Bayesian estimation of Lassa virus epidemiological parameters: implications for spillover prevention using wildlife vaccination
Scott L. NuismerChristopher H. RemienAndrew J. BasinskiTanner J. VarrelmanNathan C. LaymanKyle RosenkeBrian H. BirdMichael A. JarvisPeter A. BarryElisabeth Fichet‐Calvet
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Abstract Lassa virus is a significant burden on human health throughout its endemic region in West Africa, with most human infections the result of spillover from the primary rodent reservoir of the virus, the natal multimammate mouse, M. natalensis . Here we develop a Bayesian methodology for estimating epidemiological parameters of Lassa virus within its rodent reservoir and for generating probabilistic predictions for the efficacy of rodent vaccination programs. Our approach uses Approximate Bayesian Computation (ABC) to integrate mechanistic mathematical models, remotely-sensed precipitation data, and Lassa virus surveillance data from rodent populations. Using simulated data, we show that our method accurately estimates key model parameters, even when surveillance data are available from only a relatively small number of points in space and time. Applying our method to previously published data from two villages in Guinea estimates the time-averaged R 0 of Lassa virus to be 1.658 and 1.453 for rodent populations in the villages of Bantou and Tanganya, respectively. Using the posterior distribution for model parameters derived from these Guinean populations, we evaluate the likely efficacy of vaccination programs relying on distribution of vaccine-laced baits. Our results demonstrate that effective and durable reductions in the risk of Lassa virus spillover into the human population will require repeated distribution of large quantities of vaccine. Author Summary Lassa virus is a chronic source of illness throughout West Africa, and is considered to be a threat for widespread emergence. Because most human infections result from contact with infected rodents, interventions that reduce the number of rodents infected with Lassa virus represent promising opportunities for reducing the public health burden of this disease. Evaluating how well alternative interventions are likely to perform is complicated by our relatively poor understanding of viral epidemiology within the reservoir population. Here we develop a novel statistical approach that couples mathematical models and viral surveillance data from rodent populations to robustly estimate key epidemiological parameters. Applying our method to existing data from Guinea yields well-resolved parameter estimates and allows us to simulate a variety of rodent vaccination programs. Together, our results demonstrate that rodent vaccination alone is unlikely to be an effective tool for reducing that public health burden of Lassa fever within West Africa.Keywords:
Lassa fever
Lassa virus
Spillover effect
Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesis in humans and relevant animal models. Advancing knowledge significantly improves our understanding of Lassa virus biology, as well as of the mechanisms that allow the virus to evade the host’s immune system. However, further investigations are required in order to design improved diagnostic tools, an effective vaccine, and therapeutic agents.
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Abstract Lassa virus, a member of the Arenaviridae family, is an enveloped virus with a bisegmented, linear, single‐stranded ribonucleic acid genome. Infection with Lassa virus can result in a range of outcomes from a mild or asymptomatic infection to Lassa fever, a severe and often fatal viral haemorrhagic fever. Human infection with Lassa virus occurs through contact with the reservoir Mastomys natalensis or infected humans. There are an estimated 300 000–500 000 cases of Lassa fever in West Africa each year, with most recorded cases occurring in Sierra Leone and Nigeria. Presently, there is no licensed vaccine or immunotherapy available for preventing or treating this disease. Although the antiviral drug ribavirin can be beneficial, it must be administered at an early stage of infection to successfully alter the disease outcome, thereby limiting its utility. Key Concepts: Lassa virus, a member of the Arenaviridae family, is the aetiologic agent of Lassa fever. Infection with Lassa virus can result in a range of outcomes from a mild or asymptomatic infection to severe and often fatal viral haemorrhagic fever. Signs and symptoms of Lassa fever are highly variable, which challenges early diagnosis. Lassa virus has an enveloped virion with a bisegmented, linear, single‐stranded ribonucleic acid genome. The Lassa virus virion contains nucleoprotein NP, zinc protein Z, glycoproteins GP1 and GP2 and an unusually long and stable signal peptide SSP. Human infection with Lassa virus occurs through contact with its reservoir Mastomys natalensis or infected humans. An estimated 300 000–500 000 cases of Lassa fever occur in West Africa each year, with most recorded cases occurring in Sierra Leone and Nigeria. No licensed vaccine or immunotherapy is presently available for preventing or treating Lassa fever. The antiviral drug ribavirin can be beneficial, but must be administered early, limiting its utility.
