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Table 5 Lassa fever clinical research priorities identified

From: A rapid research needs appraisal methodology to identify evidence gaps to inform clinical research priorities in response to outbreaks—results from the Lassa fever pilot

Clinical phenotype and natural history of disease RRNA Expert panel
 Which are the populations at risk?
 What is the true incidence of asymptomatic infection; is the reported 85% of asymptomatic infections true or is there a diversity of clinical presentation?  
 What are the clinical characteristics of Lassa fever in different at-risk populations?  
 What are the long-term health sequelae and what is their frequency, severity, and duration?
 What are the underlying pathophysiological mechanisms of death and are these preventable e.g. acute kidney injuries? What is the cause of platelet dysfunction in acutely ill Lassa patients?
 What is the clinical and epidemiology relevance of Lassa virus sequence heterogeneity?  
Transmission and prevention
 What are the risks of person-to-person transmission associated with different types of exposure e.g. to what extent and how does human-human transmissions account for disease transmission? What is the risk of transmission from different body fluids and organs?
 Does disease severity vary with route of transmission?  
 Does genetic differences within and between Lassa virus strains results in differences in transmission and in disease phenotype?  
 Who are the target population for a Lassa vaccine, e.g. does asymptomatic infection protect against re-infection? Does presence of antibodies protect from re-infection?
 Does ribavirin PEP reduce the risk of Lassa virus disease, or more severe disease?  
 What is the optimal route and dosing for post-exposure prophylaxis with ribavirin (e.g. oral vs. intravenous)?
 How diverse does a vaccine need to be to protect against all strains of Lassa virus?  
Diagnostics
 Can we develop a diagnostic test that is highly sensitive and specific for all lineages?
 How does sequence variation/heterogeneity impact diagnostic methods and accuracy?  
 What is the optimal sampling time frame for diagnostics using RT-PCR? How many days after symptoms does Lassa virus become detectable by PCR?  
 Can we develop a validated point-of-care test for use in different healthcare settings, including rural health posts?
Immune response
 What are the dynamics of resistance to re-infection? What is the average kinetics of antibody responses following acute Lassa fever virus infection and what is the variability between individuals and by age?
 In what sites and for how long does virus persist? What are the risk factors for virus persistence?  
 Does previous exposure to Lassa virus result in more severe disease upon subsequent re-exposure (e.g. vaccine) as a result of antibody-dependent enhancement of infection, i.e. could a vaccine do harm?  
 What immunological end-points should be used for Lassa virus vaccine trials?  
Drug therapy and supportive care
 What is the true efficacy and safety of ribavirin for the treatment of Lassa? Can we transition acutely ill Lassa patients to oral ribavirin once viral loads are decreasing?
 Does the use of ribavirin in acute Lassa fever virus infection improve clinical outcomes compared to supportive care alone?
 What is the optimal approach to supportive care for acutely ill patients with Lassa and other VHFs?  
 What is the target therapeutic plasma and CSF concentrations of ribavirin for the treatment of Lassa fever virus infection? Do current oral and IV treatment regimens achieve these target concentrations?  
 Can type 1 interferon therapy boost the efficacy of ribavirin? Is there a role for therapies directed at host immunopathology in the management of Lassa fever?  
Risk factors for more severe disease
 Are reported differences in CFR attributable to differences in case mix (e.g. illness severity on presentation to a healthcare facility), differences in the underlying prevalence of risk factors for death, or differences in the care provided?  
 Are there clinical features or biomarkers of the risk of progression to severe disease that have clinical utility?  
 Do genetic differences within and between Lassa strains results in differences in disease phenotype and disease severity?