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1.
J Infect Dis ; 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38801652

RESUMEN

Ebola virus (EBOV) infection results in Ebola virus disease (EVD), an often severe disease with a nonspecific presentation. Since its recognition, periodic outbreaks of EVD continue to occur in sub-Saharan Africa. The 2013-2016 West African EVD outbreak was the largest recorded, resulting in a substantial cohort of EVD survivors with persistent health complaints and variable immune responses. In this study, we characterize humoral immune responses in EVD survivors and their contacts in Eastern Sierra Leone. We found high levels of EBOV IgG in EVD survivors and lower yet substantial antibody levels in household contacts, suggesting subclinical transmission. Neutralizing antibody function was prevalent but variable in EVD survivors, raising questions about the durability of immune responses from natural infection with EBOV. Additionally, we found that certain discrete symptoms-ophthalmologic and auditory-are associated with EBOV IgG seropositivity, while an array of symptoms are associated with the presence of neutralizing antibody.

3.
Cell Rep Med ; 5(2): 101392, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38280377

RESUMEN

Lassa fever (LF) is an acute viral illness that causes thousands of deaths annually in West Africa. There are currently no Lassa virus (LASV) vaccines or antivirals approved for human use. Recently, we showed that combinations of broadly neutralizing human monoclonal antibodies (BNhuMAbs) known as Arevirumab-2 or Arevirumab-3 protected up to 100% of cynomolgus macaques against challenge with diverse lineages of LASV when treatment was initiated at advanced stages of disease. This previous work assessed efficacy against parenteral exposure. However, transmission of LASV to humans occurs primarily by mucosal exposure to virus shed from Mastomys rodents. Here, we describe the development of a lethal intranasal exposure macaque model of LF. This model is employed to show that Arevirumab cocktails rescue 100% of macaques from lethal LASV infection when treatment is initiated 8 days after LASV exposure. Our work demonstrates BNhuMAbs have utility in treating LASV infection acquired through mucosal exposure.


Asunto(s)
Fiebre de Lassa , Virus Lassa , Animales , Humanos , Fiebre de Lassa/tratamiento farmacológico , Fiebre de Lassa/prevención & control , Macaca fascicularis , Inmunoterapia , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico
4.
Emerg Microbes Infect ; 13(1): 2301061, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38164768

RESUMEN

Lassa virus (LASV) is a World Health Organization (WHO) priority pathogen that causes high morbidity and mortality. Recently, we showed that a combination of three broadly neutralizing human monoclonal antibodies known as Arevirumab-3 (8.9F, 12.1F, 37.2D) based on the lineage IV Josiah strain protected 100% of cynomolgus macaques against heterologous challenge with lineage II and III strains of LASV when therapy was initiated beginning at day 8 after challenge. LASV strains from Benin and Togo represent a new lineage VII that are more genetically diverse from lineage IV than strains from lineages II and III. Here, we tested the ability of Arevirumab-3 to protect macaques against a LASV lineage VII Togo isolate when treatment was administered beginning 8 days after exposure. Unexpectedly, only 40% of treated animals survived challenge. In a subsequent study we showed that Arevirumab-3 protected 100% of macaques from lethal challenge when treatment was initiated 7 days after LASV Togo exposure. Based on our transcriptomics data, successful Arevirumab-3 treatment correlated with diminished neutrophil signatures and the predicted development of T cell responses. As the in vitro antiviral activity of Arevirumab-3 against LASV Togo was equivalent to lineage II and III strains, the reduced protection in macaques against Togo likely reflects the faster disease course of LASV Togo in macaques than other strains. This data causes concern regarding the ability of heterologous vaccines and treatments to provide cross protection against lineage VII LASV isolates.


Asunto(s)
Fiebre de Lassa , Virus Lassa , Humanos , Animales , Virulencia , Macaca fascicularis , Anticuerpos Monoclonales/farmacología
5.
J Virol ; 98(1): e0179123, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38168672

RESUMEN

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.


