Lassa virus

Lassa virus is the arenavirus that causes Lassa fever, the most common and most consequential arenaviral disease of humans and one of the leading viral haemorrhagic fevers of West Africa. It is a rodent-borne agent maintained in nature by a single reservoir species, the multimammate rat Mastomys natalensis, which sheds virus lifelong without evident harm; human infection is an accidental spillover from contact with rodent excreta, though the virus also spreads from person to person and drives hospital outbreaks. Against a backdrop of an estimated hundreds of thousands of infections each year, most of them mild or silent, a serious minority develop a multisystem illness that can end in bleeding, encephalopathy and shock.

The virus occupies an unusual place among the haemorrhagic fever agents. It kills not by wholesale tissue destruction but by disabling the early immune response and deranging the function, rather than the integrity, of the small blood vessels. Its most distinctive legacy in survivors is not a scar but a silence: permanent sensorineural hearing loss in a substantial fraction of those who fall clinically ill, which makes Lassa a leading infectious cause of acquired deafness in its endemic region. In pregnancy the disease is transformed, with fetal loss approaching certainty in the third trimester.

Lassa is a maximum-containment pathogen, handled only in biosafety level 4 laboratories, and sits on the World Health Organization’s list of priority diseases for research and development. There is no licensed vaccine, and specific treatment rests on a single antiviral drug whose benefit, long accepted, is now under fresh scrutiny.

Discovery and historical significance

Lassa virus was discovered in 1969 through a chain of infection that began in the town of Lassa in north-eastern Nigeria. A missionary nurse, Laura Wine, fell ill and died of an undiagnosed febrile illness; a nurse who cared for her, Charlotte Shaw, then contracted the same disease and died, and a third nurse, Lily Pinneo, developed severe illness but survived. Her blood carried the agent that would be isolated and named for the town.

The virus was characterised at the Yale Arbovirus Research Unit by Jordi Casals and colleagues, and its danger announced itself in the laboratory. Casals himself developed a near-fatal infection and recovered only after receiving convalescent plasma from Pinneo, and a Yale technician who had no recognised direct contact with the specimens died the following year. These events established at once that the new agent was both highly virulent and transmissible in the laboratory, and Lassa work was moved to maximum containment. Over the early 1970s field studies in Sierra Leone and Nigeria, led by researchers including Tom Monath and later Joseph McCormick, identified Mastomys natalensis as the reservoir and began to map the true burden of the disease, showing that the dramatic hospital outbreaks were the visible tip of a far larger endemic infection.

Classification, structure, and genome

Classification

Lassa virus is the species Mammarenavirus lassaense in the genus Mammarenavirus, family Arenaviridae. It belongs to the Old World arenavirus complex, the African and Eurasian group whose other human pathogens are lymphocytic choriomeningitis virus and Lujo virus, alongside several members with no known human disease such as Mopeia, Mobala and Ippy viruses. The complex is defined against the New World complex of the Americas, which contains the agents of the South American haemorrhagic fevers.

The medically relevant contrasts between the two complexes:

Feature	Old World complex	New World complex (clade B)
Main human pathogens	Lassa, lymphocytic choriomeningitis	Junin, Machupo, Guanarito, Sabiá
Region	Africa; lymphocytic choriomeningitis worldwide	The Americas
Cell-entry receptor	Alpha-dystroglycan	Transferrin receptor 1
Reservoir rodents	Murid mice, such as Mastomys and the house mouse	Cricetid mice, such as Calomys
Disease	Lassa fever; lymphocytic choriomeningitis and congenital infection	South American haemorrhagic fevers

Lassa virus is genetically diverse, and this diversity is strongly geographic rather than temporal: the virus has been evolving in place within distinct rodent populations rather than spreading as a single expanding clone. Current analyses recognise six major lineages, with the greatest diversity in Nigeria, which is consistent with a Nigerian origin for the virus. The heterogeneity is not merely academic, because it has historically defeated molecular assays designed against a single strain and complicates the design of a broadly protective vaccine.

