Meningitis and Septicaemia in Children and Adults 2015
Wednesday 4 and Thursday 5 November 2015
Royal Society of Medicine, 1 Wimpole Street, London W1G 0AE London UK
Our tenth conference brought together internationally renowned experts from a range of specialties to address the most important issues of the day, including burden of illness, recognition and treatment, vaccine development, vaccine implementation and public health policy.
Attracting delegates from around the world, this conference is a key event in the calendar for some of the foremost scientists and clinicians and provided an excellent opportunity to discuss the latest developments within the field.Download the full conference programme
Click on the name of the presentation to see the biography of the speaker, the abstract of the presentation and, where available, the presentation's slide set and audio recording.
Day 1 - Wednesday 4 November
Current issues in clinical management– Chair: Dr Simon Nadel,
St Mary's Hospital/Imperial CollegeGroup B Streptococcal and neonatal infection – Chair: Prof Robert Heyderman,
UCLMeningococcal carriage – Chair: Dr Caroline Trotter,
University of CambridgePreventing pneumococcal disease – Chair: Prof Adam Finn,
University of BristolDay 2 – Thursday 5 NovemberControlling meningococcal disease around the globe – Chair: Prof Ray Borrow,
Emergence of a virulent new meningococcal W sequence type 11 in South America and the UKControlling meningococcal disease around the globe – Chair: Prof Sir Brian Greenwood,
- The impact of MenAfriVac in the Meningitis Belt and prospects for meningococcal disease prevention through EPI and higher valent vaccines Dr Marie-Pierre Preziosi, Medical Officer, Initiative for Vaccine Research, Department of Immunization, Vaccines and Biologicals, World Health Organization
- Current epidemiology of meningococcal disease in the Meningitis Belt and new WHO outbreak response guidelines after the Meningitis Vaccine Project Dr Olivier Ronveaux, WHO meningitis team, Geneva
- Impact of Meningococcal B Vaccine (Bexsero) on University Outbreaks in the US: Epidemiology, Vaccine Uptake, and Immune Response among a High-Risk Population – Dr Nicole Basta, University of Minnesota, School of Public Health, Division of Epidemiology
Advances from research – Chair: Prof Nigel Klein,
UCLPrevention of meningococcal disease in the UK – Chair: Prof Ian Feavers,
Congratulations to Hayley Lavender
, a researcher at University of Oxford, who won first prize for her findings on what determines our susceptibility to meningitis and septicaemia, presented in her poster ‘Competition between host molecules influences susceptibility to meningococcal disease’. Read or download other poster entries
Prof Richard Beale
Guy's and St Thomas' Hospital, London
Richard Beale is a Professor of Intensive Care Medicine at King’s College, London, and a Consultant in Intensive Care Medicine at Guy’s and St Thomas’ NHS Foundation Trust, and his clinical and research interests include sepsis, haemodynamic monitoring, advanced ventilation, nutrition in the critically ill, and ICU informatics. He is Clinical Director for Perioperative, Critical Care and Pain Services at Guy’s and St Thomas’ NHS Foundation Trust. He is also Co-Leader of the Clinical Academic Group within King’s Health Partners AHSC that includes Critical Care, and is acute Clinical Academic Group Development lead for King’s Health Partners, with honorary membership of the KHP Executive. He is immediate past Chair of the Research Committee of the ESICM, and was a member of the ESICM Executive. He has been an ESICM representative on the Steering Committee of the Surviving Sepsis Campaign since 2004, and is a frequent invited speaker at national and international meetings. Professor Beale is Clinical Director for London Adult Critical Care Operational Delivery Networks.
Listen to Richard's presentation below:Return to main index
Dr Fiona McGill, University of Liverpool
Fiona is funded by a Doctoral Research Fellowship award from the National Institute for Health Research and works with the Liverpool Brain Infections Group. She is also a medical doctor specialising in Infectious Diseases and Microbiology. Fiona has previously been funded by MRF to look at the epidemiology and outcomes in meningitis in adults in the UK and is continuing this work through her NIHR funding. Her research interests include improving diagnosis and diagnostics, especially in viral meningitis, using both qualitative and quantitative methods.
Bacterial meningitis and meningococcal sepsis are relatively rare conditions in the UK with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society (predecessor of the British Infection Association) produced a consensus statement to guide the management of immunocompetent adult patients with meningitis and meningococcal sepsis. Additionally, an algorithm and poster were produced in 2003.
Since then the epidemiology has changed and there have been new developments in diagnostic methods and treatments. A proposal was made to the BIA that the 1999 consensus statement should be revised and updated. These 2015 guidelines aim to provide a standardised evidence-based approach to the management of acute community acquired meningitis, including viral meningitis, and meningococcal sepsis in adults.
A working party representing key national professional associations and consisting of infectious diseases physicians, neurologists, an acute physician, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and agreed on by the whole working party. The literature that has arisen since 1999 was then systematically reviewed and critically appraised in order to revise the recommendations accordingly. All recommendations were graded and agreed upon by the working party. The guidelines were written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. In addition to the main guideline both an updated version of the one page algorithm was produced as well as an audit tool to assist in implementation of the guideline.
The main changes from the previous guidelines will be discussed and include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of relevant investigations has been updated to include the use of such things as procalcitonin and CSF lactate; more emphasis is placed on molecular methods of diagnosis. Approaches to both antibiotic and steroid therapy have also been revised, including a pragmatic recommendation on how long after antibiotics steroids can be given; the evidence for other adjunctive therapies is also reviewed. Several recommendations have been given regarding the follow-up of patients and, for the first time, the investigation and management of viral meningitis are also considered.
A number of studies have shown that there are frequently inappropriate investigations and delays in appropriate treatment when it comes to managing patients with meningitis. Recent publications from other countries have suggested that new, up to date guidance can have a beneficial effect on mortality at a population level. It is our hope that these guidelines, which will be officially launched at the end of 2015, will have a similar impact in the UK. Return to main index
Group B Streptococcal and neonatal infectionChair: Prof Robert Heyderman
University College London
Dr Ifeanyichukwu Okike, Derby Children’s HospitalDr Okike is a Consultant Paediatrician at Derby Children’s Hospital. He is also a Fellow of the Higher Education Academy and a member of the Medical Advisory Group for Meningitis Research Foundation (MRF). During his specialist training in paediatrics he worked as a Clinical Research Fellow at St George’s, University of London and was supervised by Prof Paul T Heath. He coordinated an MRF funded bacterial meningitis in infants < 90 days of age: burden of disease and assessment of healthcare delivery study (neoMen). Both studies have been collaboration with the British Paediatric Surveillance Unit (BPSU) and Public Health England (PHE).
Abstract Bacterial meningitis in young infants remains a significant cause of mortality and morbidity. The incidence and case fatality rate in UK neonates is unchanged over the last two decades.
The most recent UK population based study showed that non-specific clinical features dominated, and fever was absent in 153 (47%) of cases at presentation. GBS (150, 50%) and Escherichia coli (40, 13%) remain the leading causes. Identified bacteria varied by age and route of admission. There were no cases of listeria meningitis in infants older than 30 days and cefotaxime alone seem to be an appropriate empiric cover for this group. At discharge, 26% had a poor early outcome (death or serious neurological complication).
The impact of the existing initiatives (vaccines and guidelines) on the burden and outcome in this age group seems to be limited. Between September 2010 and June 2013, using parental questionnaire, medical notes and expert panel review we assessed in detail the current management in the UK.
Of the 97 confirmed cases recruited across England and Wales, 66 (68%) were admitted from home (H) and 31 (32%) were already in hospital (IP) prior to the onset of the meningitis. The median age was14 days (IQR 3-25) and was higher in H cases 17 days (11- 34) compared to IP cases 1 day (0-7), p=0.0001. The median time from onset of features to first help for H cases was 4.8 hours (IQR: 2-10). Most parents 47/62 (76%) presented to hospital within 24 hours of onset of features at home. 28/66 (42%) were assessed to have encountered inappropriate pre-hospital management. At the time of presentation 40 (61%) had fever and 21 (32%) had seizures whilst 36 (55%) received at least one fluid bolus.
