Emerging Infectious Diseases

Lassa fever

Lassa fever is caused by the Lassa virus (LASV), an arenavirus which primarily spreads to humans through contact with the urine or faeces of infected rodents (Mastomys natalensis). Human-to-human transmission can also occur through direct contact with LASV-infected bodily fluids. Symptoms of Lassa fever are non-specific, making it difficult to distinguish from other viral haemorrhagic fevers and febrile diseases such as malaria, typhoid fever and bacterial sepsis.

While the majority of cases of Lassa fever are mild, in severe cases, it may cause facial swelling, fluid in the lung cavity, liver and kidney abnormalities, haemorrhage, and death. Lassa fever is endemic in parts of West Africa including Sierra Leone, Liberia, and Nigeria, where an estimated 100,000 to 300,000 infections and approximately 5,000 deaths occur annually.

Due to a lack of accurate diagnostic tests, Lassa fever often goes undetected. During the 2018 outbreak, for example, an investigation began after reports of a cluster of deaths among healthcare workers from a single facility, revealing nosocomial transmission of LASV as the cause of death – but not until more than two weeks had passed between the index case entering the facility and accurate diagnosis. For LASV, correct and timely detection can single-handedly change the course of an epidemic, especially since early treatment can significantly decrease fatality.

R&D needs

There is currently no approved vaccine for Lassa fever, resulting from the unique challenges Lassa posesgenetic heterogeneity, poorly-understood correlates of infection, the potential for immune-mediated neurological complications, and the requirement of simultaneous cell- and antibody-mediated response for optimal protection. WHO’s Lassa fever vaccine Target Product Profile for preventive use recommends a homologous vaccine which confers protection for at least three years, is safe for healthy adults and children, and provides coverage against Lassa virus lineages I to IV. Three investigational vaccines based on different platforms (DNA, measles virus vector and vesicular stomatitis virus vector) have progressed into clinical trials, but none which meet the requirement for protection across all four lineages.

Easy-to-use diagnostic tests are needed for accurate detection, ideally across the disease spectrum and for multiple lineages. Most available RDTs and immunoassays are limited to research use, while the three existing CE-IVD marked molecular tests require a laboratory with bio-containment capabilities. Zalgen’s commercially-available ReLASV® Antigen Rapid Test underwent field evaluation in 2018, performing better than currently available qPCR tests and signaling a promising advancement in Lassa diagnosis, though one that detects only three of the four known lineages. A novel, species-neutral, Double Antigen Binding Assay was recently found to have detection specificity of 83.3% from oral fluid samples.

Ribavirin, in conjunction with supportive therapy, is the current mainstay of Lassa pre- and post-exposure prophylaxis (PrEP/PEP) treatment, despite inconclusive evidence about its efficacy as PEP. Ribavirin is most effective when given intravenously and within the first six days of illness, leaving an unmet need for a stable oral therapeutic agent, effective against multiple lineages.

There is also a need for more studies on the mechanism of action, indications and optimal routes of administration of the current ribavirin-based treatment, which is backed by only one non-randomised study. A better understanding of ribavirin could open up new avenues for discovering new therapies, including combination treatments with newer candidates.

Pipeline spotlight

In 2021, following positive Phase I trial results, the International AIDS Vaccine Initiative (IAVI) plans to advance its Lassa vaccine candidate, rVSV∆G-LASV-GPC LASV, which is based on FDA approved technology, into Phase IIb clinical trials, making it the most advanced vaccine candidate in the pipeline. In 2021, Kineta Inc also announced positive Phase I trial results for the world’s first oral Lassa virus entry inhibitor LHF-535.