Day two abstracts

NOVARTIS SATELLITE BREAKFAST SESSION

CONFIDENCE IN NUMBERS: THE EVIDENCE BASE FOR ASSESSING THE PUBLIC HEALTH IMPACT OF VACCINES AGAINST INVASIVE MENINGOCOCCAL DISEASES

This Novartis Vaccines sponsored breakfast symposium explored the challenges in assessing the evidence behind vaccination against invasive meningococcal diseases.

CHAIR

EMERITUS PROF RICHARD MOXON
PROFESSOR OF PAEDIATRICS, UNIVERSITY OF OXFORD

Richard Moxon Richard Moxon MA, F.Med.Sci, FRS is Emeritus Professor of Paediatrics and a Professorial Fellow of Jesus College at the University of Oxford. His paediatric and research training was in the UK (1966-1969) and the USA (1970-1974).

He was Assistant and then Associate Professor of Paediatrics at Johns Hopkins University in Baltimore (1974-1984), becoming the Eudowood Director of Pediatric Infectious Diseases in 1981 before he was elected as Action Research Professor and Chairman of Paediatrics at Oxford University (1984-2008) and Head of the Molecular Infectious Diseases Group in the Weatherall Institute of Molecular Medicine (1988-2008).

He is a Fellow of the UK Royal College of Paediatrics and Child Health and of the UK Academy of Medical Sciences and was elected a Fellow of the Royal Society in 2007. His major research interests have been on the pathogenesis and prevention of sepsis and meningitis caused by the bacteria Haemophilus influenzae and Neisseria meningitidis.

Prof Moxon chaired the session, introduced the speakers and emphasised some of the scientific challenges underpinning the introduction of new vaccines.

DR JAMIE FINDLOW
DEPUTY HEAD OF VACCINE EVALUATION UNIT, PUBLIC HEALTH ENGLAND, MANCHESTER

Jamie Findlow Dr Findlow is the Deputy Head of the Public Health England (PHE) Vaccine Evaluation Unit (VEU) located at the Manchester Royal Infirmary.

He joined the VEU as a Clinical Scientist in 2000 and was responsible for the completion of serology from clinical trials of Neisseria meningitidis polysaccharide and conjugate vaccines.

He subsequently undertook a PhD entitled “Serological correlates for and immunogenicity of candidate serogroup B N. meningitidis vaccines.” Following his PhD, he has been involved in development and evaluation of immunoassays including those for N. meningitidis, Haemophilus influenzae type b, diphtheria, tetanus and Streptococcus pneumoniae.

Dr Findlow reviewed the evidence used to guide assumptions of disease incidence, carriage impact, herd protection and strain coverage prior to large scale implementation.

DR SIMON NADEL
CONSULTANT IN PAEDIATRIC INTENSIVE CARE, ST MARYS HOSPITAL, LONDON

Liam NorrisSimon 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 Nadel discussed the challenges of quantifying meningococcal disease mortality and morbidity.



Session 1: Current issues in clinical management



CHAIR

PROF ROBERT HEYDERMAN
MALAWI-LIVERPOOL-WELLCOME TRUST PROGRAMME

robert Heyderman Rob Heyderman is a clinician scientist who trained in London and Zimbabwe. He directs the Malawi- Liverpool-Wellcome Trust Clinical Research Programme (MLW) which has an internationally recognised translational research portfolio, linking an excellent laboratory base to strong hospital and community-based research teams (http://www.mlw.medcol.mw). The research activities of the MLW Programme are focused under four interlinked research themes Malaria; TB & HIV; Non-Communicable Diseases (NCDs); and Microbes, Immunity & Vaccines. His own research focuses on i) the endothelial biology & coagulopathy of severe infection, ii) immunity to mucosal pathogens and prevention through vaccination, iii) regulation of host inflammation, and iv) the diagnosis and management of meningitis and sepsis.

PROF MICHAEL LEVIN & DR DAVID INWALD
ST MARY’S HOSPITAL, IMPERIAL COLLEGE LONDON

DEBATE ON AGGRESSIVE VS RESTRICTED FLUID RESUSCITATION IN CHILDHOOD SEPSIS

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

David Inwald David qualified from Cambridge University and trained in adult and paediatric medicine before completing his training in paediatric intensive care medicine at Great Ormond Street Children’s Hospital. He is a Consultant in Paediatric Critical Care Medicine at St Mary’s Hospital, London and an Honorary Senior Lecturer in Paediatrics at Imperial College. He has research interests in sepsis and patient safety.