The median time from triage to first dose of antibiotics was 2.0 hours (IQR: 1.0-3.3; > 1 hour in 43 (73%)), significantly shorter in infants who had fever or seizures at presentation 1.7 hours (IQR: 1 .0-3.0) compared to those who did not 4.2 hours (IQR: 1.8- 6.3), p=0.02. The empiric antibiotics started on 35/66 (53%) were not in conformity with the NICE bacterial meningitis guideline. Follow up duration was <2 years
in 26/65 (40%) of the infants. Overall 26 (39%) either died (one case) or had a complication (25/65, 38%). For IP cases, 18/31 (58%) were admitted from the post natal ward whilst 13 (42%) were admitted from birth or were on neonatal unit. At diagnosis, 17 (55%), 12 (39%) and 8 (26%) of infants received a fluid bolus, had seizures or had fever respectively. The median time from onset to first dose of antibiotics was 2.6 hours (1.3-9.8) whilst 17/31 (55%) did not receive empiric antibiotics in conformity with appropriate NICE guideline. Follow up duration was <2 years in 5/31(16%) of the infants. 14 (45%) of the infants were reported to have a serious complication.
Although the aetiology has not changed, there is now an opportunity to rationalise our empiric antibiotics regimen by age and route of admission. The poor outcome associated with bacterial meningitis in young infants remains unacceptably high. Absence of fever in nearly half of the cases is very important and seems to contribute to the observed delay in the initiation of appropriate empiric antibiotics. Lessons from our study are being packaged into educational tool to inform clinical practice. In the meantime, work on GBS and other bacteria vaccines should continue.
Funding for the neoMen project is by Meningitis Research Foundation (MRF).
Dr Queen Dube, Queen Elizabeth Central Hospital, Malawi
Queen Dube is a Malawian paediatrician working at the largest tertiary hospital in Malawi Queen Elizabeth Central Hospital which also acts as a teaching hospital for the only medical school in Malawi. She currently heads the Department of Paediatrics and Child health at this hospital.
Dr Queen Dube did her MBBS degree at the College of Medicine in Malawi in 2000. She was awarded an RCPCH sponsorship to go and train in Paediatrics in the UK in 2005. She did her PhD with the University of Liverpool which she completed in July 2014. Her PhD research sought to determine the Aetiology and Outcome of Neonatal sepsis and meningitis in Malawi.
Dr Queen Dube has research interests in the areas of neurodevelopment, neonatal health, Group B Streptococci and HIV. She has published several papers in these areas.
She currently is a member of the national newborn steering committee and chairs the technical working group for immunization in Malawi. She is also a member of the confidential inquiry into maternal and neonatal deaths committee in Malawi.
She is currently leading a team that developed the Every Newborn Action Plan for Malawi and looks forward to a time when the neonatal mortality rate for Malawi will be less than 5 deaths per 1,000 live births.
In Malawi there has been significant progress in reducing post-neonatal and under- 5 deaths over the past decade but very little progress in reducing neonatal deaths. The major causes of neonatal deaths in Malawi are prematurity, infections and birth asphyxia. Neonatal sepsis has been shown to have long term complications ranging from motor deficits to cognitive impairment, epilepsy and behavioural disorders in preterm very low birth weight infants in the developed setting. Contrary to the epidemiology in the developed setting where neonatal sepsis is predominantly seen in preterm low birth weight infants, in the developing setting neonatal sepsis is also common among term babies. However, very little is known on the long term outcome of neonatal sepsis in the resource restrained setting. Methodology:
This study had 2 components; a cross sectional arm and a prospective cohort arm. The cross sectional study was looking at the aetiology, resistance pattern and in hospital outcome of severe neonatal infection cases presenting at QECH in Blantyre. The prospective cohort arm involved participants who were recruited in the cross sectional arm at QECH and were residing within Blantyre and infants that never had an episode of severe neonatal infection were recruited from Zingwangwa Health Centre. The infants from Zingwangwa acted as controls. The participants in the prospective cohort arm were followed up to the age of 1 year where neurodevelopmental outcomes were assessed using the Bayley’s assessment tool. These participants also had detailed neurologic examination during the follow up visits at 6 and 12 months of age. A comparison between the cases and controls was made to ascertain the impact of neonatal infection outcome. Results:
During the study a total of 412 cases were enrolled in the cross sectional arm. 75% of the cases had late onset disease. GBS was the commonest organism grown in blood culture 17/42(40%) and CSF culture 16/33(48%). 44% had abnormal serum sodium levels on admission and hypernatraemia was independently associated with an increased risk of dying in hospital (8.34[95% CI 1.95-35.7]). 51% of the gram negative organisms were multidrug resistant. In the long term outcome neonatal sepsis without overt meningitis was associated with an up to 6.6-fold (95% CI 2.38-18.4) increased risk of developmental delay at 1 year of age. Meningitis was associated with a 17-fold (95% CI 4.89- 61.7) increased risk of developmental delay at 1 year of age. Positive blood or CSF culture and being HIV exposed were independent predictors of delay at 1 year of age. Conclusion:
GBS is a significant cause of neonatal infections in Malawi. The magnitude of developmental delay observed in infants who had neonatal sepsis without meningitis is worrying, up to 35% of these infants were delayed. It is therefore important to employ measures that can prevent neonatal infections. Follow up is recommended in infants who had an episode of severe neonatal infection.Listen to Queen Dube's presentationReturn to main index
Dr Imma Margarit Y Ros, GSK, Sienna
Dr Immaculada Margarit received her PhD in Human Genetics in 1988 from the University of Rome, Italy. She has worked as researcher in the field of infectious diseases for more than twenty years, both in academia and the industry. She joined Chiron Vaccines in 2000, where she pioneered the application of genomics and proteomics to the discovery of broad-coverage vaccine combinations against human microbial pathogens. In 2006, she was appointed Research Project Leader at Novartis Vaccines (now GSK) and has brought the Group A Streptococcus (GAS) and Group B Streptococcus (GBS) research programs to clinical development stage. She is member of the American Society for Microbiology and the International Society of Vaccines. She has published more than 50 peer-reviewed papers on major scientific journals and owns more than 20 patents in the vaccine field. Since 2005, she has given Graduate courses on Microbiology and is lecturer at the Master of Vaccinology held by the University of Siena.
Abstract Streptococcus agalactiae
(Group B streptococcus, GBS) can cause invasive disease in infants born to mothers carrying the bacteria in their ano/genital tract. Neonatal GBS infections mainly occur within the first week of life (early onset disease, EOD) or between days 8-90 (late-onset disease, LOD) and are a major source of global infant sepsis and meningitis with high fatality rates. Up to 38% of infants surviving EOD/LOD may suffer from long-term sequelae. GBS is also an important cause of maternal peripartum morbidity.
Intrapartum antibiotic prophylaxis (IAP) administered to mothers at risk of transmitting neonatal disease has greatly reduced the incidence of EOD. In some regions, risk is determined by recto-vaginal screening for GBS colonisation at 35-37 weeks of gestation, while in others by specific factors including premature rupture of membranes, fever, suspected amnionitis or previous infant with GBS infection. However, precipitous labor, false negative screening or antibiotic allergies can lead to IAP failures. Furthermore, IAP has not reduced the incidence of LOD, and concerns have been raised for possible induction of antibiotic resistance and negative impact on the neonatal intestinal microbiota.