Lineage	Principal region
I	Nigeria
II	Nigeria
III	Nigeria
IV	Sierra Leone, Guinea, Liberia
V	Mali, Côte d’Ivoire
VI	Togo

Virion structure

The virion is enveloped and markedly pleomorphic, ranging from roughly 60 to 300 nanometres in diameter and often around 110 to 130 nanometres. Its surface carries evenly spaced spikes, each a complex of the two glycoprotein subunits GP1 and GP2 anchored in a lipid envelope. Inside lie two circular ribonucleoprotein complexes, one for each genome segment, and, characteristically, host ribosomes taken up during assembly, which give the arenaviruses their granular or sandy appearance under the electron microscope and their name, from the Latin for sand. Beneath the envelope, the Z protein forms a matrix layer that bridges the ribonucleoprotein core to the membrane.

Genome organisation

The genome is bisegmented, negative-sense single-stranded RNA with an ambisense coding strategy. The small segment, about 3.4 kilobases, encodes the nucleoprotein and the glycoprotein precursor; the large segment, about 7.2 kilobases, encodes the RNA-dependent RNA polymerase and the small zinc-binding Z protein. The defining ambisense arrangement means each segment carries one gene in negative sense and one in positive sense, separated by a noncoding intergenic region that folds into a stable hairpin and signals transcription to stop. Because the genes in positive orientation cannot be read directly from the incoming genome, they are expressed only after an antigenomic template has been made, which gives the virus a built-in temporal order: nucleoprotein and polymerase first, glycoprotein and matrix protein later.

The glycoprotein precursor is synthesised as a single chain and then processed in two steps. Cellular signal peptidase releases an unusually long and stable signal peptide of 58 amino acids that is retained as a functional third subunit, and the protease SKI-1/S1P then cleaves the remainder into the receptor-binding GP1 and the fusion-mediating GP2. This processing is essential for infectivity and is one target of experimental antivirals.

Replication cycle

Infection begins when the GP1 subunit binds its cell-surface receptor, alpha-dystroglycan, a widely expressed protein that links the cell to its surrounding matrix. Efficient binding depends on a particular sugar modification of alpha-dystroglycan added by the enzyme LARGE, and the genes for this pathway show signatures of natural selection in West African populations, a hint that Lassa has exerted evolutionary pressure on its human hosts. Because alpha-dystroglycan is used by non-pathogenic relatives as well, the receptor itself does not explain virulence.

After receptor binding the virion is taken into the cell by endocytosis. As the endosome acidifies, the virus performs a receptor switch, handing off from alpha-dystroglycan to the lysosomal membrane protein LAMP1, and the low pH drives a conformational change in GP2 that fuses the viral and endosomal membranes and releases the ribonucleoproteins into the cytoplasm, where the entire replication cycle takes place.

The polymerase transcribes viral messenger RNAs by cap-snatching, cleaving short capped primers from host transcripts to start its own, producing capped but non-polyadenylated messages that terminate within the intergenic hairpin. The nucleoprotein and polymerase together are the minimal machinery for RNA synthesis, while the Z protein acts as a molecular switch that shuts transcription down as it accumulates and redirects the virus toward assembly. Progeny particles bud from the plasma membrane, where Z recruits the cell’s ESCRT machinery through late-domain motifs to pinch off enveloped virions. The same non-destructive, persistent style of infection that this cycle supports underlies the lifelong, symptomless carriage seen in the reservoir rodent.

Pathogenesis

Lassa virus is inhaled or enters through mucosa and abraded skin, and its earliest targets are the sentinel cells of the immune system: dendritic cells and macrophages, which the virus infects and amplifies without triggering their activation. Infected antigen-presenting cells fail to raise their surface activation markers or to release the inflammatory signals that would normally alert the rest of the immune system, so the infection advances behind a screen of silence before spreading through lymphoid tissue to the liver, spleen, adrenal glands, lungs and, in pregnancy, the placenta.