ABSTRACT

Early management of paediatric sepsis consists of supportive therapy, antibiotics and source control. Currently there are no adjunctive therapies which have been proven in clinical trials. Supportive therapy consists of ABC management including fluid bolus therapy and early initiation of intensive care for children with fluid resistant shock, including intubation, mechanical ventilation, inotropes and organ support. The debate will focus on the ongoing controversy about fluid management in critically ill children, looking at the evidence for and against generous fluid bolus therapy in severe infection.

41,358 paediatric cases were seen overall in five clinics over the six-month intervention period with 101 Emergency, 14,284 Priority and 26,973 non- priority or Queue cases. High levels of agreement (kappa = 0.71) were reached following training between low cadre health worker triage outcomes and clinically trained health staff. Overall 644 (1.6%) cases were referred: 100 of these had been defined as Emergency representing 15.5% of total referrals. A significant number were Priority case referrals (74% of all referrals) whilst 62 cases who had been clinically triaged as non-Priority or Queue, were referred. Of all 644 referrals made, only 240 (37.3%) actually reached QECH, showing a large dropout between primary level referral and arrival at tertiary care. Worryingly 67% of all Emergency referrals never arrived at QECH, but mean time from referral for those Emergency cases that reached QECH was 3.5 hours. The intervention was well received by primary health workers and patients and pre and post evaluation showed a substantial improvement on patient flows and experiences within the clinic.

Our pilot intervention study has shown that establishing an mHealth phone-based triage system is feasible and acceptable at primary health level and that it has the potential to significantly improve patient pathways. We are currently working with the Ministry of Health to develop a full intervention on the impact of the phone-based algorithm and to address other priority gaps in community responses to severe paediatric illness in Malawi.

Michael Levin's presentation




David Inwald's presentation


DR SIMON NADEL
ST MARY’S HOSPITAL, LONDON

ROUND UP OF NEW DEVELOPMENTS IN CLINICAL MANAGEMENT OF MENINGITIS OR SEPSIS IN PAEDIATRIC AND ADULT SETTINGS

Simon Nadel 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.

ABSTRACT

Simon Nadel summarises recent developments in the management of sepsis and meningitis, focussing on emergency care and management of complications. This includes a summary of advances in fluid management, organ failure and neuroprotection.

Prospects for further development will also be discussed.


DR LOUISA POLLOCK
WELLCOME TRUST TROPICAL CENTRE, LIVERPOOL

MANAGEMENT OF SEPSIS AND MENINGITIS IN DEVELOPING COUNTRIES

Louisa Pollock Louisa Pollock is a general paediatrician with a special interest in infectious diseases and global child health. While working as a paediatric registrar in Malawi in 2006-2007, she gained perspective on the challenges of providing emergency care in resource-limited settings. She became actively involved in ETAT (Emergency Triage, Assessment and Treatment), a WHO training programme which aims to improve paediatric emergency care. In 2008 she led a national ETAT “training of trainers” programme in Malawi with funding from the Scottish Government.

On completion of her higher specialist training she worked as a clinical research fellow with Professor Beate Kampmann’s team at Imperial College London and MRC - The Gambia. She assisted with research studies in infant immunology and tuberculosis and helped establish a new training programme in child TB and adapt ETAT to a Gambian setting.

In 2013 Louisa was awarded a Wellcome Trust Clinical PhD Fellowship, based at the Wellcome Trust Tropical Centre, Liverpool. Her overall research aim is to address high-burden, high-mortality paediatric problems in resource-limited settings. She is particularly motivated by the inequity of the paediatric research gap - the lack of child-specific data, particularly in diagnostics and in clinical trials, which deprives children worldwide of evidence-based healthcare. She continues to support ETAT training in Malawi as a trustee of the charity Children’s Medical Care Malawi, and is a consultant mentor for the RCPCH ETAT programme in Uganda.

ABSTRACT

What are the essential requirements to effectively manage sepsis? Inotropes and mechanical ventilation? Broad-spectrum antibiotics and saline? Or maybe nurses and electricity?

Low income countries face the highest burden of sepsis and meningitis, with the most limited resources. Access to care is challenging, and standard of care is often poor. As a result case- fatality rates and risk of sequelae may be at least twice as high as in high-income countries.
Global initiatives to develop and implement evidence- based guidelines for the management of sepsis and meningitis have delivered improved outcomes in high- income countries, but are such guidelines feasible in resource-limited settings? If partial implementation is necessary, which elements will result in the greatest impact, for the least cost?

The evidence base for the management of sepsis and meningitis is limited, particularly in children. Initial research is often undertaken in high-income countries, but differences in aetiology, co-morbidities and health systems may mean that results may not be generalisable to low and middle income countries with the highest burden of disease. Well conducted clinical trials based in countries where the potential for positive impact is greatest are essential. The FEAST trial, investigating fluid management in shock in African children, is an excellent example, although its unexpected results may have generated more questions than answers.