To date, there are no available anti-GBS vaccines. Yet, the capsular polysaccharide (CPS), its most important GBS pathogenicity factor, shows great promise as antigen target. Ten CPS serotypes have been characterised and found to be antigenically unique, and five of them (Ia, Ib, II, III, V) account for more than 90% of cases globally. Remarkably, anti-CPS maternal antibody levels have been shown to be associated with serotype-specific reduction of neonatal disease risk. Therefore, vaccination of pregnant women may represent an effective strategy for neonatal disease prevention in the form of placentally-transferred anti-CPS antibodies. Antibody thresholds predictive of neonatal protection have been derived from observational studies comparing anti-CPS IgG titers in sera from colonized mothers and those delivering non-infected babies, and could constitute the basis for establishing GBS vaccine protection serocorrelates. An important question concerns the relationship between maternal CPS-specific antibody concentrations and functional activity, and how natural exposure and vaccination affect these two variables. Recent PhI/II clinical studies have shown that multivalent vaccines based on CPS conjugates of major serotypes are safe for the mother and the infant, and elicit functional anti-GBS IgGs transferred with high rates to the fetus. These results shed new optimism onto the concept that maternal conjugate vaccines are technically feasible for the prevention of such a devastating disease.Listen to Imma Magarit Y Ros' presentationReturn to main index
Meningococcal carriage and herd protectionChair: Dr Caroline Trotter
University of Cambridge
Prof Sir Brian Greenwood, London School of Hygiene and Tropical Medicine
Brian Greenwood qualified in medicine at the University of Cambridge, UK in 1962. Following house-officer appointments in London, he spent 3 years in Western Nigeria as a medical registrar and research fellow at University College Hospital, Ibadan. After receiving training in clinical immunology in the UK, he returned to Nigeria in 1970, this time to help in establishing a new medical school at Ahmadu Bello University, Zaria where he developed his research interests in malaria and meningococcal disease whilst continuing to teach and practice clinical medicine.
In 1980, he moved to the UK Medical Research Council Laboratories in The Gambia which he directed for the next 15 years. In The Gambia, he helped to establish a multi-disciplinary research programme which focused on some of the most important infectious diseases prevalent in The Gambia and neighbouring countries such as malaria, pneumonia, measles, meningitis, hepatitis and HIV. Work undertaken during this period included demonstration of the efficacy of insecticide treated bednets in preventing death from malaria in African children and demonstration of the impact of Haemophilus influenzae type b and pneumococcal conjugate vaccines when deployed in sub-Saharan Africa.
In 1996, he was appointed to the staff of the London School of Hygiene and Tropical Medicine where he is now Manson Professor of Clinical Tropical Medicine. From 2001-2009 he directed the Gates Malaria Partnership which supported a programme of research and capacity development in many countries in Africa directed at improving treatment and prevention of malaria. In 2008, he became director of a new capacity development initiative supported by the Wellcome Trust, the Bill & Melinda Gates Foundation, and the Malaria Capacity Development Consortium (MCDC), which operates a post-graduate malaria training programme in five countries in sub-Saharan Africa. He also directs the African Meningococcal Carriage Consortium which, with support from the Wellcome Trust and the Bill & Melinda Gates Foundation, has investigated the pattern of meningococcal carriage in seven countries in the African meningitis belt and demonstrated the impact of the serogorup A meningococcal conjugate vaccine (MenAfriVac®) on meningococcal meningitis and carriage in Chad.
The African Meningococcal Carriage Consortium (MenAfriCar) was established in 2007 as a partnership between seven African research centres and twelve partners from five northern countries to study carriage of Neisseria meningitidis
in countries of the African meningitis belt prior to and after introduction of the serogroup A meningococcal conjugate vaccine PSa-TT (MenAfriVac®) which was then being developed. The reasons why this initiative was undertaken, some of the challenges that it met and the consortium’s main findings will be presented.
During the course of over 20 cross-sectional surveys undertaken in age-stratified populations in seven African meningitis belt countries, nearly 50,000 pharyngeal swabs were collected. The overall prevalence of carriage of N. meningitidis across all surveys was lower than expected at 4%. The prevalence of carriage and the predominant serogroup varied markedly between countries and over time, as did the prevalence and species distribution of non-meningococcal Neisseria
Transmission of N. meningitidi
s was studied in 133 households in whom a carrier was identified during the course of one of the cross-sectional surveys. Serogroup W was the most prevalent serogroup identified in these studies and showed a substantial level of transmission within households, but evidence for transmission of N. meningitidis
outside households was found also. The average duration of carriage, around 3 months, was less than that usually found in industrialised countries. Measurement of meningococcal serogroup A specific IgG and bactericidal antibodies in six and two countries respectively showed high pre-vaccination antibody titres, as has been noted previously in the African meningitis belt. Seroprevalence by age was used in a catalytic model to determine the force of infection in six countries. Collection of blood samples at the start of the household studies will allow correlates of protection against carriage of some meningococcal serogroups to be investigated.
Methods of facilitating carriage studies were investigated in The Gambia where it was found that culture of swabs in broth overnight followed by identification of meningococcal DNA by PCR doubled the isolation rate. Adoption of this method could help to reduce the size of the populations needed to demonstrate differences in carriage prevalence in vaccine impact studies, and to improve the validity of longitudinal studies on the dynamics of transmission.
An important objective of the consortium was to demonstrate the impact of MenAfriVac® on carriage and it was planned initially to undertake these studies in Mali and Niger but no serogroup A meningoccci were found in the pre-vaccination surveys in these countries. However, carriage of serogroup A N. meningitidis
was found in Chad and, in this country, it was shown that MenAfriVac® not only reduced substantially carriage of serogroup A N. meningitidis
but that it also halted an epidemic caused by this bacterium.
The MenAfriCar consortium has received funding from the Bill & Melinda Gates Foundation and the Wellcome Trust. Return to main index
Prof Martin Maiden, University of OxfordAfter an initial training in microbiology, during which he developed an enduring interest in infectious disease and public health, Martin Maiden’s graduate studies used molecular, genetic, and biochemical techniques to study sugar transport in Escherichia coli. He became interested in multi-disciplinary and evolutionary approaches to investigating biological problems and, after a two-year MRC Training Fellowship, began his independent research career at the National Institute for Biological Standards and Control, where he was a group leader for nine years, including a sabbatical year at the Max-Planck-Institut für Molekulare Genetik, Berlin. In this period he worked mainly on the biology of Neisseria meningitidis and its implications for vaccination. In 1997 he moved to a Wellcome Trust Senior Fellowship in Oxford and was appointed Professor of Molecular Epidemiology and a Fellow of Hertford College in 2004. He became a Fellow of the Royal College of Pathologists in 2010 and a Fellow of the Society of Biology in 2012.
AbstractSuccessful long-term control of meningococcal disease depends on two key insights, which are not immediately apparent when considering the devastating effects of meningococcal disease on individuals:
- First, the bacterium Neisseria meningitidis is not principally a pathogen. It is a normally a harmless part of the microbiota, the natural community of microbes, present at the back of human throats.
- Second, the meningococcus is a highly diverse bacterium and its very many different variants exhibit different characteristics, including the propensity to cause disease and the expression of antigens useful for vaccines. Very few meningococcal types cause disease frequently.
These two factors need to be central features of vaccine design, but, perhaps even more importantly, of vaccine implementation if disease control is to be achieved and maintained.
We have tackled these issues for nearly 20 years by combining high-resolution genetic characterisation of meningococci with large-scale carriage studies that sample the natural population of meningococci.
From 1999 -2001 the UKMenCar1-3 carriage surveys established that the principal reason for the success of the meningococcal C (MenC) conjugate vaccines was that they disrupted transmission of the epidemic group C meningococcus among UK teenagers, the main reservoir of this organism due to their social behaviour. This protected the unvaccinated and the ineffectively vaccinated. Without this ‘herd immunity’ effect there would have been substantially more cases of serogroup C disease to this day. These insights have led to the progressive alteration of the UK immunisation programme to exploit herd immunity more effectively and was used in the design of the highly successful implementation of the MenAfriVac® group A (MenA) vaccine in Africa.