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Arenaviruses are segmented negative-sense RNA (nsRNA) viruses that are closely related to those of the Bunyaviridae and Orthomyxoviridae families. The Lassa Virus (LASV), the agent of Lassa illness, is a member of the family Arenaviridae. LASV was first identified in 1969 by a missionary nurse working at a clinic in a small community named Lassa in northern Nigeria. She had likely got contact with the virus from a LASSA-based infection of an obstetrical patient and had died within a week following the onset of her symptoms1. One of the nurses who had treated the first patient also contracted what would later become Lassa fever and died. It is estimated that between 100 000 and 300 000 people were infected with LASV annually, leading to roughly 5000 deaths. The reservoir rodent, Mastomys natalensis, may be found all over West Africa and is responsible for the spread of the LASV. Human infections have been confirmed through serology in the countries of Senegal, Guinea, Sierra Leone, Liberia, and Nigeria (Figs. 1 and 2). From the late 1970s until the early 1990s, eastern Sierra Leone was host to the sole long-term investigation of Lassa disease in all of West Africa. After repeated requests from the government of Sierra Leone to research epidemics in the eastern province, the Centers for Disease Control and Prevention (CDC) developed and funded the project2.Figure 1: Lassa fever recorded cases from 1969 to 2022.Figure 2: Spread of LASSA Fever 1969–2022.The clinical presentation, epidemiology, immunology, pathophysiology, and treatment of Lassa fever have all been elucidated throughout the years. Not only have war and social unrest over the past decade hampered ongoing research and prevented new ones from taking place, but they have also likely contributed to a rise in disease rates in these places. Between 7 and 21 days is the incubation period for Lassa fever3. The initial stages of the clinical sickness are similar to the flu, including high fever, overall weakness and overall lethargy, sore throat, cough, and severe headache. Nausea, vomiting, and diarrhea are among the common gastrointestinal symptoms that may appear early on. Despite the absence of major hemorrhagic signs, vascular dysfunction is believed to be an important part of the pathobiology of Lassa fever given its association with a dismal prognosis4. Facial edema, pleural effusions, and pericardial effusions are all symptoms of a vascular permeability problem5. Lassa fever patients typically begin to feel better 8–10 days after becoming unwell6. In extreme cases, between the 6th and 10th day of the sickness, the patient’s health rapidly deteriorates with significant pulmonary edema, acute respiratory distress, encephalopathy signs, and fatal shock. Despite being common, mucosal surface bleeding seldom causes shock. sensorineural deafness is common in severe disease or early recovery7. Arenaviridae virus Lassa is encapsulated, single-stranded, bi-segmented RNA. LASV, like other arenaviruses, lacks negative-strand coding and the virus isolates varied genetically, serologically, and pathologically. LASV is spherical and 70–150 nm wide, glycoprotein-built T-shaped spikes measure 7–10 nm on its smooth surface envelope. The single-stranded arenavirus genome has two RNA fragments, respectively. The sRNA encodes the viral glycoprotein precursor protein (GPC) and nucleoprotein (NP), while the lRNA encodes the viral polymerase and a tiny, zinc-binding (Z) protein28. New full-length sRNA amplification methods aid arenavirus identification and molecular analysis29. LASV sRNA sequencing identified and molecularly characterized four strains. Sequencing of LASV sRNA showed a lot of genomic diversity1. It can be speculated from the available data (data acquired from the CDC) that the spread of LASSA is unusual and mostly in the first six months of the year (Table 1)8. According to the climatology reports9, the temperature between December to June is 26.9–31⁰C. The temperature could be a factor; however, more research should be done to better understand this. Virus isolation is the best LASV diagnostic method, but BSL-4 biocontainment makes it unfeasible in endemic areas. ELISA or RT-PCR are the most frequent methods for detecting viral proteins or LASV-specific IgM or IgG antibodies. The immunofluorescence assay (IFA) was utilized to detect LASV antibodies; however, it required BSL-4 biocontainment, highly trained workers, and low sensitivity. Clinical and laboratory use persists. In an orthogonal diagnostic system, PCR-based molecular assays like RT-PCR give the most confidence in results10. Due to the genetic heterogeneity in LASV strains throughout a wide geographic area, primer and probe failures are more likely in PCR-based experiments. Most assays target the short RNA that encodes the GPC precursor and NP. Because LASV-specific IgG is produced later in the infection, this assay is limited in patient diagnosis11. LASV diagnostics should be simple, robust, sensitive, and affordable, considering LASV lineage genetic and geographical variability. Diagnostic advances in LASSA fever will improve treatment, control, and prevention in endemic areas. Point-of-care immunological and/or PCR-based assay equipment will soon bring diagnostics to patients to improve treatment decisions and patient outcomes. LASV antibody frequency in known and potential endemic places will improve risk maps. Metagenomics in outbreaks and rodent reservoir hosts will enhance LASV eco-epidemiology the most. This method could answer issues about LASV incidence, transmission bottlenecks, and reservoir host virus variety. Our defense against emerging and re-emerging viruses like LASV will involve a better understanding of the virus circulating in the environment, sickness in humans, and virus maintenance in rodent reservoir hosts. Diagnostics are best for LASSA fever prevention today and in the future. Table 1 - Places of origin and places where it spread between 1969 and 2022. Place of origin Places affected Recorded year Country Continent Country Continent Estimated month of infection 1969 Nigeria Africa United States North America 1971 Sierra Leone Africa United Kingdom Europe 1971 Sierra Leone Africa United Kingdom Europe 1972 Sierra Leone Africa United Kingdom Europe 1974 Nigeria Africa Germany Europe 1975 Nigeria Africa United Kingdom Europe 1975 Sierra Leone Africa United States North America March 1976 Sierra Leone Africa United States North America February 1976 Nigeria Africa United Kingdom Europe December 1980 Upper Volta Africa Netherlands Europe 1981 Nigeria Africa United Kingdom Europe 1982 Nigeria Africa United Kingdom Europe 1984 Sierra Leone Africa United Kingdom Europe 1985 Sierra Leone Africa United Kingdom Europe 1987 Liberia Africa Israel 1987 Sierra Leone Africa Japan Asia 1989 Nigeria Africa Canada North America 1989 Nigeria Africa United States North America 1994 Nigeria Africa Sierra Leone Africa 2000 Ghana/Burkina Faso/Cote d voire Africa Germany Europe 2000 Sierra Leone Africa United Kingdom Europe 2000 Nigeria Africa Germany Europe 2000 Sierra Leone Africa Netherlands Europe 2003 Sierra Leone Africa United Kingdom Europe 2004 Sierra Leone Africa United States North America March 2006 Africa Germany Europe June 2012 Nigeria Africa Nigeria Europe April 2015 Africa United States North America May 2016 Nigeria Africa Nigeria Africa May 2016 Benin Africa Benin Africa May 2016 Togo Africa Togo Africa January 2016 Africa Germany Europe February 2016 Africa Sweden Europe March 2016 Liberia Africa Liberia Africa March 2016 Burkina Faso Africa Burkina Faso Africa April 2016 Nigeria Africa Nigeria Africa April 2016 Benin Africa Benin Africa May 2017 Benin Africa Benin Africa March 2017 Togo Africa Togo Africa March 2017 Burkina Faso Africa Burkina Faso Africa March 2017 Nigeria Africa Nigeria Africa June 2018 Nigeria Africa Nigeria Africa June 2019 Nigeria Africa Nigeria Africa February 2021 Nigeria Africa Nigeria Africa March 2021 Liberia Africa Liberia Africa June 2021 Nigeria Africa United Kingdom Europe June 2021 Nigeria Africa Netherlands Europe June 2021 Sierra Leone Africa Germany Europe June 2021 Sierra Leone Africa Sierra Leone Africa June 2022 Nigeria Africa Nigeria Africa June 2022 Nigeria Africa United Kingdom Europe June 2022 Sierra Leone Africa Ireland Europe February 2022 Togo Africa Togo Africa February 2022 Guinea Africa Guinea Africa February 2022 Sierra Leone Africa Netherlands Europe March 2022 Sierra Leone Africa Sierra Leone Africa May According to the findings of an intriguing new paper, there might be a connection between the etiology of human odontogenic tumors and arenavirus infection12,13. This publication acts as both a catalyst and a call to action for future research into the role that the virus plays in the development of tumors. On the other hand, a number of studies have found evidence that the virus inhibits the growth of cancerous cells. For example, the Lassa-vesicular stomatitis chimeric virus is able to successfully eradicate brain tumors without causing any harm. In point of fact, the expressional pathway analysis indicated a common link between the pathogenesis of Lassa fever and carcinogenesis. Furthermore, it has been established that the anticancer treatment is efficient in preventing the entry of the LASV into cells14. Due to this, additional study in clinical medicine is still required in order to understand the precise nature of the relationship between the LASV and the tumor. Ethical approval Ethics approval was not required for this correspondence. Consent Informed consent was not required for this correspondence. Sources of funding Not applicable. Author contribution J.A. and M.A.B.: conceptualization; M.S. and M.M.: investigation; M.M., M.S., and J.A.: writing original draft; M.B.: writing review and editing; J.A.: supervision. Conflicts of interest disclosures The authors declare no conflicts of interest. Research registration unique identifying number (UIN) Not applicable. Guarantor Melaku Ashagrie Belete. Data availability statement Not applicable.
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Lassa fever is an acute immunosuppressive illness of increasing public health concern causing severe morbidity and significant mortality especially in epidemic cases. Lassa fever is an acute viral zoonotic illness caused by Lassa virus, an arenavirus known to be responsible for a severe haemorrhagic fever characterised by fever, muscle aches, sore throat, nausea, vomiting, chest and abdominal pain. The virus exhibits persistent, asymptomatic infection with profuse urinary virus excretion in the ubiquitous rodent vector, Mastomys natalensis. Lassa fever is endemic in West Africa and has been reported from Sierra Leone, Guinea, Liberia, and Nigeria. The virus replicates through a strategy known as the Ambisense, where two RNA strands code for genes in both the sense and antisense direction that is rapid and demonstrate temporal control in replication. Different diagnostic tests for the virus are available, which range from viral culture to serological and molecular diagnostic tests. There is an urgent need to develop drugs and vaccines against the virus because the World Health Organization (WHO) has identified Lassa virus as one of the viruses that is likely to cause a future epidemic, although a research is ongoing to evaluate Lassa virus vaccine immunogenicity in the CBA/J-ML29 mouse model. This review gives an overview on the structure, replication cycle, pathogenesis and diagnosis of the virus. Keywords: Lassa fever, Lassa virus, Arenavirus, Replication, Pathogenesis, Diagnosis
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Lassa Virus, a member of Arenaviridae family causes Lassa fever which is a hemorrhagic disease with symptoms of fever, weakness, nausea, muscular pain, and vomiting with mucosal bleeding. Lassa fever is endemic in Nigeria, Sierra Leone, Guinea, and Liberia, covering majorly the parts of West Africa which have a large population of Mastomys natalensis (rodents that colonize near human homes), a natural host of this virus. Human transmission of this virus is mostly by contact with the contaminated urine or feces of the Mastomys rats, or direct contact with the patient. It is spherical in shape with an envelope of glycoprotein encapsulating the bisegmented single-stranded RNA material. This viral infection is susceptible to all age groups with around 80% of nonsymptomatic patients and has an estimated case fatality of approximately 15%. There are several complications associated with Lassa virus infection; the most recurrent is deafness. There are various measures taken to avoid the spread of infection namely wearing gloves, goggles, or gowns. Although scientists are working on developing vaccines effective against the virus with many at the step of animal trials, no vaccine is fully approved and developed, leaving hygiene and safety precautions as the main preventive measures from the Lassa Fever Virus.
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Lassa fever is an acute viral disease caused by Lassa virus(LASV). The virus is mainly transmitted to humans by a rodent reservoir, Mastomys natalensis. The infection is endemic in West African countries, resulting in hundreds of thousands of cases annually, and causing approximately thousands of deaths each year. Due to its high pathogenicity, LASV is recognized as a potential agent of bio-warfare. Currently, there are no licensed vaccines for Lassa fever. Studies have shown that the vaccine prepared by in-activated LASV is not ideal for eliciting a protective immune response. Recently, several promising vaccine candidates against Lassa fever have been developed, such as replication-competent virus-vectored vaccines, replication-deficient virus-vectored vaccines and DNA vaccines. However, these novel types of vaccine candidates against Lassa fever remain to be pre-clinically and/or clinically evaluated.
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A Lassa fever outbreak in Nigeria and neighbouring nations has caused concern among World Health Organization officials about the speed of its spread.
Lassa virus is a haemorrhagic fever similar to Ebola that spikes every year in west Africa from December to April. Last year’s outbreak was unusually deadly, claiming 171 lives, and in the first weeks of 2019 the confirmed cases climbed even more quickly.
Six weeks into the outbreak the number …
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Lassa fever is an acute febrile disease of West Africa, where there are as many as 300,000 infections a year and an estimated 3000 deaths. As control of the rodent host is impracticable at present, the best immediate prospect is vaccination. We tested as potential vaccines in rhesus monkeys a closely related virus, Mopeia virus (two monkeys), and a recombinant vaccinia virus containing the Lassa virus glycoprotein gene, V-LSGPC (four monkeys). Two monkeys vaccinated with the New York Board of Health strain of vaccinia virus as controls died after challenge with Lassa virus. The two monkeys vaccinated with Mopeia virus developed antibodies measurable by radioimmunoprecipitation prior to challenge, and they survived challenge by Lassa virus with minimal physical or physiologic disturbances. However, both showed a transient, low-titer Lassa viremia. Two of the four animals vaccinated with V-LSGPC had antibodies to both Lassa glycoproteins, as determined by radioimmunoprecipitation. All four animals survived a challenge of Lassa virus but experienced a transient febrile illness and moderate physiologic changes following challenge. Virus was recoverable from each of these animals, but at low titer and only during a brief period, as observed for the Mopeia-protected animals. We conclude that V-LSGPC can protect rhesus monkeys against death from Lassa fever.
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