MRF Conference 2017

Danny Sweatman - Meningitis Research Foundation Ambassador

“I’m Danny Sweatman, 32 years old and living in Norwich with my wife Susanna and our two children, Maxwell and Matilda. I am currently Head of Nurture Provision at Aylsham High School, supporting a vulnerable group of students in year 7 and 8. I am also an ambassador for the Meningitis Research Foundation.

On 6th January 2012 my brother and my best friend Ryan aged only 19 died in his sleep from meningococcal septicaemia whilst he was at Sheffield Hallam University studying a sports degree. We also lost my younger brother Joe to meningitis 21 years previous to this when he was just two months old. I could not possibly put in to words how it has deeply affected our family and friends. We have currently raised in excess of £114,000 and I continue to be driven to raise awareness of Meningitis and support the implementation of the MenB vaccine thus preventing more families going through what we have.”

See Danny's mum, Gina, talk about losing two sons to meningitis here

Dr Simon Nadel, St Mary's Hospital/Imperial College London

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.

Rob Dawson, Meningitis Research Foundation

Rob Dawson is MRF's Head of advocacy, communications and support

Rob joined the charity in 2016 having worked in communications for a range of sectors, bringing experience from industry, charities and government.

Abstract

In March 2015, the government announced that all babies in the UK would be offered vaccination against meningococcal B (MenB) disease as part of the national childhood immunisation programme. The announcement came almost a year to the day after the announcement that the vaccine had been recommended for routine use in babies aged 2, 4 and 12 months by the Joint Committee on Vaccination and Immunisation (JCVI), the UK’s technical immunisation advisory group. 

The JCVI recommendation itself was not straightforward. Their initial analysis found the vaccine unlikely to be cost effective. When the JCVI invited comment on this MRF provided crucial evidence to highlight the value of this vaccine, expressing our concerns that parameters used in the cost effectiveness analysis undervalued the impact of the disease, and underlining the difficulty the JCVI faced in fairly assessing the health impact of severe childhood disease within the existing cost effectiveness framework. Some of our members took part in a study about the family impact of meningitis and septicaemia and evidence from this study formed a key component of our response. In light of the new evidence the JCVI were able to make a positive recommendation.

However, implementation of the vaccine was delayed, apparently by lengthy price negotiations. Supporters of Meningitis Research Foundation were crucial in seeing the vaccine rolled out. Two petitions were delivered to Downing Street totalling more than 50,000 signatures to which Health Secretary Jeremy Hunt personally responded.  Members and supporters joined our #WheresOurVaccine campaign, sending selfies to Mr Hunt, hundreds of tweets, writing to their MPs and prospective parliamentary candidates, and appearing in hundreds of newspapers throughout the country to demand, #WheresOurVaccine?

Hundreds of leading clinicians, scientists and medical associations supported letters to Mr Hunt. The letters were organised by MRF, led by Dr Simon Nadel, and published in the Times and featured in national news items in broadcast and print media.

When the Department of Health at last announced that the MenB vaccine would be introduced for babies, this was swiftly implemented into the immunisation programme in the UK, achieving a world first. However, although the incidence of MenB infection is highest in infants, vaccinating babies alone is predicted to prevent only around 25% of cases.

Cases of MenB infection in children too old to be eligible for the vaccine attracted widespread media attention. The death of a two-year-old girl in 2016 led to the largest ever petition on health, calling for greater access to the vaccine.

MRF used the momentum from this petition to advocate for addressing the bias in the rules for cost-effectiveness evaluations in health so that vaccines against severe childhood illnesses (including MenB) no longer face an uphill struggle. MRF represented meningitis and liver disease charities on the Department of Health’s Cost-Effectiveness Methodology for Immunisation Programmes and Procurements working group, set up to consider reforms to the rules and has continued to campaign for public consultation on the resulting report. We also helped to enable a study to determine if vaccinating adolescents – the main carriers of meningococcal bacteria – could protect the whole population by stopping transmission.

Dr Hannah Christensen, University of Bristol

Hannah is a lecturer in infectious disease mathematical modelling at the University of Bristol, UK.

Her research focuses on using models to predict the potential impact of interventions (particularly vaccination) on infectious diseases.  Hannah was recently responsible for developing models of meningococcal disease and vaccination used by policy makers in the UK and several countries in Europe to inform their decisions about the use of Bexsero and MenACWY vaccines against meningococcal disease.  She is currently undertaking research to better understand how public preferences about vaccines and their benefits can be included in the tools used by decision makers.

Abstract

When policy makers make decisions about which treatments and vaccinations will be made available to the public, they use cost-effectiveness analyses as part of the process.  An estimate of the amount of benefit from the treatment or vaccination is needed for this, and in the UK this is often done using ‘QALYs’ or quality adjusted life years.  These QALYs are assumed to be valued equally regardless of how they are gained.  For example one QALY gained by one child is the same as ten children gaining 10% of a QALY, and QALYs gained from preventing mild disease are valued the same as QALYs gained from preventing severe disease.  However, there is some evidence to suggest people do not value health gains in this way and if this is true this should be taken into account in the decision making.  We did face to face interviews with members of the general public and used this to develop a discrete choice experiment questionnaire to assess the UK general public’s preferences for health gains from different types of vaccination.  In this talk I’ll share what we found and the implications of this for vaccine decision making in the UK.

External funding

This research was funded by Meningitis Research Foundation.

HC is supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Evaluation of Interventions at the University of Bristol in partnership with Public Health England. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England.

Presentation

Dr Koonal Shah, Office for Health Economics London

Koonal is a Senior Economist at the Office of Health Economics, a registered charity and research organisation based in London.

His research interests include the measurement and valuation of health, stated preference methods, and the application of social value judgements in health care decision making. He recently contributed to a project examining how the value of vaccines is assessed. The project included a review of economic evaluations of meningococcal vaccines and interviews with vaccine assessment experts in seven countries.

Koonal has a BA in Economics and Philosophy from the University of Nottingham, an MSc in Health Economics from the University of York, and a PhD in Health Economics from the University of Sheffield. He is a member of the EuroQol Group, a network of multidisciplinary researchers that developed the widely-used EQ-5D instrument, and currently serves as co-chair of the Group’s Scientific Plenary Meeting, an annual conference.

Abstract

The adoption of a new health intervention often requires an assessment as to whether it represents an effective use of public resources, i.e. whether it offers value for money. This is commonly assessed by comparing the cost-effectiveness of the new intervention with alternative options. For vaccines, the evaluation of cost-effectiveness hinges on whether all effects (outcomes) have been identified and valued appropriately, particularly given that the benefits can be accrued wider than just the individual vaccinated and the benefits tend to occur far into the future.

In this presentation, Koonal Shah will provide an overview of a recent study conducted by OHE Consulting examining how the value of vaccines is assessed. The study involved a review of economic evaluations of meningococcal vaccine strategies and interviews with experts from seven countries (Australia, France, Germany, Italy, Japan, Netherlands and New Zealand). Koonal will highlight the key findings of the project, focusing on how elements such as quality of life, discounting and herd immunity were considered in the various studies included in the review. He will then provide examples of decision criteria that are commonly and less commonly considered in the seven countries of interest. Finally, he will explain how the value of vaccines to society may be underestimated if ‘peace of mind’ benefits and public preferences are not considered in decision making processes.

Koonal will conclude by setting out the Meningitis Research Foundation’s ‘key asks’ arising from the study and by explaining the next steps for the work – specifically, the convening of an expert meeting with the aim of identifying gaps in research which need to be filled in order to strengthen future meningococcal vaccine evaluations.

Presentation

Prof David Stephens, Emory University School of Medicine, USA

David S. Stephens, MD, is the Stephen W. Schwarzmann Distinguished Professor of Medicine at Emory University.

He also serves as the Vice President for Research in the Robert W. Woodruff Health Sciences Center (WHSC) and is the Interim Dean of the Emory School of Medicine.

After receiving his MD degree from Wake Forest University School of Medicine, Dr. Stephens conducted research at Walter Reed Army Medical Center and the National Institutes of Health (NIH). He completed his clinical training in internal medicine and infectious diseases and a research fellowship in microbial pathogenesis at Vanderbilt University School of Medicine.

Dr. Stephens joined Emory’s Department of Medicine faculty in 1982 and was named director of the Division of Infectious Diseases in 1992. He served in that role until 2013 and led the development of very successful programs in infectious diseases and microbial pathogenesis. He has been a major contributor to the creation and development of the NIH-funded Emory Vaccine Center, the Emory Center for AIDS Research and the Serious Communicable Diseases Unit at Emory.

Dr. Stephens is also professor of microbiology and immunology in the School of Medicine and professor of epidemiology at Emory's Rollins School of Public Health. His laboratory is an international leader in efforts to define the molecular basis for the virulence of and vaccines to prevent bacterial meningitis, especially disease caused by Neisseria meningitidis and Streptococcous pneumoniae. He has contributed to more than 300 publications in infectious diseases, molecular pathogenesis, epidemiology, vaccinology and immunology.

Abstract

Neisseria meningitidis is on the decline worldwide as a cause of human disease. The decline is due in part to a better understanding of the epidemiology of meningococcal disease combined with advances in prevention through vaccines and in chemoprophylaxis.  But in order to continue this success significant challenges remain. New vaccines (meningococcal polysaccharide- protein conjugate vaccines targeting A, C, W, and/or Y such as MenAfriVac for serogroup A in sub-Saharan Africa, and the new protein–based serogroup B vaccines) provide individual as well as, for the conjugate vaccines, significant herd protection. The targeted, but also wide spread, use of antibiotics that reduce meningococcal carriage and reductions in some environmental risk factors for meningococcal transmission (e.g. smoking) have also contributed to this decline. Challenges to control of meningococcal disease include gaps in vaccine coverage (e.g. certain serogroup B subtypes, serogroup X), waning vaccine efficacy and effectiveness over time, limited vaccine efficacy in certain high risk populations (e.g. individuals with complement deficiencies such as those receiving eculizumab), delays and the costs of the global introduction of effective vaccines, an incomplete understanding of the variables contributing to cyclic changes in meningococcal disease incidence, and the emergence of new meningococcal clades/clonal complexes causing disease (e.g. ST-11.2 clade and meningococcal urethritis). Despite advances in the global control of meningococcal disease, much work remains. The importance of active surveillance, of new molecular approaches (e.g. whole genome sequencing) to meningococcal pathogenesis and epidemiology, and of the global introduction of effective vaccine prevention strategies is emphasized.