Since 2001 meningococcal disease has declined substantially in the UK from almost three thousand per year to a few hundred. This includes serogroup B meningococci, even though no vaccine has been used: the reasons for this decline must, therefore, reside in the naturally circulating population of meningococci. To investigate this, we undertook a fourth survey, UKMenCar4, from autumn 2014 to spring 2015, to enable comparisons of disease and carriage isolates from a high (1999-2001) with a low incidence period. This study has proved timely, as the dramatic rise in serogroup W disease, has prompted the introduction of tetravalent MenACWY vaccines in teenagers. In addition to the original aim, there is now an opportunity to investigate the effect of the MenACWY vaccine with a further survey, UKMenCar5. The UKMenCar4 survey recruited nearly 22,000 participants identifying and collecting meningococci and questionnaire data. Analysis of this very large sample set is on-going, but preliminary indications are that meningococcal carriage is substantially reduced compared to 1999-2001 and that this is probably attributable to changes in teenage behaviour.
It is highly unlikely that meningococcal disease will be satisfactorily controlled until the circulation of all invasive meningococci is curtailed. This can only be achieved by deploying vaccines designed to block their transmission deployed in populations that transmit them, perhaps in combination with social measures designed to limit transmission. Our studies continue to play a central role in achieving this goal. Return to main index
Preventing pneumococcal diseaseChair: Prof Adam Finn
University of Bristol
Professor Miller is a Consultant Epidemiologist, in the Immunisation Hepatitis and Blood Safety Department, Public Health England, in Colindale North West London. She first became involved in vaccine safety research in 1978 when she joined the then Public Health Laboratory Service to work on the large post-licensure safety and efficacy studies of pertussis vaccines that were being conducted following the collapse of the UK whooping cough immunisation programme in the mid 1970s. This experience prompted her continuing interest in the risks and benefits of vaccination programmes and organising trials of new vaccines. She has been involved with trials of acellular pertussis, MMR, Hib, meningococcal C vaccines and more recently the pneumococcal and HPV vaccines. Her other interests include seroepidemiology and mathematical modelling, and viral infections in pregnancy. With colleagues at PHE she has conducted many vaccine safety studies eg to investigate the associations between MMR and autism, convulsions, “immune overload”, H1N1 vaccine and narcolepsy, thiomersal and developmental delay, oral polio vaccine and intussusception, meningococcal C conjugate vaccine and nephrotic syndrome. She was one of the founder members of the WHO Global Advisory Committee on Vaccine Safety and served for 6 years as a member of the WHO Strategic Advisory Group of Experts.
Pneumococcal infection is a major cause of morbidity and mortality in young children and those aged 65 years and over. In children the manifestations of pneumococcal disease include septicaemia, pneumonia and empyema, septic arthritis and meningitis. Pneumococcal meningitis has a particularly high mortality and is associated with lifelong sequelae. The advent of pneumococcal conjugate vaccines, in which the serotype-specific capsular polysaccharides from the key disease causing strains are conjugated to a protein carrier, offered for the first time the potential to radically reduce the incidence of this disease both in young children and older age groups through the induction of herd immunity. The first generation pneumococcal conjugate vaccine (PCV) protected against seven serotypes, with higher valency vaccines protecting against 10 or 13 serotypes being developed within a few years to provide broader coverage and to combat the increase in certain non-vaccine serotypes that followed the introduction of PCV7. The UK PCV7 and PCV13 programmes have been highly successful with PCV7 disease now reduced by 97% compared with the pre-vaccine era in all age groups and overall reduction in invasive pneumococcal disease due to the 6 additional serotypes in children under 2 year of 78% within 4 years of its introduction in 2010. Meningitis due to vaccine serotypes in young children has now virtually disappeared. However, increases in non-vaccine type serotypes is now occurring with PCV13 as with PCV7 though the replacing serotypes have less of a propensity to cause meningitis than the vaccine serotypes. The latest data surveillance data on pneumococcal disease will be presented and prospects for third generation pneumococcal vaccines discussed. Listen to Elizabeth Miller's presentationReturn to main index
Dr Mark Alderson, PATH, Seattle
Dr Alderson is Director of PATH’s Pneumococcal Vaccine Project (PVP) and Meningococcal Vaccine Project Polyvalent (MVPP) which seek to accelerate the development and licensure of promising pneumococcal and meningococcal vaccines and ensure their availability and use in developing countries. Dr Alderson has more than 30 years of experience in medical research, biotechnology, pharmaceuticals and vaccine development. He joined PATH in August, 2006, serving initially as PVP Scientific Director until his appointment as PVP Director in July, 2007. He was appointed MVPP director in February, 2012. Prior to joining PATH, Dr Alderson was Director of Immunology at GlaxoSmithKline Biologicals, Seattle, where he led preclinical work on synthetic adjuvants for a variety of vaccine targets. Prior to GSK, he was Senior Director of Immunology at Corixa Corporation where he was responsible for the preclinical discovery and evaluation of adjuvants and vaccines for tuberculosis, Chlamydia and HSV. Dr Alderson has extensive experience in vaccine development and has published over 60 manuscripts in peer reviewed journals. He served as an Affiliate Associate Professor, Department of Pathobiology at the University of Washington from 2002 until 2006. Dr Alderson earned his PhD in immunology at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia and his MBA at Seattle University.
Current pneumococcal conjugate vaccines (PCVs) approved for use in children are effective against serotypes included in the vaccines, but they do not cover all pneumococcal serotypes. They are also complicated and relatively expensive to manufacture, making vaccine access difficult for poorer countries without substantial donor assistance. While Gavi, the Vaccine Alliance; the Advance Market Commitment funding mechanism, and other international donors are funding the introduction of current PCVs in low-income countries, new vaccines are needed to focus protection and achieve more inherent affordability for the developing world.
The goal of PATH’s pneumococcal vaccine project is to accelerate the development of promising new pneumococcal vaccines that are safe and effective in young children, and to ensure their affordability, availability, and use in low-resource countries. As part of this project, we are developing a portfolio of vaccine candidates that includes low-cost PCVs but with a particular emphasis on common protein vaccines. Vaccines containing proteins that are common to all pneumococcal serotypes could provide broad and affordable protection to children worldwide. Our lead protein vaccine candidate, being developed in collaboration with Boston Children’s Hospital, is an inactivated, whole cell vaccine (SPWCV) designed to offer broad serotype-independent coverage coupled with low manufacturing costs. Preclinical studies have demonstrated protection against both nasopharyngeal carriage (T-cell mediated) and invasive pneumococcal disease (antibody mediated). We recently completed a randomised, double blind, placebo-controlled Phase 1 study designed to assess the safety, tolerability and immunogenicity of SPWCV formulated with aluminum hydroxide adjuvant (PATH-wSP) in healthy adults. PATH-wSP was found to be safe and well tolerated, and induced both antibody and T-cell responses among vaccinated subjects. We are currently conducting a Phase 1/2 dose-escalation, age de-escalation study in Kenya.
We are also exploring strategies to incorporate common protein antigens as carriers for a novel PCV. This hybrid approach is designed to take advantage of the regulatory path established for licensure of new PCVs and to offer the further benefit of broader coverage by adding a pneumococcal protein antigen. Overall, pneumococcal protein vaccines offer considerable promise, either alone or in combination with PCVs; yet, the clinical and regulatory challenges for eventual licensure are considerable.Listen to Mark Alderson's presentationReturn to main index
Controlling meningococcal disease around the globeChair: Prof Ray Borrow
Public Health England Vaccine Evaluation Unit, Manchester
Emergence of a virulent new meningococcal W sequence type 11 in South America and the UK
Dr Marco Sáfadi, Department of Pediatrics, FCM da
Santa Casa de Sao Paulo
Marco Sáfadi is an Associate Professor of Pediatrics at the Santa Casa de São Paulo School of Medicine, Brazil. After receiving his degree in medicine and a residency in pediatrics, he continued his medical training in pediatric infectious diseases at the Federal University of São Paulo. He subsequently received a master’s degree in pediatrics studying congenital toxoplasmosis in children, and a PhD studying the impact of rotavirus vaccine on gastroenteritis hospitalizations in children. At Santa Casa de São Paulo School of Medicine, Prof Safadi is currently the Head of the Department of Pediatrics and a Member of the Permanent Advisory Board on Immunization Practices for the Secretary of Health in the State of Sao Paulo and for the Ministry of Health in Brazil. Prof Sáfadi is an active member of many societies, including the Committee of Pediatric Infectious Diseases for the Society of Pediatrics, São Paulo,and for the Brazilian Society of Pediatrics, SLIPE (Sociedad Latinoamericana de Infectología Pediátrica), WSPID (World Society for Pediatric Infectious Diseases) and ESPID (European Society of Pediatric Infectious Diseases). He was appointed in 2011 a liaison representative for SLIPE at the Committee on Infectious Diseases (COID) – Red Book, from the American Academy of Pediatrics. Prof Sáfadi is a member of the editorial board of the Journal of the Pediatric Infectious Diseases Society (JPIDS) and has authored original papers and book chapters, namely on immunisation, meningococcal and pneumococcal infections, influenza, rotavirus gastroenteritis, pertussis, HPV, dengue, congenital and community-acquired infections.
