finlay.edu.cu Keywords: Adjuvant, Vaccine, Neisseria meningitidis, AFCo1, AFPL1 Introduction Outer membrane vesicles (OMV) from microorganisms have been demonstrated to be a good target for vaccine development. A meningococcal VA-MENGOC-BC® vaccine has been used since 1988 in Cuba and abroad with more than 60 million doses applied without severe adverse events. Adjuvants are essential vaccine components that immunopotentiate (IP) the innate immunity, deliver antigens to desired places, and polarize (Pz) the adaptative immune response to the desired level. Adjuvants are not licensed and are mainly kept by companies to develop their own vaccines and to avoid competitors. Furthermore, there are currently no licensed adjuvants capable of enhancing immune responses at mucosal surfaces where the majority of infectious agents enter or establish in the host. Therefore, the development of adjuvants is mandatory to any pharmaceutical companies dedicated to vaccine development, particularly for mucosal applications. Aims To demonstrate and characterize the adjuvant effect of OMV and to develop the Finlay Adjuvant Platform (FAP). Results The FAP consists of a series of detergent-extracted OMV called Proteoliposome (PL) because of their high protein content in addition to lipids and their transformation into Cochleates (Co) named AFPLn and AFCon, respectively. In addition, AFCo3x not-derived from Proteoliposome was also developed. The former (i.e. AFPLn and AFCon) contain several protective proteins (which permit it to be used as a specific vaccine candidate) and several synergistic microbial-associated molecular patterns (MAMP, which permit it to be used as vaccine adjuvant). The most studied are AFPL1 and AFCo1 derived from Neisseria meningitidis serogroup B. They contain: LPS, Porins, and a trace of bacterial DNA as the main synergistic IP; non-living delivery systems based in lipids; LPS as a main Pz driving to Th1 and CTL immune responses; and particles as nano- or micro-particles. They induce long-lasting memory response and could be used with diverse antigens and by parenteral or mucosal routes. The AFCo3 contains particular MAMP, which reduces the cost and has possible uses in veterinary vaccines. Last but not least, finding a good mucosal adjuvant will permit the development of Single Time Vaccination Strategies which combine parenteral and mucosal vaccination simultaneously. Conclusion FAP seems to be very promising.

V58 Development of a flow cytometric antibody-mediated complement deposition assay for Group B Streptococcus
S. Thomas, A. Gorringe, M. Hudson, S. Taylor Microbiological Services Porton, Health Protection Agency, Porton Down, Salisbury, UK Keywords: GBS, Flow-cytometry, complement, vaccine, immunity Background Group B streptococcus (GBS) is the leading cause of severe bacterial infection in newborns. Specific and functional IgG raised to GBS antigens together with opsonising complement components, have key roles in the opsonisation of bacteria during infection. Therefore, seroepidemiological and vaccine assessment studies have measured functional immunity to GBS using the opsonophagocytic killing assay (OPKA). However, higher throughput assays such as an antibody-mediated complement deposition assay (CDA) could act as a surrogate for the more technically challenging OPKA, allowing the testing of large numbers of sera from a very small volume (<20µL). The measurement of complement deposition onto GBS bacterial surfaces is a potential surrogate of protection in assessing the efficacy of candidate GBS vaccines. This study aimed to develop a novel, potentially high-throughput assay for use in the investigation of functional immunity in GBS neonatal disease and vaccine assessment. Methods The CDA was adapted and optimised for use with GBS from a pre-existing assay developed for Neisseria meningitidis. Strains of GBS, representing the five prevalent serotypes in the UK, were grown and killed (2% formaldehyde) and added to a 96-well plate containing IgGdepleted human plasma and test sera. An antibody (sheep anti-human) specific to C3c (binding both C3b and iC3b) conjugated to a fluorescent label (FITC) was added to the test samples. Samples were then analysed using flow cytometry. Results Investigation of the growth and killing parameters revealed that CDA performed with GBS harvested at OD600nm of 0.1 and killed with 2% formaldehyde gave excellent correlations to CDA performed with live mid-log cultures with an R of 0.74 and 0.96 (p=<0.01) respectively. Optimisation assessed assay blocking buffer, complement concentration and incubation method. Serum dilution proved to be of great importance where there was a requirement for differentiating between samples with low responding sera. Following optimisation of the CDA, good serotype-specific responses for GBS were obtained with sera raised against polysaccharide antigens. Conclusions The CDA has been successfully optimised for use with the 5 most prevalent serotypes of GBS currently circulating in the UK. The assay was sensitive for the measurement of antibody-mediated deposition by the complement components C3b and iC3b, and is reproducible between assays. Correlations with OKPA will be determined and the CDA will then be used in large scale epidemiological studies and to assist in the assessment of immune responses to candidate vaccines.