Presentation

Prof Richard Malley, Harvard Medical School, USA

Rick Malley, M.D., began his education at the Ecole Active Bilingue in Paris, France, getting his Baccalaureate in 1982. 

He received his B.A. from Yale University, his M.D. from Tufts University in 1990, and pediatric infectious diseases and emergency medicine training at Boston Children’s Hospital. In 1997, a chance meeting with Dr. Porter Anderson (one of the co-inventors of the Haemophilus influenzae type b conjugate vaccine) led to his interest in the development of a species-specific pneumococcal vaccine for use in developing countries and vaccinology in general.  Under Dr. Anderson’s mentorship, he shifted his research to the development of novel vaccines against pneumococcus and other pathogens, leading to numerous scientific publications describing various aspects of pneumococcal pathogenesis and prevention, such as acquired and innate immunity, correlates of protection, and mechanisms of protection from nasopharyngeal colonization.

Dr. Malley is the Kenneth McIntosh Chair in Pediatric Infectious Diseases at Boston Children’s and Professor of Pediatrics at Harvard Medical School.  Dr. Malley runs a research laboratory with past and present funding from the Meningitis Research Foundation, NIH, PATH and the Bill and Melinda Gates Foundation (BMGF), focusing on vaccine development for pneumococcus, Staphylococcus aureus, Salmonella typhi and paratyphi, and Mycobacterium tuberculosis.  Following initial funding from the MRF, and subsequently in collaboration with PATH and the BMGF, Dr. Malley initiated an international effort for the development of a whole cell pneumococcal vaccine for developing countries. A Phase II trial of the whole cell vaccine in toddlers is nearing completion in Kenya.  In 2014, Dr. Malley and collaborators started Affinivax, a biotechnology company seed-funded by BMGF and based on a novel technology called MAPS (Multiple Antigen Presenting System) to develop vaccines for developing countries. Streptococcus pneumoniae is the lead target being developed at Affinivax.

Abstract

The advent and success of conjugate pneumococcal vaccines brought about the hope of reducing, or even potentially eliminating, Streptococcus pneumoniae as a major scourge of humanity. Since then, much has been learned about the ability of anticapsular antibodies to reduce the burden of pneumococcal diseases both directly and indirectly via the establishment of herd protection. However, pneumococcus has demonstrated its capacity to adapt to changes in the environment, overcome immunological pressures, and thus potentially reduce the overall impact of an effective vaccine strategy, mainly through serotype replacement.  An additional hurdle is that current pneumococcal vaccines are very complex and expensive to produce, potentially limiting their availability in low- or middle-income countries that arguably need them the most.

Over the past several decades, scientific investigations focused on the discovery of novel approaches to provide broad systemic and mucosal immunity to this pathogen. These efforts remain an urgent priority to this day, both for developing and developed countries. Several approaches are under intense investigation.  These include the development of low(er)-cost pneumococcal conjugate vaccines, the use of purified proteins as stand-alone vaccines, combinations of proteins and conjugate vaccines, new platforms that incorporate pneumococcal proteins as carriers (and immunogens) for polysaccharides, and a killed whole cell pneumococcal vaccine (whose initial development was funded by MRF and is now in Phase 2 clinical trials).

This talk will briefly review the immunological basis for each of these strategies and how they differ.   The current status of the most advanced publically disclosed programs will be reviewed as well.  The talk will also explore issues surrounding the selection of clinical endpoints for strategies that incorporate conserved pneumococcal proteins and for which correlates of protection have not (yet) been defined.  Finally, the many regulatory hurdles that some of these approaches face will be discussed, as well as potential strategies that may circumvent them.

Presentation 

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 epidemic 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 in West Africa including 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. This was succeeded by  the Malaria Capacity Development Consortium which continued post graduate training in malaria research in five countries in sub-Saharan Africa. From  2009 – 2016 he directed the African Meningococcal Carriage Consortium which, with support from the Wellcome Trust and the Bill and Melinda Gates Foundation,  investigated the pattern of meningococcal carriage in seven countries in the African meningitis belt and demonstrated the impact of the serogroup A meningococcal conjugate vaccine (MenAfriVac) on meningococcal meningitis and carriage in Chad. During the past two years, he has helped in establishing a new research centre in Kambia, Sierra Leone where a trial of the Johnson and Johnson Ebola vaccine is being conducted with support from Innovative Medicines Initiative. 

Dr Marie-Pierre Preziosi, World Health Organization, Geneva

Marie-Pierre Preziosi was appointed in March 2012 as the new director of the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, established in 2001 through a grant from the Bill & Melinda Gates Foundation, with the mission 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 most recently 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).

Vinny Smith, Chief Executive, Meningitis Research Foundation

Vinny Smith is the Chief Executive of Meningitis Research Foundation and joined in 2015 to lead the organisation through an exciting time of change.

Vinny has worked with the team to open new doors for the organisation, from engaging with new international partners, to playing an instrumental role in the battle to unlock protection against MenB for everyone; in April 2016 Vinny presented evidence at the Health Select Committee highlighting the need for changes to the unfair rules that govern vaccines eligibility.

Vinny was previously Director of STAND Consulting which advised non-profits in the UK, Africa and US on strategic planning, fundraising and organisational development. Vinny also previously worked at Cancer Research UK for 7 years and later became Chief Operating Officer in the international development and domestic violence sectors. Vinny is an author on a conference report on the use of mobile health and technology in West Africa following the Ebola outbreak; and a guest lecturer at the University of the West of England on Organisational Development.

Abstract

In May 2017, Wilton Park hosted an international gathering of experts to outline a vision for meningitis to 2030. Led by the Meningitis Research Foundation in collaboration with the World Health Organization more than 50 people including representatives from governments, global health organisations, public health bodies, academia, private sector and civil society shared expertise and perspectives, concluding with a call for a new global plan to defeat meningitis by 2030.

This session will update conference on how that meeting came about, progress that has been made since, and planned next steps to embed meningitis as a global priority aligned to the UN Sustainable Development Goals.

Dr Uduak Okomo, Medical Research Council Unit The Gambia

Dr. Okomo is a paediatrician and infectious disease epidemiologist with the MRC Unit The Gambia (MRCG).

Prior to joining the MRC in 2004, she worked as a pediatrician in Nigeria. From 2007 through 2010, she established a paediatric HIV/AIDS cohort in The Gambia and provided specialist clinical capacity to the Gambian government health service, including training of health workers. She also led a team that wrote the first National Paediatric HIV/AIDS treatment guidelines. Her research interests are in maternal newborn and child health, with focused professional interest in serious bacterial infections among newborns and infants. Her objective is to engage in research which will result in the improvement of maternal, newborn and child and adolescent health through engagement in research aimed at informing national and international health policy.

Since 2011 Dr. Okomo has been a Consultant Paediatrician and Clinical lecturer with the School of Medicine & Allied Health Sciences, University of The Gambia. She is currently the secretary of the Faculty of Paediatrics, West African College of Physicians. Dr. Okomo is also involved in evidence-based medicine and systematic reviews, and is co-reviewer of the British Medical Journal Clinical Evidence review on Sickle Cell Disease. She is a member of the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Abstract

In 2015, sepsis and meningitis accounted for an estimated 401,600 deaths per year or 15% of the world’s 2.6 million annual neonatal deaths. A disproportionate number of these deaths occur in resource-limited settings in sub-Saharan Africa (sSA) and South Asia. In sSA approximately 181,000 neonatal deaths a year are caused by sepsis and meningitis, accounting for 17% of neonatal deaths in the region, but 45% of global neonatal sepsis and meningitis deaths. This represents a significant burden for conditions that are mostly preventable.

To inform interventions, aetiology-specific data are crucial, yet remain a “black box” in sSA. Pathogens associated with neonatal sepsis and meningitis may differ from other regions of the world and between countries in sSA, particularly given diversity, with differing rates of risk factors such as preterm birth or maternal HIV infection, and also varying health system context with facility birth rates varying from 5 to 99% across the continent.

Case definitions are challenging. Blood cultures are the gold standard for diagnosis of neonatal sepsis but have low sensitivity for invasive infection. However, blood cultures alone are not sufficient to make a diagnosis of meningitis for which culture of the cerebrospinal fluid (CSF) is critical, as up to 15-30% of infants with CSF culture-proven meningitis will have negative blood cultures in the presence of normal CSF parameters (white blood cells, glucose, and protein). In sSA access to these microbiological, haematologic and biochemical laboratory diagnostic tools is limited, even in tertiary referral centres; the World Health Organisation’s (WHO) Integrated Management of Childhood Illness (IMCI) algorithm is used for clinical diagnosis of possible serious bacterial infection (pSBI), which encompasses neonatal sepsis, meningitis and pneumonia, and also many non-bacterial illness or indeed no identified infection.