Historically, meningococcal disease (MD) caused by serogroup W (MenW) was rarely observed in South America. However, around 2001 MenW disease emerged, initially in Brazil, and subsequently in Argentina and Chile, becoming endemic in these countries. In Argentina the prevalence of this serogroup increased from 6% of cases in 2006 to 47% in 2010 and 50% in 2013 (in 2006, there were only four invasive MenW isolates detected in Argentina, increasing to 96 isolates in 2012 and 77 in 2013). Likewise, in Chile since 2010 a year-on-year increased number of MenW cases was reported and by 2013, serogroup W accounted for 66% of all MD cases (in 2010 only six MenW isolates were reported, increasing to 22 in 2011, 60 in 2012 and 79 in 2013). Overall Incidence rates in Argentina and Chile, during this recent period of MenW predominance were between 0.6 and 1 cases/100,000 habitants, with the highest incidence rate reported in infants. A peak was also observed in persons >60 years in Chile, whereas the number of cases in adolescents was consistently low in both countries.
Case fatality rates (CFR) associated to MenW cases reported during 2012 in Chile were as high as 27%. The clinical presentation distribution of the cases, showing almost 70% of cases presenting with meningococcemia, has been postulated as the probable reason for this finding.
Preliminary MLST analyses were not able to distinguish the emergence of MenW disease in South America from the hypervirulent Hajj clone W135:P1.5,2:ST11 (ST11/ET37 clonal complex), which emerged in 2000 and has since spread internationally. However, more recently, whole genomic sequencing analysis demonstrated that the MenW:cc11 strain which is currently endemic in Brazil, Argentina and Chile is distinct and unrelated to the Hajj outbreak strain.
In response to the increased number of MenW cases and the associated CFR observed, the Ministry of Health in Chile decided to implement a reactive immunisation campaign, using tetravalent (ACWY) conjugate vaccines. The campaign commenced in 2012, targeting children aged 9 months to 5 years, with a roll out to the whole country during the first months of 2013. Coverage for the first dose of the vaccine was almost 100% for the targeted age group. A second dose was given for children from 9 months to less than 2 years. Interestingly, preliminary analysis of the current epidemiologic situation in Chile showed that, after the Men ACWY immunisation, protection was observed only for the age groups targeted for the vaccine, without early indirect effects. The overall incidence rates of serogroup W MD in 2013 and 2014 were similar to 2012. The effectiveness of the vaccination program implemented in Chile is of great importance globally, as lessons learned here could be used in other countries with similar epidemiologic situation. New potential strategies, including immunisation of young infants and a catch-up campaign targeting adolescents and young adults, are being discussed to optimise the impact of the vaccination program in Chile. Return to main index
Dr Jay Lucidarme, Public Health England Vaccination Unit, Manchester
Jay Lucidarme began working at the Public Health England Vaccine Evaluation and Meningococcal Reference Units in 2007. In 2012 he obtained his PhD entitled Potential Coverage of an Investigational Multicomponent Meningococcal Vaccine, with a focus on the ST-269 clonal complex. He has since been involved in projects investigating meningococcal genomic epidemiology and the vaccine candicacy of meningococcal haemoglobin receptors. He is currently undertaking an investigation of within-host meningococcal microevolution during progression from a harmless commensal to invasive pathogen. He is co-author on 20 peer-reviewed publications.
(the meningococcus) is feared worldwide as a leading agent of meningitis and septicaemia. The ST-11 clonal complex (cc11) is a particularly virulent strain associated with high rates of morbidity and mortality and a propensity to cause outbreaks and epidemics. High profile episodes of cc11 disease include widespread meningococcal C (MenC) outbreaks in universities in the late 1990s, a global Hajj-associated meningococcal W (MenW) outbreak in 2000, and several devastating MenW epidemics in Africa. England and Wales are currently experiencing year-on-year increases in endemic MenW cc11 disease - a cause for considerable concern following similar increases in South Africa and South America where mortality rates have reached 28%. Beyond the capsule the poor discriminatory value of routine typing schemes against cc11 organisms causes uncertainty as to the relatedness of current and historical cases and the provenance of emerging strains. Making use of recent advances in genomic research, we sought to address these questions by delineating a high resolution population structure.Methods
: A geographically and temporally diverse panel of 923 meningococcal cc11 genomes (643MenW, 246 MenC and 34 MenB) and subsets thereof were compared in terms of up to 1546 core genes. Resultant distance matrices underwent phylogenetic network analyses to generate a cc11 population structure framework.Results:
cc11 constitutes a diverse population comprising two main divergent lineages (lineages 11.1 and 11.2) and a number of sublineages. The MenW isolates were segregated to a distal (relative to the origin) portion of lineage 11.1 whilst the MenB and MenC isolates were broadly interspersed elsewhere. The Hajj-associated MenW isolates were tightly clustered within one of two relatively recently divergent MenW sublineages, alongside the closely related endemic South African strain. The other MenW sublineage comprised the endemic South American and English and Welsh isolates arranged (relative to the origin) in order of their emergence in their respective countries.Conclusion:
A novel, highly virulent MenW cc11 strain that has recently expanded in South America is currently expanding in the UK. This strain is distinct from that of the Hajj-associated outbreak of 2000 and a closely related strain recently responsible for elevated endemic disease in South Africa. Identification of this strain and knowledge of its aggressiveness elsewhere supported the decision to introduce a MenACWY vaccination programme for UK13-18 year-olds beginning from August 2015. Return to main index
Prof Philippe de Wals, Laval University, Quebec CityPhilippe De Wals is Professor at the Department of Social and Preventive Medicine, Laval University, in Quebec City, Canada. Professor De Wals gained his Medical Degree and a Doctorate in Public Health in his home country of Belgium, at the Louvain Catholic University. His early academic and professional career combined epidemiology research studies at the School of Public Health at the Louvain Catholic University with the practice of general medicine. Between 1980 and 2000 he worked as an epidemiologist for EUROCAT, a European network of population-based registries for the epidemiologic surveillance of congenital anomalies. In 1990, he moved to Canada and became the Head of the Department of Community Health Sciences at the University of Sherbrooke. In 1997, he was appointed visiting Professor at the School of Public Health at the University of North Carolina in Chapel Hill, USA. Professor De Wals’ research is centered on the epidemiology of infectious diseases, reproductive abnormalities, and the assessment of health services and public health programs and policies. He is the author of over 150 published articles in scientific journals and has contributed several chapters to textbooks. Currently, Professor De Wals is a member of the research centers at Quebec University Hospital and the Sherbrooke University Hospital and is a medical advisor to the Quebec National Institute of Public Health. In 2011, he was appointed as Scientific Director of the Evaluation Platform on Obesity Prevention at the Quebec Cardiology and Pneumology Institute. In 1990, Professor De Wals was awarded the Jean Van Beneden Prize in recognition of his excellent work in the public health field, and in 2005, he was elected to the Royal Academy of Medicine of Belgium.