This presentation will begin with an overview of the clinical context of sepsis and meningitis in developing countries, including the challenges to providing effective care. Current efforts to develop and implement evidence-based guidelines appropriate to resource-limited settings will be summarised, and the impact of recent research discussed.

Finally, ongoing research gaps will be highlighted.


Session 2: Preventing pneumococcal disease



CHAIR

PROF RAY BORROW
PUBLIC HEALTH ENGLAND, MANCHESTER

Ray Borrow Professor Ray Borrow is Head of the Vaccine Evaluation Unit at Public Health England (formerly Health Protection Agency), 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 gained his PhD in 1994, his MRCPath in 2003 and he became a Professor of Vaccine Preventable Diseases in the Faculty of Medical and Human Sciences at the University of Manchester in 2009 and Visiting Professor at the School of Healthcare Sciences, Manchester Metropolitan University in 2011. His scientific findings have resulted in over 240 peer reviewed published papers. Until recently he served as a member of the DH Joint Committee on Vaccination and Immunisation (JCVI) and continues to date as an expert advisor. He is an ad hoc advisor to WHO on both meningococcal and pneumococcal vaccines. He chairs the scientific advisory panel for Meningitis Research Foundation.
PROF DAVID GOLDBLATT
INSTITUTE OF CHILD HEALTH, UNIVERSITY COLLEGE LONDON

CURRENT EPIDEMIOLOGY AND SUMMARY OF VACCINES IN DEVELOPMENT; THE NEED FOR HIGHER-VALENT AND ALTERNATIVE VACCINES

David Goldblatt David Goldblatt is Professor of Vaccinology and Immunology and Head of the Immunobiology Unit at the Institute of Child Health, University College London (UCL). He is a Consultant Paediatric Immunologist at the Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH) where he is also Director of Clinical Research and Development and Director of the National Institute for Health Research GOSH/ UCL Biomedical Research Centre. He 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, United Kingdom.

He has a long-standing interest in the immune response to vaccines and infectious diseases. He has an active research programme studying bacterial conjugate vaccines in the young and the elderly, the ontogeny of the immune response to bacterial carriage and infection and evaluation of functional immunity to S. pneumoniae proteins. He has been a regular advisor to the World Health Organisation (WHO) on bacterial conjugate vaccines and is Director of the WHO Reference Laboratory for Pneumococcal Serology based at the UCL Institute of Child Health in London. He has served on numerous committees including United Kingdom Department of Health Joint Committee on Vaccines and Immunisation and MRC and Wellcome Trust funding panels.

ABSTRACT

The first pneumococcal conjugate vaccine was licensed by the FDA in 2000 and immediately introduced in the infant immunisation programme in the USA. The vaccine, a mixture of seven capsular polysaccharides each individually conjugated to a protein carrier molecule, proved highly successful in reducing the incidence of infection due to the serotypes in the vaccine in immunised children. The vaccine was also shown to prevent the acquisition of pneumococci in the nasopharynx (NP), thus preventing the spread of pneumococci and reducing the incidence of disease in the unvaccinated and suebsequently became widely used around the world.

The consequence of reduced NP carriage of the 7 serotypes in the vaccine resulted in replacement carriage by serotypes not in the vaccine and a proportion of these emerged as causes of infection. In 2009/10 two new extended valency conjugates were licensed, containing 10 and 13 serotypes respectively. These vaccines have proven to be efficacious although with only 3 years of follow up since their widespread introduction more time is required to understand their potential for mediating an indirect effect and the possibility of further replacement disease. Looking at emerging serotypes post PCV13 introduction does provide an insight into the possible design of future conjugates. There is burgeoning interest in new approaches to providing non-serotype specific immunity. Protein containing vaccines might be one way of achieving this, either using relevant pneumococcal proteins as carrier molecules, or indeed standalone pneumococcal protein vaccines, although the route to licensure for the latter is complicated.


PROF ANTHONY SCOTT
LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE

PNEUMOCOCCAL CONJUGATE VACCINE IMPLEMENTATION IN AFRICA WITH A FOCUS ON KENYA

David Goldblatt Anthony Scott trained in clinical infectious diseases and epidemiology before moving to the KEMRI- Wellcome Trust Research Programme in Kilifi, Kenya in 1993. He has spent most of the last 20 years in Kenya, studying pneumococcal disease and pneumonia in children and adults, and vaccines to prevent them. Currently a Wellcome Trust Senior Research Fellow in Clinical Science, Anthony works in clinical paediatrics in Kilifi. He joined the London School of Hygiene and Tropical Medicine in January 2013 after 15 years based at Oxford University and teaches on the short course on the Epidemiological Evaluation of Vaccine, the Intensive Course on Epidemiology and Medical Statistics and the Diploma course in Tropical Medicine & Hygiene. In addition to research Anthony has developed a surveillance network for invasive bacterial diseases in East Africa and co-directs the Kilifi Health and Demographic Surveillance System. He works frequently with WHO and GAVI on vaccine preventable diseases and with the Ministry of Health in Kenya on the evaluation of pneumococcal vaccine.

