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Discovery & Development Drug Discovery, Vaccines

Searching for a Lassa Fever Vaccine

The World Health Organization has deemed Lassa fever a priority for disease for R&D. Currently, there are no approved vaccines or cures. Many people who are infected with the Lassa virus have no symptoms, but a small percentage develop Lassa fever, which can cause severe disease and death, and long-term complications in survivors.

Researchers from Texas Biomedical Research Institute, the Scripps Research Institute and the National Institute of Allergy and Infectious Diseases (NIAID) have been working to develop a vaccine – with a recent study published in npj Vaccines showing a potential breakthrough. Guinea pigs injected with the experimental vaccine (rLASV/IGR-CD) were 100 percent protected from lethal Lassa virus exposure. We spoke with Juan Carlos de la Torre, professor in the department of immunology and microbiology at Scripps research, and one of the authors of the paper, about the results.

How dangerous is the Lassa virus?
 

Lassa virus (LASV) is endemic to large regions within Western Africa, where it is estimated to cause tens to hundreds of thousands of human infections yearly, resulting in a high number of Lassa fever (LF) cases, a disease associated with high morbidity and a case-fatality rate that can be as high as 60 percent among hospitalized LF patients. A high percentage of people who recover from LF have long-term sequela, which often includes sensorineural hearing loss.

Recent studies indicate that LASV endemic regions are expanding. Increased travel has also led to the importation of LF cases into non-endemic metropolitan areas, as recently illustrated by a fatal case of LF in Iowa, USA, from a patient who returned from a trip to West Africa in 2024. An analysis of risk factors contributing to zoonotic virus spillover and spread in humans ranked LASV as number 1 among the top 50 wildlife viruses.

Why is there no approved vaccine to date?
 

The main obstacles are:

  • Lack of economic incentive for big pharma to dedicate resources to develop a vaccine – for which a return on investment is highly uncertain. 
  • The complications of organizing clinical trials in the LASV endemic regions to test vaccine efficacy.

You’ve been working on a Lassa virus vaccine for 10 years. What first inspired your interest in this area?
 

The focus of our research is the molecular and cell biology of mammarenaviruses (a group of viruses in the Arenaviridae family that mainly infect rodents). We want to understand how mammarenaviruses establish long-term persistent infections in their natural reservoirs in the absence of noticeable clinical symptoms, but upon zoonotic events then have the potential to cause severe disease in humans, such as LF caused by LASV. 

We leverage knowledge from basic science research studies to develop novel therapeutic strategies (both vaccines and antivirals) to combat human pathogenic mammarenaviruses, including LASV.

How has your work advanced over the years and what have been the biggest challenges?
 

Over the last 10 years, we have made significant progress in elucidating several key processes in the molecular and cell biology of mammarenavirus. We have also developed tools and assays that have allowed us to identify several promising antiviral drug candidates to inhibit multiplication of LASV, as well as other hemorrhagic fever causing mammarenaviruses. We have uncovered ways to manipulate the mammarenavirus genome to generate attenuated, and stable, forms of the virus for the development of live-attenuated vaccines (LAV) to prevent Lassa fever. Importantly, similar strategies are likely to work with other human pathogenic mammarenaviruses.

One of the biggest challenges over the years has been securing funding for our research activities. Biosafety level (BSL) 4 facilities are required when working with live LASV, which complicates the logistics and costs of the experimental work. At Texas Biomedical Research Institute and the Integrated Research Facility at Fort Detrick (IRF-Frederick), we are fortunate to have access to high containment BSL4 laboratories to conduct research with viruses responsible for causing hemorrhagic fever disease in humans.  

Tell us about the lead up to this latest work in guinea pigs…
 

We first used a related virus – the lymphocytic choriomeningitis virus (LCMV) – to generate proof of concept results. LCMV and LASV have a similar genome organization, consisting of two segments, called S (for small) and L (for large). We created two recombinant (r) forms of LCMV; one using a weakened glycoprotein in the S segment (rLCMV/GPCCD), and a second containing a modified genome regulatory in the L segment (rLCMV/IGR(S-S)). Both could grow well in Vero cells and were fully attenuated in vivo. They provided complete protection, upon a single administration, against a lethal challenge with wild-type LCMV in a mouse model of LCMV lethal infection. These findings led us to design and execute similar studies with LASV. We developed rLASV/IGR(S-S) or rLASV/GPCCD. Again, we demonstrated high titers in Vero cells, full attenuation in vivo, and protection against a lethal challenge of wild type LASV.

