Lassa Fever Is Surging in West Africa. Researchers Want To Know Why

IRRUA, NIGERIA, AND KENEMA, SIERRA LEONE—Sitting on a bench outside the Irrua Specialist Teaching Hospital (ISTH) in Edo state in southwestern Nigeria in September 2023, Muhammed Luqman Dagana recounted his ordeal earlier in the year with Lassa fever, a deadly hemorrhagic disease of West Africa. At first the 33-year-old wasn’t alarmed—his fever, headache, body aches, and cough were innocuous enough. A doctor at his local clinic gave him antibiotics for typhoid fever and antimalarial drugs. But his symptoms persisted, so he tried another clinic. Again, the diagnosis was malaria and typhoid.

Dagana continued to decline, his fever fluctuating wildly. When a third clinic referred him to the general hospital here, he was barely able to walk and was having trouble breathing. Ten days after his symptoms began, he was finally diagnosed with Lassa fever and immediately transferred to the hospital’s high-containment isolation ward. By then Dagana was in and out of consciousness, with acute renal failure.

The experience was “terrible, horrible,” said Dagana, who is married and has a young son. “People were suffering around me. I could hear them crying out.” A member of his community was brought in unconscious; 20 minutes later he was dead. “I was so frightened.”

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He spent more than 1 month in the hospital and underwent five rounds of dialysis. As of September 2023, his kidney function was still not back to normal. And yet he’s one of the lucky ones. Although about 80% of Lassa virus infections are mild or asymptomatic, 15% to 20% of cases of severe disease are fatal—a number that can reach 70% in some places and in some epidemics. “That’s up there with Ebola,” says virologist Robert Garry of the Tulane University School of Medicine.

Lassa fever kills far more people than Ebola does—10,000 or more a year, some researchers suspect, although no one knows for sure. But except for a small cadre of dedicated researchers, it has been largely ignored. Identified only half a century ago, the rodent-borne disease, which can more rarely be transmitted between people via body fluids, affects the rural poor, who live far from any health center. Most cases go undiagnosed and unreported, and many people die in their villages.

“It is the most neglected of neglected diseases,” says Sylvanus Okogbenin, an obstetrician who chairs a working group at ISTH’s Institute of Viral and Emergent Pathogens Control and Research.

A record-shattering epidemic in 2018 in Nigeria, the hardest hit country, put Lassa fever on the map, prompting both the World Health Organization (WHO) and the Nigerian government to declare a public health emergency. Confirmed cases, which numbered roughly 25 to 100 in previous outbreak years, reached 633, and 171 people died, including 45 health care workers.

Cases in Nigeria have continued to climb each year since then. Infections still surge in the dry season, which runs from about December to May, but since 2018 have been occurring year-round. Most worrisome, cases are popping up outside the four known endemic countries: Nigeria, Sierra Leone, Guinea, and Liberia.

As a result Lassa fever has vaulted up on the global health agenda, earning a spot on WHO’s list of notorious pathogens that have epidemic or pandemic potential and urgently require countermeasures. Several groups are working on badly needed diagnostics and drugs. The nonprofit Coalition for Epidemic Preparedness Innovations (CEPI) has named Lassa fever one of its priority diseases, investing in vaccine development and funding the largest ever study of Lassa’s true burden. And researchers in Africa and abroad are scrambling to learn why it is on the march—whether because of better surveillance, some change in the virus or in the rodents that carry it, a growing population, or a changing environment. “With climate change, what we saw 5 years ago doesn’t hold anymore,” says Gabrielle Breugelmans, director of epidemiology and data science at CEPI. “The hot spots of today are not the hot spots of tomorrow.”

IN 1969, two missionary nurses in the remote village of Lassa, in Borno state in northeastern Nigeria, were stricken by a mysterious febrile disease. Both died. When a third nurse who cared for the second case, Penny Pinneo, fell ill with a spiking fever, chills, an ulcerated throat, and profound weakness, she was evacuated to New York Presbyterian Hospital. After a devastating and prolonged illness, she slowly recovered.