Central to this stealth is active suppression of innate immunity. The nucleoprotein carries an exonuclease that degrades the double-stranded RNA the cell would otherwise sense, and it blocks the signalling that would switch on type I interferon, while the Z protein interferes with the intracellular sensor RIG-I. The result is a poor early interferon response, and the decisive control of the infection falls to virus-specific T cells rather than to antibody, which appears late and neutralises weakly. Fatal cases are marked by a defective, delayed T-cell response together with an uncontrolled rising viral load, and the strongest laboratory predictor of death is the height of the viraemia.

Severe disease is a disorder of vascular function more than of vascular structure. The virus does not lyse endothelium wholesale, and there is increased capillary permeability with relatively little actual vascular damage, so the leak of fluid, the hypotension and the shock arise from deranged endothelial and platelet function rather than destruction. Bleeding, when it occurs, owes more to thrombocytopenia and to an inhibitor of platelet aggregation in the plasma than to consumption of clotting factors: unlike the filoviruses, Lassa does not usually produce florid disseminated intravascular coagulation or a cytokine storm. The liver shows multifocal hepatocellular necrosis, the most consistent pathological finding, yet the damage is too patchy to cause liver failure and does not correlate with the height of the transaminases, so hepatic injury is a marker of the systemic disease rather than its fatal mechanism.

The sensorineural hearing loss that follows Lassa fever has a different character again. It appears in convalescence, after the virus has been controlled, and does not track with the severity of the acute illness or the level of viraemia, which points to an immune-mediated injury to the inner ear rather than direct viral destruction.

Epidemiology

Lassa fever is endemic across rural West Africa, with the heaviest recognised burden in Nigeria, Sierra Leone, Liberia and Guinea, and with circulation now documented more widely, including Mali, Ghana, Benin, Togo, Burkina Faso and Côte d’Ivoire. The endemic zone maps onto the range of the reservoir, Mastomys natalensis, which lives in and around houses and cultivated land and maintains the virus largely by passing it to its own offspring.

The scale of infection is large but imprecisely known. Estimates commonly cited put it at ~100,000 to 300,000 infections and several thousand deaths a year, though poor surveillance makes any figure uncertain, and the case fatality depends heavily on which denominator is used. About 80% of infections are mild or subclinical, so the case fatality across all infections is low, whereas among patients ill enough to be admitted to hospital it is far higher, reaching a fifth or more in some series and higher still in outbreaks. Transmission peaks in the dry season, from around November to April, when rodents move into homes and stored food.

People acquire the virus by contact with rodent excreta, through inhaling contaminated dust, eating contaminated or rodent-caught food, or contaminating broken skin, so exposure follows housing conditions and food storage. Lassa is also, importantly, transmissible from person to person, with well-documented nosocomial outbreaks driven by contaminated needles and unprotected care, and an estimated fifth of cases in some settings acquired this way. The virus is shed in urine and semen during convalescence, with urinary shedding recorded for up to around 67 days, so late and even sexual transmission can occur after apparent recovery. Beyond the endemic zone, Lassa is a recognised importation risk: cases are periodically exported to Europe and North America in travellers and evacuees, though onward spread in well-resourced settings under barrier nursing has been very rare.

Natural history

After an incubation of about 6 to 21 days, most often 10 to 14 days, the illness begins insidiously rather than abruptly. The large majority of infections are mild or entirely silent and resolve without specific care. In the symptomatic, the first days bring non-specific fever, malaise, headache and sore throat that are easily mistaken for malaria or a bacterial infection, and it is only across the first week that a minority declare themselves as severe disease.

In that minority the second week is the dangerous one. The illness progresses to facial and neck swelling, mucosal bleeding, effusions, encephalopathy and circulatory collapse, and death, when it comes, is usually in this phase. Those who survive the acute illness enter a prolonged convalescence, and it is here, as the fever settles, that sensorineural hearing loss may appear, along with transient hair loss, and, less often, a self-limiting disturbance of balance and coordination. The hearing loss is frequently permanent. The natural history is entirely different in pregnancy, where severe disease and fetal loss are the rule rather than the exception.