Asunto(s)
Investigación Biomédica , Contención de Riesgos Biológicos , Virología , Humanos , COVID-19 , Estados Unidos , Virus , Investigación Biomédica/normas
6.
J Infect Dis ; 228(Suppl 6): S359-S375, 2023 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-37849403

RESUMEN

Lassa virus (LASV), Junin virus (JUNV), and several other members of the Arenaviridae family are capable of zoonotic transfer to humans and induction of severe viral hemorrhagic fevers. Despite the importance of arenaviruses as potential pandemic pathogens, numerous gaps exist in scientific knowledge pertaining to this diverse family, including gaps in understanding replication, immunosuppression, receptor usage, and elicitation of neutralizing antibody responses, that in turn complicates development of medical countermeasures. A further challenge to the development of medical countermeasures for arenaviruses is the requirement for use of animal models at high levels of biocontainment, where each model has distinct advantages and limitations depending on, availability of space, animals species-specific reagents, and most importantly the ability of the model to faithfully recapitulate human disease. Designation of LASV and JUNV as prototype pathogens can facilitate progress in addressing the public health challenges posed by members of this important virus family.


Asunto(s)
Arenaviridae , Virus Junin , Animales , Humanos , Replicación Viral , Virus Junin/fisiología , Virus Lassa , Modelos Animales
7.
bioRxiv ; 2023 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-37745602

RESUMEN

Zoonotic spillovers of viruses have occurred through the animal trade worldwide. The start of the COVID-19 pandemic was traced epidemiologically to the Huanan Wholesale Seafood Market, the site with the most reported wildlife vendors in the city of Wuhan, China. Here, we analyze publicly available qPCR and sequencing data from environmental samples collected in the Huanan market in early 2020. We demonstrate that the SARS-CoV-2 genetic diversity linked to this market is consistent with market emergence, and find increased SARS-CoV-2 positivity near and within a particular wildlife stall. We identify wildlife DNA in all SARS-CoV-2 positive samples from this stall. This includes species such as civets, bamboo rats, porcupines, hedgehogs, and one species, raccoon dogs, known to be capable of SARS-CoV-2 transmission. We also detect other animal viruses that infect raccoon dogs, civets, and bamboo rats. Combining metagenomic and phylogenetic approaches, we recover genotypes of market animals and compare them to those from other markets. This analysis provides the genetic basis for a short list of potential intermediate hosts of SARS-CoV-2 to prioritize for retrospective serological testing and viral sampling.

8.
Proc Natl Acad Sci U S A ; 120(34): e2304876120, 2023 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-37590417

RESUMEN

There are no approved treatments for Lassa fever (LF), which is responsible for thousands of deaths each year in West Africa. A major challenge in developing effective medical countermeasures against LF is the high diversity of circulating Lassa virus (LASV) strains with four recognized lineages and four proposed lineages. The recent resurgence of LASV in Nigeria caused by genetically distinct strains underscores this concern. Two LASV lineages (II and III) are dominant in Nigeria. Here, we show that combinations of two or three pan-lineage neutralizing human monoclonal antibodies (8.9F, 12.1F, 37.D) known as Arevirumab-2 or Arevirumab-3 can protect up to 100% of cynomolgus macaques against challenge with both lineage II and III LASV isolates when treatment is initiated at advanced stages of disease on day 8 after LASV exposure. This work demonstrates that it may be possible to develop postexposure interventions that can broadly protect against most strains of LASV.


Asunto(s)
Fiebre de Lassa , Virus Lassa , Animales , Humanos , Fiebre de Lassa/prevención & control , África Occidental , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Macaca fascicularis
9.
Curr Top Microbiol Immunol ; 440: 165-192, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37106159

RESUMEN

Lassa fever is caused by Lassa virus (LASV), an Old World Mammarenavirus that is carried by Mastomys natalensis and other rodents. It is endemic in Sierra Leone, Nigeria, and other countries in West Africa. The clinical presentation of LASV infection is heterogenous varying from an inapparent or mild illness to a fatal hemorrhagic fever. Exposure to LASV is usually through contact with rodent excreta. After an incubation period of 1-3 weeks, initial symptoms such as fever, headache, and fatigue develop that may progress to sore throat, retrosternal chest pain, conjunctival injection, vomiting, diarrhea, and abdominal pain. Severe illness, including hypotension, shock, and multiorgan failure, develops in a minority of patients. Patient demographics and case fatality rates are distinctly different in Sierra Leone and Nigeria. Laboratory diagnosis relies on the detection of LASV antigens or genomic RNA. LASV-specific immunoglobulin G and M assays can also contribute to clinical management. The mainstay of treatment for Lassa fever is supportive care. The nucleoside analog ribavirin is commonly used to treat acute Lassa fever but is considered useful only if treatment is begun early in the disease course. Drugs in development, including a monoclonal antibody cocktail, have the potential to impact the management of Lassa fever.


