Deciphering the enigma of Lassa virus transmission dynamics and strategies for effective epidemic control through awareness campaigns and rodenticides.

This study aims to formulate a mathematical framework to examine how the Lassa virus spreads in humans of opposite genders. The stability of the model is analyzed at an equilibrium point in the absence of the Lassa fever. The model's effectiveness is evaluated using real-life data, and all the parameters needed to determine the basic reproduction number are estimated. Sensitivity analysis is performed to pinpoint the crucial parameters significantly influencing the spread of the infection. The interaction between threshold parameters and the basic reproduction number is simulated. Control theory is employed to devise and evaluate strategies, such as awareness campaigns, advocating condom usage, and deploying rodenticides to reduce the possibility of virus transmission efficiently.

Double stigma: a cross-sectional study of Lassa patients with hearing loss in North Central Nigeria.

Introduction: Lassa fever is a zoonotic infectious disease endemic in West Africa with a high case-fatality rate and reported stigmatization of surviving patients. This study examines discrimination among survivors of Lassa fever (LF) complicated by hearing loss (HL). Methods: This cross-sectional qualitative study used an in-depth interview guide to collect information from patients with HL about their experience of stigma. Interviews were conducted by a trained team of interviewers at the Jos University Teaching Hospital between January and April 2022 in Hausa language after informed consent was obtained. Recordings of the interviews were transcribed and translated from Hausa to English. Data analysis was conducted using NVivo software using a thematic framework approach. Results: Most (73%) respondents were male (n = 11); 27% were female (n = 4). The median age was 35 years (interquartile range, 16.5). Some Lassa fever patients experienced stigma and discrimination (53%) including isolation and withdrawal of family and community support during and after illness. HL increased stigma, as some patients were labeled "deaf" by other community members, increasing perceived stigma and devaluation. HL affected the socio-economic wellbeing of some who could not communicate well with their families and customers and constrained social interactions, evoking pain and apathy. Some survivors of LF and victims of its sequelae of HL experienced double stigmatization. While they were ill with LF, a third of respondents reported avoidance and isolation by family and community members who withdrew care and support both to them and their close family members. These forms of stigmatization strained their relationships. Conclusion: There is a need to address stigma in LF survivors who develop HL through concerted community-owned awareness to improve their quality of life along with a robust social support system to aid prevention.

Modelling Lassa virus dynamics in West African Mastomys natalensis and the impact of human activities.

Lassa fever is a West African rodent-borne viral haemorrhagic fever that kills thousands of people a year, with 100 000 to 300 000 people a year probably infected by Lassa virus (LASV). The main reservoir of LASV is the Natal multimammate mouse, Mastomys natalensis. There is reported asynchrony between peak infection in the rodent population and peak Lassa fever risk among people, probably owing to differing seasonal contact rates. Here, we developed a susceptible-infected-recovered ([Formula: see text])-based model of LASV dynamics in its rodent host, M. natalensis, with a persistently infected class and seasonal birthing to test the impact of changes to seasonal birthing in the future owing to climate and land use change. Our simulations suggest shifting rodent birthing timing and synchrony will alter the peak of viral prevalence, changing risk to people, with viral dynamics mainly stable in adults and varying in the young, but with more infected individuals. We calculate the time-average basic reproductive number, [Formula: see text], for this infectious disease system with periodic changes to population sizes owing to birthing using a time-average method and with a sensitivity analysis show four key parameters: carrying capacity, adult mortality, the transmission parameter among adults and additional disease-induced mortality impact the maintenance of LASV in M. natalensis most, with carrying capacity and adult mortality potentially changeable owing to human activities and interventions.

A systematic review of mathematical models of Lassa fever.