Virologist Jordi Casals-Ariet and his team at the Yale University Arbovirus Research Unit analyzed blood samples from the nurses in search of what they suspected was a new virus. They isolated a single-stranded RNA virus in what became known as the Arenavirus family and named it for the village where it was discovered. But Casals-Ariet became infected while handling the samples and almost died, saved only by a risky transfusion of antibodies from Pinneo’s blood. When Casals-Ariet’s technician, Juan Roman, also became infected and died, Yale immediately halted work with the live virus and transferred it to the “hot” lab at what is now the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta.

The United States now classifies the Lassa virus as a biosafety level-4 pathogen, so dangerous that the live virus can only be studied in the highest security laboratories.

In 1972, during a Lassa fever outbreak in Eastern Province in Sierra Leone, Thomas Monath, then a virus hunter at CDC, and his colleagues set out to find the animal reservoir. Similar viruses were known to be spread by small vertebrates, so they trapped 641 animals and removed tissue and blood samples.

Bats, shrews, monkeys, and a single turtle turned up nothing. But Monath eventually isolated the virus from 14 specimens of multimammate mouse, Mastomys natalensis, so-called because of its long rows of nipples for nursing big litters. Ubiquitous across sub-Saharan Africa, M. natalensis, often referred to as the common African rat, is a denizen of poor villages, scurrying in and out of houses for food—especially during the dry season when farmers burn the fields after harvest, driving out the mice.

The virus couldn’t have picked a better host. Prolific breeders, females bear 10 to 12 pups every 45 days, and an infected female passes the virus to her offspring. They aren’t sickened by the virus, but they are thought to carry and shed it for the rest of their lives. “That’s the definition of a good reservoir,” says rodent ecologist Elisabeth Fichet-Calvet of the Bernhard Nocht Institute for Tropical Medicine (BNITM), who has spent 2 decades studying the complex interplay of the Lassa virus and its host.

Since 2016, several other rodent species in Nigeria, Guinea, Ghana, and Benin have been shown to harbor the virus. But M. natalensis remains the main driver of deadly outbreaks In contrast to Ebola, where one spillover from bat to human can set off a chain of human-to-human transmission, the Lassa virus is usually contracted by direct contact with an infected rodent—young boys hunt and eat them—or its saliva, urine, and droppings. But the virus also spreads person to person, mostly when unsuspecting health workers without personal protective equipment (PPE) are exposed to an infected person’s blood or bodily fluids. “We lose a lot of specialized health care workers,” says Ifedayo Adetifa, director of the Nigeria Centre for Disease Control and Prevention (NCDC).

Family clusters occur, too. In 2022, for example, a man returned to the United Kingdom from a trip to Mali and was hospitalized with what was later confirmed to be Lassa fever. He passed the virus on to his wife and child, and the child died. Infectious virus can persist in the body and semen for months after recovery, posing a long-term transmission risk.

LONG AFTER THE DISEASE was identified, it went largely unrecognized in West Africa, even as communities in Nigeria and the other endemic countries began to document outbreaks of acute febrile illness. In January 1987, physician Felix Okogbo saw a rash of patients at his clinic in Ekpoma, Nigeria, near Irrua. Cases declined in March, then came back with a vengeance the following January. So he called the illness January fever.

Then in January 1989, a woman in Ekpoma died of what was diagnosed as malaria, and her husband died soon after. After their two sons came home to bury them, both succumbed to the mysterious illness. One had already returned home to Chicago, where physicians were startled to find Lassa virus antigens during a postmortem.

Okogbo himself fell ill in 1990, then lost his pregnant wife to a hemorrhagic illness the following year, during an outbreak that also killed 24 students at the university where she taught.

Virologists came to investigate, and one sent a sample of Okogbo’s blood to CDC, where testing revealed antibodies to the Lassa virus. “That’s when I connected the dots,” says Okogbo, who joined ISTH in 1999. People blamed witchcraft for the deaths, Okogbo says. “I told them it is not witchcraft, it is a virus.”

Survivors’ stories

Many of those who recover from Lassa fever have dealt with life-changing consequences. Some are shunned by their communities, and many have permanent hearing loss. Health care workers face a particularly high risk of infection.

Even now, few health care workers suspect the disease when a patient arrives with fever and malaise, as Dagana learned last year. There are no cheap, rapid diagnostic tests that can be used in community clinics as exist for malaria. Only when a patient doesn’t respond to antimalarials or antibiotics, or health workers get sick, does Lassa come to mind—if it does at all. Patients often reach the hospital too late for supportive care, and some even die in the ambulance. “Every day is key when you are talking about survival,” Okogbenin says.

As the disease progresses, patients develop a sore throat, chest pain, abdominal pain, diarrhea, and vomiting. Once they begin bleeding from various orifices, the prognosis is grim. Seizures, confusion, and shock also portend a fatal outcome. Patients often die of renal failure, septic shock, or other complications about 14 to 21 days after the onset of symptoms. Lassa fever is especially dangerous during pregnancy and is usually fatal for the developing fetus.

No specific drugs exist, but IV fluids, oxygen, blood transfusions, and prophylactic antibiotics to prevent secondary infections can help. So can the antiviral drug ribavirin, although solid data are lacking.

Many survivors are left with temporary or permanent hearing loss, which can rob them of jobs and livelihoods. The financial burden of treatment can be overwhelming, says Esther Okogbenin, a psychiatrist and researcher at ISTH who is married to Sylvanus Okogbenin. Stigma is intense, and survivors are often shunned by their communities, she says. Many suffer from post-traumatic stress disorder and depression.

Only around 2003 did ISTH gain the ability to diagnose Lassa fever—by sending patient samples to collaborators with polymerase chain reaction (PCR) labs at the University of Lagos and at BNITM. But the results would take weeks to come back, and in the meantime, patients would die. With the help of international partners, the hospital opened its own PCR lab in 2008. The turnaround time is now less than a day.

But limited surveillance and testing continue to obscure the incidence of infection and disease across West Africa. One oft-cited figure of 100,000 to 300,000 infections a year and up to 5000 deaths was extrapolated from a small study in the 1980s in Sierra Leone, Breugelmans says. She and other researchers suspect the burden is far higher. Adetifa estimates that 2 million new infections occur each year, with 300,000 to 500,000 clinical cases and 10,000 deaths. A recent study in PLOS Computational Biology ups the annual death toll to 18,000.

The CEPI-funded Enable study, launched in 2020, aims to firm up the numbers. Researchers have been following about 23,000 people over 2 years in Nigeria, Sierra Leone, Benin, Guinea, and Liberia. Community health workers check in with each household every 2 weeks to see whether anyone has an acute febrile illness. If they test positive for Lassa fever, they are immediately isolated and hospitalized. So far, the study has found 39 cases—most of them at a study site in Edo—and five deaths. Many of those infected also had malaria.

Enable is also periodically testing a subset of participants for asymptomatic infections. Preliminary results from the first 12 months, released in October 2023, suggest they are common: In Nigeria and in Liberia, 39% and 48% of participants, respectively, have antibodies to the virus in their blood. These findings will help researchers select sites for future vaccine trials, ideally conducted in communities with plenty of circulating virus and minimal immunity from previous exposure, which means a high risk of infection and illness.

“WHEN THE PAVED road ends, you know you are entering a Lassa community,” says Lansana Kanneh, a field surveillance officer in the Viral Hemorrhagic Fever Program at Kenema Government Hospital (KGH). It’s mid-September, and Kanneh is driving down a pitted dirt road, past women washing clothes in a muddy creek, to the remote village of Ngeihun, in the lower Bambara Chiefdom in Sierra Leone’s Eastern Province.

This is M. natalensis territory, Kanneh says. Around Ngeihun, the fields and lush vegetation provide an ideal habitat for rodents. The flimsy housing here, made of crumbling mud brick with thatch or rusted tin roofs, does little to keep out the mice and the virus they carry.

Kanneh points out the gaps under the front doors, the holes in the walls, the food stored in open containers. The small, windowless bedrooms are so dark that a rodent can happily spend its entire day in there, he says. Gutters are often clogged with garbage, and without running water, people have difficulty keeping dishes clean.

“The houses where Lassa is are a five-star hotel for a rodent,” says Donald Grant, director of the KGH program. In some villages around the small city of Kenema, up to 80% of the population has antibodies that show they have been exposed to the virus. Every time a Lassa fever case is detected, the outreach team from KGH visits the affected village within 24 hours. With the chief’s permission, they hold a community meeting with videos explaining the signs and symptoms of the disease, how it is transmitted, and the importance of proper food storage. They monitor the patient’s caregivers for the next 21 days. Then the ecology team sets live rodent traps in the house and around the community, baited with nut paste, ground cassava, oats, and dried fish.

The following morning, clad in full PPE, the team removes the traps and any rodents they contain, and resets them. Most of the time they catch M. natalensis, says Ibrahim Abu Zacharia of the ecology team, and about two of every five animals are infected.

How to catch a mouse

The rodents that carry the Lassa virus are denizens of poor villages in West Africa, where they scurry in and out of houses in search of food. Researchers at the Kenema Government Hospital in Sierra Leone trap them, both for research and to remove them from the villages.

Kenema has long been one of the hottest hot spots for Lassa fever in this part of West Africa, but recently cases have been declining. KGH is now seeing about 50 cases a year, as opposed to 150 or 200 before 2013, Garry says. This could be evidence of more widespread immunity or a sign that community education about keeping out rodents has paid off. But Garry and others here fear the decline is illusory. A string of hardships in the region has bred mistrust of the health care system and the government, perhaps keeping people from seeking care.

The Blood Diamond Wars, a devastating civil conflict lasting from 1991 to 2002, forced CDC to abandon its long-term Lassa fever research and control project there. Then in 2013, the largest ever Ebola outbreak hit Liberia, Guinea, and Sierra Leone, with Kenema at the epicenter. More than 11,000 people died, including 4000 Sierra Leoneans. Rumors swirled that Western health care workers had brought in the virus to kill them.

“I still see the scars at the community level,” Grant says, “especially among those whose family came into the hospital and never left.”

DEADLY VIRUSES leave marks on the human genome as well. In 2007, as a postdoc at the Broad Institute, computational geneticist Pardis Sabeti developed an innovative method to mine the human genome for signals of recent, positive natural selection. The single strongest signal in the human population turned up in the Yoruba people in Nigeria: an increased frequency of a variant in a gene called LARGE. The gene encodes an enzyme that modifies a surface receptor to which the Lassa virus binds to gain entry into cells. Sabeti and colleagues suspected the variant may confer protection against Lassa fever, but didn’t have enough sequence data to know for sure.

“I had gone to medical school, and we had never learned about Lassa fever,” Sabeti says. Yet here it was, linked to the strongest signal of selective pressure on the human genome. “I thought, this is the most interesting virus ever, and hardly anyone is studying it.”

So she and her group jumped in. They teamed up with molecular biologist Christian Happi, who now directs the African Centre of Excellence for Genomics of Infectious Diseases at Redeemer’s University in Nigeria, and together they set up collaborations with Lassa researchers at ISTH and KGH, training African scientists and providing research equipment and medical supplies. Already, Garry had established a training and research partnership with KGH, and virologist Stephan Günther at BNITM was beginning his long-term collaboration with researchers at ISTH.

From those partnerships came the deepest dive yet into Lassa virus genomics and evolution. With a large team of African, European, and U.S. researchers, Sabeti and Happi analyzed blood samples collected earlier from Lassa fever patients at ISTH and KGH and sequenced 183 viral genomes, as well as 11 more from M. natalensis field samples.

Their analysis of genetic variation among the viral sequences, published in Cell in 2015, confirmed previous suggestions that the virus has ancient origins, likely emerging in present-day Nigeria more than 1000 years ago, traveling westward to Guinea and Liberia about 400 years ago, and reaching Sierra Leone about 150 years ago.

It is also one of the most genetically diverse viruses known—an order of magnitude more diverse than the Ebolavirus, for example. Seven distinct lineages have been identified so far, and “the genetic diversity continues to rise,” Garry says. “When it pops up in a new place, it has changed.”

Each lineage is largely confined to a specific geographic area, suggesting the virus has been happily evolving and mutating in rodent populations that do not mix. “If you look at different viral lineages, they are very defined by river lines,” Sabeti says. She and others suspect some lineages may have evolved to become more virulent than others, which could help explain the severity of certain outbreaks. “A virus with that diversity has lots of ways it can go,” Sabeti says.

Now, in new work published 17 years after Sabeti’s initial observation, she, Happi, and colleagues report that the LARGE variant is associated with a reduced likelihood of getting Lassa fever in a Nigerian cohort, but not a Sierra Leonean one. Their new study, published this month in Nature Microbiology also sheds light on the long-standing mystery of why some people develop severe disease and some mild. They identified two human genetic variants associated with Lassa fever fatality, although more work is needed to nail down their possible roles.

THE EXPLOSIVE 2018 outbreak in Nigeria caught the hospital in Irrua off-guard. The Lassa Fever Isolation Ward was overflowing, Sylvanus Okogbenin recalls. “When the ward was full, we went to tents. When the tents were full, we moved into buildings that were not finished.”

To see whether the virus had recently mutated to become more virulent or more transmissible person to person, researchers at the Broad Institute and Redeemer’s quickly began to sequence viral genomes from patients, feeding the information in real time to NCDC. They found no evidence of a new, more virulent strain, just the same hodgepodge as from previous years, Happi says. And the data were consistent with multiple spillovers from rodents to humans, not increased human-to-human transmission.

And yet Lassa fever is clearly on the rise—and on the move: In the past few years, some states in northern Nigeria have reported cases for the first time. Mali, Togo, and Benin have all reported their first cases in the past decade.

If the virus hasn’t changed, what has? “Basically we don’t know fully,” says Danny Asogun, a public health physician at ISTH. Perhaps an increase in the number of rodents or the levels of virus they carry plays a role. Population growth, migration, crowding, and encroachment on wild lands are bringing people into closer contact with rodents, Asogun says. And new hosts, especially the Guinea multimammate mouse M. erythroleucus, which is also found in Nigeria, could be contributing, Fichet-Calvet says.

Researchers have long puzzled over why Lassa fever cases are concentrated in specific hot spots in just four endemic countries when M. natalensis is all over sub-Saharan Africa. If they can figure out what determines this fragmented distribution, they may be better able to predict what other areas are at risk. Explanations abound. Perhaps only certain subspecies of M. natalensis carry the Lassa virus. Or in some regions the rodents may be coinfected with other arenaviruses that outcompete Lassa. But most attention has focused on ecological factors that favor virus circulation, perhaps by influencing its survival outside the host, or rodent behavior. Rainfall and to a lesser extent temperature seem to be key, Fichet-Calvet and David Rogers of the University of Oxford proposed in a 2009 study.

Recent modeling by Raphaëlle Klitting and a team of international collaborators suggests current viral hot spots have a very particular combination of annual rainfall, annual temperature, and type of land cover.

All of those conditions could change as the climate does, so the researchers modeled the possible distribution of the Lassa-friendly habitats in the coming decades under three climate change scenarios, adding other factors such as the conversion of forests to agriculture and population growth.

By 2070, under a “moderate” climate change scenario, areas suitable for Lassa virus circulation could cover most of the region between Guinea and Nigeria. Susceptible regions could also appear for the first time in parts of Central and East Africa, Klitting’s team reported in 2022 in Nature Communications. In the worst case—that is, if the virus settles in all suitable habitats—by 2070 up to 700 million people could be at risk of Lassa fever, up from 92 million today. “This is not going to be a problem that goes away,” says Klitting, who is now head of genomics at the National Reference Center for Arboviruses in Marseille, France.

She suspects the virus is likely to move slowly, based on its past dispersal patterns. Then again, “We’ve seen Lassa virus move long distances in the past,” she says, citing its westward migration from Nigeria hundreds of years ago. And she notes that Ebola, considered a disease of Central Africa, suddenly emerged in West Africa in late 2013, with devastating effects. “We don’t know how often these big jumps happen,” she says, “but it could happen.”

WHEN IT COMES to countermeasures, “I think we have turned a corner,” Garry says. “When I started working on Lassa fever 20 years ago, there was nothing you could do.”

Now, several groups are developing affordable, rapid diagnostic tests for use in rural communities. A new small molecule drug, Favipiravir, which interferes with viral genome replication and is already licensed in Japan to treat influenza, has just finished a phase 2 trial for Lassa fever at ISTH. “It’s a huge, huge development, but it’s still early stages,” says Günther, a partner on the study. “Maybe in 5 to 7 years we might have several drugs with better efficacy than ribavirin.”

Meanwhile, CEPI is supporting the development of three vaccine candidates, each of which uses a viral vector to deliver a Lassa virus protein that triggers an immune response. CEPI aims to have one of these vaccines licensed in 5 to 10 years, Breugelmans says. Two are in phase 1 trials in healthy volunteers, and one may soon enter a larger phase 2 trial in several endemic countries. CEPI is also providing up to $40 million to support early work on a messenger RNA vaccine. Günther has a “very good feeling” about vaccines but cautions that “everything takes more time than you think in low-resource settings.” Access and affordability are issues. “Can we get vaccines and drugs to people who need them most?” Garry asks. Establishing vaccine manufacturing capabilities in Africa is part of the solution, Happi adds.

Complicating all these efforts is the genetic diversity of the virus. In the best case, diagnostics, drugs, and vaccines would work against all Lassa virus strains. So far vaccinemakers have focused on lineage IV, prevalent in Sierra Leone, Guinea, and Liberia, with the hope that the shots will be cross-protective. But only large-scale trials will tell.

Even without a specific drug, Nigeria has been making steady progress in reducing the death rate, thanks in part to better supportive care. ISTH has purchased dialysis machines, introduced an improved, lower dose regimen for ribavirin, and taken a new approach to treating pregnant women. Previous guidelines called for terminating the pregnancy to save the mother’s life, but Sylvanus Okogbenin and others have found that when the disease is still mild, supportive care can save both mother and fetus. The perinatal mortality rate, which was 80% to 95% in 2018, has dropped to 50% to 65%, he says.

But at 17.9%, the overall Lassa fever fatality rate in Nigeria “is still unacceptably high,” Adetifa says. “We want to bring it to the single digits.”

In Kenema, the rate is still 70%. Garry, Grant, and others think lineage IV, which circulates there, may be more virulent than the others. Late diagnosis could also be a factor, Garry says, or simply quality of care. Sierra Leone is one of the poorest countries in the world, and the government hospital cannot afford dialysis machines.

LAST YEAR WAS THE WORST on record for Lassa fever in Nigeria, with 9155 suspected cases, 1270 confirmed, and 227 deaths. ISTH was better prepared than in 2018, but it still had to open an overflow ward. The power supply was unstable, and clean linens and even soap were sometimes in short supply.

Already, case counts suggest this year will be even worse.

No one expects the Lassa virus to spark a global pandemic—unlike respiratory viruses such as SARS-CoV-2 or influenza that easily spread from one person to another. But for those who study the disease and treat its victims, the steady march of the disease is alarming. “Lassa fever is already in all of West Africa,” Sylvanus Okogbenin says. “That’s pandemic enough, really.”

Correction, 23 February, 5:10 p.m.: This story has been updated to correct the percentages of people in the Enable study who have antibodies to the virus in their blood.