Data will be presented from a recent unpublished systematic review of neonatal infection aetiology in sSA. No population-based studies were found, and 137 hospital-based studies were included, with the biggest number being from Nigeria. Overall Klebsiella species, Escherichia coli, Staphylococcus aureus, Group B Streptococci (GBS), and Enterococcus were the top five reported bacterial causes of sepsis and meningitis. In terms of subregional variation, Klebsiella dominated in all regions except West Africa, where S. aureus was more frequent. Notable differences were found for GBS. The Southern African region reported the most cases of invasive GBS disease, and West Africa the least, although it remains unclear if this is true epidemiological variation or due to low case ascertainment or laboratory detection. Application of the Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE-NI) checklist highlighted wide variation in reporting across studies, impeding comparability. Nevertheless, except for the difference in the reported occurrence of GBS, these data suggest that the major pathogens associated with neonatal sepsis and meningitis in sSA are similar within and between regions but differ from that observed in neonates in developed countries where GBS, E.coli and coagulase negative staphylococci dominate.

Despite the challenges in the data, it is clear that there is a major problem with hospital acquired infections in sSA, and also may be potential for prevention through maternal immunisation.

Dr Caroline Trotter, University of Cambridge

Dr Caroline Trotter is a Senior Lecturer in Epidemiology at the University of Cambridge.

Her research concentrates on understanding the epidemiology of vaccine-preventable diseases and the impact of immunisation. With a main focus on meningococcal infection, she also leads current research projects on group B streptococcus, norovirus and rabies. She uses a range of methods including analysis of large databases, systematic reviews, prospective clinical/ field studies, health economics, seroprevalence studies and mathematical modelling. She is most interested in applying these methods to research questions of direct relevance for vaccine policy. She is an honorary epidemiologist at Public Health England and a consultant to the World Health Organisation.

Abstract

Group B Streptococcus (GBS) is a leading cause of meningitis and septicaemia in babies up to 3 months of age. Several GBS vaccines are in development which offer new prospects for reducing the burden of GBS disease. In the UK, any new vaccine being considered for introduction into the immunisation programme must be supported with evidence of cost-effectiveness. We estimated the potential impact and cost-effectiveness of maternal immunisation against neonatal and maternal invasive group B streptococcal (GBS) disease in the UK. We developed a static decision tree model to capture the health and economic consequences of neonatal and maternal GBS disease. The latest surveillance data on disease incidence informed the model, along with new data on the health of GBS survivors. We investigated the sensitivity of our results to changes in model parameters, discount rates and difference scenarios (e.g. prevention of stillbirths).   Overall, we conclude that maternal immunisation is likely to be a cost-effective intervention against maternal and neonatal GBS disease in the UK, even at a relatively high vaccine price.

Presentation

Dr Kirsty Le Doare, Centre for International Child Health, Imperial College London and St. George’s University of London

Dr. Kirsty Le Doare is a Bill and Melinda Gates Foundation and National Institute for Health Research funded clinical senior lecturer and co-director of the Centre for International Child Health (CICH) at Imperial College London that brings together cross-cutting themes from across Imperial College to improve child health around the world.

She has over 15 years of clinical and research experience in childhood infection. She completed her undergraduate medical training and paediatric academic training in London, UK. During her PhD she investigated Group B Streptococcal functional antibody and its role in protection against infant colonisation in the Gambia using a novel complement deposition assay. She leads a neonatal immunology network, an international network of clinicians and scientists working together in neonatal GBS that extends to 12 countries worldwide.  She has successfully obtained funding from the Royal Society, London for a neonatal Hooke symposium, which was the first meeting of its kind, dedicated to infant immunology.

She is currently leading a Bill and Melinda Gates Foundation funded international collaboration to standardize assays to measure antibody against GBS with the aim of facilitating the development of an immune correlate of protection against GBS colonization and disease.

Her main research interests are age-related immune responses to infectious diseases, in particular to Group B-streptococcus (GBS) in neonates and maternal vaccination. She is involved in pre-clinical vaccine development, multi-centre clinical trials and infectious diseases epidemiology research in the UK and in Africa.

Abstract

Group B Streptococcus GBS) is a leading cause of infant sepsis and meningitis for which a vaccine has been in development for over 30 years. Whilst intrapartum antibiotic prophylaxis (IAP) given in labour have reduced the incidence of early onset disease (first seven days of life) in some countries, antibiotics in labour have no impact on late onset disease (7-90 days). In addition, IAP coverage is often incomplete and there is a theoretical risk of increased antimicrobial resistance with widespread IAP use. A vaccine given to pregnant women is thought to be the most beneficial strategy to protect against both forms of GBS disease globally. Several vaccine candidates are currently undergoing phase I/II trials including capsular polysaccharide protein-conjugate vaccines and protein vaccines. However, barriers to licensure exist, including the sample size required to establish vaccine efficacy and the need to develop serocorrelates of protection against invasive GBS disease. It is now widely accepted that getting a suitable vaccine licensed and implemented may require the combination of a clinical efficacy trial in settings of high disease burden with determination of serocorrelate of protection against disease, through studies of natural immunity in settings where the incidence is lower.

Presentation

Dr Jethro Herberg, Imperial College London

Dr Jethro Herberg is a Clinical Senior Lecturer in Paediatric Infectious Diseases at Imperial College London, and honorary consultant at St Mary’s Hospital, Imperial College Healthcare NHS Trust.

He attended medical school at University College London, following undergraduate studies in Biochemistry at Oxford University, and PhD in human immunogenetics at the Imperial Cancer Research Fund, in London. He has worked at Imperial College since 2008.

His research focuses on the discovery and clinical translation of host biomarkers for febrile children with infectious and inflammatory conditions. Current projects include the EUCLIDS study (www.euclids-project.eu), which investigates genetic predisposition to severe sepsis, and the PERFORM study (www.perform2020.eu), which will validate identified host RNA and protein biomarkers of bacterial, viral and inflammatory illness in a large international study of febrile children. His specialist clinical interests include management of children with Kawasaki disease.

Abstract

There is a lack of accurate clinical or laboratory tests that discriminate bacterial infection, viral infection and inflammatory illness in children presenting with fever. Many children therefore receive unnecessary antibiotic treatment whilst awaiting the results of bacterial investigations, whilst bacterial infection is missed in others.

Advances in proteomic and transcriptomic analysis of children with different types of infectious or inflammatory diseases have led to the discovery of highly discriminatory biomarkers that hold potential for use in a new generation of diagnostic tests based on the host response.

The use of host biomarkers based on whole blood gene expression is attractive, as clinically indistinguishable diseases caused by different pathogens or inflammatory conditions can have a distinctive transcriptomic pattern, and measurement of the expression level of small numbers of genes in a sample of peripheral blood taken from a patient may allow accurate phenotyping of the patient. Thus, gene expression 'signatures' in the blood have exciting potential for the diagnosis of infectious and inflammatory diseases, where current diagnostics are inaccurate and slow, and measurement of a few key genes may guide diagnosis, prognosis and treatment decisions for the patient.

In order to derive diagnostic biomarkers capable of distinguishing between children with bacterial and viral infection, we have recruited children presenting with infections and inflammatory conditions to prospective, observational studies which aim to identify pathogen-specific signatures of gene and protein expression, and to identify pathways implicated in patients with severe disease.  This talk will present the work that has led to the identification of a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.

We have identified a 2-transcript signature that accurately discriminates bacterial and viral infection. This signature predicts that almost half of children with uncertain diagnosis, but treated with antibiotics, had a viral signature. Our signature has potential for development as a diagnostic test that could help reduce unnecessary antibiotic use in febrile children, and our next challenge is to turn small gene expression signatures into useful clinical tests.

Presentation

Prof Adam Finn, University of Bristol

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

He studied Medical Sciences at Cambridge University and then moved to University of Oxford Medical School to complete his clinical degree in 1983. After qualifying he did training jobs in paediatrics in Sheffield, Bristol and Guy’s Hospital London before taking up a fellowship in Infectious Diseases at the Children’s Hospital of Philadelphia in 1987. He completed his academic training as Lecturer in Immunology at the Institute of Child Health, Great Ormond St, London where he wrote his PhD.

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

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

Abstract

The interruption of transmission of hyper-invasive strains of meningococcus within human populations as an efficient - and possibly to only totally effective - primary prevention strategy reached maturity with the recent introduction of universal teenage ACWY-conjugate vaccine in the UK. This was a response to alarmingly rapid rise in numbers of cases of invasive group W disease during the first half of the present decade. The aim and justification for the approach is that by reducing carriage among adolescents, dissemination amongst them and to other susceptible age groups will be prevented and disease will die out as it did 15 years earlier for group C disease by the exact same mechanism. The remarkable difference between the two programmes, namely the complete omission of younger children from the more recent of the two, reflects the recognition that it is now indirect effects that really matter in conjugate meningococcal vaccine deployment. However our knowledge of meningococcal carriage and transmission is based almost entirely on detailed molecular analysis of isolates from cross-sectional carriage studies. Understanding of what enables meningococci to invade, although very incomplete, is much more detailed than understanding of what enables them to successfully colonise and transmit. By undertaking longitudinal studies, evaluating alternative sampling and detection methods, exploring the role of co-colonising bacterial species and of intercurrent respiratory viral infections and undertaking analysis of gene expression by the bacteria in the upper respiratory tract, we have been increasing our understanding of the factors that influence normal (rather than pathological) meningococcal behaviour. These studies should assist improved design of future vaccines and of intervention studies to establish how best to impact on colonisation and transmission at the population level using the currently available tools.

Presentation

Prof Helen Marshall, University of Adelaide, Australia

Professor Marshall is a medical researcher with specialist training in child health, public health and vaccinology having completed a Bachelor of Medicine and Surgery, Doctorate of Medicine, Master in Public Health and Diploma in Child Health at the University of Adelaide and completed the international Advanced Vaccinology Course at the Pasteur Merieux Institute, France. 