V57 Evaluation of the immunological properties of the Neisserial Heparin Binding Antigen (NHBA)
Santini Laura, Irene Vacca, Biolchi Alessia, Elena Del Tordello, Brunelli Brunella, Giuseppe Boccadifuoco, Bambini Stefania, Maurizio Comanducci, Alessandro Muzzi, Duccio Medini, John J. Donnelly, Rino Rappuoli, Mariagrazia Pizza, Marzia M. Giuliani, Serruto Davide* Novartis Vaccines and Diagnostics, Via Fiorentina 1, Siena, Italy *contact email: davide.serruto@novartis.com Keywords: vaccine, serum bactericidal activity, NHBA, competitive SBA, recombinant strains Neisserial Heparin Binding Antigen (NHBA) is a surface-exposed lipoprotein of Neisseria meningitidis which binds heparin-like molecules. NHBA is an antigen of the multicomponent 4CMenB vaccine able to induce bactericidal antibodies in laboratory animals and humans. The aim of this study is to investigate the potential cross protection of NHBA-induced bactericidal antibodies against a panel of N. meningitidis strains. We used various approaches to investigate the level of cross protection mediated by human anti-NHBA antibodies. In order to characterize only the immunological properties of NHBA we selected N. meningitidis strains mismatched for the other vaccine antigens (fHbp, NadA and PorA1.4). These strains have been tested in a Serum Bactericidal Assay using human complement (hSBA) and human sera from different age groups vaccinated with the 4CMenB vaccine. To further prove that the immune response was directed against NHBA, we performed a competitive hSBA using the NHBA recombinant antigen and also generated NHBA deletion mutants in different genetic backgrounds. The hSBA analysis showed that human sera raised against the 4CMenB vaccine are able to kill natural N. meningitidis strains harboring different NHBA amino acidic sequences. We also demonstrated that the addition of recombinant NHBA antigen or the deletion of nhba gene abolished or significantly decreases bactericidal titers. To evaluate the contribution of amino acid sequence variability to vaccine coverage, we constructed a strain that is susceptible to bactericidal killing only by anti-NHBA antibodies and engineered it to express equal levels of different NHBA peptides under an inducible promoter. This ongoing approach will be useful to further evaluate the level of cross-protection of NHBA and assess the relation between level of expression and bactericidal killing mediated by NHBA. The results obtained so far demonstrate that NHBA is an important vaccine antigen able to induce cross-protective bactericidal antibodies against genetically different strains in different age groups vaccinated with the 4CMenB vaccine.

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Conference Steering Committee
Professor Ray Borrow Head of Vaccine Evaluation Unit, Health Protection Agency, Public Health Laboratory Manchester, Manchester Royal Infirmary, Manchester, UK Professor Brian Greenwood Manson Professor of Clinical and Tropical Medicine, London School of Hygiene and Tropical Medicine, UK Professor George Griffin Head of Division of Cellular and Molecular Medicine, St George’s, University of London, UK Professor David Lalloo Professor of Tropical Medicine, Liverpool School of Tropical Medicine, UK Professor Andrew Pollard Professor of Paediatric Infection and Immunity, Director of the Oxford Vaccine Group, University of Oxford & Honorary Consultant Paediatrician, Children’s Hospital, Oxford, UK Dr Mary Ramsay Consultant Epidemiologist, Health Protection Agency, Colindale, London, UK Dr Simon Nadel Consultant in Paediatric Intensive Care, St Mary’s Hospital and Imperial College London, UK Professor Christoph Tang Professor of Cellular Pathology, Sir William Dunn School of Pathology, University of Oxford, UK Dr Caroline Trotter Senior Research Fellow, School of Social and Community Medicine, University of Bristol, UK Linda Glennie Head of Research and Medical Information, Meningitis Research Foundation, Bristol, UK

