Model overview
We developed an epidemiological model projecting human Lassa fever burden over a 10-year time horizon across the 15 countries of continental West Africa (Benin, Burkina Faso, Côte d’Ivoire, The Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Mali, Mauritania, Niger, Nigeria, Senegal, Sierra Leone and Togo) and their 183 level 1 subnational administrative units. These units have different names in different countries (for example, regions in Guinea, counties in Liberia and departments in Benin) but herein are collectively referred to as ‘districts’. Due to large gaps in Lassa fever surveillance and limited case reporting throughout much of its endemic range3, we favored a bottom-up modeling approach, synthesizing best available ecological, epidemiological, clinical and economic data to project the cumulative health and economic burden of disease.
Our model consists of six main components (see model schematic in Extended Data Fig. 1). First, a previously published geospatial risk map was used to predict the risk of zoonotic LASV transmission from M. natalensis to humans (‘spillover’) at the level of 0.05° × 0.05° spatial pixels throughout West Africa14. Second, modeled spillover risk estimates were used as inputs in a generalized linear model (GLM) to predict human LASV seroprevalence. Third, modeled human LASV seroprevalence estimates were used as inputs in a serocatalytic model including country-level population projections to predict spillover infection incidence. Fourth, spillover infections were aggregated at the district level, and a stochastic branching process model was used to simulate onward human-to-human LASV transmission. Fifth, a computational algorithm was applied retrospectively to spillover infections and ensuing transmission chains to simulate a range of reactive and preventive vaccination campaigns and to project the number of infections averted by vaccination. (Separate model components used to simulate Lassa-X transmission and vaccination are described below.) Sixth, modeled estimates of LASV infection, and of infections averted due to vaccination or occurring in vaccinated individuals, were used as inputs in a probabilistic decision-analytic model used to project the health burden of Lassa fever and associated economic costs and the health and economic burden averted due to vaccination over 10 years.
Lassa fever burden
Our model predicts a heterogeneous distribution of zoonotic LASV infection throughout West Africa (Fig. 1). In the absence of vaccination, the mean annual number of LASV infections throughout the region was estimated at 2.7 million (95% uncertainty interval (UI): 2.1–3.4 million) or 27.2 million (20.9–34.0 million) over the full 10-year simulation period (Extended Data Table 1). Just over half of all infections occurred in Nigeria (mean, 52.9%), and the vast majority (mean, 93.7%) resulted from zoonotic spillover as opposed to human-to-human transmission, due to LASV’s low estimated basic reproduction number (R0). At the district level, annual LASV infection incidence was highest in Margibi, Liberia (1,198 (943–1,475) infections per 100,000 population), followed by Denguélé, Côte d’Ivoire (1,032 (880–1,200) per 100,000 population) and Nasarawa, Nigeria (978 (803–1,162) per 100,000 population). Over 10 years, LASV infection throughout West Africa led to an estimated 5.4 million (2.7–9.9 million) mild/moderate symptomatic cases, 237,000 (148,600–345,600) hospitalizations and 39,300 (12,900–83,300) deaths, resulting in 2.0 million (793,800–3.9 million) disability-adjusted life years (DALYs). See Supplementary Appendix E for more detailed estimates of Lassa fever burden.
Fig. 1: Maps of West Africa showing reported Lassa fever endemicity and estimated LASV spillover incidence.
Top, map showing the classification of Lassa fever endemicity for different countries and ‘districts’, as defined by the US CDC and the WHO (Supplementary Appendix C.2). Middle, the median annual incidence of zoonotic LASV infection per 100,000 population as estimated by our model at the level of 5-km grid cells. Bottom, the median total annual number of zoonotic LASV infections as estimated by our model at the level of 5-km grid cells.