She holds the position Professor in Vaccinology in the Adelaide Medical School and is the Deputy Director, Clinical and Translational Research of the Robinson Research Institute at the University of Adelaide, Senior Medical Practitioner and Medical Director of VIRTU, the Vaccinology and Immunology Research Trials Unit, in the Department of Paediatrics at the Women’s and Children’s Hospital. She has been awarded two National Health and Medical Research Council, Research Fellowships in 2011 and 2015. In recognition of her research leadership she was awarded the South Australia Science Award for Excellence in Research for the Public Good in 2010 and a national Public Health Association of Australia Fellowship in 2013.

Professor Marshall’s research program aims to address urgent priorities in infectious disease prevention to reduce the burden of disease from serious infections in infants and children.  Her main interests include meningococcal, human papillomavirus, influenza and pertussis infections and their prevention by immunisation.

She is the Principal Investigator on the South Australian Meningococcal B vaccine carriage study ”B Part of It” and has completed numerous clinical trials on the safety and immunogenicity of meningococcal vaccines.  Her research program includes clinical trials in investigational vaccines, infectious and social epidemiology and public health. She has published over 120 peer-reviewed papers in high quality general medicine and specialist journals across diverse disciplines. She has been awarded 10 National Health and Medical Research Council grants and received funding from the Australian Research Council, Government, Foundation and Industry grants totalling >$25 million.

Abstract

Introduction

In South Australia (SA), which has the highest rate of meningococcal disease nationally, serogroup B predominates, causing >80% of cases. No funded MenB vaccine program exists due to insufficient data on vaccine effectiveness and evidence of herd immunity. Carriage prevalence of Neisseria meningitidis in Australian adolescents is unknown.

Aims

The SA MenB vaccine herd immunity study “B Part of It” aims to estimate the difference in carriage prevalence of all N. meningitidis serogroups causing disease, in school students receiving two doses of 4CMenB compared to unvaccinated students at 12 months post-vaccination. A pilot study in first year university students was conducted to determine carriage prevalence and identify risk factors associated with carriage.

Materials and Methods

In the longitudinal carriage study of university students a posterior pharyngeal swab was collected at baseline and 3 months later to determine PCR porA positivity and genogroups.

From April-June 2017, senior school students (years 10-12) were recruited to the cluster RCT. All SA schools (metropolitan, rural, remote, very remote) were invited to participate and randomised to Group A intervention (4CMenB) or Group B control (no vaccine). Posterior pharyngeal swabs were obtained from all students at the first school visit with Group A students receiving 2 doses of 4CMenB, 2 months apart. At 12 months post dose 1 all students are re-swabbed.  The study is implemented through the school immunisation program with immunisation providers trained in a standardised posterior pharyngeal swab technique. Swabs are placed in transport medium (STGG) and sent to a central state pathology collection centre. DNA extraction and porA real time PCR analysis performed. Positive PCR samples are cultured for Neisseria species on selective agar. In an add-on study a 1 ml saliva sample was collected from each participant, added to STGG and underwent real time PCR.

Results

Pilot university carriage study

421 university students were enrolled and 258 completed both day 0 and 3-4 months swabs. Only 1.9% of students smoked cigarettes and 3.3% used a water-pipe. Baseline and 3 month carriage prevalence was 6.2%; serogroup Y (2.8%, 2.3%), serogroup B (1.7%, 1.2%), serogroup W (0.7%, 0%). Baseline carriage of those attending a second visit was 3.9% compared to 9.8% in those only attending the first visit. 32% of those who only attended the first visit compared to 13% of those attending both visits, visited pubs/clubs ≥ 2 nights per week (p<0.001).   In an add-on study in which saliva was collected at visit 2 (n=238), carriage prevalence was 5.5%; serogroup B (1.3%), serogroup W (0.4%), serogroup Y (2.1%).

Cluster RCT in school students

Over 95% of schools participated (n=237) with consent forms distributed to 58,000 students. 37,410 students consented with 34,461 participating at the first visit including 17,912 (52%) females.  The majority were from metropolitan schools (74%), followed by rural (23%), remote (2.4%) and very remote (0.6%). Students will return in April 2018 for a repeat swab and vaccination of Group B students.

Conclusions

Carriage prevalence is low in first year university students in South Australia, likely due to very low rates of smoking and social behaviour.

Funding (source): GlaxoSmithKline Biologicals SA. Add-on saliva study funded by Women’s and Children’s Health Network, South Australia

Dr Stephanie Lo, Wellcome Trust Sanger Institute, UK 

I am currently a bioinformatician for the Global Pneumococcal sequencing (GPS) project.

The primary goal of GPS project is to assess the impact of pneumococcal conjugate vaccine (PCV) on bacterial population structure, serotype dynamics and antimicrobial resistance, through sequencing and comparison of over 20,000 genomes of Streptococcus pneumoniae collected before and after introduction of PCVs worldwide (http://www.pneumogen.net/gps/).

I graduated with a BMedSci in Clinical Laboratory Science (Shanghai Jiao Tong University) and a PhD in Microbiology (The University of Hong Kong). My research is focused on using genomic data from a large cohort of individuals:

• To identify high-risk clones of public health importance, especially those with multidrug resistance
• To reveal evolutionary history of the high-risk clones of public health importance
• To investigate horizontal transfer of genes conferring resistance to clinically important antibiotics

This works ultimately seek to provide evidences for decision-making in important public health issues at both regional and global level.

Abstract

The recent deployment of pneumococcal conjugate vaccines (PCV) has significantly reduced the incidence of invasive pneumococcal disease (IPD) in children and is estimated to have saved 11.4 million days of antibiotic use annually due to the dramatic decrease of pneumonia cases worldwide. However, surveillance following the introduction of PCV showed an increasing proportion of IPD caused by non-PCV serotype pneumococci among young children. To provide an evidence base for vaccine impact on the pneumococcal population and future vaccine design, the Global Pneumococcal Sequencing (GPS) project was set out to capture the emerging invasive serotypes and lineages in children through sequencing a global collection of pneumococcal isolates. First, we delineated a species-wide population structure based on 12,242 pneumococcal isolates collected from 51 countries using Hierarchical Bayesian analysis of population structure (HierBAPs). The analysis clustered the species into 70 pneumococcal lineages (GPSC1-GPSC70). Next, we extracted country-based datasets which span at least 2 years before and after introduction of PCV10/PCV13 to capture the emerging serotypes and lineages. By overlaying the in-silico prediction of serotype and antibiotic resistance onto the lineages, we revealed that the significant decrease of vaccine serotypes (VT) following the PCV introduction was attributed to the substantial decline in VT lineages, including those associated with multidrug resistance. The most prevalent non-VT in the post-PCV period varied between different geographical locations and each emerging serotype was associated with multiple lineages that were majorly composed of non-VT. These non-VT lineages were generally susceptible to commonly used antibiotics, except for lineage GPSC67 (MLST clonal complex 989) which predominantly expressed serotype 12F. Expansion of non-VT within lineages that were previously predominantly VT also contributed to the increase of non-VTs in the post-PCV era.  Finally, an evolutionary mathematical model was applied to predict the potential outcome of theoretical PCV formulations based on the emerging serotypes.

Dr Ado Bwaka, WHO-IST, Ouagadougou

Ado Bwaka is the EPI/Polio Team Leader at the Inter-Country Support Team (IST) West Africa, WHO, based in Ouagadougou, Burkina Faso.

Prior to joining this position, Ado Bwaka was the Polio Consultant in charge of the Democratic Republic of Congo (DRC) for McKing Consulting Corporation, a Bill and Melinda Gates (BMGF) funded US Consulting firm in charge of coordination and administration consultancy support in polio affected
countries.

He supported the Ministry of Health and GPEI partners in providing oversight of the implementation of emergency plans to stop polio.

Dr Bwaka previously worked as the State Coordinator in Nigeria with WHO for ten years. He provided technical assistance and leadership in polio eradication, surveillance and improving routine immunization and maternal and child health. He supported the implementation of the Integrated Disease Surveillance and Response (IDSR) and contributed to the control of meningitis and other vaccine preventable diseases outbreaks that occurred during his assignment in the northern Nigeria.

Dr Bwaka also held the position of Africa Regional Coordinator with the Emmaus Suisse, an NGO supporting tuberculosis and leprosy Programmes in Cameroon and Central Africa Republic.

He was assigned as a CDC Consultant with the STOP Programme in Niger Republic in 2004. The same year, he worked as Health and Nutrition Coordinator with COOPI/UNHCR in Sudanese refugees’ camp in Eastern Chad.

In his earlier days, Ado served in various positions in the DRC Ministry of Public Health from a district medical officer to a provincial coordinator and surveillance focal point.

He volunteered himself to clinically managed patients who were quarantined at the early stage of the Ebola Virus Disease outbreak in Kikwit, DRC in 1995.

Dr Ado Bwaka received his medical degree from the University of Kinshasa, DRC and a master’s degree in public health from the Catholic University of Louvain, Brussels, Belgium.

Abstract

Meningococcal meningitis epidemics remain a dramatic public health problem in Africa.  Before 2010, these epidemics were predominantly due to Neisseria meningitidis serogroup A (NmA). Since the first introduction of MenAfriVac conjugate vaccine in 2010, around 300 million people aged 1 – 29 years have been vaccinated through campaigns in 21 of the 26 countries of the African meningitis belt. Seven of these countries have already introduced MenAfriVac into their routine immunization programmes: Ghana and Sudan in 2016; Mali, Burkina Faso, Central African Republic, Chad and Niger in 2017.  Other countries are planning to do so in 2018-2019, together with mass vaccination campaigns where relevant.