Anthony Scott’s main research interests are in child health and vaccines in East Africa. He runs the Pneumococcal Conjugate Vaccine Impact Study, an effectiveness evaluation of vaccine introduction in Kenya, and a series of associated studies of transmission and modelling of pneumococcal disease, evaluation of vaccine safety, and pathogen population structure. Anthony also works closely with the International Vaccine Access Center at John Hopkins School of Public Health on a project called PERCH (Pneumonia Etiology Research for Child Health) which is a 7-site case-control study of the aetiology of pneumonia in children. Anthony is interested in the epidemiology of invasive bacterial infections in children and the way that they shape childhood mortality, and in international vaccine policy and the economic and epidemiological evaluations required to support that policy.

ABSTRACT

Pneumococcal disease is a frequent cause of pneumonia, meningitis and sepsis in Africa. According to a WHO, pneumococcal disease is estimated to have caused 447,000 deaths among African children aged < 5 years in the year 2000. In a trial in The Gambia, 9-valent Pneumococcal Conjugate Vaccine had an efficacy of 37% against radiologically-confirmed pneumonia and 16% against all-cause mortality in children aged 6-29 months. A trial in South Africa confirmed the utility of the vaccine in countries with high HIV prevalence. Pneumococcal conjugate vaccines were introduced into the routine national immunisation programme (NIP) in the USA and the UK in 2000 and 2006, respectively. The first introduction of PCV into an African NIP took place in 2009 (Rwanda) and since 2011 the vaccine has been introduced widely with support from the GAVI Alliance. To date, 39 African countries have been approved for GAVI support for PCV introduction.

Across Africa surveillance mechanisms and tailored studies to evaluate the impact of the vaccine are relatively sparse. The Invasive Bacterial Diseases arm of the WHO Vaccine Preventable Diseases surveillance is collating information on bacterial meningitis from 49 sentinel surveillance sites and of bacteraemic pneumonia from a handful of sites. Because of logistic and technical reasons the frequency of isolation of S. pneumoniae in the baseline surveillance is relatively low. The GAVI Alliance has funded specific studies of vaccine impact in South Africa (case-control study) and in Kenya (before-after study). Other before-after studies are taking place in The Gambia, Malawi, Togo, Mozambique and Zambia.

To date there are no published results from any of these studies. However, the surveillance for Invasive Pneumococcal Disease taking place at the KEMRI- Wellcome Trust Research Programme in Kilifi, Kenya, is published monthly and the impact of the vaccine is already evident in the frequency of cases observed (http://www.kemri-wellcome.org/index.php/en/studies_ inner/75).

The 10-valent PCV was introduced in January 2011, including a catch-up campaign for children aged <5 years. The baseline frequency of IPD of vaccine serotypes was 15-40 cases per year. Following vaccine introduction VT IPD cases have been progressively reduced and in 2013 there have been no cases at all so far.

Introduction of PCV7 in the USA and the UK was associated with considerable herd protection and with a variable degree of ‘serotype replacement disease’. Nasopharyngeal carriage of vaccine serotypes was virtually eliminated from the vaccinated population. The magnitude of these effects in Africa will be critical to cost-effectiveness analyses of the vaccine and to the sustainability of the vaccine programme. The talk will present recently published or emerging data on the impact of PCV in Africa on transmission, carriage and indirect vaccine protection.

Session 3: Prevention of meningitis and septicaemia



CHAIR

PROF ANDREW POLLARD
UNIVERSITY OF OXFORD

Andrew Pollard 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 guidelines development group, and 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 and from October 2013 chairs the Joint Committee on Vaccination and Immunisation. He runs a paediatric research group 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.
DR MARY RAMSAY
PUBLIC HEALTH ENGLAND, LONDON

CURRENT ISSUES WITH MENINGOCOCCAL VACCINE PROGRAMMES IN THE UK

Mary Ramsay Dr Mary Ramsay obtained her medical degree at University College in London. Before joining the Health Protection Agency she held an academic post at St Mary’s Hospital Medical School in London. She became a Consultant Epidemiologist in 1994 with responsibility for the national surveillance of vaccine preventable diseases, blood-borne hepatitis and transfusion transmissible infections. Since 2009 she has been Head of Immunisation at the Health Protection Agency, and now in Public Health England.

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. She is joint Chief Editor of Immunisation Against Infectious Diseases - the recognised national source of advice on vaccination, last published in 2006 and with subsequent updated chapters. She has also been involved in several national guidance documents on public health policy in her disease areas.