This systematic review, conducted following the PRISMA guidelines, scrutinizes mathematical models employed in the study of Lassa fever. The analysis revealed the inherent heterogeneity in both models and data, posing significant challenges to parameter estimation. While health and behavioral interventions exhibit promise in mitigating the disease's spread, their efficacy is contingent upon contextual factors. Identified through this review are critical gaps, limitations, and avenues for future research, necessitating increased harmonization and standardization in modeling approaches. The considerations of seasonal and spatial variations emerge as crucial elements demanding targeted investigation. The perpetual threat of emerging diseases, coupled with the enduring public health impact of Lassa fever, underscores the imperative for sustained research endeavors and investments in mathematical modeling. The conclusion underscored that while mathematical modeling remains an invaluable tool in the combat against Lassa fever, its optimal utilization mandates multidisciplinary collaboration, refined data collection methodologies, and an enriched understanding of the intricate disease dynamics. This comprehensive approach is essential for effectively reducing the burden of Lassa fever and safeguarding the health of vulnerable populations.

Potent immunogenicity and protective efficacy of a multi-pathogen vaccination targeting Ebola, Sudan, Marburg and Lassa viruse.

Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused substantial morbidity and mortality in West and Central Africa. In 2022, an Ebola disease outbreak in Uganda caused by Sudan virus resulted in 164 cases with 55 deaths. In 2023, a Marburg disease outbreak was confirmed in Equatorial Guinea and Tanzania resulting in over 49 confirmed or suspected cases; 41 of which were fatal. There are no clearly defined correlates of protection against these VHF, impeding targeted vaccine development. Any vaccine developed should therefore induce strong and preferably long-lasting humoral and cellular immunity against these viruses. Ideally this immunity should also cross-protect against viral variants, which are known to circulate in animal reservoirs and cause human disease. We have utilized two viral vectored vaccine platforms, an adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA), to develop a multi-pathogen vaccine regime against three filoviruses (Ebola virus, Sudan virus, Marburg virus) and an arenavirus (Lassa virus). These platform technologies have consistently demonstrated the capability to induce robust cellular and humoral antigen-specific immunity in humans, most recently in the rollout of the licensed ChAdOx1-nCoV19/AZD1222. Here, we show that our multi-pathogen vaccines elicit strong cellular and humoral immunity, induce a diverse range of chemokines and cytokines, and most importantly, confers protection after lethal Ebola virus, Sudan virus and Marburg virus challenges in a small animal model.

Identification of a macrocyclic compound targeting the lassa virus polymerase.

There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.

Analysing the association between perceived knowledge, and attitudes on Lassa Fever infections and mortality risk factors in lower Bambara Chiefdom.

BACKGROUND: Lassa fever (LF) presents significant public health challenges in Sierra Leone, particularly in the Lower Bambara Chiefdom. This study aims to deeply understand how knowledge and attitudes towards LF correlate with community-driven prevention and control measures. METHODS: A descriptive cross-sectional quantitative approach was used to conduct the research. Data from 2167 participants were collected using an Android-based survey from 1st February 2022 to 14th February 2022. Respondents' knowledge of LF causes, risk factors, transmission modes, and preventive measures were evaluated through a multiple-choice questionnaire, and attitudes toward prevention and control were measured on a 5-point Likert scale. Quantitative data were analyzed using SPSS version 26.0 and frequencies were presented in count, percentage, and table. Chi-square statistics were used to test for associations. RESULTS: Among the 2167 participants, over half were males (1184, 54.60%), farmers (1406, 64.90%), married (monogamous) (1428, 65.90%), and had never attended school (1336, 61.70%). Respondents demonstrated high knowledge levels of LF across socio-demographic groups (33% to 100%) and shared a positive attitude towards prevention and control (mean score of 26.77 on a 5-40 scale). Educational level, religious beliefs, and occupational status significantly influenced LF knowledge (p < 0.05). Specifically, illiterates had a high knowledge score of 48.24%, while those with tertiary education had the highest score at 83.33%. Additionally, a Pearson correlation analysis revealed a positive linear relationship between the degree of knowledge and positive attitude towards LF infection and mortality risk factors (r = 0.090, p = 0.02). CONCLUSION: High LF knowledge in Lower Bambara Chiefdom positively influences prevention attitudes. Education, religion, and occupation are key factors. Tailored interventions enhance public health efforts.