Asunto(s)
Fiebre de Lassa , Humanos , Fiebre de Lassa/diagnóstico , Fiebre de Lassa/tratamiento farmacológico , Fiebre de Lassa/epidemiología , Virus Lassa/genética , África Occidental , Sierra Leona/epidemiología , Anticuerpos Antivirales
10.
Curr Top Microbiol Immunol ; 440: 147-164, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37100973

RESUMEN

Lassa virus (LASV) is the causative agent of Lassa fever, an often-fatal hemorrhagic fever that is endemic in West Africa. LASV virions are enveloped and contain two single-stranded RNA genome segments. Both segments are ambisense and encode two proteins. The nucleoprotein associates with viral RNAs forming ribonucleoprotein complexes. The glycoprotein complex mediates viral attachment and entry. The Zinc protein serves as the matrix protein. Large is a polymerase that catalyzes viral RNA transcription and replication. LASV virion entry occurs via a clathrin-independent endocytic pathway usually involving alpha-dystroglycan and lysosomal associated membrane protein 1 as surface and intracellular receptors, respectively. Advances in understanding LASV structural biology and replication have facilitated development of promising vaccine and drug candidates.


Asunto(s)
Fiebre de Lassa , Virus Lassa , Humanos , Virus Lassa/genética , Virus Lassa/metabolismo , Fiebre de Lassa/prevención & control , Biología , África Occidental
11.
medRxiv ; 2023 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-36993465

RESUMEN

Background: Lassa fever (LF) is a rodent-borne disease endemic to West Africa. In the absence of licensed therapeutics or vaccines, rodent exclusion from living spaces remains the primary method of preventing LF. Zoonotic surveillance of Lassa virus (LASV), the etiologic agent of LF, can assess the burden of LASV in a region and guide public health measures against LF. Methods: In this study, we adapted commercially available LASV human diagnostics to assess the prevalence of LASV in peri-domestic rodents in Eastern Sierra Leone. Small mammal trapping was conducted in Kenema district, Sierra Leone between November 2018-July 2019. LASV antigen was detected using a commercially available LASV NP antigen rapid diagnostic test. LASV IgG antibodies against LASV nucleoprotein (NP) and glycoprotein (GP) were tested by adapting a commercially available semi-quantitative enzyme linked immunosorbent assay (ELISA) for detection of mouse-related and rat-related species IgG. Findings: Of the 373 tested specimens, 74 (20%) tested positive for LASV antigen. 40 (11%) specimens tested positive for LASV NP IgG, while an additional 12 (3%) specimens only tested positive for LASV GP IgG. Simultaneous antigen presence and IgG antibody presence was linked in Mastomys sp. specimens (p < 0.01), but not Rattus sp. specimens (p = 1). Despite the link between antigen presence and IgG antibody presence in Mastomys sp., the strength of antigen response did not correlate with the strength of IgG response to either GP IgG or NP IgG. Interpretation: The tools developed in this study can aid in the generation of valuable public health data for rapid field assessment of LASV burden during outbreak investigations and general LASV surveillance. Funding: Funding for this work was supported by the National Institute of Allergy and Infectious Diseases National Institute of Health, Department of Health and Human Services under the following grants: International Collaboration in Infectious Disease Research on Lassa fever and Ebola - ICIDR - U19 AI115589, Consortium for Viral Systems Biology - CViSB - 5U19AI135995, West African Emerging Infectious Disease Research Center - WARN-ID - U01AI151812, West African Center for Emerging Infectious Diseases: U01AI151801.