In addition she provides expert clinical and public health advice in the field of vaccination and blood borne virus prevention. Her work has directly contributed to several major decisions on national vaccination policy, that, in turn has provided benefits for public health.
She often acts as a temporary advisor to WHO on vaccine preventable diseases and advises the European Centre for Disease Control on surveillance and epidemiology of vaccine preventable diseases.

Since April this year, her department in Public Health England has now taken on responsibility for implementation and planning of immunisation programmes, requiring her to provide clinical expert leadership to the Screening and Immunisation Teams based in NHS England. Dr Ramsay’s research interests involve establishing the potential role for new vaccines.

ABSTRACT

Introduction: MenC conjugate vaccination was introduced into the UK infant schedule in 1999, accompanied by a catch-up programme to 18 years, later extended to those under 25 years. Coverage in school aged cohorts and pre-school children was high and led to an immediate and dramatic fall in MenC cases which has been now been sustained for over 10 years. In 2004, following evidence of declining individual protection from MenC given at 2, 3, 4 months, the 2 month dose was removed from the infant schedule and booster dose of vaccine (combined with Hib) was added for toddlers.

Methods and results: Surveillance of meningococcal disease relies on confirmed cases ascertained by Public Health England. MenC cases are followed individually to determine vaccination status and risk factors for infection. Recent trends in MenC cases are consistent with excellent control of disease. Fewer than 30 cases are reported annually, many occurring in adults and older children who have not been vaccinated – often because they were born and raised overseas. Travel is also commonly reported. MenC vaccine failures are unusual but have been reported even after a full primary course (or two or three doses) plus booster. Although results are consistent with high short term protection, there is evidence of declining protection with age. The excellent control is therefore probably attributable to indirect protection from the impact of the catch-up programme on carriage. Numbers of cases due to serogroups other than B remain uncommon although recent increases in MenY and MenW have been observed. Sero-prevalence studies are performed using serum bactericidal assays on residual sera collected from microbiology laboratories across the country. The most recent study suggested that those children vaccinated in the catch-up programme in 1999-2000 are still relatively well protected. Antibody levels in those vaccinated in infancy, however, appear to decline with age and very limited benefit appears to have accrued from the toddler booster. A range of clinical studies have been conducted to look at antibody responses to various schedules in infancy. These suggest that immune responses to different MenC conjugate vaccines vary and the degree of boosting achieved by the toddler dose is affected by the conjugate received in infancy. Studies of boosting in teenagers have recently commenced.

Discussion: Post-marketing surveillance of MenC, suggests that most children vaccinated in infancy, with or without a toddler booster, will be unprotected by teenage years. In 2013 the UK schedule was modified to be based on a single dose of MenC (at 3 months) followed by a toddler MenC/Hib booster. A teenager booster is due to commence in Year 10 (14- 15 years) the 2013/14 academic year, with a catch-up programme for university students commencing in 2014-2015.



DR FIONA VAN DER KLIS
PUBLIC HEALTH INSTITUTE OF THE NETHERLANDS (RIVM)

CURRENT ISSUES WITH MENINGOCOCCAL VACCINE PROGRAMMES IN THE NETHERLANDS: TIMING OF ADOLESCENT BOOSTER AFTER SINGLE PRIMARY MENC IMMUNISATION AT YOUNG AGE - THE TIM-STUDY, AN INTERVENTION STUDY AMONG DUTCH TEENAGERS

Fiona van der Klis Fiona van der Klis, PhD, is Head of the Department Immunesurveillance within the Centre Infectious Disease Control of the Public Health Institute of the Netherlands (RIVM).

Fiona obtained her PhD in endocrinology and immunology before accepting a research position in the Dutch Antilles. In 2000, she joined the RIVM and has since then increased her knowledge on infectious diseases.

Here she leads a group of scientists working in the field of vaccine preventable diseases. The department has extensive experience in monitoring seroprevalence (all components of the national immunisation program), measuring immune responses to natural infection or vaccination and determining the duration of immunity. For this, state of the art techniques are implemented at the laboratory that can measure the quantity and quality of the immune responses after vaccination. The department is one of the leading laboratories in the multiplexed serology field and conducts clinical trials to optimise the national immunisation program.

Fiona is involved in several (inter)national projects covering multiple pathogens and themes e.g. MenC immunity (second immunisation study), HPV immunity (monitoring effect of introduction of vaccine, high risk groups like MSM), measles antibodies and elimination goal (WHO, SSI), vaccine responses in immune compromised adolescents and vaccine responsiveness in the ageing population.

Fiona is the project leader of a large population- based study monitoring the protection against the vaccine preventable diseases. This study is an important part of the evaluation of the Dutch National Immunisation program. In addition, she is also project leader of the harmonisation of the immunisation programme of the Dutch Caribbean Islands.