Hexestrol, an estrogen receptor agonist, inhibits Lassa virus entry.

Lassa virus (LASV) is the causative agent of human Lassa fever which in severe cases manifests as hemorrhagic fever leading to thousands of deaths annually. However, no approved vaccines or antiviral drugs are currently available. Recently, we screened approximately 2,500 compounds using a recombinant vesicular stomatitis virus (VSV) expressing LASV glycoprotein GP (VSV-LASVGP) and identified a P-glycoprotein inhibitor as a potential LASV entry inhibitor. Here, we show that another identified candidate, hexestrol (HES), an estrogen receptor agonist, is also a LASV entry inhibitor. HES inhibited VSV-LASVGP replication with a 50% inhibitory concentration (IC50) of 0.63 µM. Importantly, HES also inhibited authentic LASV replication with IC50 values of 0.31 µM-0.61 µM. Time-of-addition and cell-based membrane fusion assays suggested that HES inhibits the membrane fusion step during virus entry. Alternative estrogen receptor agonists did not inhibit VSV-LASVGP replication, suggesting that the estrogen receptor itself is unlikely to be involved in the antiviral activity of HES. Generation of a HES-resistant mutant revealed that the phenylalanine at amino acid position 446 (F446) of LASVGP, which is located in the transmembrane region, conferred resistance to HES. Although mutation of F446 enhanced the membrane fusion activity of LASVGP, it exhibited reduced VSV-LASVGP replication, most likely due to the instability of the pre-fusion state of LASVGP. Collectively, our results demonstrated that HES is a promising anti-LASV drug that acts by inhibiting the membrane fusion step of LASV entry. This study also highlights the importance of the LASVGP transmembrane region as a target for anti-LASV drugs.IMPORTANCELassa virus (LASV), the causative agent of Lassa fever, is the most devastating mammarenavirus with respect to its impact on public health in West Africa. However, no approved antiviral drugs or vaccines are currently available. Here, we identified hexestrol (HES), an estrogen receptor agonist, as the potential antiviral candidate drug. We showed that the estrogen receptor itself is not involved in the antiviral activity. HES directly bound to LASVGP and blocked membrane fusion, thereby inhibiting LASV infection. Through the generation of a HES-resistant virus, we found that phenylalanine at position 446 (F446) within the LASVGP transmembrane region plays a crucial role in the antiviral activity of HES. The mutation at F446 caused reduced virus replication, likely due to the instability of the pre-fusion state of LASVGP. These findings highlight the potential of HES as a promising candidate for the development of antiviral compounds targeting LASV.

An mRNA-LNP-based Lassa virus vaccine induces protective immunity in mice.

The mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV underscores the urgent need for the development of novel LASV vaccines, which has been hampered by the requirement for a biosafety level 4 facility to handle live LASV. Here, we investigated the efficacy of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), in mice. Two doses of LASgpc- or LCMnp-mRNA-LNP administered intravenously (i.v.) protected C57BL/6 mice from a lethal challenge with a recombinant (r) LCMV expressing a modified LASgpc (rLCMV/LASgpc2m) inoculated intracranially. Intramuscular (i.m.) immunization with two doses of LASgpc- or LCMnp-mRNA-LNP significantly reduced the viral load in C57BL/6 mice inoculated i.v. with rLCMV/LASgpc2m. High levels of viremia and lethality were observed in CBA mice inoculated i.v. with rLCMV/LASgpc2m, which were abrogated by i.m. immunization with two doses of LASgpc-mRNA-LNP. The protective efficacy of two i.m. doses of LCMnp-mRNA-LNP was confirmed in a lethal hemorrhagic disease model of FVB mice i.v. inoculated with wild-type rLCMV. In all conditions tested, negligible and high levels of LASgpc- and LCMnp-specific antibodies were detected in mRNA-LNP-immunized mice, respectively, but robust LASgpc- and LCMnp-specific CD8+ T cell responses were induced. Accordingly, plasma from LASgpc-mRNA-LNP-immunized mice did not exhibit neutralizing activity. Our findings and surrogate mouse models of LASV infection, which can be studied at a reduced biocontainment level, provide a critical foundation for the rapid development of mRNA-LNP-based LASV vaccines.IMPORTANCELassa virus (LASV) is a highly pathogenic mammarenavirus responsible for several hundred thousand infections annually in West African countries, causing a high number of lethal Lassa fever (LF) cases. Despite its significant impact on human health, clinically approved, safe, and effective medical countermeasures against LF are not available. The requirement of a biosafety level 4 facility to handle live LASV has been one of the main obstacles to the research and development of LASV countermeasures. Here, we report that two doses of mRNA-lipid nanoparticle-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of lymphocytic choriomeningitis virus (LCMV), a mammarenavirus genetically closely related to LASV, conferred protection to recombinant LCMV-based surrogate mouse models of lethal LASV infection. Notably, robust LASgpc- and LCMnp-specific CD8+ T cell responses were detected in mRNA-LNP-immunized mice, whereas no virus-neutralizing activity was observed.