Since then, the incidence of NmA meningitis has declined by 99%. While an overall 58% reduction in incidence of meningitis and 60% decrease in risk of epidemics have been observed, other types of meningitis (NmC, , NmW, NmX and S. pneumoniae) are still being observed. During the 2017 epidemic season, 24 546 suspected cases of meningitis of which 1 612 deaths (CFR: 6.6%) were recorded as of week 26. A total of 125 districts reached the alert threshold and an additional 52 districts reached the epidemic threshold. The predominant germs were NmC (36.5%), S. pneumoniae (27.6%), NmX (13.5%) and NmW (9.9%); while 2 NmA cases were confirmed one each in Nigeria and Guinea. NmC meningitis outbreaks were reported in Nigeria (14 542 suspected cases; 1 166 deaths), Niger (3 317 suspected cases, 198 deaths), Cameroon (Yaoundé central prison: 16 suspected cases, 8 deaths)  and Liberia (meningococcemia, 31 suspected cases, 13 deaths). An NmW outbreak was reported in Togo (517 suspected cases, 35 deaths), and a mixed NmW & S.pneumoniae outbreak in Ghana (827 suspected cases, 78 deaths). In addition NmX was reported in atypical high proportions in Chad and Niger (43% and 18% of all positive CSF samples, respectively).

In response to these epidemics, meningitis surveillance was strengthened and the WHO protocol for case management was implemented. Additionally, with the support of the International Coordinating Group on vaccine provision, reactive vaccination campaigns using multivalent polysaccharides vaccines (ACWY, ACW and AC) were carried out in Nigeria, Niger, Cameroon and Togo. Conjugate C vaccines were administered only in Nigeria.

The control of meningitis outbreak is faced with challenges of insufficient funding to implement epidemic preparedness and response plans, low laboratory capacity for outbreak confirmation, lack of national contingency stockpiles of vaccines, scarcity of the global vaccine supply, and unaffordability of multivalent conjugate vaccines.

Presentation

Prof James Stuart, University of Bristol 

After qualifying in medicine in 1974, James Stuart worked for ten years as a clinical doctor in the UK and rural South Africa before specialising in public health and epidemiology of infectious diseases, particularly meningococcal disease.

He has been involved in the investigation and control of outbreaks of meningococcal disease in the UK and international level, and has published extensively on the epidemiology of meningococcal disease and carriage.

Through the London School of Hygiene and Tropical Medicine, James was involved in MenAfriCar, a major research project into meningococcal carriage during the introduction of MenAfriVac across the African meningitis belt. In recent years he has been working with WHO on meningitis surveillance and outbreak response in the meningitis belt, and on guidance for the use of Ebola vaccine. He has just been appointed as Chair of the MRF Scientific Advisory Panel. 

Pneumococcal meningitis has a high case fatality, is difficult to treat and is frequently associated with severe sequelae. In the meningitis belt of sub-Saharan Africa, the epidemiology of pneumococcal meningitis follows closely that of meningococcal meningitis. The incidence in the dry season is up to ten times higher than in the wet season, with most cases occurring in older children and young adults. In 2016 the largest recorded epidemic of pneumococcal meningitis to date, predominantly due to serotype 1, occurred in central Ghana with over 800 suspected cases. Challenges arising during this outbreak included timeliness of laboratory diagnosis, uncertainty about recommended antibiotic treatment regimes, and questions around potential reactive vaccination. The outbreak occurred despite prior introduction of pneumococcal conjugate vaccine (PCV13) into vaccination programmes designed primarily to provide direct protection to infants at high risk of pneumococcal disease. Particularly in the meningitis belt, priority should also be given to adopting vaccination schedules that maximise indirect protection to older children and adults.

Abstract

Pneumococcal meningitis has a high case fatality, is difficult to treat and is frequently associated with severe sequelae. In the meningitis belt of sub-Saharan Africa, the epidemiology of pneumococcal meningitis follows closely that of meningococcal meningitis. The incidence in the dry season is up to ten times higher than in the wet season, with most cases occurring in older children and young adults. In 2016 the largest recorded epidemic of pneumococcal meningitis to date, predominantly due to serotype 1, occurred in central Ghana with over 800 suspected cases. Challenges arising during this outbreak included timeliness of laboratory diagnosis, uncertainty about recommended antibiotic treatment regimes, and questions around potential reactive vaccination. The outbreak occurred despite prior introduction of pneumococcal conjugate vaccine (PCV13) into vaccination programmes designed primarily to provide direct protection to infants at high risk of pneumococcal disease. Particularly in the meningitis belt, priority should also be given to adopting vaccination schedules that maximise indirect protection to older children and adults.

Presentation

Dr Matthew Coldiron, Epicentre

Matt is a medical epidemiologist. He graduated from Princeton magna cum laude with a degree in Classics, and holds an MD and MPH from Emory University.

He completed residency in internal medicine at NYU/Bellevue Hospital.  He has worked at Epicentre-Médecins Sans Frontières in Paris since 2011, working on a variety of studies in complex settings.  His main thematic areas of interest include meningococcal meningitis and malaria in the Sahel.

Poster

Epidemics of meningococcal meningitis are common in the African meningitis belt. Reactive vaccination campaigns during an epidemic have been estimated to avert 10% of cases. Supply of vaccine against newly-emerged serogroup C meningococcus is limited. New strategies are therefore needed. We conducted a three-arm cluster-randomized trial of single-dose ciprofloxacin prophylaxis as an epidemic response in Madarounfa District, Niger (clinicaltrials.gov NCT02724046). Villages were randomized in a 1:1:1 ratio to receive standard care (control arm), prophylaxis for households of suspected meningitis cases, or village-wide distribution of ciprofloxacin within 72 hours of the notification of the first suspected case in a village. Dosing was age-based and directly-observed. The primary outcome was attack rate at the end of the epidemic. Comparisons were made using a cluster-level t-test of the log-transformed attack rates, using inverse variance weights to account for different cluster sizes and numbers of cases. Attack rates were then adjusted for age, vaccination status, time from beginning of epidemic, and time relative to the first rainfall. 50 villages (total population 72 910) were randomized between 21 April-18 May 2017. Attack rates in the control, household prophylaxis and village prophylaxis arms were 432, 385, and 194 per 100 000, respectively. The crude and adjusted attack rate ratios (ARR) between the household prophylaxis and control arms were 0.89 (95%CI 0.44-1.82, p=0.75), and 0.87 (0.51-1.47, p=0.61), respectively. Crude and adjusted ARR between the village prophylaxis and control arms were 0.44 (0.18-1.12, p=0.08), and 0.45 (0.23-0.88, p=0.02), respectively. In the village-wide prophylaxis arm, ARR were lower among women than among men, and with increasing age. Results were similar when taking into account only PCR-confirmed cases. Village-wide distribution of ciprofloxacin after notification of a case reduced the meningitis attack rate by 55%. Given the low price of ciprofloxacin, its ability to be stocked in-country, and the limited supply of NmC-containing vaccine for reactive vaccination campaigns, this novel strategy is promising as an epidemic response in the African meningitis belt.

Presentation

Dr Judith Mueller, EHESP French School of Public Health and Institut Pasteur

Dr. Judith Mueller is professor in epidemiology at the EHESP French School of Public Health and group leader at Institut Pasteur. She holds a PhD from Pierre and Marie Curie University (Paris), an MPH from Harvard School of Public Health (Boston) and an MD from the Technical University of Munich.

After a junior researcher position at the GSF National Research Institut (Neuherberg, Germany) during 2000-2002, she was program leader on Meningitis and Pneumonia Research at Agence de Médecine Préventive (Paris) from 2002 to 2011.

Her research interests carry on vaccination strategies, structured on two axes: understanding population preferences regarding vaccination for adapted vaccination programmes; and understanding the phenomenon of the African meningitis belt with focus on adapted surveillance and vaccination strategies. For the latter, she has 15 years of experience in operational research in Burkina Faso, Niger and Togo.

Poster

Background

Serogroup A meningococcal conjugate vaccine (PsA-TT) was introduced through a mass campaign in Burkina Faso in December 2010, targeting the 1- to 29-year-old population. We evaluated population level persistence of immune protection until 2016 and estimated future persistence compared to pre-vaccination levels.

Methods

In three cross-sectional surveys (approximately one, three and five years after the campaign), we included representative samples (around 600 participants each) of the 6-month to 33-year-old urban population of Bobo-Dioulasso. Standardized questionnaires were administered and blood samples drawn. Serum bactericidal antibody (SBA) titers were measured using rabbit complement against serogroup A reference strain F8236 (SBA-ref; all samples) and strain 3125 (SBA-3125; 200 randomly chosen samples at each visit), which is supposed to be more specific for vaccine response (Tall 2015); and serogroup A-specific IgG concentrations using ELISA. Time of return to pre-vaccination immune levels (reported in Trotter 2013) was estimated using linear extrapolation of age-specific geometric means from 2013 and 2016. Putatively protective titres or concentrations were defined as ≥128 for both SBA and ≥2 µg/mL for IgG.

Results

During the 2016 survey, children aged 6.1-7.0 years had the lowest antibody levels, and adolescents aged 10.1-14.9 years among the highest. In these two age groups, GMT were 524 and 1603, respectively, for SBA-ref (relative change since 2011: -87% and -38%), 14 and 406 for SBA-3125 (-99% and -59%), and GMC of IgG 1.7 and 6.6 µg/mL (-89% and 65%). Seroprevalence of putatively protective titres/concentration was 88% and 99% for SBA-ref (2011: 100% and 99%), 32% and 83% for SBA-3125 (2011: 100% and 100%), and 44% and 90% for IgG (2011: 100% and 96%).

Among children aged 1-4 years at the time of the PsA-TT campaign, complete return to pre-vaccination levels is expected in 2022, 2018 and 2016, respectively, based on SBA-ref, SBA-3125, and IgG. Among persons aged 5-14 years at the time of the campaign, complete return is expected after 2022 (both SBAs) and 2019 (IgG). Among adults aged 15-29 years at the time of the campaign, complete return to baseline can be expected in 2021 (both SBAs) and after 2022 (IgG).