ABSTRACT

Background: The main purpose of vaccination is achieving long-term individual (and herd) immunity. For many infectious diseases, this requires a booster vaccination in addition to primary vaccination. As has been shown previously, immunity against Meningococcal serogroup C disease (MenC) wanes after several years in infants and toddlers, indicating that also for MenC a booster vaccination might be necessary. Young children between 0-5 years of age are most vulnerable to invasive MenC disease. Vaccination at a young age is therefore most appropriate but does not lead to long term protection. Since teenagers aged between 12-18 years are also at risk for developing invasive MenC disease, a booster MenC vaccination during or prior to adolescence can be considered. Determining the appropriate age for this booster vaccination is a challenge as a booster vaccination during late adolescence probably leads to more prolonged individual (and herd) protection, but leaves the young adolescents at risk. In an attempt to determine the optimal age for a booster (second) vaccination, a study is currently conducted in The Netherlands (TIM study). In the Dutch immunisation program, MenC is administered at the age of 14 months as a single dose vaccination.

Aim: To establish an appropriate age for an adolescent MenCC booster vaccination.

Methods: Three age-groups were recruited with healthy 10 year olds (n=91), 12 year olds (n=91) and 15 year olds (n=86). All participants were primed with MenC-PS tetanus toxoid conjugated vaccine (NeisVac C™) 9 years earlier, and received the same MenCC vaccination at the beginning of the study.

Blood samples were collected prior to (T0) and 1 month (T1) and 1 year (T2) after vaccination. MenC- PS specific IgG levels, avidity and IgG subclasses were measured using a fluorescent-bead-based multiplex immunoassay (MIA). Functional antibody levels were measured using the serum bactericidal antibody assay (SBA).

Results: 268 participants were enrolled, 259 (96.6%) completed all study visits. Nine years after primary MenCC vaccination, 45% of the 15 year olds still had protective antibody levels against MenC compared to 34% of the 12 year olds and 19% of the 10 year olds. All participants developed extremely high serum MenC-PS specific IgG levels and SBA titre 1 month after the study MenCC vaccination. At T2, 100% of all age groups still had protective antibody levels against MenC, but the 15 year-olds remained the highest serum MenC-PS specific IgG levels and SBA titre and showed the lowest level of decrease in antibody levels.

Conclusion: Nine years after their primary MenCC vaccination, all participants developed considerably high antibody levels in response to the study vaccination and all participants were still well protected one year later. One year after the study vaccination, the oldest age group remained the highest (protective) antibody levels and showed the lowest level of antibody decrease. This suggests that persistence of individual - and indirectly herd-immunity increases with the age at which an adolescent booster is administered.



DR CAROLINE TROTTER
UNIVERSITY OF CAMBRIDGE

PROF STEPHEN GORDON
LIVERPOOL SCHOOL OF TROPICAL MEDICINE


CARRIAGE STUDIES – WHAT DO THEY ADD? HUMAN BACTERIAL CHALLENGE EXPERIMENTS AS AN ALTERNATIVE

Caroline Trotter Dr Caroline Trotter is an infectious disease epidemiologist at the University of Cambridge. Her research focuses on assessing the potential and actual impact of vaccination against different forms of bacterial meningitis on a population level. She uses a range of research methods including mathematical modelling, cost- effectiveness analyses, carriage studies, analyses of large databases and seroprevalence studies. She is currently working with the African Meningococcal Carriage Consortium, MenAfriCar.

Stephen Gordon Professor Gordon joined the Liverpool School of Tropical Medicine in 2005, with a remit to establish laboratory and clinical research on susceptibility to pulmonary infections in the School. Prior to his appointment, he had completed two Wellcome Trust Research Fellowships in Blantyre, Malawi and a Clinical Lectureship in the University of Sheffield.

Stephen’s research in Sheffield and Malawi focused on susceptibility to respiratory infection and in particular, on the effect of HIV infection on susceptibility to pneumococcal disease. The work demonstrated that pulmonary mucosal defence is regulated differently than systemic defence against infection, and can be perturbed by environmental exposures including indoor air pollution. The Respiratory Infection laboratory now focuses on mechanisms for antigen presentation to the mucosal surface leading to effective mucosal defence against bacterial infections. They also study the effect of biomass fuel smoke on defence against infection.

Recent work includes a study of inhaled pneumococcal polysaccharide vaccine, assessment of the pulmonary response to pneumococcal conjugate vaccine and the current study of experimental pneumococcal carriage as a pulmonary antigen challenge. Work on biomass fuel smoke indicates that acute and chronic exposures result in very different immune responses, probably leading to altered defence against infection and COPD by different mechanisms.

