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Preventing death from severe infections

  • This Programme links hospital and community-based studies of infection. It is vaccine-oriented, and is underpinned by our excellent laboratories, particularly in diagnostic microbiology, as well as our close integration with the clinical services in adult medicine and paediatrics. We will achieve the Aim of preventing death in severe infections by addressing Specific Objectives in sepsis, meningitis, pneumonia, antimicrobial resistance (AMR) malaria and diarrhoeal disease. The cohesion of this Programme is ensured by the close clinical collaborations within the MOP and with clinical colleagues that we have built over 20 years.
  • MLW studies were the first to show invasive non-typhoidal Salmonellae (iNTS) as the most common cause of sepsis in HIV infected adults, and have now demonstrated the importance of other enteric pathogens, Klebsiella, and pneumococcus. The iNTS isolates were shown to be antibiotic resistant, recurrent from sequestration in patient bone-marrow and clonally related with newly-emerged genomic degradation matched to the immunosuppressed niches in HIV-infected adults and children. This work resulted in altered antibiotic policy and a dramatic reduction in recurrent infections and deaths from iNTS. Epidemics within Malawi, and across the sub Saharan continent, of multiple pathovars of NTS and more recently S.typhi have been driven by multidrug resistance, and emerged as a significant problem. Molecular epidemiology, transmission, pathogenicity and vaccine studies are in the set up phase (WT Strategic award, BMGF award) along with studies of current antibiotic use, stewardship, and emerging AMR. 
    Neonatal sepsis has remained stubbornly high despite improvements in under 5 mortality in Malawi. MLW and MEIRU studies of neonatal and infant deaths in hospital and community settings (French, Bar Zeev and Crampin) have resulted in a focus on GBS. Population based studies including GBS in Blantyre.
  • Pneumococcal research at MLW first observed an eight fold increase in disease associated with HIV, high mortality and a pneumococcal serotype distribution not preventable by the 7-valent vaccine. Subsequently, serotype specific protection was shown in HIV infected adults using conjugate vaccine (French, Gordon et al NEJM) and MLW advised GAVI in the Malawi introduction of the 13-valent pneumococcal conjugate vaccine in 2012. Now, MLW post-vaccine surveillance in Blantyre, Mchinji and Karonga has shown limited herd effect and mucosal studies have shown increased carriage in HIV infected adults on HAART. Further, we have a major investment in influenza surveillance and prevention (CDC Cooperative Agreement) and have demonstrated a dramatic interaction of influenza with HIV and identified flu as a major contributor to hospitalised severe acute respiratory infection (WTCPP Ho). Urgent further prevention strategies, including the effect of HIV and flu, are needed to prevent pneumococcal sepsis, meningitis and pneumoniaRecent breakthrough discovery science has shown specific pneumococcal genes associated with progression from sepsis to meningitis. Knockout mutants of these genes are unable to progress to meningitis in murine models and recombinant protein vaccine protects murine models from meningitis. We have developed a world-leading collaborative pneumococcal group including hospital based studies, experimental human pneumococcal challenge (EHPC, globally unique), pathogen genomics, mucosal immunity and (with MEIRU) large vaccine studies.
  • Landmark meningitis studies at MLW defined the high burden of cryptococcal and pneumococcal meningitis with 100% and 66% mortality respectively. Subsequent high impact clinical intervention trials (2 papers NEJM) have tested novel therapies and emphasised the impact of early health seeking behaviour, nursing care and appropriate antibiotics - but outcomes remain poor. Current work shows promise in testing amphotericin for cryptococcal meningitis and novel adjunct therapies for pneumococcal meningitis have been suggested by MLW work demonstrating that fatality was associated with high CSF pneumolysin.
  • MLW has a 25yr history of world-class severe malaria research which has helped to define those at greatest risk of death, improved our understanding of severe disease and improved outcomes in patients with cerebral malaria. Working together with the MoH, we have seen a dramatic reduction in malaria deaths nationally. Work on the Paediatric Research Ward (PRW) has identified increased brain volume as a major contributor to death in children with stringently defined cerebral malaria; 37% of retinopathy-positive children with CM do not survive. Clinical trials targeting this group can be accomplished more efficiently on the PRW than anywhere else in the malaria-endemic world. As the PRW is an international standard facility for diagnosis and treatment of children requiring intensive monitoring (including MRI and complex neurological assessment), it also accommodates studies of severe anaemia, meningitis and aparasitaemic coma as well as PK/PD studies and parasite clearance studies to determine AMR.
  • MLW has an outstanding record in the initial descriptions of rotavirus incidence, development of rotavirus vaccine, clinical trials leading to licensure and post-vaccine surveillance including 2 current WT Clinical Fellows (all led by Cunliffe).  Exciting recent data indicate that the failure of the vaccine to reach expected protective efficacy in Malawi can be explained by serotype diversity and is correctable by vaccine modification.
     
    1. Local reduction in mortality among admissions for sepsis, pneumonia and meningitis by improved diagnosis and clinical care.  Published findings cited in new treatment guidelines.
    2. Improved understanding of AMR and the mechanism by which it is acquired.  Published data leading to appropriate antibiotic stewardship with citation in guidelines.
    3. Establish Experimental Human Pneumococcal Carriage model for vaccine testing and pathogenesis studies (Gordon WTIA).
    4. Clinical vaccine trials including RSV, rotavirus and novel pneumococcal vaccines to optimise protection in adults and children and among susceptible groups (e.g. HIV infected).
    5. Trial of clinical management in cryptococcal meningitis.
    6. Development of Malawian scientists (e.g. J Cornick and T Nyirenda to senior postdoc and PI level).
    7. Treatment intervention studies to improve outcome in cerebral malaria.
    8. Childhood diarrhoea studies –post-vaccine surveillance for rotavirus and new studies in norovirus.