Over 10 years, Lassa fever treatment was projected to incur $338.9 million ($206.6–$506.3 million) in government-reimbursed treatment costs and $166.9 million ($116.0–$289.3 million) in out-of-pocket medical costs, resulting in catastrophic expenditures for 232,300 (145,600–338,700) individuals and pushing 167,000 (104,700–243,600) individuals below the international poverty line (Supplementary Tables E.3 and E.4). Missed work due to illness totaled $1.1 billion ($380.5 million–$2.2 billion) in productivity losses, primarily due to mortality in actively employed adults. Productivity losses outranked treatment costs in driving an estimated $1.6 billion ($805.1 million–$2.8 billion) in total cumulative societal costs. Hospitalization costs, not outpatient costs, were the main driver of treatment costs, but mild to moderate disease in the community resulted in greater productivity losses than severe disease in hospital (Supplementary Fig. E.2). Lassa fever DALYs were valued at $287.7 million ($115.4–$562.9 million) using country-specific cost-effectiveness thresholds. Finally, an alternative measure of Lassa fever’s economic burden, the value of statistical life (VSL) lost due to Lassa fever mortality, was projected at $15.3 billion ($5.0–$32.4 billion). Uncertainty in health-economic outcomes was primarily driven by uncertainty in risks of hospitalization and death (Supplementary Fig. D.2)
Simulating Lassa vaccination campaigns
Vaccination is introduced into the population via a series of six scenarios designed to reflect realistic assumptions about vaccine stockpile, administration and efficacy (Extended Data Table 2). In all six scenarios, we include reactive vaccination, in which Lassa fever outbreaks trigger the local deployment of a limited vaccine stockpile in affected districts. In scenarios 2–6, we also include preventive vaccination in the form of mass, population-wide campaigns rolled out over 3 years and focusing primarily on regions classified as Lassa fever ‘endemic’. The 15 countries included in our model are categorized as high endemic, medium endemic or low endemic according to classifications published by the US Centers for Disease Control and Prevention (CDC), and districts within high-endemic countries are further classified as endemic or non-endemic according to classifications published by the WHO (Fig. 1 and Supplementary Appendix C.2). Two main mechanisms of vaccine efficacy are considered: protection against infection prevents individuals from acquiring LASV infection from either M. natalensis or other humans, and protection against disease prevents vaccinated individuals who become infected from progressing to disease, thus averting outpatient consultation, hospitalization, chronic sequelae and death. In our simulations, we project impacts of a vaccine that is 70% or 90% effective only against disease or 70% or 90% effective against both infection and disease. We do not consider other potential mechanistic impacts of vaccination, such as reduced infectiousness or altered behavior among vaccinated individuals, as such factors are less relevant given low estimated rates of human-to-human LASV transmission.
Health-economic impacts of vaccination against Lassa fever
The considered vaccination scenarios varied considerably in their projected impacts, with scenario 4 leading to the greatest reductions in Lassa fever burden over 10 years (Extended Data Fig. 2 and Table 2). In this scenario, in addition to reactive vaccination triggered in districts experiencing local outbreaks, preventive vaccination was administered to 80% of the population in WHO-classified endemic districts as well as to 5% of the population in all other districts throughout West Africa. For a vaccine 70% effective against disease with no impact on infection, over 10 years this strategy averted a mean 456,000 (226,400–822,700) mild/moderate symptomatic cases, 19,900 (12,700–28,800) hospitalizations, 3,300 (1,100–7,000) deaths and 164,100 (66,700–317,700) DALYs. Over this period, this strategy further prevented 19,800 (12,600–28,500) and 14,200 (9,000–20,500) individuals, respectively, from experiencing catastrophic or impoverishing out-of-pocket healthcare expenditures and averted $128.2 million ($67.2–$231.9 million) in societal costs, or $1.3 billion ($436.8 million–$2.8 billion) in VSL lost.
Table 2 Projected 10-year impacts of Lassa vaccination
Other vaccination scenarios used fewer doses of vaccine and, in turn, averted less of Lassa fever’s health-economic burden. Scenario 3, which limited preventive vaccination to high-endemic countries, was the scenario resulting in the second greatest health-economic benefits, including the aversion of 141,400 (57,600–273,200) DALYs and $112.8 million ($59.2–$203.8 million) in societal costs. Scenarios 2, 5 and 6 varied considerably in terms of which individuals were vaccinated but ultimately resulted in similar cumulative health-economic benefits across the region, because the overall number of doses delivered under each scenario was essentially the same. By contrast, scenario 1 included only reactive and not preventive vaccination, averting just 13,700 (5,500–26,800) DALYs and $10.3 million ($5.3–$18.8 million) in societal costs, thus having approximately one-tenth the overall health-economic benefits of scenario 4.