12.
PLoS One ; 18(3): e0283643, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36996258

RESUMEN

BACKGROUND: Lassa fever (LF), a haemorrhagic illness caused by the Lassa fever virus (LASV), is endemic in West Africa and causes 5000 fatalities every year. The true prevalence and incidence rates of LF are unknown as infections are often asymptomatic, clinical presentations are varied, and surveillance systems are not robust. The aim of the Enable Lassa research programme is to estimate the incidences of LASV infection and LF disease in five West African countries. The core protocol described here harmonises key study components, such as eligibility criteria, case definitions, outcome measures, and laboratory tests, which will maximise the comparability of data for between-country analyses. METHOD: We are conducting a prospective cohort study in Benin, Guinea, Liberia, Nigeria (three sites), and Sierra Leone from 2020 to 2023, with 24 months of follow-up. Each site will assess the incidence of LASV infection, LF disease, or both. When both incidences are assessed the LASV cohort (nmin = 1000 per site) will be drawn from the LF cohort (nmin = 5000 per site). During recruitment participants will complete questionnaires on household composition, socioeconomic status, demographic characteristics, and LF history, and blood samples will be collected to determine IgG LASV serostatus. LF disease cohort participants will be contacted biweekly to identify acute febrile cases, from whom blood samples will be drawn to test for active LASV infection using RT-PCR. Symptom and treatment data will be abstracted from medical records of LF cases. LF survivors will be followed up after four months to assess sequelae, specifically sensorineural hearing loss. LASV infection cohort participants will be asked for a blood sample every six months to assess LASV serostatus (IgG and IgM). DISCUSSION: Data on LASV infection and LF disease incidence in West Africa from this research programme will determine the feasibility of future Phase IIb or III clinical trials for LF vaccine candidates.


Asunto(s)
Fiebre de Lassa , Humanos , Estudios de Cohortes , Inmunoglobulina G , Incidencia , Fiebre de Lassa/epidemiología , Fiebre de Lassa/diagnóstico , Virus Lassa , Liberia , Estudios Prospectivos , Estudios Multicéntricos como Asunto
13.
PLoS Negl Trop Dis ; 17(2): e0010938, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36758101

RESUMEN

BACKGROUND: Lassa virus (LASV), the cause of the acute viral hemorrhagic illness Lassa fever (LF), is endemic in West Africa. Infections in humans occur mainly after exposure to infected excrement or urine of the rodent-host, Mastomys natalensis. The prevalence of exposure to LASV in Sierra Leone is crudely estimated and largely unknown. This cross-sectional study aimed to establish a baseline point seroprevalence of IgG antibodies to LASV in three administrative districts of Sierra Leone and identify potential risk factors for seropositivity and LASV exposure. METHODOLOGY AND PRINCIPAL FINDINGS: Between 2015 and 2018, over 10,642 participants from Kenema, Tonkolili, and Port Loko Districts were enrolled in this cross-sectional study. Previous LASV and LF epidemiological studies support classification of these districts as "endemic," "emerging," and "non-endemic", respectively. Dried blood spot samples were tested for LASV antibodies by ELISA to determine the seropositivity of participants, indicating previous exposure to LASV. Surveys were administered to each participant to assess demographic and environmental factors associated with a higher risk of exposure to LASV. Overall seroprevalence for antibodies to LASV was 16.0%. In Kenema, Port Loko, and Tonkolili Districts, seroprevalences were 20.1%, 14.1%, and 10.6%, respectively. In a multivariate analysis, individuals were more likely to be LASV seropositive if they were living in Kenema District, regardless of sex, age, or occupation. Environmental factors contributed to an increased risk of LASV exposure, including poor housing construction and proximity to bushland, forested areas, and refuse. CONCLUSIONS AND SIGNIFICANCE: In this study we determine a baseline LASV seroprevalence in three districts which will inform future epidemiological, ecological, and clinical studies on LF and the LASV in Sierra Leone. The heterogeneity of the distribution of LASV and LF over both space, and time, can make the design of efficacy trials and intervention programs difficult. Having more studies on the prevalence of LASV and identifying potential hyper-endemic areas will greatly increase the awareness of LF and improve targeted control programs related to LASV.


Asunto(s)
Fiebre de Lassa , Virosis , Animales , Humanos , Sierra Leona/epidemiología , Estudios Transversales , Estudios Seroepidemiológicos , Fiebre de Lassa/epidemiología , Virus Lassa , Murinae , Anticuerpos Antivirales , Inmunoglobulina G
14.
Curr Top Microbiol Immunol ; 440: 1-22, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-32458151

RESUMEN

Lassa fever was first described as a clinical entity fifty years ago. The causative agent Lassa virus was isolated from these first known cases. This chapter reviews the key publications on Lassa fever research that appeared in the scientific literature at that time and over the ensuing decades.