Sponsors and exhibitors
Novartis Vaccines – A Global Force Novartis Vaccines and Diagnostics is a global leader in the research, development, manufacture and marketing of vaccines and diagnostic tools worldwide. The current portfolio includes more than 20 marketed vaccines worldwide and more than 15 potential new vaccines in various stages of clinical development1. The current head of Research, Dr Rino Rappuoli, is a world leading innovator in vaccination research. He is the pioneer of one of the most recent innovations in vaccination research – reverse vaccinology – which has helped create new solutions to finding candidate vaccines for diseases, such as Meningococcal serogroup B, which, in the past, had evaded scientists using more traditional methods. The Novartis meningococcal franchise is a cornerstone of the division. Meningococcal disease causes approximately 50,000 deaths a year globally2. Because almost all cases of infection are caused by five serogroups – A, B, C, W-135 and Y – and the distribution of strains varies greatly over time and location, Novartis is working to deliver vaccines with broad coverage and the potential to protect all age groups at risk. The Novartis vaccine, Menjugate®, induces protective antibodies against the serogroup C, and is a key part of the vaccination programme in the UK where cases have fallen by more than 90%3. Novartis Vaccines also developed and manufactures Menveo (MenACWY-CRM), a conjugated quadrivalent meningococcal vaccine for the prevention against the A, C, W-135 and Y serogroups of meningococcal meningitis. A Novartis candidate vaccine has shown the potential to be the first vaccine to provide broad coverage against meningococcal B disease and was filed for licensure consideration with the European Medicines Agency in December 2010.
1. Data on file. NVD-GEN-P-S-179—642011. 2. World Health Organisation. Control of epidemic meningococcal disease. WHO practical guidelines. 2nd edition. Available at: http://www.who.int/csr/resources/publications/meningitis/whoemcbac983.pdf Accessed Oct 2011 3. Health Protection Agency. Laboratory confirmed cases of serogroup C disease only by age and epidemiological year, England and Wales 1998-99 to 2009-10. Available at: http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1234859709051 Accessed Oct 2011.

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Sponsors and exhibitors
Meningitis Research Foundation would like to thank the major sponsors:

Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with haemophilia, immune disorders, infectious diseases, kidney disease, trauma, and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.

GSK is one of the world's leading research-based pharmaceutical and healthcare companies, whose mission is to improve the quality of human life by enabling people to do more, feel better and live longer. We produce medicines for a wide range of therapy areas, including anti-virals, anti-infectives and cancer treatments, and are researching medicines and vaccines for the priority diseases identified by the WHO – HIV/AIDS, tuberculosis and malaria. Our vaccines business, GSK Biologicals, is one of the leading innovators and producers of vaccines globally and is dedicated to providing vaccines to everyone who needs them, no matter where they live. For further information: www.gsk.com

Also exhibiting:
The Health Protection Agency (HPA) is an independent UK organisation that was set up by the government in 2003 to protect the public from threats to their health from infectious diseases and environmental hazards. It does this by providing advice and information to the general public, to health professionals, and to national and local government. The HPA has responsibility for monitoring cases of meningitis, and the impact of vaccines against meningitis at a national level. Through its local teams, HPA staff are responsible for contact tracing around cases and clusters of meningitis.

Pfizer Vaccines has a long history and strong heritage in public health. Through innovative research, we have pioneered the development, licensing and manufacture of several vaccines to improve the nation’s health. Our commitment to vaccines spans well into the future, with research and development currently looking across a broad range of diseases and populations, including infants, children, adolescents, and adults.

From April 2013 the HPA will become part of Public Health England.

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Notes

Notes

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Meningitis Research Foundation
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