Clinical presentations and complications

Acute Lassa fever

The onset is gradual, with fever, profound malaise, headache, sore throat, retrosternal or epigastric pain, myalgia and, characteristically, proteinuria; the pharynx may be inflamed or exudative and mimic streptococcal infection, and vomiting and abdominal pain can suggest a surgical abdomen. The best early clinical predictors of Lassa rather than another febrile illness are the combination of fever, sore throat, retrosternal pain and proteinuria, since none is specific alone. Most patients improve from here.

In severe disease the picture worsens over the first week into swelling of the face and neck, bleeding from mucosal surfaces, pleural and pericardial effusions, encephalopathy with tremor and seizures, and shock. Overt haemorrhage is a late and relatively infrequent sign rather than the dominant feature, and its presence carries a poor prognosis. A rising aspartate aminotransferase above roughly 150 international units per litre and a high viraemia both mark a high risk of death. In children a distinct and often fatal presentation, the swollen baby syndrome, combines widespread oedema, abdominal distension and bleeding.

Sensorineural hearing loss

The signature complication of Lassa fever is sensorineural hearing loss, affecting roughly a quarter to a third of survivors of clinical disease, which makes the virus a leading infectious cause of acquired deafness in the endemic region. It is one- or two-sided, appears during convalescence rather than in the acute illness, and is unrelated to how severe the acute disease was, consistent with an immune-mediated mechanism. In around two-thirds of those affected the loss is permanent. Because most infections are mild or subclinical, the proportion is much lower when counted against all infections than against hospitalised cases, and the figure should always be read with its denominator in mind.

Lassa fever in pregnancy

Pregnancy transforms the disease. Maternal mortality is high, and fetal loss approaches 100% in the third trimester, with the illness presenting as spontaneous abortion, vaginal bleeding and fever. Evacuation of the uterus improves the mother’s chance of survival, which reflects a very high viral load in the products of conception, though the procedure itself carries a substantial risk of transmission to attendants and must be done under strict precautions.

Diagnosis

Reverse transcription polymerase chain reaction (RT-PCR) is the diagnostic mainstay, detecting viral RNA in the majority of cases within the first ten days of illness, returning an answer within hours, and, when quantitative, offering prognostic information because a high viral load predicts a poor outcome. Assays must target conserved regions of the genome to cope with the virus’s genetic diversity, which earlier defeated primers designed against a single lineage. A negative result early in a strongly suspected case does not exclude the diagnosis, and the test should be repeated while the patient is managed as a presumed case in the interim.

Antigen detection and antibody testing complement the molecular approach. Because circulating antigen falls as immunoglobulin M rises, antigen-capture and IgM assays are run together to cover successive phases of the illness, and in combination they reach high sensitivity and specificity. Serology has real limitations for diagnosis: IgM can persist for months and is an unreliable marker of recent infection, antibody can wane after infection, and antibodies raised against related non-pathogenic West African arenaviruses cross-react. Virus isolation is definitive but confined to maximum-containment laboratories and too slow for clinical decisions. A recombinant-antigen rapid lateral-flow test has been developed for field use. Throughout, malaria must be actively excluded in parallel, since it is far more common, presents similarly, and may coexist.

Management

Care is principally supportive and best delivered at intensive-care level, with close attention to haemodynamics, electrolytes and bleeding. Fluid replacement must be cautious, because the increased vascular permeability makes these patients prone to pulmonary oedema and third-spacing, and aggressive rehydration can do harm. Salicylates and other non-steroidal anti-inflammatory drugs are avoided for their effect on bleeding and platelets, intramuscular injections are minimised, and empirical treatment for malaria and bacterial sepsis is given until those are excluded.

The specific antiviral is ribavirin, a nucleoside analogue given intravenously, which has been the agent of choice for four decades on the strength of an influential 1980s study in Sierra Leone that reported a large reduction in mortality when treatment was started within the first six days of illness. It is best regarded as most useful early, and given by the intravenous route because oral absorption is unreliable in a vomiting patient. Its principal toxicity is a dose-dependent, reversible haemolytic anaemia, and it is teratogenic, though it is still used in pregnancy as a potentially life-saving measure given the near-certain fetal loss. The strength of the evidence for ribavirin is now genuinely debated: re-analyses of the original trial have questioned its methods, and better-designed studies are considered necessary, so its benefit, long treated as settled, should be held with appropriate uncertainty. A number of other agents, including favipiravir and monoclonal antibodies derived from survivors, are in development.