Discussion

Especially in older age groups, antibody have well persisted since the PsA-TT campaign. SBA-3125 appears be a more appropriate indicator of protection conferred by PsA-TT-induced antibody. Based on SBA-3125, a booster campaign would be required in 2018 for children aged 1-4 years during the PsA-TT campaign, to sustain direct immune protection.

Dr Joanne Langley, Dalhousie University

Joanne Langley is a Professor of Pediatrics (Division of Infectious Diseases) and Community Health and Epidemiology at Dalhousie University, and holds the Canadian Institutes of Health Research - GlaxoSmithKline Chair in Pediatric Vaccinology at Dalhousie Medical School.

She is a practicing pediatric infectious disease consultant at the IWK Health Centre.  Dr. Langley currently serves as  Associate Director (Clinical Evaluation Unit) of the Canadian Center for Vaccinology (http://centerforvaccinology.ca/), and as lead for the Clinical Trials Network within the Canadian Immunization Research Network (CIRN; www.cirnetwork.ca). She is a former chair of the National Advisory Committee on Immunization (NACI) (2007-2011) and member of the Canadian Task for on Preventive Health Care..

Poster

Background

Emergency vaccination programs are often needed to control outbreaks of Meningococcal B (MenB) disease in young adults attending university. The 4CMenB vaccine (Bexsero®, GlaxoSmithKline) is authorized for persons 2 months through 17 years in Canada, but there are limited data on safety and immunogenicity in persons >17 years or on various dosing schedules.

Methods

A randomized, controlled, observer-blinded trial compared an accelerated 4CMenB schedule (0, 21 days) to a standard schedule (0, 60 days) during the 2015/16 academic year in 17- 25year old students, at 3 CIRN sites. Hepatitis A (HAV) vaccine was administered as a control on day 21 or 60 to participants randomized to the accelerated and standard schedules, respectively. Sera was drawn at days 0, 21, 42, 81 and 180 and human serum bactericidal(hSBA) titers were performed using MenB strains 5/99, H44/76 and NZ98/254.

Results

Among 121 participants the mean age was 21.4 years; 69.4% (n=84) were female. Any solicited adverse event (AE) was more common in M recipients after all 3 doses (95% - 100%). The most common solicited AE day 0-6 post-vaccination was local: pain at the injection site in 95% -100% after 4CMenB, v. 30% - 46.6% in HAV recipients. Grade 3 pain (interferes with normal activity) was reported by 8.3 - 32.8% post 4CMenB. Muscles aches were the most common general AEs (M:46.7% - 55.2% v. H: 11.7% - 24.1%). Fever ≤ 39.0°C occurred in 2 participants, post dose 2 in the accelerated group. One serious AE (fractured patella) occurred. Overall, reactogenicity was similar in the two schedules. hSBA titers were low in all groups at day 0. Participants in the accelerated schedule had higher titers at day 42 to all 3 MenB antigens (Geometric mean (GM) 298.2 vs. 151.8 to 5/99, p = 0.01; GM 76.3.3 vs. 20.8 to H44/76, p <0.001 and GM 72.0 vs. 24.6 to NZ98/254, p<0.001), but titers were not significantly different at days 81 or 180 in the 2 groups, except to strain 5/99, which was higher in the standard group (GM 462.2 v.250.1, p = 0.03) at day 81.

Conclusion

In a blinded multicenter study conducted in 17 to 25-year olds during an academic year, the most common AEs were injection site pain and muscles aches, which were more frequent in 4CMenB recipients regardless of schedule. AEs did not interfere with study completion (120/121 participants received all doses). hSBA titers increased rapidly post vaccination, and were higher earlier in the accelerated schedule. An accelerated 4CMenB schedule (0,21 days) could be used to control outbreaks in adolescents/young adults.

Presentation

Dr Jay Lucidarme, Public Health England

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.

Poster

Introduction

The Meningitis Research Foundation Meningococcus Genome Library (MGL) is a comprehensive, open access, online database containing draft meningococcal genomes and metadata (serogroup, year, epidemiological year and region) from UK cases of invasive meningococcal disease (IMD). It was established in 2012 as a collaboration between Public Health England (PHE), the Wellcome Trust Sanger Institute and the University of Oxford and was funded by the Meningitis Research Foundation to include all English, Welsh and Northern Irish IMD isolates received by the PHE Meningococcal Reference Unit over three epidemiological years (2010/11 to 2012/13). The database continues to be populated on an ongoing basis and has expanded to include isolates received by the Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory since 2009.

Aims

The MGL aims ‘to enable advancement in serogroup B meningococcal (MenB) vaccine research, making a lasting contribution to MenB vaccine development. This has been, and continues to be a major focus of work at MRF, whose trustees place particular emphasis on research into prevention of serogroup B meningococcal disease’. Here we describe the current contents of the library and summarise research to which it has contributed.

Materials and methods

The MGL (http://www.meningitis.org/research/genome) is hosted on the PubMLST/Neisseria platform. Data were extracted using the ‘export dataset’ analysis tool. PubMed and Google Scholar were interrogated using the search terms “meningococcus genome library” and “meningococcal genome library”.

Results

The MGL contained 3230 genomes (accessed 08 May 2017) pertaining to 2913 English, Welsh and Northern Irish cases, and 317 Scottish cases. At the time of writing we identified 40 peer review publications citing the MGL. Approximately a quarter of these were concerned with subcapsular vaccine development or determining the potential strain coverage, mainly among MenB, of licensed/developmental subcapsular vaccines. A further half of publications were concerned with IMD epidemiology or meningococcal/neisserial population structure (or means of resolving this), and the distribution of antigens, virulence factors, pathogenicity determinants, phase variation, evolutionary determinants and clinical characteristics. Also included were several outbreak analyses and review articles encompassing several of the above themes.

Conclusion

The MGL is an invaluable tool that has facilitated numerous global research projects concerning diverse aspects of not only of serogroup B (consistent with its original aims), but of all meningococci, as well as other Neisseriaceae. The actual number of publications citing the MGL is likely to exceed that stated here since some may be missed by the methods employed or are uncited.

Jane Plumb, Group B Strep Support

Following a career in HR consulting, Jane became a stay-at-home Mum. 3 years later, in 1996, her second child, Theo, died aged 17 hours from group B Strep infection.

Jane and her husband, Robert set up UK charity Group B Strep Support to improve the prevention of life-threatening group B Strep infections in newborn babies; support families affected by GBS and their health professionals; and support relevant research.

Group B Strep Support is supported by a highly respected medical advisory panel, and in 2016 was the primary provider of patient information materials on group B Strep to the NHS. Jane continues to lead the charity, and has worked with many UK medical bodies to improve national standards of prevention, including the Royal College of Obstetricians & Gynaecologists, the UK National Screening Committee and the National Institute for Clinical Excellence (NICE). She has also worked with MPs and the Department of Health on improving the prevention of GBS infection in newborn babies. Jane has acted as a coapplicant, stakeholder or PPI on many GBS research studies, and co-authored several medical papers.

In the 2012 New Year Honours List, Jane was an awarded an MBE for services to Child Healthcare. In 2014, she won the Tesco Campaigning Mum of the Year Award.

Poster

Objectives

GBS is the UK’s most common cause of life threatening infection in newborn babies, and the main cause of meningitis and sepsis. Research has rarely focused on the family experience of EOGBS both at the time of the baby’s illness and subsequently. We use survey data to explore the health, social and financial issues faced by affected families, with a focus on meningitis and sepsis.

Methods

An online survey (n=939) of parents and carers of babies affected by EOGBS, commissioned by the charity Group B Strep Support. Participants were asked questions about their awareness of GBS status in pregnancy and about whether IV antibiotics were administered in labour. They were then asked about the clinical course of their baby’s EOGBS infection, and finally about the longer-term health, social and financial consequences of their baby’s illness.

Results

Over 69% of babies made a full recovery, 24% recovered with long-term sequelae and 7% died. These are higher than BPSU (2014/15) figures suggest. The most common clinical presentations of EOGBS in this sample were sepsis (35%) and meningitis (17%).

Hospital stays were significant, with 64% of all babies requiring a stay of 1 week or longer. Babies where meningitis was the primary clinical presentation had significantly longer hospital stays. During the time their baby was in hospital, parents reported a number of practical difficulties, including caring for other children at home, obtaining food and drink for themselves and finding accommodation, and also financial difficulties including taking time off work and paying for parking.

The impact of EOGBS continued long after the initial illness. This was particularly the case where the primary presentation had been meningitis or sepsis. Family dynamics were changed, with 30% of parents reporting that other siblings at home were affected by the baby’s illness, 71% of parents reporting that their own mental health was affected by their baby’s EOGBS and 76% reporting that their enjoyment of subsequent pregnancies was reduced. Where babies had survived with long-term sequelae, families frequently reported financial hardship as a direct result of these.

Conclusions

These data give a unique insight into what families may be experiencing during the immediate time of the EOGBS infection, and afterwards including in subsequent pregnancies. These data allow health professionals to reflect on the care, support and information which these families may need; these needs may be different where meningitis and sepsis have been the primary presentations.

Presentation

Prof David Goldblatt, University College London

David Goldblatt is Professor of Vaccinology and Immunology and Head of the Immunobiology Section at the Great Ormond Street Institute of Child Health, University College London (UCL) where he also holds the role of Institute Deputy Director for NHS Engagement.

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 where he was Director of the National Institute for Health Research GOSH/UCL Biomedical Research Centre from 2007 to 2017. 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 was awarded NIHR Senior Investigator status in 2012 which was renewed in 2016.

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, evaluation of functional immunity to S. pneumoniae proteins, the development of new pneumococcal vaccines and the development of functional assays for evaluating immunity to bacterial candidate vaccines. He is a regular advisor to the World Health Organisation (WHO) on vaccines and is Director of the WHO Reference Laboratory for Pneumococcal Serology based at the UCL Great Ormond Street Institute of Child Health in London. He serves on subcommittees of the United Kingdom Department of Health Joint Committee on Vaccines and Immunisation (JCVI) has advised the US FDA and EMA on vaccine evaluation and has served as a member of MRC, Wellcome Trust and US NIH funding panels.