AbstractBackground: In 2003, a virulent Serogroup BST269 meningococcal clone emerged in Quebec.The Saguenay-Lac-Saint Jean (SLSJ) region was particularly affected with a Serogroup B disease rate of 3.6/100 000 person-years in 2006-2012, more than 10 times the Canadian average. Genotyping showed that 96% of ST-269 strains from Quebec may express two antigens similar to 4CMenB vaccine components: fHbp peptide 15 and NHBA peptide 21. On this basis, a mass immunisation campaign targeting individuals 2 months to 20 years of age resident or attending school in SLSJ was launched. The campaign startedin May 2014 and recruitment ended in December2014.
Methods: Prospective registration of 4CMenB administration by the public health services was implemented. The passive vaccine adverse event reporting system (ESPRI) was complemented with active web-based surveillance. Pediatricians in the region were alerted as to the occurrence of specific outcomes including Kawasaki disease. Reinforced meningococcal disease surveillance was also undertaken with the collaboration of hospita lmicrobiology laboratories in the region, the Provincial Reference Laboratory (LSPQ-INSPQ) in Montreal and the National Microbiology Laboratory in Winnipeg.Vaccine effectiveness was estimated by comparinginvasive meningococcal disease rates in vaccinatedand unvaccinated individuals in the region. Thecampaign effectiveness was estimated usingdynamic time-series modeling and younger/oldermeningococcal disease cases ratio.
Results: 82% of the approximately 58,000 people targeted received ≥ 1 vaccine dose and 70% a second dose. Vaccination coverage was particularly low in the 15-20 years age group. Fever and local pain were the most frequently reported reactions following vaccine administration. Antipyretic prophylaxis (acetaminophen mainly) was 50%effective in preventing the occurrence of fever in children less than 5 years of age but not in older age groups. Absenteeism during the 2 days following administration of the first vaccine dose was reported in 3.7% of vaccinees. Overall, 4 cases of benign convulsion were reported and only one case of Kawasaki disease. As of June 30, 2015, no case of meningococcal disease had been recorded in vaccinees, meaning a 100% protection during the first year following administration of the first vaccine dose. In March-April 2015, two Serogroup B cases occurred in unvaccinated adults in the SLSJ region. One additional case occurred in an unvaccinated 13-year old person from Quebec City during a holiday stay in the SLSJ region. The estimated effectiveness of the campaign to reduce disease incidence in the region was between 40% and 75% according to the method used.
Conclusions: Results are reassuring as to the safety of 4CmenB and are in line with a high level of direct protection during the first year following administration of the first vaccine dose. The campaign failed however, to provide indirect (herd)protection in adults.
Listen to Philippe's presentation below:
Controlling meningococcal disease around the globeChair: Prof Sir Brian Greenwood
London School of Hygiene and Tropical Medicine
Dr Marie-Pierre Preziosi, WHO, GenevaMarie-Pierre Preziosi is currently Medical Officer at the Initiative for Vaccine Research, Department of Immunization, Vaccines and Biologicals, World Health Organization (WHO). From 2012-2014, she was director of the Meningitis Vaccine Project (MVP), a partnership between the WHO and PATH, established in 2001 through a grant from the Bill & Melinda Gates Foundation. The MVP mission has been to eliminate epidemic meningitis as a public health problem in sub-Saharan Africa through the development, testing, introduction, and widespread use of conjugate meningococcal vaccines. A project member since 2003, Dr. Preziosi previously served as the director of clinical development, as part of her role as WHO Medical Officer. In this role, she has led the strategy and implementation of the MVP clinical development work, has helped foster strong relationships between the MVP partner organizations, in particular WHO and PATH, and has contributed technical guidance to meningococcal vaccine introduction activities and research to define evidence-based policy for optimal vaccine use. Prior to joining MVP, she was a visiting assistant professor at the Rollins School of Public Health at Emory University in Atlanta, where she conducted research on pertussis vaccination. As an epidemiologist at the Institute for Research and Development, she spent several years in Senegal conducting pertussis vaccine trials. Her interest in vaccines started with Hib vaccine studies at Pasteur Mérieux. Marie-Pierre Preziosi earned her medical degree from Claude Bernard University in Lyon and her PhD in epidemiology from Victor Segalen University in Bordeaux (France). She trained in tropical medicine at the Prince Léopold Institute of Tropical Medicine in Antwerp (Belgium) and in field epidemiology at the Centers for Disease Control and Prevention in Atlanta (USA).
AbstractFor over a century, group A meningococcus has been the main cause of large and recurrent meningitis epidemics in the African meningitis belt, where epidemics occur in the dry season from December to June, and epidemic waves can last two to three years, with a break during the intercurrent rainy seasons. Following the devastating epidemic of the 1990s, African leaders called for the development of a vaccine that would eliminate, once and for all, group A meningitis epidemics in Africa. The Meningitis Vaccine Project (MVP) was established in 2001 as a partnership between the World Health Organization (WHO) and PATH, funded by the Bill & Melinda Gates Foundation, with a single goal to eliminate epidemic meningitis as a public health problem in sub-Saharan Africa through the development, testing, licensure, introduction, and widespread use of affordable meningococcal conjugate vaccines.
Following international standards, an affordable monovalent group A meningococcal conjugate vaccine, MenAfriVac, was developed through an innovative public-private partnership and obtained marketing authorisation from India in December 2009 and WHO prequalification in June 2010 (PsA-TT 10 micrograms, Serum Institute of India, Ltd). Since then, MenAfriVac has been introduced at public-health scale in African countries with a single dose targeting 1-to-29-year-olds in countrywide or large vaccination campaigns.
Since mass introduction campaigns started in September 2010, over 220 million persons have received the vaccine in 16 countries of the African meningitis belt: Benin, Burkina Faso, Cameroon, Chad, Côte d’Ivoire, Ethiopia, Ghana, Guinea, Mali, Mauritania, Niger, Nigeria, Senegal, Sudan, The Gambia and Togo. Evaluation of vaccine safety and effectiveness consistently demonstrated that MenAfriVac had a good safety profile and induced a dramatic reduction of carriage and invasive disease in vaccinated districts among both vaccinees and non-vaccinees, thereby suggesting a robust herd protection effect. Mass immunisation campaigns will continue until 2016 to cover at-risk populations in the 26 belt countries where disease burden is greatest. Following the initial campaigns, countries will have to protect new birth cohorts so that population protection is maintained in the long term. A single vaccine dose (MenAfriVac 5 micrograms) administered through routine immunisation at 9-to-18 months of age could provide sustained and long-lasting protection.
Considering the impressive immediate impact of the MenAfriVac wide-scale vaccination programme in Africa and the planned introduction of the vaccine into routine immunisation programmes, the deadly and devastating meningitis A epidemics in sub-Saharan Africa could soon belong to the past. Nevertheless, non-group A meningococci are still causing disease and regularly causing outbreaks threatening to assume epidemic proportions. Therefore, the need to pursue enhanced meningitis surveillance in Africa remains a high priority to document the impact of MenAfriVac and to monitor the distribution of disease-causing agents. In parallel, current efforts toward the development of affordable polyvalent meningococcal conjugate vaccines are looking promising and must be sustained.
Dr Olivier Ronveaux, World Health Organization meningitis team, Geneva
Olivier Ronveaux, from Belgium, is a medical doctor trained in field epidemiology (Epiet programme). He joined WHO in 2001, initially in vaccine preventable diseases control and now as the meningitis focal person for the organization. Between 2010 and 2013, he was based in Burkina Faso; his current work essentially consists of supporting sub Saharan countries in their fight against epidemic meningitis.
Since 2010 and the roll-out of the serogroup A meningococcal conjugate vaccine in countries of the meningitis belt, epidemics due to the Neisseria meningitidis
serogroup A (Nm
A) are disappearing. However, epidemics from other serogroups continue to occur, mainly Nm
W and more recently NmC, which has emerged in North West Nigeria in 2013 and is since expanding. Between February and June 2015, an unexpectedly large epidemic struck Nigeria and Niger, causing 5000 and 8000 cases (including capital city Niamey) respectively, with more than 800 deaths. NmC was the major pathogen isolated (in >75% of CSF samples) and in both countries, the strain was identified as ST10217, belonging to an unassigned clonal complex. The epidemic response included the vaccination of 1.5 million people with a multivalent polysaccharide vaccine (ACW and ACYW) and, for the first time in Africa, the vaccination of 200,000 persons with a multivalent conjugate vaccine in Niger.