Prevention and public health

Vaccination

There is no licensed Lassa vaccine, and developing one is a stated global priority; Lassa sits on the World Health Organization’s research and development priority list. The correlate of protection appears to be a T-cell response rather than neutralising antibody, which shapes vaccine design. The most advanced candidate is a recombinant vesicular stomatitis virus expressing the Lassa glycoprotein (rVSVΔG-LASV-GPC), which protects in animal models after a single dose and has entered later-stage clinical trials in West Africa; other platforms in development include a measles-vectored vaccine, a DNA vaccine, and a reassortant construct combining Lassa and Mopeia virus genes. The genetic diversity of the virus across its lineages is a central challenge for achieving broad protection.

Infection prevention and control

Every clinically compatible case is treated as infectious. Care is delivered under viral haemorrhagic fever precautions: isolation, gloves, gown and apron, face and eye protection, and safe handling and disposal of sharps and body fluids, with added respiratory protection for aerosol-generating procedures. Diagnostic specimens are handled as maximum-hazard material and processed only in appropriate containment, with confirmatory work at biosafety level 4. Under barrier nursing the secondary attack rate is low and onward chains are usually short, but breakdowns in these measures, particularly reused needles and unrecognised early cases, are what turn a single importation into a hospital outbreak.

Post-exposure prophylaxis

For a defined high-risk exposure, such as unprotected contact with the blood or body fluids of a confirmed case, oral ribavirin can be given as post-exposure prophylaxis, converted to intravenous treatment if illness develops. It is not indicated for lower-risk contact, and given the generally low secondary attack rate it is used selectively rather than routinely.

Surveillance and notification

Lassa fever is a notifiable condition in endemic countries and internationally, and case detection triggers contact tracing and monitoring. Unprotected contacts are followed for 21 days, the longest incubation period, with daily temperature checks and prompt isolation if fever develops, and convalescent patients are counselled on the risk of sexual transmission during the weeks after recovery.

South African context

Lassa fever is not endemic to South Africa, where no reservoir population of Mastomys natalensis carrying the virus is recognised, but it is a real importation risk in travellers, migrants and medical evacuees arriving from the endemic zone of West Africa, where the disease is common. Any such case would be one of the imported viral haemorrhagic fevers for which the country maintains a standing preparedness.

A suspected case is managed through the national viral haemorrhagic fever pathway, the same system used for the region’s other haemorrhagic fevers: early recognition and risk assessment, strict isolation, safe specimen packaging and transport, and confirmatory testing centralised at the maximum-containment reference laboratory. The detailed South African approach to recognition, notification and laboratory handling is set out in dedicated national guidance. Lassa fever is a category 1 notifiable medical condition, requiring immediate reporting on suspicion, and specific treatment with ribavirin is arranged through the same referral channels once a case is identified.

References and recommended reading

• Radoshitzky SR, Buchmeier MJ, de la Torre JC. Arenaviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The principal source for arenavirus classification, virion and genome organisation, the ambisense strategy, receptor use and the replication cycle set out here.
• Bausch DG. Arenaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. The source for the clinical course, diagnostic strategy, ribavirin evidence and infection-control practice.
• Burrell CJ, Howard CR, Murphy FA. Arenaviruses. In: Fenner and White’s Medical Virology, 5th edition, Chapter 30. Elsevier / Academic Press; 2017. The concise account of the Old World and New World split, reservoir ecology and Lassa pathogenesis.
• Hewson R. Understanding Viral Haemorrhagic Fevers: Virus Diversity, Vector Ecology, and Public Health Strategies. Pathogens. 2024;13(10):909. Current taxonomy, reservoir ecology and the vaccine-development landscape.
• Florez-Alvarez L, et al. Hemorrhagic fever viruses: pathogenesis, therapeutics, and emerging antivirals. 2022. The comparative pathophysiology of the haemorrhagic fever viruses and the state of specific therapeutics.