A vaccine effective against infection in addition to disease was found to have moderately increased impact. In scenario 4, for instance, $20.1 million ($8.2–$39.0 million) in DALY value was averted by a vaccine 70% effective only against disease, whereas $27.1 million ($11.0–$52.5 million) was averted when also 70% effective against infection (Table 2). By comparison, a vaccine 90% effective only against disease averted $25.8 million ($10.5–$50.1 million) in DALY value (Supplementary Table E.9), having similar impact to a vaccine 70% effective against both infection and disease. In the best-case scenario of a vaccine 90% effective against both infection and disease, scenario 4 averted up to 3.1 million (2.4–3.7 million) infections, 240,100 (97,500–464,900) DALYs valued at $29.5 million ($12.0–$57.2 million) and $1.9 billion ($638.5 million–$4.1 billion) in VSL lost.
Geographic variation in vaccine impact depended primarily on which districts were classified as endemic and, hence, targeted for vaccination (Extended Data Fig. 2). Overall impacts of vaccination were greatest in Nigeria, but impacts per 100,000 population were greatest in other endemic countries (Guinea, Liberia and Sierra Leone), because Nigeria had a larger number of individuals but a smaller share of its total population living in districts classified as endemic. In turn, approximately 16% of the total population of Nigeria and 33% of the combined population of Guinea, Liberia and Sierra Leone were vaccinated by 10 years under scenarios 3 and 4 (Fig. 2). Given a vaccine 70% effective only against disease, these scenarios averted 10.5% of DALYs in Nigeria, 20.3% of DALYs in Liberia, 23.6% of DALYs in Guinea and 28.1% of DALYs in Sierra Leone. For a vaccine 90% effective against infection and disease, these scenarios averted 15.3% of DALYs in Nigeria, 29.4% of DALYs in Liberia, 34.1% of DALYs in Guinea and 40.7% of DALYs in Sierra Leone.
Fig. 2: Vaccination coverage and corresponding reductions in Lassa fever burden vary greatly across countries.
a, Share of the total population vaccinated by 10 years in each vaccination scenario (x axis) and aggregated across three geographic levels (y axis). b, Share of cumulative DALYs due to Lassa fever averted over 10 years by vaccination. Impacts vary greatly depending on the vaccination scenario (x axis), the assumed vaccine efficacy (y axis) and the geographic location (panels).
Threshold vaccine costs
Projected economic benefits of Lassa vaccination were used to calculate the threshold vaccine cost (TVC). This can be interpreted as the maximum cost per dose at which vaccination has a benefit-to-cost ratio above 1, in the specific context of our modeled vaccination campaigns and corresponding dosage assumptions (that is, a single-dose primary series followed by a single-dose booster after 5 years, with 10% dose wastage). TVCs were similar across all five preventive campaigns (scenarios 2–6) but lower for reactive vaccination (scenario 1) (Supplementary Table E.12). Estimated TVCs ranged from $0.51 ($0.30–$0.80) to $21.15 ($7.28–$43.97) depending on the economic perspective considered, the vaccination campaign evaluated and the vaccine’s efficacy against infection and disease. TVCs were lowest from the perspective considering only healthcare costs and monetized DALYs (range of means, $0.51–$0.91) but more than doubled given a perspective considering all societal costs (healthcare costs and productivity losses) in addition to monetized DALYs ($1.18–$2.20) and increased by more than 20-fold when considering healthcare costs and VSL ($10.54–$21.15).
Modeling ‘Lassa-X’
In addition to our analysis of Lassa fever, we modeled the emergence of ‘Lassa-X’, a hypothetical future variant of LASV with pandemic potential due to both elevated clinical severity and increased propensity for human-to-human transmission. In this analysis, Lassa-X was assumed to emerge in humans after a single spillover event, where the probability of emergence in each district is directly proportional to the estimated share of all zoonotic LASV infections occurring in each district. We assumed that prior LASV immunity, whether natural or vaccine derived, offers no protection against Lassa-X. We conceptualized Lassa-X as having Ebola-like transmission characteristics and, under baseline assumptions, a 10-fold increase in hospitalization risk relative to Lassa fever. Lassa-X transmission parameters were quantified using Ebola case data from the 2013/2016 West Africa epidemic, resulting in simulated Lassa-X outbreaks lasting for approximately 2 years before subsiding. A range of reactive 100 Days Mission vaccination scenarios were then evaluated, considering different delays to vaccine initiation, rates of vaccine uptake and degrees of efficacy against infection and disease. Finally, as for Lassa fever, we used a probabilistic decision-analytic model to project the health and economic burden of Lassa-X and burden averted as a result of vaccination.
Projected burden of Lassa-X
Under our modeling assumptions, the emergence of Lassa-X led to explosive outbreaks throughout West Africa (Fig. 3), spreading to 88.3% (63.9%–94.0%) of the 183 districts included in our model (Supplementary Fig. F.1). In total, there were 1.7 million (230,100–4.2 million) Lassa-X infections, and Nigeria accounted for by far the greatest share of infections, followed by Niger and Ghana (Supplementary Tables G.1 and G.2). The projected burden of Lassa-X infection was associated with a high degree of uncertainty, driven predominantly by the highly stochastic nature of simulated outbreaks (Supplementary Fig. G.2).
Fig. 3: Projected burden of Lassa-X infection and impacts of vaccination.
a–c, Maps of West Africa showing, for each district: the population size (a), the probability of Lassa-X spillover (b) and the mean cumulative number of Lassa-X infections over the entire outbreak (approximately 2 years) (c). d,e, The second row depicts the median cumulative incidence of Lassa-X infection over the entire outbreak (d) and the median cumulative incidence over the entire outbreak per 100,000 population in the absence of vaccination (e). Interquartile ranges are indicated by error bars (n = 10,000). f, The total number of Lassa-X infections over time in six selected countries in one randomly selected outbreak simulation in which the initial Lassa-X spillover event occurred in Niger (the red dot highlights the initial detection of the epidemic at time 0). Lines show how a vaccine with 70% efficacy against infection and disease influences infection dynamics, where line color represents the delay to vaccine rollout, and line dashing represents the rate of vaccination (the proportion of the population vaccinated over a 1-year period). g, The mean cumulative number of deaths averted due to vaccination over the entire outbreak and across all countries, depending on vaccine efficacy (panels), the rate of vaccination (x axis) and the delay to vaccine rollout (colors). Interquartile ranges are indicated by error bars (n = 10,000). yr, year.
In our baseline analysis, Lassa-X resulted in 149,700 (19,700–374,400) hospitalizations and 24,800 (2,400–76,000) deaths, causing 1.2 million (132,500–3.7 million) DALYs valued at $191.1 million ($18.4–$575.2 million). Out-of-pocket treatment costs were estimated at $118.5 million ($12.2–$317.3 million), resulting in catastrophic healthcare expenditures for 147,400 (18,500–372,500) individuals and pushing 103,100 (13,600–254,300) individuals below the poverty line. Lassa-X also resulted in $737.2 million ($56.4 million–$2.4 billion) in productivity losses to the greater economy and $10.1 billion ($625.9 million–$34.1 billion) in VSL lost. In alternative scenarios where Lassa-X infection was just as likely or one-tenth as likely to result in hospitalization as LASV infection, estimates of the health-economic burden were approximately one and two orders of magnitude lower, respectively (Supplementary Table G.4).
Vaccination to slow the spread of Lassa-X
Impacts of vaccination on the health-economic burden of Lassa-X depend on the delay until vaccination initiation, the rate of vaccine uptake in the population and the efficacy of vaccination against infection and/or disease (Table 3). In the most ambitious vaccination scenario considered, vaccine administration began 100 d after initial detection of the first hospitalized case of Lassa-X at a rate equivalent to 40% of the population per year across all countries in West Africa. Assuming a vaccine 70% effective only against disease, this vaccination scenario averted 276,600 (38,000–755,900) DALYs. However, in contrast to LASV vaccination, vaccine impact was more than three-fold greater when effective against infection as well as disease. For a vaccine 70% effective against both, this most ambitious vaccination scenario averted 1.2 million (201,300–2.7 million) infections and 916,400 (108,000–2.6 million) DALYs, representing approximately 74% of the DALY burden imposed by Lassa-X. Vaccinating at half the rate (20% of the population per year) averted approximately 55% of the DALYs imposed by Lassa-X, whereas vaccinating at a low rate (2.5% of the population per year) averted just 11% of DALYs (Supplementary Tables G.5–G.8). Benefits of delivering vaccines at a higher rate outweighed benefits of initiating vaccination earlier (100 d versus 160 d from outbreak detection), which, in turn, outweighed benefits of a vaccine with greater efficacy against infection and disease (90% versus 70%).
Table 3 Projected impacts of 100 Days Mission vaccination campaigns in response to Lassa-X
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