This epidemiological transition triggered the need to review the evidence and recommendations for epidemic control as they were directed mainly at the control of NmA epidemics (Weekly Epidemiological Record 2014; 89:580-6).
- Analyses performed on non-A serogroup epidemics showed that shortening the emergency vaccination response time had a greater impact on improving cost-effectiveness of vaccination than lowering the epidemic threshold for response and hence the threshold was maintained at 10 cases/100,000 in 1 week. The alert threshold was lowered from 5 to 3 cases/100,000 to improve the timeliness of response and the potential, with a good surveillance system, to bring forward vaccination as soon as possible after the epidemic threshold is crossed.
- Rapid diagnostic tests were recommended for use in the investigation of meningitis outbreaks and the need to promote the development and evaluation of affordable tests was highlighted.
- For treatment of suspected bacterial meningitis in epidemics, given the proportion (average 9%) of meningitis due to other bacterial pathogens such as Haemophilus influenzae type b and Streptococcus pneumoniae, a standard 5-day course of ceftriaxone was recommended, replacing the previous recommendation of one day treatment with oily chloramphenicol or ceftriaxone.
- No change was brought to the previous recommendation relating to antibiotic prophylaxis: ciprofloxacin (ceftriaxone an alternative) is still recommended as a prophylactic measure for household contacts of all ages in non-epidemic periods, but not during epidemics.
The risk of further regional expansion of Nm
C highlights the importance of continued strengthening of outbreak detection and rapid laboratory identification capacity in the region. The persistence of non-A epidemics stresses the need for the development of an affordable multivalent conjugate vaccine. Meanwhile, securing polysaccharide vaccine production and availability for outbreak response remains a necessity. Listen to Olivier's presentation
Dr Nicole Basta, University of Minnesota, School ofNicole E. Basta, PhD MPhil, is an Assistant Professor in the Division of Epidemiology at the University of Minnesota School of Public Health, a Visiting Research Collaborator at Princeton University, and a Research Associate in the US National Institutes of Health (NIH) Research and Policy for Infectious Disease Dynamics program. As an infectious disease epidemiologist, Dr. Basta investigates the impact of vaccines and vaccination programs, evaluates the causes and consequences of heterogeneity in immune response to vaccination, and examines factors driving vaccine-preventable disease epidemiology with a particular focus on meningococcal disease. Dr. Basta specialises in conducting large-scale, prospective epidemiological studies and is currently PI for two longitudinal studies assessing the impact of meningococcal A vaccines (in Mali) and meningococcal B vaccines (in the US). Dr. Basta is a recipient of the NIH Director’s Early Independence Award and several grants from Princeton University. She obtained a PhD in Epidemiology from the University of Washington, read for an MPhil in Epidemiology at the University of Cambridge as a Gates-Cambridge Scholar, and graduated from Princeton University with a degree in Ecology and Evolutionary Biology.
Public Health, Division of Epidemiology
AbstractBackground: In December 2013, a novel meningococcal B vaccine (4CMenB, Bexsero®), not then licensed in the US, was offered to students at a New Jersey university to control an ongoing MenB outbreak. Evidence from the Meningococcal Antigen Typing System (MATS) and pooled sera from a clinical trial suggested that the vaccine would protect against the outbreak strain.
Methods: To understand the impact of 4CMenB on immunity during the outbreak, we conducted a cross-sectional seroprevalence survey four months after vaccine introduction and a pre-/post-vaccination immunogenicity study among incoming students during the following academic year. We assessed vaccination status and collected sera to determine the proportion with serum bactericidal antibody titers using human complement (hSBA)≥4 (proportion seropositive) against the outbreak strain and against two reference strains used in vaccine development (44/76-SL [fHbp] and 5/99 [NadA]). The fHbp and NHBA components of 4CMenB were similar to those expressed by the outbreak strain.
Results: In the seroprevalence study, 607 students enrolled. 66% (95% CI: 62-70%) of those who received two doses of vaccine two months apart as recommended were seropositive against the outbreak strain along with 59% (95% CI: 33-82%) of those who received only the first dose and 21% (95% CI: 6-46%) of those who remained unvaccinated. Among a random subset of participants receiving two doses as recommended but who had no detectable immunity against the outbreak strain, 87% (95% CI: 76-94) were seropositive against 44/76-SL and 100% (95% CI: 94-100) were seropositive against 5/99. Among unvaccinated participants, seropositivity was 33% (95% CI: 13-59) against 44/76-SL and 6% (95% CI: 0.1-27) against 5/99. In the pre-/post-vaccination immunogenicity study, 92 students provided paired sera. 19% (95% CI: 10-31) of those who received two doses of 4CMenB demonstrated a 4-fold rise in titers against the outbreak strain, while none of the unvaccinated exhibited a 4-fold rise (0% [95% CI: 0-11]).
Conclusions: Following 4CMenB introduction to control this outbreak, no cases occurred among vaccinated students, though one case occurred in a contact. Our study is the first evaluation of the impact of 4CMenB during an ongoing outbreak. We found that immunity against the outbreak strain was lower than the immune response against two vaccine reference strains. These results present key evidence needed to inform public health policy for the future prevention and control of MenB in high-risk populations.
Advances from researchChair: Prof Nigel Klein
University of London
Prof Michael Levin, Imperial College London/St Mary’s Hospital
Michael Levin is Professor of Paediatrics and International Child Health 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 is the co-ordinator of a European Commission FP7 award studying the genetic basis of meningococcal and other life threatening bacterial infections of childhood; and is the Principal Investigator on a newly awarded Horizon 2020 European Commission project to improve diagnosis and management of febrile patients.
There is now clear evidence that host genetic factors are major determinants of both susceptibility to and outcome of meningococcal disease. In addition to the well established Mendelian defects in the complement pathway that predispose to meningococcal disease, evidence from both candidate gene studies and genome wide association studies (GWAS) has identified a number of validated gene associations for susceptibility to meningococcal disease.
A European consortium (EUCLIDS) supported by MRF and the European union has undertaken GWAS studies on UK, central European and Spanish cohorts, that has identified variants in the Factor H and FH related gene region that control susceptibility and resistance to disease. This talk will review recent information on fine mapping of the region to identify the causal mechanisms, and functional correlates of the gene variants.
Exome sequencing is a recently available approach to identify rare variants that might influence disease susceptibility. The EUCLIDS consortium has undertaken exome sequencing on families with meningococcal disease leading to identification of novel rare variants underlying disease.
Genes controlling severity and outcome of the disease are also being identified using the GWAS approach, and progress in identifying genes controlling outcome will also be reviewed.Return to main index
Prof Xavier Nassif, INSERM Paris
Xavier Nassif is an MD/PhD specialising in infectious diseases and is working in Paris at the medical school Necker Enfants Malades. He is the head of clinical microbiology department of the Hopital Necker in Paris and is the Director of the Institut Necker Enfants Malades, a research center of around 250 scientists. In this Institute, he is scientifically responsible for a group working on the pathogenesis of Neisseria meningitidis
and more specifically in the understanding of the mechanisms used by this pathogen to cross the blood brain barrier and cause meningitis.