Stephen holds an Honorary Consultant Contract in General Medicine in the Royal Liverpool University Hospital and University Hospital Aintree. He combines Respiratory and General Medicine with research and teaching in the School.

ABSTRACT

Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae are the major causes of bacterial meningitis worldwide and share a home in the human nasopharynx. Studying nasopharyngeal carriage is essential as this state is the natural reservoir, the source of transmission and the pre- requisite of invasive disease including meningitis. A full understanding of carriage will not only inform the epidemiology of infection but also help in prediction and measurement of control measures’ impact. Many studies of carriage have been conducted, particularly in the context of vaccination. Caroline Trotter will briefly review some major findings, strengths and weaknesses of these carriage studies and pose the question whether alternative approaches are required. Stephen Gordon will address the role of controlled human infection studies, focusing on experimental human pneumococcal carriage, and ask if the study of healthy volunteers will be sufficiently informative as to be ethically justified in the search for new vaccines to prevent meningitis.



Caroline Trotter's presentation






Stephen Gordon's presentation




Session 4: Future prospects for prevention of meningococcal disease



CHAIR

PROF IAN FEAVERS
NATIONAL INSTITUTE FOR BIOLOGICAL STANDARDS AND CONTROL (NIBSC)

Ian FeaversIan 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.
DR MATTHEW SNAPE
UNIVERSITY OF OXFORD

NON-ROUTINE USE OF MENINGOCOCCAL VACCINES IN OUTBREAKS AND FOR INDIVIDUALS WITH CLINICAL RISK FACTORS

Matthew Snape Dr Matthew Snape is a consultant in General Paediatrics and Vaccinology at the Oxford University Hospitals NHS trust and an Honorary Senior Clinical Lecturer at the University of Oxford.

After completing basic training in paediatrics at the Royal Children’s Hospital, Melbourne, he spent 18 months working in the paediatric intensive care unit at St Mary’s Hospital, London. While caring for children suffering overwhelming infections he developed an interest in the prevention of these illnesses by immunisation. This led him to the Oxford Vaccine Group, University of Oxford, where he has been the principal investigator on paediatric studies of meningococcal, pneumococcal, influenza and Hepatitis B vaccines.

Dr Snape is partially funded by the Oxford Partnership Comprehensive Biomedical Research Centre.

ABSTRACT

In view of their increased risk for meningococcal disease, specific immunisation guidelines have been developed for individuals who are immunodeficient, are on immunomodulatory treatment or have occupational exposure to Neisseria meningitidis. These recommend the use of additional dose(s) of plain polysaccharide and/ or protein-polysaccharide conjugate serogroup A, C, W and Y vaccines. Where applicable these are to be administered prior to commencing immunosuppressive therapy. Recent developments in this area include the extension of approved age ranges for the protein-polysaccharide MenACWY vaccines and the increasing use of eculizumab, a recombinant humanized monoclonal IgG that specifically inhibits the complement cascade, thus rendering recipients at increased risk of meningococcal disease. Furthermore, the recent interim statement from the Joint Committee on Vaccines and Immunisation (JCVI) has recommended the use of the licensed serogroup B meningococcal vaccine in the same high risk groups as defined for the quadrivalent MenACWY vaccines. This presentation will review the evidence base underpinning existing guidelines, and what further research is required. The use of the above vaccines in outbreak settings will also be discussed.

Listen to Matthew Snape's presentation


PROF ADAM FINN
UNIVERSITY OF BRISTOL

MENINGOCOCCAL VACCINES - HAVE WE BEEN ASKING THE WRONG QUESTIONS?

Adam Finn Adam Finn is Professor of Paediatrics and a member of the Schools of Clinical Sciences and of Cellular and Molecular Medicine at the University of Bristol and an honorary Consultant in Paediatric Infectious Diseases and Immunology at Bristol Royal Hospital for Children. He is director of the South West Medicines for Children Research Network and heads the Bristol Children’s Vaccine Centre. He trained in Infectious Diseases at the Children’s Hospital of Philadelphia and in Immunology at the Institute of Child Health in London where he obtained his PhD.

He worked in Sheffield between 1992 and 2001 where he was involved in several trials of meningococcal group C and other vaccines. His current main research interest is the biology of respiratory infections and how vaccines affect transmission of infections.