A novel BSL-2 Lassa virus reverse genetics system modelling the complete viral life cycle.

Lassa virus (LASV), a risk-group 4 pathogen, must be handled in biosafety level-4 (BSL-4) conditions, thereby limiting its research and antiviral development. Here, we developed a novel LASV reverse genetics system which, to our knowledge, is the first to study the complete LASV life cycle under BSL-2 conditions. Viral particles can be produced efficiently when LASV minigenomic RNA harbouring minimal viral cis-elements and reporter genes is transfected into a helper cell line stably expressing viral NP, GP, Z and L proteins. The resulting defective virions, named LASVmg, can propagate only in the helper cell line, providing a BSL-2 model to study the complete LASV life cycle. Using this model, we found that a previously reported cellular receptor α-dystroglycan is dispensable for LASVmg infection. Furthermore, we showed that ribavirin can inhibit LASVmg infection by inducing viral mutations. This new BSL-2 system should facilitate studying the LASV life cycle and screening antivirals.

Reservoir displacement by an invasive rodent reduces Lassa virus zoonotic spillover risk.

The black rat (Rattus rattus) is a globally invasive species that has been widely introduced across Africa. Within its invasive range in West Africa, R. rattus may compete with the native rodent Mastomys natalensis, the primary reservoir host of Lassa virus, a zoonotic pathogen that kills thousands annually. Here, we use rodent trapping data from Sierra Leone and Guinea to show that R. rattus presence reduces M. natalensis density within the human dwellings where Lassa virus exposure is most likely to occur. Further, we integrate infection data from M. natalensis to demonstrate that Lassa virus zoonotic spillover risk is lower at sites with R. rattus. While non-native species can have numerous negative effects on ecosystems, our results suggest that R. rattus invasion has the indirect benefit of decreasing zoonotic spillover of an endemic pathogen, with important implications for invasive species control across West Africa.

Rodent control strategies and Lassa virus: some unexpected effects in Guinea, West Africa.

The Natal multimammate mouse (Mastomys natalensis) is the host of Lassa mammarenavirus, causing Lassa haemorrhagic fever in West Africa. As there is currently no operational vaccine and therapeutic drugs are limited, we explored rodent control as an alternative to prevent Lassa virus spillover in Upper Guinea, where the disease is highly endemic in rural areas. In a seven-year experiment, we distributed rodenticides for 10-30 days once a year and, in the last year, added intensive snap trapping for three months in all the houses of one village. We also captured rodents both before and after the intervention period to assess their effectiveness by examining alterations in trapping success and infection rates (Lassa virus RNA and IgG antibodies). We found that both interventions reduced the rodent population by 74-92% but swiftly rebounded to pre-treatment levels, even already six months after the last snap-trapping control. Furthermore, while we observed that chemical control modestly decreased Lassa virus infection rates annually (a reduction of 5% in seroprevalence per year), the intensive trapping unexpectedly led to a significantly higher infection rate (from a seroprevalence of 28% before to 67% after snap trapping control). After seven years, we conclude that annual chemical control, alone or with intensive trapping, is ineffective and sometimes counterproductive in preventing Lassa virus spillover in rural villages. These unexpected findings may result from density-dependent breeding compensation following culling and the survival of a small percentage of chronically infected rodents that may spread the virus to a new susceptible generation of mice.

Trend of Lassa fever cases and factors associated with mortality in Liberia, 2016 - 2021: a secondary data analysis.

Introduction: Lassa fever (LF) is endemic in Liberia and is immediately reportable. Suspected cases are confirmed at the National Public Health Reference Laboratory. However, there is limited information on the trend and factors associated with mortality. We described the epidemiological characteristics of LF cases and determined factors associated with mortality in Liberia from 2016 to 2021. Methods: we reviewed 867 case-based LF surveillance data from 2016 to 2021 obtained from the National Public Health Institute of Liberia (NPHIL). The cases that met the suspected LF case definition were tested with RT-PCR. Using Epi Info 7.2.5.0. We conducted univariate, bivariate, and multivariate and analysis. We calculated frequencies, proportions. Positivity rate, case fatality rate, and factors associated with LF mortality using chi-square statistics and logistics regression at 5% level of significance. Results: eighty-five percent (737/867) of the suspected cases were tested and 26.0% (192/737) were confirmed LF positive. The median age of confirmed LF cases was 21(IQR: 12-34) years. Age 10-19 years accounted for 24.5% (47/192) and females 54.2% (104/192). Bong 33.9% (65/192), Grand Bassa 31.8% (61/192), and Nimba counties, 21.9% (42/192) accounted for most of the cases. The median duration from symptom onset to hospital admission was 6 (IQR: 3-9) days. A majority, 66% (126/192) of the cases were reported during the dry season (October-March) and annual incidence was highest at 12 cases per 1,000,000 population in 2019 and 2020. The overall case fatality rate was 44.8%. Non-endemic counties, Margibi, 77.8% and Montserrado, 66.7% accounted for the highest case fatality rate (CFR), while 2018, 66.7% and 2021, 60.0% recorded the highest CFR during the period. Age ≥30 years (aOR=2.1,95% CI: 1.08-4.11, p=0.027) and residing in Grand Bassa County (aOR=0.3, 95% CI: 0.13-0.73, p=0.007) were associated with LF mortality. Conclusion: Lassa fever was endemic in three of the fifteen counties of Liberia, case fatality rate remained generally high and widely varied. The high fatality of LF has been reported to the NPHIL and is currently being further investigated. There is a need to continuously train healthcare workers, especially in non-endemic counties to improve the LF treatment outcome.

Spatio-temporal spread and evolution of Lassa virus in West Africa.

BACKGROUND: Lassa fever is a hemorrhagic disease caused by Lassa virus (LASV), which has been classified by the World Health Organization as one of the top infectious diseases requiring prioritized research. Previous studies have provided insights into the classification and geographic characteristics of LASV lineages. However, the factor of the distribution and evolution characteristics and phylodynamics of the virus was still limited. METHODS: To enhance comprehensive understanding of LASV, we employed phylogenetic analysis, reassortment and recombination detection, and variation evaluation utilizing publicly available viral genome sequences. RESULTS: The results showed the estimated the root of time of the most recent common ancestor (TMRCA) for large (L) segment was approximately 634 (95% HPD: [385879]), whereas the TMRCA for small (S) segment was around 1224 (95% HPD: [10301401]). LASV primarily spread from east to west in West Africa through two routes, and in route 2, the virus independently spread to surrounding countries through Liberia, resulting in a wider spread of LASV. From 1969 to 2018, the effective population size experienced two significant increased, indicating the enhanced genetic diversity of LASV. We also found the evolution rate of L segment was faster than S segment, further results showed zinc-binding protein had the fastest evolution rate. Reassortment events were detected in multiple lineages including sub-lineage IIg, while recombination events were observed within lineage V. Significant amino acid changes in the glycoprotein precursor of LASV were identified, demonstrating sequence diversity among lineages in LASV. CONCLUSION: This study comprehensively elucidated the transmission and evolution of LASV in West Africa, providing detailed insights into reassortment events, recombination events, and amino acid variations.

MHC-I alleles mediate clearance and antibody response to the zoonotic Lassa virus in Mastomys rodent reservoirs.

West African Mastomys rodents are the primary reservoir of the zoonotic Lassa virus (LASV). The virus causes haemorrhagic Lassa fever and considerable mortality in humans. To date, the role of Mastomys immunogenetics in resistance to, and persistence of, LASV infections is largely unknown. Here, we investigated the role of Major Histocompatibility Complex class I (MHC-I) on LASV infection status (i.e., active vs. cleared infection, determined via PCR and an immunofluorescence assay on IgG antibodies, respectively) in Mastomys natalensis and M. erythroleucus sampled within southwestern Nigeria. We identified more than 190 and 90 MHC-I alleles by Illumina high throughput-sequencing in M. natalensis and M. erythroleucus, respectively, with different MHC allele compositions and frequencies between LASV endemic and non-endemic sites. In M. natalensis, the MHC allele ManaMHC-I*006 was negatively associated with active infections (PCR-positive) and positively associated with cleared infections (IgG-positive) simultaneously, suggesting efficient immune responses that facilitate LASV clearance in animals carrying this allele. Contrarily, alleles ManaMHC-I*008 and ManaMHC-I*021 in M. natalensis, and MaerMHC-I*008 in M. erythroleucus, were positively associated with active infection, implying susceptibility. Alleles associated with susceptibility shared a glutamic acid at the positively selected codon 57, while ManaMHC-I*006 featured an arginine. There was no link between number of MHC alleles per Mastomys individual and LASV prevalence. Thus, specific alleles, but not MHC diversity per se, seem to mediate antibody responses to viremia. We conclude that co-evolution with LASV likely shaped the MHC-I diversity of the main LASV reservoirs in southwestern Nigeria, and that information on reservoir immunogenetics may hold insights into transmission dynamics and zoonotic spillover risks.

Lassa fever vaccine use cases and demand: Perspectives from select West African experts.

Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic to several West African countries. Approximately 300-500,000 cases occur annually across all ages with 10-20% case fatality rates. A LF vaccine is a recognized public health priority, with several candidates entering clinical trials. However, the perspectives of regional experts regarding critical vaccine properties, ideal delivery methods, and priority target populations remain unclear. Using a mixed methods approach with a standardized questionnaire, we individually interviewed 8 West African stakeholders, each with extensive knowledge and experience of LF. They strongly favored the use of a mass, proactive campaign strategy to immunize a wide age range of people in high-risk areas, including pregnant women and health care workers. We estimated that these and other plausible delivery scenarios could result in an initial demand of anywhere from 1 to 100 million doses, with most demand coming from Nigeria. These findings may help inform LF vaccine development and deployment efforts.

The Importance of Lassa Fever and Its Disease Management in West Africa.

Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been emphasized as one of the greatest public health threats in West Africa, with up to 300,000 cases and 5000 associated deaths per year. This, and the fact that the disease has been reported in travelers, has driven a rapid production of various vaccine candidates. Several of these vaccines are currently in clinical development, despite limitations in understanding the immune response to infection. Alarmingly, the host immune response has been implicated in the induction of sensorineural hearing loss in LF survivors, legitimately raising safety questions about any future vaccines as well as efficacy in preventing potential hearing loss. The objective of this article is to revisit the importance and prevalence of LF in West Africa, with focus on Nigeria, and discuss current therapeutic approaches and ongoing vaccine development. In addition, we aim to emphasize the need for more scientific studies relating to LF-associated hearing loss, and to promote critical discussion about potential risks and benefits of vaccinating the population in endemic regions of West Africa.

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.