(also known as the meningococcus) is responsible for bacteremia which can lead to meningitis after the crossing of the blood brain barrier and/or septicemia associated with a thrombotic syndrome. In mild forms this thrombotic syndrome causes limited skin purpuric lesions, in addition to the meningeal inflammation. However in more severe forms, it is responsible for extensive thrombosis and necrotic purpura associated with massive vascular leakage and shock, known as purpura fulminans
. These symptoms are very uncommon in other Gram negative sepsis, thus suggesting that the pathogenesis of N. meningitidis
is not just a consequence of the in vivo
bacterial dissemination and/or multiplication. In vivo
observations have clearly shown that Neisseria meningitidis
, once in the bloodstream, interact closely with the microvessels, suggesting that the clinical specificities of meningococcal infections are correlated with its ability to colonise the microvasculature. The aim of this presentation will be to decipher the molecular mechanisms of the interaction of the bacteria with the microvasculature and the consequences of this vascular colonisation responsible for the specificities of meningococcal infections. Return to main index
Prof Robert Heyderman, Malawi-Liverpool-Wellcome Trust ProgrammeRob Heyderman is a clinician scientist whose work bridges clinical practice and fundamental understanding of the mechanisms of infectious disease. He has recently moved to UCL after directing the Malawi- Liverpool-Wellcome Trust Programme (MLW) for 8 years. MLW has an internationally leading translational research portfolio that links an excellent laboratory base to strong hospital and community-based research teams. Led by Malawian & International Scientists, MLW is focused on conducting cutting-edge research in a robust research training environment, the development of globally competitive research leaders and the translation scientific advances into human health improvements. His research focuses on the endothelial biology and coagulopathy of severe infection; the microbial and immunological basis of severe infection by mucosal pathogens and their prevention through vaccination; regulation of host inflammation; and the diagnosis and management of meningitis and sepsis.
AbstractAcross sub-Saharan Africa, non-typhoidal Salmonella (NTS) is a leading but under-appreciated cause of life-threatening bacterial disease among young children and HIV-infected adults. Previously widely thought of as a cause of self-limited gastroenteritis, NTS presents in these vulnerable populations both as severe sepsis and meningitis, and is associated with a case fatality that exceeds 20%. Furthermore, as pathogens such as Haemophilus influenzae type b (Hib), Neisseria meningitidis serogroup A, and Streptococcus pneumoniae are targeted by highly effective protein-conjugate vaccines, NTS is likely to become a more prominent disease control priority.
We are still largely ignorant of the total burden of invasive NTS disease (iNTS), the routes of transmission and reservoirs of infection. Most iNTS in Africa is caused by Salmonella Typhimurium, Salmonella Enteritidis, and Salmonella Dublin fluctuate in prominence over time. Antimicrobial drug resistance is an increasing threat to effective case management. In western Kenya, in particular, multidrug resistant extended-spectrum βß-lactamase producing Salmonella Typhimurium has become prominent. Advances in high-throughput whole genome sequencing have allowed us to better understand the origin and epidemiology of these NTS epidemics. Although in development, NTS vaccines.
Prevention of meningococcal disease in the UKChair: Prof Ian Feavers
National Institute for Biological Standards and Control
Dr Mary Ramsay, Public Health England, London
As a consultant epidemiologist and Head of Immunisation for PHE, Mary Ramsay’s department is responsible for the national surveillance of vaccine preventable diseases and for the planning and implementation of routine immunisation programmes in England. She has also provided expert advice to a range of UK and international agencies on vaccination policy and acted as PHE medical advisor to the UK’s Joint Committee on Vaccination and Immunisation. Mary is the PHE lead on the joint NIHR Health Protection Research Unit on Immunisation (with the London School of Hygiene and Tropical Medicine) and has served for many years on Meningitis Research Foundation’s Scientific Advisory Panel.
The UK has the highest incidence of invasive meningococcal disease (IMD) in Europe. In England, capsular groups B, W and Y are responsible for nearly all IMD. Routine meningococcal C (MenC) conjugate vaccination has nearly eliminated MenC IMD in England. MenB disease decreased from 2002 but remains the leading cause of IMD in the UK and a major public health problem. The introduction of Bexsero:
In 2010, the Joint Committee on Vaccination and Immunisation (JCVI) convened a sub-committee to conduct a comprehensive assessment of MenB vaccine development, impact and cost-effectiveness of potential MenB immunisation strategies. In June 2013, the JCVI received a request from the Secretary of State for Health for a recommendation on the possible introduction of a routine MenB immunisation programme.
The JCVI has since regularly reviewed available evidence on disease epidemiology, vaccine efficacy and safety and cost-effectiveness of a MenB immunisation programme: in March 2014, it recommended routine infant MenB immunisation following a 2+1 schedule at 2-4-12 months of age. Negotiations to procure vaccine at cost-effective price concluded in March 2015.
From September 2015 the UK became the first country to offer routine vaccination against MenB disease, using Bexsero® vaccine offered routinely to babies born from July 2015. Bexsero® has the potential to prevent around 73-88% of MenB UK IMD strains. The 2-4-12 month schedule was chosen to provide maximal protection in infants before the peak at 5 months. MenB carriage in infants and toddlers is very low, so indirect protection from the programme is not expected.
Delivery of this programme presents a number of challenges, in particular: the recommendation to routinely administer prophylactic paracetamol to reduce fever; the unique approach of a reduced schedule with limited catch-up and; multiple injections at each visit.
The introduction of ACWY vaccination: Since 2009, England has experienced a steady increase in MenW IMD; initially in older adults extending to adolescents and young children. This increase was due to the emergence of a specific virulent clone (of the ST-11 clonal complex) associated with increased disease and high case fatality, most recently MenW in South America and South Africa. In 2015, PHE reported a continued increase in MenW disease across all ages and all geographical regions. The JCVI considered this situation a public health emergency.
MenW incidence has been highest in infants and teenagers. Immunising infants would offer them direct protection but, because their carriage rates are low, has no wider population effect. The chosen outbreak control strategy therefore targets the highest carriers, aged 14-18 years, with Menveo® and Nimenrix® MenACWY vaccines over two years. It is important that the catch-up is completed quickly to generate herd protection and slow the rate of increase. MenACWY vaccine has also replaced MenC vaccination for University Freshers who are at increased risk of IMD. School leavers (born 1/9/ 1996-31/8/1997) have been offered MenACWY vaccine from August as an urgent catch-up campaign and MenACWY vaccine will replace the routine MenC school-based programme for 13-15 year olds this school year.
Whilst the highest incidence group (infants) may not benefit for several years, evidence suggests Bexsero® may provide protection against this strain of MenW, and therefore mitigate against the immediate risk in infants.
Prof Ray Borrow, Public Health England Vaccine Evaluation Unit, Manchester
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 in2011. 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.
On the 1st September 2015, Bexsero®, the meningococcal group B vaccine, was introduced into the infant immunisation schedule. Although this vaccine has been given to over 5,000 infants/ toddlers, it is newly licensed, and there are lessons to be learned as to how it will work in preventing disease against meningococcal serogroup B and other meningococcal serogroups, for example serogroup C and W. This, coupled with the introduction of meningococcal ACYW conjugate vaccine in adolescents has required for enhanced surveillance to be initiated, full details may be found at: https://www.gov.uk/government/uploads/ system/uploads/attachment_data/file/457723/ MeningoEnhancedSurveillancePlan_01092015_ v1.1.pdf
The main objectives of the surveillance for group B are to monitor the impact and age-specific vaccine-effectiveness of Bexsero® immunisation programme in children, to continue to monitor the phenotypic and genetic characteristics of invasive meningococcal isolates. All invasive meningococcal isolates are characterised by the usual phenotypic methodologies and then whole genome sequenced. Group B isolates are further investigated by the Meningococcal Antigen Typing Scheme to ascertain whether these contain antigens that are covered by Bexsero®. About 50% of cases are only confirmed through non-culture techniques, these cases are genogrouped and then two of the main vaccine antigens, PorA and factor-H binding protein, are sequenced directly from the clinical sample. Also of importance is to describe the clinical characteristics, risk factors and outcomes of invasive meningococcal disease as well as investigating the serological response in children aged <5 years with laboratory-confirmed disease following the introduction of the Bexsero® immunisation programme. To conclude, a huge step forward has been taken but we must now understand how this new vaccine will work as well as maintaining research into meningococcal serogroup B disease and vaccinology. Listen to Ray Borrow's presentationReturn to main index
Meningitis and Septicaemia in Children and Adults 2015's major sponsors are: