Title: Molecular Epidemiology for Vaccination Policy (MEVACP).
Funder: Department of Health and Social Care

Abstract: Meningitis caused by encapsulated bacteria is a global health problem and Africa suffers the greatest burden of disease. Meningitis is predominantly caused by Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae and molecular typing approaches have significantly improved the ability to detect these pathogens. Nevertheless, every year a large proportion of cases remain uncharacterised. This presents crucial challenges, e.g. incomplete surveillance data, potentially delayed diagnoses and recognition of meningitis outbreaks, and the overuse of broad-spectrum antimicrobials at a time of ever-increasing problems of antimicrobial resistance. The key aim of MEVacP will be to improve and enhance the surveillance of meningitis caused by these pathogens in the African meningitis belt. The first step will be to produce a systematic review and up-to-date evaluation of all related molecular diagnostic assays. After laboratory validation where necessary, this will lead to public dissemination of optimised and standardised protocols for the detection of these pathogens. The last such review was undertaken in 2011 (1) and many innovative approaches have subsequently been published, including major advances in quantitative PCR methods. Furthermore, a substantial amount of whole genome sequence (WGS) data from these pathogens has now become available. Using the research team s extensive experience in the analysis of genomic data, the second key component will be to provide a comprehensive characterisation of the genetic diversity among capsule loci from all three pathogens. Current vaccines are designed to illicit an immune response to the polysaccharide capsule. Understanding capsule-specific sequence variation within genes that encode the capsule is important for designing sequence-based serotyping/serogrouping methodology, monitoring vaccine effectiveness and informing the design of future vaccines. We have experience in such analyses and have existing databases populated with thousands of genomes of these pathogens to use in analyses (2-4) (https://pubmlst.org). The third component will be the implementation of an online platform enhancing the surveillance of bacterial meningitis in the African meningitis belt. Currently, both the WHO and MenAfriNet provide online bulletins detailing meningitis outbreaks; however, inevitably, delays occur between the identification of infection to data becoming available due to the need to await clinical diagnostic results. It will be possible for the emergence of outbreaks to be detected sooner through the use of event-based internet surveillance tools where diverse sources of public information ranging from news articles, messages on forums, blogs, and social media can be used by the community to rapidly communicate the possibility of meningitis cases, in turn facilitating a more targeted and rapid response to the outbreak (5). Our online platform will have multiple layers of complexity, ranging from real-time outbreak communications identified through engine-based internet searches to clinical diagnostic results and epidemiology. A key feature of this platform is that it will be accessible to people at all levels of expertise: clinicians, policy makers, public health officials, families, parents and schools. Combined, these methods and approaches will ensure that surveillance of bacterial meningitis is enhanced across the meningitis belt and will expedite the timely deployment of vaccines and other preventative measures.

Lay abstract: Meningitis is a life-threatening and global health problem: >1.2 million cases of bacterial meningitis are estimated to occur worldwide every year, despite the availability of vaccines and antimicrobials. In addition to causing many deaths, some meningitis sufferers are left with major physical disabilities, resulting in a family caring burden. Africa is particularly affected by meningitis in that severe outbreaks occur from time-to-time and are a serious threat to the health and economic development of Africa. Our programme of research and training will significantly advance progress in fighting meningitis and related diseases in Africa.Three types of bacteria most commonly cause meningitis: Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. These are different bacteria that require different vaccines and antibiotic treatments, but the diseases they cause are similar and can be easily confused. We will improve the detection of these pathogens by determining the best laboratory methods to correctly and rapidly identify each of them. We will make these methods freely available on a website that will be written in both English and French and we will provide key resources for African and international communities such as: current meningitis data; best practice meningitis diagnosis, treatment and clinical management; visualisation for clinicians, scientists, governments, policy makers, local communities, schools and parents; vaccine information. We will also use genome sequence data to define variation among the genes that encode the capsule (a protective coat the bacteria possess to protect them from the human immune system) among all three pathogens. Current vaccines prompt an immune response to the capsule and variation in these genes might mean the vaccines will not work as expected. We will decipher the best laboratory assays to detect the capsule, which will lead to improved diagnostics, more accurate capsule data and better vaccination policies. Most importantly, we will be training African scientists to develop the skills and expertise they need to reduce meningitis in Africa. We will run training programmes for laboratory and clinical staff and will recruit African researchers to six month training fellowships in the UK for hands-on training in molecular typing, data interpretation, bioinformatics and genomic analyses. This project will focus on the critical public health issue of meningitis; however, this framework of laboratory work, local training and online data sharing will be implemented for other pathogens and regions in due course.

Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION