Salmonella (PIs: Gordon M, Feasey)
In the last seven years, MLW has established a leading position in both typhoid and invasive non-typhoidal Salmonella (iNTS) disease, modelling disease incidence and publishing the first estimate of the global burden of iNTS disease. Experimental medicine studies uncovering the cellular and molecular basis of pathogenesis proved the value of early ART initiation and treatment to penetrate intracellular niches, improving case fatality. Data on disruptions of cellular and antibody defence have driven design and evaluation of the three current candidate iNTS vaccines. Phylogenomic descriptions of three Salmonella epidemics have demonstrated the critical role of multidrug antimicrobial resistance in transmission, and altered national antimicrobial policy, improving outcomes. Understanding the niche adaptions of genomically micro-evolved African Salmonella strains is driving fundamental studies of bacterial biology.
Pneumococcus (PIs: Gordon S, French)
MLW has been at the leading edge of pneumococcal science for the past 20 years, growing to a world-leading collaborative group which includes hospital based studies, controlled hu-man infection model (CHIM), pathogen genom-ics, mucosal immunity, community surveillance and large vaccine studies with synergistic sup-port from two MRC programme grants. We have described the burden of pneumococcal disease by syndrome in adults and children and the critical interaction with HIV. Serotype specific protection was shown in HIV infected adults using conjugate vaccine. MLW sci-entists advised GAVI in the Malawi introduc-tion of the 13-valent pneumococcal conjugate vaccine in 2012 and established a national net-work for infant vaccine programme evaluation. Recent discovery science has identified key characteristics of the bacteria that control recombination in the genome and shown specific pneumococcal genes associated with progression from sepsis to meningitis with recombinant protein vaccines derived from these genes able to protect murine models from meningitis. The CHIM model has allowed efficient vac-cine testing and given unique insight into the mucosal regulation of carriage and lung defence, nasal microbiota regulation and pulmonary response to vaccination.
Meningitis (PIs: Desmond, Heyderman, Lalloo)
Landmark meningitis studies at MLW defined the high burden and high case fatality rate of cryptococcal and pneumococcal meningitis and the important contribution of group B strepto-coccus to neonatal disease. Subsequent high impact clinical intervention trials have tested adjunctive therapies in bacterial and cryptococcal meningitis and emphasised the impact of early health seeking behaviour, nursing care and appropriate antibiotics - but outcomes remain poor . A trivalent glycoconjugate Group B streptococcal vaccine was evaluated in an early phase study in HIV-infected women confirming immunogenicity. Initial studies of health seek-ing behaviour in meningitis led to subsequent MRF funded work on improving the response to severe illness in children in primary health care systems through use of an Emergency Triage As-sessment and Treatment (ETAT) package using digital health technology. This successful approach is now being rolled out nationally and is included in the new Malawi Essential Health Package.
Rotavirus (PIs: Bar-Zeev, Cunliffe)
In work spanning 20 years, MLW has completed several landmark studies of rotavirus gastroenteritis. These include the most comprehensive clinical description of rotavirus and HIV infec-tion ever undertaken; the first clinical trial of a modern rotavirus vaccine in Africa leading to a global vaccine recommendation; and the first description from a low income country of real-world impact of routine rotavirus vac-cination including ~ 40% reduction in child deaths due to diarrhoea (unpublished]. The biological basis of reduced vaccine perfor-mance compared with high income countries is currently being explored.
Malaria (PIs: Taylor, Mwapasa, Terlouw)
MLW has a 25 year 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 patho-physiology, including the importance of retin-opathy and improved outcomes in patients with cerebral malaria. 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 imaged with MRI; 37% of retinopathy-positive children with CM and in-creased brain volume do not survive.
Impact story: Rotavirus
- Surveillance of diarrhoeal disease in Malawi since 1996
- Published first detailed estimates of contribution of rotavirus to diarrhoea in children (including HIV positive)
- First rotavirus trial (2010) led to WHO recommendation for use
- Malawi surveillance data supported case to GAVI for financial support
- Post-introduction surveillance demon-strated real world effectiveness of vaccine, cost-effectiveness and efficacy of accelerated schedules
- Recent work demonstrating reduction in diarrhoeal deaths
- Current work looking at failures, house-hold transmission and planned new vaccine trials
Malawi’s success in achieving MDG targets for reduction is child mortality can be partly attributed to a 37% reduction in malaria mortality. MLW researcher have contributed substantial to the evidence base on malaria case management, including the switch to ACT’s for uncomplicated malaria and parenteral artesunate for severe malaria and epidemiological work has strongly informed and influenced malaria control and national policy in Malawi. We have now developed novel surveil-lance methodologies for affordable fine-scale mapping to demonstrate heterogeneity in transmission - an understanding of this is critical for improving control.
Work on PKPD dose-optimization of antimalarials in vulnerable subgroups has been influen-tial in changing WHO treatment guidelines for DHA-PPQ, the main candidate drug for mass drug administration in southern and eastern Africa. Results of a major trial examining anti-malarial and antiretroviral interactions are currently being analysed.
HIV (PIs: Corbett, Desmond, Mwandumba, Jambo)
MLW hosted the first large-scale population-based HIV self-testing study globally, defining and evaluating a semi-supervised volunteer distribution model that is now recommended by WHO and UNAIDS as safe, accurate, highly scalable and associated with increased de-mand for ART. Regional scale up through a large implementation research grant from UNITAID ($46 million) is now sup-porting interdisciplinary research accompanying 2.7 million HIV self-tests in Southern Africa, including Malawi.
Mwandumba’s lab has developed novel ap-proaches to detecting HIV infection at single cell level, allowing isolation of high quality nu-cleic acids from pure populations of HIV-infected cells and detection of unique compartmental reservoirs, and enabling novel study of HIV clearance from different body compartments.
Impact story: HIV self testing
- Recognition of need of new modalities of HIV testing, particularly for under served groups such as adolescents and men
- First demonstration of feasibility, safety and preference for self testing in certain groups
- Cost effectiveness, encouragement of linkage to care and minimal social harms all demonstrated
- Influenced national and international policy and uptake of self testing into national and international guidelines
Since demonstrating reduction in undiagnosed TB in Zimbabwe, leading to WHO policy change in 2013, Liz Corbett (WT Senior Fellow) has introduced spatial and enhanced TB recording in Blantyre. Our 2011-16 database of >12,000 TB cases confirms population-level impact from active case-finding, suggesting lasting behaviour change as a key mechanism, and quantitative support for an emerging theme of marginalisation of male needs.
In the lab, we have described incomplete restoration of anti-TB immunity in HIV-infected patients on ART, supporting need for prolonged preventive therapy for HIV patients.
Respiratory infections and pneumonia (PIs: Everett, French)
MLW supports the only respiratory virus surveillance in Malawi. We have demonstrated that 58% of severe hospitalised influenza in adults is attributable to HIV, pregnant women are at major risk (Ho PhD 2016) and amongst children with severe respiratory syndromes, RSV and Influenza are major causes but multiple viral co-infections may be a major driver of this syndrome in Malawi. MLW has led post-vaccine surveillance in Blantyre, Mchinji and Karonga since 2011 and has recently shown limited herd effect associated with pneumococcal conjugate vaccine implemen-tation. Mucosal studies have shown increased carriage of pneumococci in HIV infected adults on HAART, continued early acquisition of pneumococci by young infants with siblings a major reservoir of transmissible pneumococci. This has very significant national implications for disease control.
Respiratory infections are the most common cause of adult admission to QECH. A large cohort study has shown that mortality is associated with clinical features including hypoxia, anaemia and failure to stand. Follow-up work showed that only 10% of hypoxic cases were routinely provided oxygen and 90% of hypoxic cases were corrected with simple concentrator oxygen supply. Poor prognosis in pneumonia is also associated with TB or lack of a specific aetiology (Aston PhD 2017).
Lung Health (PIs: Gordon S, Rylance)
MLW has just published the largest study of chronic lung disease in Africa and made the novel observation that 38% of Malawians have abnormal spirometry, mainly restrictive (small) lungs. Small lungs are associated with chronic lung disease and acute pneumonia (Jary - Thorax in press) and the high observed prevalence indicates that as the population ages, a large burden of pneumonia driven by underlying lung disease will present. The largest intervention study ever to reduce household air pollution has just been published; use of an improved cook stove had no effect in reducing childhood pneumonia.
Chronic HIV and stroke (PIs: Mwandumba, Benjamin)
Stroke is common, severe and particularly disabling for Malawians given the lack of rehabilitation specialty care. The association of stroke with a high prevalence of hypertension in the elderly is expected, but novel recent MLW studies have identified HIV as the leading correlate of hospitalised stroke in younger adults. Current work continues to explore the association between inflammation and stroke in this population.