A systematic review of the clinical profile of patients with bubonic plague and the outcome measures used in research settings.

BACKGROUND: Plague is a zoonotic disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. Drugs that are currently recommended in treatment guidelines have been approved based on animal studies alone-no pivotal clinical trials in humans have yet been completed. As a result of the sparse clinical research attention received, there are a number of methodological challenges that need to be addressed in order to facilitate the collection of clinical trial data that can meaningfully inform clinicians and policy-makers. One such challenge is the identification of clinically-relevant endpoints, which are informed by understanding the clinical characterisation of the disease-how it presents and evolves over time, and important patient outcomes, and how these can be modified by treatment. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review aims to summarise the clinical profile of 1343 patients with bubonic plague described in 87 publications, identified by searching bibliographic databases for studies that meet pre-defined eligibility criteria. The majority of studies were individual case reports. A diverse group of signs and symptoms were reported at baseline and post-baseline timepoints-the most common of which was presence of a bubo, for which limited descriptive and longitudinal information was available. Death occurred in 15% of patients; although this varied from an average 10% in high-income countries to an average 17% in low- and middle-income countries. The median time to death was 1 day, ranging from 0 to 16 days. CONCLUSIONS/SIGNIFICANCE: This systematic review elucidates the restrictions that limited disease characterisation places on clinical trials for infectious diseases such as plague, which not only impacts the definition of trial endpoints but has the knock-on effect of challenging the interpretation of a trial's results. For this reason and despite interventional trials for plague having taken place, questions around optimal treatment for plague persist.

Seroepidemiology of Lassa virus in pregnant women in Southern Nigeria: A prospective hospital-based cohort study.

BACKGROUND: There is limited epidemiological evidence on Lassa fever in pregnant women with acute gaps on prevalence, infection incidence, and risk factors. Such evidence would facilitate the design of therapeutic and vaccine trials and the design of control programs. Our study sought to address some of these gaps by estimating the seroprevalence and seroconversion risk of Lassa fever in pregnant women. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a prospective hospital-based cohort between February and December 2019 in Edo State, Southern Nigeria, enrolling pregnant women at antenatal clinic and following them up at delivery. Samples were evaluated for IgG antibodies against Lassa virus. The study demonstrates a seroprevalence of Lassa IgG antibodies of 49.6% and a seroconversion risk of 20.8%. Seropositivity was strongly correlated with rodent exposure around homes with an attributable risk proportion of 35%. Seroreversion was also seen with a seroreversion risk of 13.4%. CONCLUSIONS/SIGNIFICANCE: Our study suggests that 50% of pregnant women were at risk of Lassa infection and that 35.0% of infections might be preventable by avoiding rodent exposure and conditions which facilitate infestation and the risk of human-rodent contact. While the evidence on rodent exposure is subjective and further studies are needed to provide a better understanding of the avenues of human-rodent interaction; public health measures to decrease the risk of rodent infestation and the risk of spill over events may be beneficial. With an estimated seroconversion risk of 20.8%, our study suggests an appreciable risk of contracting Lassa fever during pregnancy and while most of these seroconversions may not be new infections, given the high risk of adverse outcomes in pregnancy, it supports the need for preventative and therapeutic options against Lassa fever in pregnancy. The occurrence of seroreversion in our study suggests that the prevalence obtained in this, and other cohorts may be an underestimate of the actual proportion of women of childbearing age who present at pregnancy with prior LASV exposure. Additionally, the occurrence of both seroconversion and seroreversion in this cohort suggests that these parameters would need to be considered for the development of Lassa vaccine efficacy, effectiveness, and utility models.

Transplacental transfer of Lassa IgG antibodies in pregnant women in Southern Nigeria: A prospective hospital-based cohort study.

BACKGROUND: Evidence from previous studies suggest that Lassa fever, a viral haemorrhagic fever endemic to West Africa has high case fatalities, particularly in pregnancy. While there have been remarkable innovations in vaccine development, with some Lassa vaccines undergoing early clinical trials. An understanding of Lassa antibody kinetics and immune responses will support vaccine design and development. However, there is currently no evidence on the antibody kinetics of Lassa (LASV) in pregnancy. Our study sought to estimate the efficiency of transplacental transfer of LASV IgG antibodies from the mother to the child. METHODOLOGY/PRINCIPAL FINDINGS: The study made use of data from a prospective hospital-based cohort of pregnant women enrolled at the antenatal clinic and followed up at delivery between February and December 2019. Blood samples from mother-child pairs were evaluated for antibodies against Lassa virus. The study demonstrates a transplacental transfer of LASV IgG of 75.3% [60.0-94.0%], with a significant positive correlation between maternal and cord concentrations and a good level of agreement. The study also suggests that transfer may be more variable in women with 'de novo' antibodies compared to those with pre-existing antibodies. CONCLUSIONS/SIGNIFICANCE: The study shows that maternal antibody levels play an important role in determining transfer efficiency of Lassa antibodies to the new-born; and while the evidence is preliminary, the study also suggests that transfer efficiency may be less stable in acute or recent infection, as such timing of vaccination before pregnancy, that is in women of childbearing age may be more appropriate for protection of both pregnant women and their neonates.

A standardised Phase III clinical trial framework to assess therapeutic interventions for Lassa fever.

BACKGROUND: Only one recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care. This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago-the methodology and results of which have recently come under scrutiny. The requirement for novel therapeutics and reassessment of ribavirin is therefore urgent. However, a significant amount of work now needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence. METHODOLOGY: We convened a consultation group to establish the position of clinicians and researchers on the core components of future trials. A Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV) were developed through the process of a multi-stakeholder consultation that took place using a modified-Delphi methodology. RESULTS: A consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future LF clinical trials. The framework consists of 8 core criteria, as well as additional considerations for trial protocols. CONCLUSIONS: This project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement. Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level.

Clinical REsearch During Outbreaks (CREDO) Training for Low- and Middle-Income Countries.

We describe a pilot of the Clinical REsearch During Outbreaks (CREDO) initiative, a training curriculum for researchers in epidemic-prone low- and middle-income countries who may respond to disease outbreaks. Participants reported improved confidence in their ability to conduct such research and overall satisfaction with the course structure, content, and training.