ABSTRACT

Over the last decade many of the precepts which drove the development, licensure and implementation of conjugate vaccines, including those used to prevent meningococcal vaccines, have not turned out to represent the primary mechanism of their effectiveness. Accumulating evidence suggests that these vaccines efficiently block acquisition of nasopharyngeal carriage in recently immunised individuals. This effect may be mediated by high levels of anticapsular IgG exhibited on mucosal surfaces and its consequences for downstream transmission may surpass, by some distance, the importance of direct protective effects of immunisation which have driven the design and implementation of vaccine programmes to date. The very different composition of new meningococcal vaccines, which do not contain capsular antigens, adds to the uncertainties around their effectiveness which beset all vaccines designed to prevent very unusual, severe infections, since it cannot be assumed they will have the same or similar mucosal effects. Finding out has not, to date, been a major priority. The last ten years have also seen the general acceptance and implementation of cost-effectiveness evaluation as the driver for introduction of novel health service interventions. As the concept that healthcare costs have to be contained and resources rationally disbursed takes root, this approach raises questions about how best to attribute value to the benefits of approaches that are very diverse. Efforts to assess whether the funding decisions reached by this process match the priorities favoured by the public and healthcare professionals charged with their delivery are only just getting underway. That evaluation of the questions whether any particular infectious disease merits prevention through universal immunisation and at what cost should follow rather than precede the development of vaccines to do so is an anomalous consequence of the timing of the evolution of this process and this chronology should probably change in the future. In the meantime, we have to confront the present and how primary prevention of meningococcal disease can progress. Since everyone wants this to happen, the question is not really whether, but when and how to move forward. Occasional stumbles need not develop into headlong falls.

Listen to Adam Finn's presentation

IMMUNISATION AGAINST SEROGROUP B MENINGOCOCCAL DISEASE - HOPES AND FEARS

PANEL DISCUSSION MODERATED BY PROF PAUL HEATH
PANELISTS: PROF ADAM FINN, UNIVERSITY OF BRISTOL, DR SIMON NADEL, PROF ROBERT READ, DR MATTHEW SNAPE AND DR CAROLINE TROTTER


Paul HeathPaul 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 recently, 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 research committee of the European Society of Paediatric Infectious Diseases and a member of the steering committee of the international Brighton Collaboration on vaccine safety.


Adam Finn Adam Finn is Professor of Paediatrics and a member of the Schools of Clinical Sciences and of Cellular and Molecular Medicine at the University of Bristol and an honorary Consultant in Paediatric Infectious Diseases and Immunology at Bristol Royal Hospital for Children. He is director of the South West Medicines for Children Research Network and heads the Bristol Children’s Vaccine Centre. He trained in Infectious Diseases at the Children’s Hospital of Philadelphia and in Immunology at the Institute of Child Health in London where he obtained his PhD.

He worked in Sheffield between 1992 and 2001 where he was involved in several trials of meningococcal group C and other vaccines. His current main research interest is the biology of respiratory infections and how vaccines affect transmission of infections.

Simon Nadel 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.


Robert ReadProfessor Robert Read undertook clinical and research training in Leeds, Bristol, London, Nottingham and San Francisco. He was appointed as an academic infectious disease physician
at the University of Sheffield in 1995 and served as Professor of Infectious Diseases there from 2002-2012, prior to moving to Southampton in September 2012.

Professor Read has research interests in the pathogenesis and prevention of rapidly lethal infectious diseases, especially meningococcal and pneumococcal disease, and influenza.

He is the chairman of the Infectious Diseases and Microbiology Speciality Group for the NIHR clinical research network, and chairs the postdoctoral awards panel for the NIHR Personal Training Fellowships scheme. He is the current chairman of the Annual Meeting Program Committee of the Infectious Disease Society of America.

He is Editor in Chief of the Journal of Infection and Current Opinion in Infectious Diseases, and is author and co-author of 200 publications mainly in the field of infectious diseases. He was appointed as a member
of the UK’s Joint Committee on Vaccination and Immunisation (JCVI) in September 2013

Matthew Snape Dr Matthew Snape is a consultant in General Paediatrics and Vaccinology at the Oxford University Hospitals NHS trust and an Honorary Senior Clinical Lecturer at the University of Oxford.

After completing basic training in paediatrics at the Royal Children’s Hospital, Melbourne, he spent 18 months working in the paediatric intensive care unit at St Mary’s Hospital, London. While caring for children suffering overwhelming infections he developed an interest in the prevention of these illnesses by immunisation. This led him to the Oxford Vaccine Group, University of Oxford, where he has been the principal investigator on paediatric studies of meningococcal, pneumococcal, influenza and Hepatitis B vaccines.

Dr Snape is partially funded by the Oxford Partnership Comprehensive Biomedical Research Centre.

Caroline Trotter Dr Caroline Trotter is an infectious disease epidemiologist at the University of Cambridge. Her research focuses on assessing the potential and actual impact of vaccination against different forms of bacterial meningitis on a population level. She uses a range of research methods including mathematical modelling, cost- effectiveness analyses, carriage studies, analyses of large databases and seroprevalence studies. She is currently working with the African Meningococcal Carriage Consortium, MenAfriCar.

Hear the discussion


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