Abstract

The first pneumococcal vaccine (7 valent vaccine, PC7 Prevenar©) was licensed as a 4 dose schedule and first introduced at 2, 4, 6 and 12-15 months in the US immunisation schedule. Immunogenicity studies of a 2+1 schedule (at 2/4 and 12 months of age) suggested that for the majority of serotypes the immunogenicity was comparable and thus this schedule was used to introduce PCV7 in the UK. The direct and indirect impact of PCV7 in a 2+1 schedule in the UK was dramatic and this schedule was adopted by many countries worldwide. As of 2017, 54 countries are using a 2+1 schedule with only 23 using a 3+1 schedule. In GAVI eligible countries however, the majority use a 3+0 schedule which is compliant with the WHO’s recommended Expanded Programme of Immunisation. Two major issues under discussion at the moment are whether countries using a 3+0 schedule might be better served using a 2+1 schedule and whether developed countries with mature PCV programmes and little disease due to the serotypes in the vaccines might consider moving to a 1+1 schedule. Both topics will be discussed and data from a recently completed UK randomised control trial of PCV13 administered at 2+1 vs 1+1 will be presented.

Presentation

Prof Kim Mulholland, London School of Hygiene Tropical Medicine & Murdoch Children’s Research Institute, Australia

Kim Mulholland is an Australian paediatrician, trained at Melbourne University and the Royal Children’s Hospital, Melbourne. 

With post-graduate training in immunology, respiratory medicine and tropical medicine he joined the Medical Research Council Laboratories in 1989, where he developed a program of research covering all aspects of the problem of childhood pneumonia.  This included studies of the aetiology, clinical signs, and treatment of pneumonia cases, with particular reference to very young infants and malnourished children.  These studies guided WHO policy in the field and contributed to the development of the strategy of Integrated Management of Childhood Illness (IMCI), as well as guiding oxygen and antibiotic management for hospitalized children.  His Hib vaccine trials were the first to demonstrate the capacity of conjugate vaccines to prevent bacterial pneumonia, and paved the way for Hib vaccine introduction in Africa.  After six years in the Gambia he joined WHO where he oversaw the development of standardized methods for the evaluation of pneumonia vaccines in developing countries.  Since leaving WHO in 2000 he has continued to work in the pneumonia field with particular emphasis on vaccines.  He was one of the founders of the Global Action Plan for Pneumonia, and one of the leaders of the successful Hib Initiative project that saw the introduction of Hib vaccines into the poorest countries of the world.  During the same period he established leading pneumococcal microbiology and immunology laboratories at the Murdoch Childrens Research Institute (MCRI), Melbourne, along with major field research programs in Vietnam, Fiji and Mongolia, and growing programs in Indonesia and Laos. He currently holds professorial appointments at the MCRI in Melbourne and the London School of Hygiene and Tropical Medicine in UK.

Abstract

The first pneumococcal conjugate vaccine (PCV) to be licenced was the 7-valent product produced by Wyeth Vaccines (now Pfizer) known as Prevnar-7® or PCV7.  This vaccine proved to be highly effective in developed countries, with substantial reductions in vaccine type invasive pneumococcal disease (IPD) offset by some degree of serotype replacement.  Ecological studies in the US and Australia showed significant reductions in childhood pneumonia admissions.  It was used in only two African countries, with some reduction in overall IPD but no clear impact on radiological pneumonia incidence.  The second generation of PCVs, Synflorix® (PCV10, GSK) and Prevnar-13® (PCV13, Pfizer) were licensed in 2009 and 2010 respectively.  Both vaccines have proved to be highly, and similarly effective in preventing IPD caused by vaccine types.  In developing countries PCV10 has been evaluated in Kenya and Brasil, while PCV13 has been evaluated in South Africa and Gambia.  Effectiveness/impact studies in Asia are underway in Nepal, Laos and Mongolia (all PCV13). Effectiveness against vaccine type IPD in these settings is comparable to that in more developed countries.  PCV13 has three additional serotypes compared with PCV10 – 3, 6A and 19A.  For 6A and 19A there is evidence that PCV10 (which contains the cross reacting serotypes 6B and 19F) is also protective against IPD, but probably to a lesser degree than PCV13.  Serotype 3 was a component of the earlier version of PCV10, but was removed as the vaccine was shown to be ineffective against serotype 3.  At this time there is no conclusive evidence that PCV13 is effective against IPD due to serotype 3.  Both vaccines reduce nasopharyngeal carriage of vaccine types, leading to herd immunity.  PCV13 does not appear to provide herd protection against 19A.  As the public health utility of these vaccines in developing countries is dependent on their ability to prevent pneumonia and pneumonia mortality, it is important to evaluate their effectiveness against pneumonia.  This is being done in several settings where pneumonia surveillance is underway, including Gambia and Kenya.  Serotype replacement is already evident with the new vaccines in developed countries.  The extent to which this erodes the effectiveness of the vaccines in developing countries remains to be seen.

Presentation

Dr Sema Mandal, Public Health England, London

Sema Mandal (MBBS, MRCP, MSc FFPH) is a medical consultant epidemiologist in in the Immunisation, Hepatitis and Blood Safety Department at Public Health England (PHE). 

Dr Mandal is the PHE viral hepatitis lead and her portfolio includes overseeing the introduction of universal hepatitis B immunisation into the routine childhood programme in 2017.  In addition to her lead role in strategic and responsive work in PHE, Dr Mandal is a co-applicant and PI on several hepatitis research projects and is an honorary senior clinical lecturer at UCL. During the 2014-15 West Africa Ebola epidemic Dr Mandal was seconded to WHO Geneva as a co-investigator on the successful “Ebola- ca suffit!” phase III rVSV-EBOV vaccine trial in Guinea and continues to work with WHO on developing   an R&D  blueprint for clinical trials during public health emergencies.

Prior to joining PHE’s national immunisation and hepatitis team in 2013, Sema spent 4 years at the US Centers for Disease Control (CDC) in Atlanta working on national and international immunisation programmes for bacterial vaccine preventable diseases. Along with leading the field response to multiple domestic pertussis and meningococcal outbreaks including a meningococcal B outbreak in a US university, she led projects in sub-Saharan Africa (Burkina Faso, Mali, Nigeria and Niger) on meningitis surveillance capacity building and vaccine evaluation. Dr Mandal completed specialist registrar training in public health in London, followed by the Epidemic Intelligence Service (EIS) Fellowship at CDC, Atlanta. Prior to entering public health, she worked in internal medicine, GUM and A&E in the UK and Australia. She also previously worked with Médecins sans Frontières as a field medical doctor in hospital paediatric and primary care support programmes in Wau, South Sudan.

Dr Sarah Meyer, Centers for Disease Control and Prevention, Atlanta

Sarah Meyer, MD MPH serves as a medical epidemiologist in the Meningitis and Vaccine Preventable Diseases Branch (MVPDB) at the U.S. Centers for Disease Control and Prevention and focuses on surveillance, vaccine evaluations, and policy for meningococcal disease and vaccines in the United States and sub-Saharan Africa.

She is currently the CDC lead for the Advisory Committee on Immunization Practices Meningococcal Vaccines Work Group. Dr. Meyer also completed the Epidemic Intelligence Service fellowship in MVPDB. She is a board-certified pediatrician who trained at Harvard University and Boston University in Boston, Massachusetts, and is currently an Instructor of Pediatrics at Emory University School of Medicine, where she sees patients in the Division of Pediatric  Emergency Medicine.

Abstract

In recent years, several outbreaks of capsular group B meningococcal disease have been reported in university settings in the United Kingdom and the United States. The availability of licensed group B meningococcal (MenB) vaccines provides a new tool in the public health response to these outbreaks. However, important questions remain about the optimal use of these vaccines to control outbreaks of group B meningococcal disease in this population. We report on recent US and UK experiences of group B meningococcal disease outbreaks in universities, describing the epidemiology and the public health response. We reflect on the challenges and lessons learned in responding to these outbreaks, and how our understanding of group B outbreaks may inform thresholds for intervention and revised guidance on management of outbreaks in university settings.

Presentation

Helen Campbell, Public Health England, London

Helen Campbell joined Public Health England as a Senior Clinical Scientist in 2001 after working as a Senior Scientist in the Immunisation Team at the Department of Health and as consultant research manager for Health Promotion England.

She is the epidemiological lead for pertussis and invasive meningococcal disease (Groups C, W and Y). She provides scientific support for parvovirus and rubella in pregnancy and leads on PHE co-ordinated UK surveillance of inadvertent vaccination of pregnant women. She provides scientific support for surveys of parental attitudes to immunisation, now led by PHE. Teaching on public health courses at postgraduate level and teaching on PHE and local training programmes and study days are key aspects of her role within PHE alongside the development of parental resources and health professional training materials.

Abstract

Historically, group W meningococcal (MenW) disease was responsible for less than 5% of all IMD cases in England. Since 2009/10, however, there have been annual increases in MenW disease across all regions and age groups in England, initially older adults and teenagers then infants and toddlers.  This increase has been almost entirely due to rapid expansion of one MenW strain belonging to the highly virulent ST-11 clonal complex, which is associated with high rates of morbidity and mortality. By the 2015/16 epidemiological year, MenW accounted for 26% of all IMD cases in England. These increases led to MenACWY vaccine replacing the existing time-limited ‘freshers’ programme from August 2015 and replacing MenC vaccine in the routine adolescent schools programme from Autumn 2015. In addition, teenagers between these two age groups have been targeted as part of a 2-year catch-up campaign.