However, further work showed that mice that received (rLCMV/IGR(S-S) and rLCMV/GPCCD developed symptoms of fatal lymphocytic choriomeningitis disease and succumbed to infection. The two versions of the LCMV virus swapped genetic material (reassorted), leading to a virus that resembled the wild-type strain and caused lethal disease.  

These findings, together with documented naturally occurring LASV reassortants and our limited knowledge of LASV ecology, raised the concern that LASV reassortants with increased virulence could emerge in an individual vaccinated with rLASV/IGR(S-S) or rLASV/GPCCD LAV and infected closely in time with a circulating natural LASV strain.

We investigated this issue by generating rLCMV/IGR-CD, which combines the safety features of both. This rLCMV/IGR-CD exhibited excellent safety, protective efficacy, and genetic stability profiles. Importantly, mice co-infected with rLCMV/IGR-CD and either rLCMV/IGR(S-S) or rLCMV/GPCCD did not show clinical symptoms and LCMV reassortants with wild type-like genome organization did not emerge. These findings provided us with the rationale and foundations for the generation and testing of the LASV counterpart: rLASV/IGR-CD. The results we recently published in npj Vaccines strongly support the safety and efficacy of rLASV/IGR-CD as a LAV candidate for LASV.

How did you feel when you saw the results?
 

The results we recently published strongly support the safety and efficacy of rLASV/IGR-CD as a LASV candidate LAV. It was scientifically very satisfying to see how the predictions we had based on our results with LCMV translated very accurately to LASV, supporting the high degree of conservation among mammarenaviruses regarding key aspects of their molecular and cell biology. Our results also demonstrate the value of using LCMV as a BSL2 model system to generate proof of concept principles that can be explored with other mammarenaviruses, including LASV, later at BSL4.

What can you tell us about how the vaccine works?
 

We do not have a complete understanding of the immune mechanisms by which immunization with rLASV/IGR-CD provides full protection against a lethal challenge with wild type LASV. However, based on findings with LCMV, it is likely that CD8 T cell responses play a critical role mediating protection.

What are the next steps?
 

We need to obtain a detailed understanding of the mechanisms of protection, as well as examining whether the current rLASV/IGR-CD can protect against genetically distantly related strains of LASV, or whether a vaccine combination approach will be required to generate a pan-LASV vaccine. Likewise, it would be critically important to assess the durability of the vaccine. We will also be looking to demonstrate the same safety, immunogenicity, stability, and protection efficacy results in a non-human primate model of LF.

What are the other important implications of the work?
 

Our results provide strong support for further studies aimed at developing rLASV/IGR-CD as a LASV live-attenuated vaccine. In addition, it should be noted that research with LASV is currently restricted to BSL4 laboratories to handle live forms of the virus. Biologically contained viruses have been developed for several viruses, but not yet for LASV. Unequivocal evidence that rLASV/IGR-CD could be safely used, upon completion of comprehensive experimental safety testing, without the need of BSL4 containment, will accelerate research on the development of prophylactic and/or therapeutics against LASV. In this regard, studies on LASV involving gain of function represent a biosafety concern that could be addressed using attenuated forms of the virus, such as rLASV-IGR/CD, which are incapable of causing disease.

Why is it so important for pharma companies and government institutions to support vaccines and therapeutics for rare diseases?
 

In addition to their impact on human health, endemic viral infections such as LF, also have a significant negative impact on the economies of the affected regions. Moreover, in the 21st century, infectious diseases are not restricted to localized geographic areas; imported cases of LF have been reported over the years in non-endemic metropolitan areas around the globe. 

We also cannot rule out that viruses may acquire the mutations required for efficient human-to-human transmission while retaining their virulent phenotype, which would make them a global health threat. 

Image credit: NIAID

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About the Author
Stephanie Vine

Making great scientific magazines isn’t just about delivering knowledge and high quality content; it’s also about packaging these in the right words to ensure that someone is truly inspired by a topic. My passion is ensuring that our authors’ expertise is presented as a seamless and enjoyable reading experience, whether in print, in digital or on social media. I’ve spent fourteen years writing and editing features for scientific and manufacturing publications, and in making this content engaging and accessible without sacrificing its scientific integrity. There is nothing better than a magazine with great content that feels great to read.

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