Public Health England (PHE) conducts enhanced national IMD surveillance in England, where 84% of the UK population resides. National Health Service hospital laboratories routinely submit local invasive meningococcal isolates to the Public Health England Meningococcal Reference Unit for confirmation and characterisation, with national PCR-testing also offered. Confirmed case-patients are routinely followed-up for additional details, including vaccination history and outcome.

Preliminary coverage data for the first cohorts to be routinely offered MenACWY vaccine in schools from September 2015 and evaluated up to the end of August 2016 was 71.8%-84.1%. Encouraging uptake in school leavers who have been vaccinated by general practice has been more challenging. Vaccine coverage estimates for school leavers in 2015 and 2016 evaluated to end August 2017 was 39.7% and 35.5% respectively. We are in the final catch-up phase of the MenACWY vaccination programme in England and concerted effort has gone into trying to better target and engage the 2017 school leaver cohort. Routine immunisation at 13/14 years of age continues.

Confirmed MenW cases in England continued to increase after the MenW vaccination programme began; from 211 cases in 2015/16 to 225 in 2016/17 (6.6% increase). Around a third of MenW cases in 15-19 year olds have been fatal but increases in those targeted by MenACWY vaccination have not continued. To date there have been no cases of MenACWY disease in eligible teenagers vaccinated under the current programme and early impact on MenW disease has been shown.

Presentation

Dr Shamez Ladhani, Public Health England, London

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

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

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

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

Abstracts

In September 2015, the UK became the first country to introduce the multi-component, protein-based meningococcal group B (MenB) vaccine (4CMenB) into the national infant immunisation programme. The vaccine was offered at a reduce 2-dose priming schedule at 2 and 4 months of age, with a booster at 12 months, alongside a limited catch-up for 3- and 4-month olds attending their routine immunisations at the start of the programme. Within 10 months, cases in vaccine-eligible infants nearly halved, with an estimated vaccine-effectiveness of 83% against invasive MenB disease in England. In May 2016, the infants became eligible for their 12-month booster and, over the next 12 months, cases in 1 year-olds declined significantly compared to the pre-vaccine period. So far, more than 3 million doses have been administered in the UK and, so far, there have been no major safety concerns.

Dr Matthew Snape, Oxford Vaccine Group

Matthew Snape is a consultant in General Paediatrics and Vaccinology at the Oxford University Hospitals NHS trust, a Jenner Investigator and an Honorary Senior Clinical Lecturer at the University of Oxford.
 
Dr Snape trained at the Royal Children's Hospital, Melbourne, and at St Mary's Hospital, London. While caring for children suffering overwhelming infections on the St Mary’s paediatric intensive care unit he developed an interest in the prevention of these illnesses by immunisation.

To this end he has worked at the Oxford Vaccine Group (University of Oxford Department of Paediatrics) since 2003, conducting research related to vaccines against meningococcus, pneumococcus, group B streptococcus, influenza RSV and Ebola.  Amongst over 90 publications are 12 manuscripts reporting clinical trials of capsular group B meningococcal vaccines in children and young adults conducted at the Oxford Vaccine Group.

Dr Snape was recently appointed as Director of the National Immunisation Schedule Evaluation Consortium (NISEC), a Department of Health funded consortium conducting clinical trials relevant to the UK immunisation schedule. He continues to work as a general paediatrician at the Children’s Hospital, Oxford (Oxford University Hospitals NHS trust), and receives salary support from the NIHR Oxford Biomedical Research Centre.

Abstract

The introduction of a MenB immunisation campaign in the UK in 2015 was a bold step towards reduction of childhood meningitis, and has been shown to effectively reduce the incidence of group B meningococcal disease in immunized cohorts. In order to deliver this campaign in a cost effective manner, the 4CMenB vaccine was administered in a 2, 4 and 12 month dosing schedule, primarily based on data showing immune responses in the majority of children to the first two doses of a 2, 4, 6 and 12 month schedule.

In 2016/2017 the Oxford Vaccine Group, Public Health England and University College London undertook the ‘Sched 3’ study, a randomised controlled trial whose primary objective was to compare the immunogenicity of two alternative pneumococcal vaccine (PCV13) schedules (2 dose vs single dose infant priming).  This study was funded by the Bill and Melinda Gates foundation and by the National Vaccine Evaluation Consortium (NVEC). The study design also provided the opportunity to generate immunogenicity data on the currently employed 4CMenB schedule in a UK context.

Accordingly blood samples taken at 5 and 13 months of age were analysed for serum bactericidal activity (SBA) against reference MenB strains in the presence of human complement at Public Health England Manchester.

This determined that at 5 months of age, 95.3% (82/86, 95% CI: 88.5 – 98.7) of participants receiving the current UK immunisation schedule had SBA titres ≥ 4 for strain 44/76. For strains 5/99 and NZ98/254 these proportions were 100% (87/87, 95.8 – 100.0) and 88.5% (77/87, 79.9 – 94.3%), respectively. At 13 months of age these proportions were 92.4% (73/79, 84.2-97.2) for 44/76, 100% (79/79, 95.4-100) for 5/99 and 88.6% (70/79, 79.5-94.7) for NZ98/254.   SBA GMTs at 13 months were no higher than those at 5 months for strain 44/76. Co-administration with a 1+1 PCV13 schedule (rather than 2+1) had no significant impact on SBA titres.

These results provide important context for the emerging data from PHE surveillance suggesting a significant impact on MenB disease with the current 4CMenB schedule, and are an important step towards better understanding what constitutes a ‘sufficient’ immune response to 4CMenB immunisation.

Ongoing surveillance will determine if the effectiveness of the UK 4CMenB campaign is maintained through pre-school years, and further follow-up of the Sched3 study cohort will be important to provide serological surveillance to inform these population-level data.

Similarly, ongoing surveillance of 4CMenB efficacy in populations at increased risk of meningococcal disease (e.g. those with terminal complement deficiencies or receiving eculizumab therapy) is important to better understand the nature of the immune protection provided by 4CMenB. Immunisation of children in these risk groups results in little increase in SBA titres against reference MenB strains when tested with endogenous complement. Whether 4CMenB immunisation in these individuals can be protective through non-complement mediated pathways (e.g. opsonophagocytosis) is currently unknown, although emerging case reports of invasive meningococcal disease in eculizumab-treated adults despite 4CMenB immunisation argue for ongoing vigilance and antibiotic prophylaxis even after immunisation.

Dr Janine Paynter, University of Auckland, New Zealand

Janine is a public health epidemiologist working with Conectus at the University of Auckland, New Zealand.

Janine’s broader research experience includes research on non-communicable disease, tobacco control. This research informed policy change on tobacco displays. More recently her research projects have focussed on vaccine effectiveness and safety, including a study of the safety of pertussis immunisation in pregnancy and the impact of the pneumococcal vaccines in New Zealand. Janine’s strengths are in quantitative data analysis and data linkage. She is a member of a team which has been investigating the impact of the meningococcal B OMV vaccine on gonorrhoea.

Abstract

A meningococcal B vaccine has been available on the routine childhood immunisation schedule in the UK since 2015. This vaccine shares an outer membrane vesicle component with the New Zealand meningococcal B vaccine (MeNZB™). Ecological data from Cuba and NZ suggest a decline in rates of gonorrhoea may occur following the use of group B meningococcal Outer Membrane Vesicle (OMV) vaccines.

We evaluated vaccine effectiveness (VE) of the NZ MeNZB™ 3+0 schedule against laboratory confirmed gonorrhoea using two observational studies - a retrospective case-control study of laboratory confirmed clinic diagnoses and cohort study of hospitalisations due to gonorrhoea.

Datasets

Cohort: NZ hospital discharge data, vaccines given and date, travel to and from NZ, demographic variables including gender, ethnicity, month and year of birth. ICD10 coding identified individuals hospitalised for gonorrhoea. Case control: National Health Index (demographics), sexual health clinics, National Immunisation Register linked using unique identifier. Controls were positive chlamydia test, negative gonorrhoea.

Participants

ohort* Data available for over 1.1 million individuals resident in NZ 2004-2015. Case control NZers born 1984-1998 eligible to receive vaccine, aged 15-30 years during 2004-2014. Analyses Cohort: Cox’s proportional hazard modelling with Firth correction to estimate adjusted relative risks of hospitalisation for vaccinated versus unvaccinated. Covariates included gender, ethnicity, deprivation, age category. Case control: Odds ratio estimated using unconditional logistic regression. VE as % (1-Odds Ratio).

Results

Vaccinated individuals in their early teens at the start of the vaccination programme were significantly less likely to be hospitalised with gonorrhoea, Hazard Ratio 0.53, (95% CI 0.34-0.82), corresponds to VE estimate of 47% (95% CI 18-66). 14,730 cases and controls (1,241 incidences gonorrhoea, 12,487 chlamydia, 1,002 co-infection). Vaccinated individuals in the case-control study were significantly less likely to be cases, 41% vs 49% (adjusted OR 0.69 (95%CI 0.61-0.79). VE estimate for MeNZB™ against gonorrhoea after adjustment for ethnicity, deprivation, geographic area, gender 31% (95% CI 21-39).

Conclusion

Ecological and empirical data support an effect of MeNZB™ OMV vaccine on both clinic-diagnosed gonorrhoea infection and hospitalisation. Results may inform development of more effective gonorrhoea vaccines. With increasing multiple drug resistance, combined vaccination of school aged children against meningococcal B and Neisseria gonorrhoea may have considerable public health benefits.

*Access to the data for the cohort study to be presented was managed by Statistics New Zealand under strict micro-data access protocols and in accordance with the security and confidentiality provisions of the Statistic Act 1975. Our findings are not Official Statistics. The opinions, findings, recommendations, and conclusions expressed are those of the researchers (Conectus, University of Auckland), not Statistics NZ.

Presentation