Asunto(s)
Fiebre de Lassa , Humanos , Fiebre de Lassa/diagnóstico , Virus Lassa/genética
15.
Nat Rev Microbiol ; 21(2): 87-96, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36097163

RESUMEN

Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in Lassa fever, a viral haemorrhagic fever (VHF) associated with a high case fatality rate. Despite advances, fundamental gaps in knowledge of the immunology, epidemiology, ecology and pathogenesis of Lassa fever persist. More frequent outbreaks, the potential for further geographic expansion of Mastomys natalensis and other rodent reservoirs, the ease of procurement and possible use and weaponization of LASV, the frequent importation of LASV to North America and Europe, and the emergence of novel LASV strains in densely populated West Africa have driven new initiatives to develop countermeasures for LASV. Although promising candidates are being evaluated, as yet there are no approved vaccines or therapeutics for human use. This Review discusses the virology of LASV, the clinical course of Lassa fever and the progress towards developing medical countermeasures.


Asunto(s)
Fiebre de Lassa , Vacunas Virales , Humanos , Fiebre de Lassa/epidemiología , Fiebre de Lassa/prevención & control , Virus Lassa , África Occidental/epidemiología
17.
PLoS Negl Trop Dis ; 16(11): e0010882, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36441765

RESUMEN

INTRODUCTION: Lassa virus is a priority pathogen for vaccine research and development, however the duration of cellular immunity and protection in Lassa fever (LF) survivors remains unclear. METHODS: We investigated Lassa virus specific CD8+ T cell responses in 93 LF survivors. Peripheral blood mononuclear cells from these individuals were infected with recombinant vesicular stomatitis virus encoding Lassa virus antigens and virus specific T cell responses were measured after 18-hour incubation. Participants who had undetectable CD8+ T cell response underwent further analysis using a 10-day T cell proliferation assays to evaluate for low T cell precursor frequency. RESULTS: Forty-five of the 93 LF survivors did not have a Lassa virus specific CD8+ T cell response. Of those with responses and a known date of onset of LF (N = 11), 9 had LF within the last ten years. Most participants without a measurable CD8+ T cell response were more than 10 years removed from a clinical history of LF (N = 14/16). Fourteen of 21 patients (67%) with undetectable CD8+ T cell response had a measurable Lassa virus specific CD8+ T cell response with the 10-day assay. DISCUSSION: Despite reports of strong CD8+ T cell responses during acute Lassa virus infection, circulating Lassa virus-specific CD8+ T cells declined to undetectable levels in most Lassa fever survivors after ten years when evaluated with an 18-hour T cell stimulation. However, when Lassa virus-specific T cells were expanded prior to restimulation, a Lassa virus-specific CD8+ T cell response could be detected in many if the samples that were negative in the 18-hour stimulation assay, suggesting that prolonged cellular immunity does exist in Lassa fever survivors at low frequencies.


Asunto(s)
Fiebre de Lassa , Células Precursoras de Linfocitos T , Humanos , Virus Lassa , Leucocitos Mononucleares , Inmunidad , Linfocitos T CD8-positivos
18.
Sci Transl Med ; 14(668): eabq0991, 2022 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-36288283

RESUMEN

Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.


Asunto(s)
Fiebre de Lassa , Vacunas Virales , Animales , Humanos , Virus Lassa , Microscopía por Crioelectrón , Anticuerpos Neutralizantes , Epítopos , Glicoproteínas , Polisacáridos , Antivirales , Mamíferos
19.
Proc Natl Acad Sci U S A ; 119(40): e2211107119, 2022 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-36173950

Asunto(s)
COVID-19 , Furina , Humanos , SARS-CoV-2
20.
Nat Commun ; 13(1): 5596, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-36167835

RESUMEN

Lassa fever is a severe viral hemorrhagic fever caused by a zoonotic virus that repeatedly spills over to humans from its rodent reservoirs. It is currently not known how climate and land use changes could affect the endemic area of this virus, currently limited to parts of West Africa. By exploring the environmental data associated with virus occurrence using ecological niche modelling, we show how temperature, precipitation and the presence of pastures determine ecological suitability for virus circulation. Based on projections of climate, land use, and population changes, we find that regions in Central and East Africa will likely become suitable for Lassa virus over the next decades and estimate that the total population living in ecological conditions that are suitable for Lassa virus circulation may drastically increase by 2070. By analysing geotagged viral genomes using spatially-explicit phylogeography and simulating virus dispersal, we find that in the event of Lassa virus being introduced into a new suitable region, its spread might remain spatially limited over the first decades.


Asunto(s)
Fiebre de Lassa , Virus Lassa , Animales , Humanos , Fiebre de Lassa/epidemiología , Virus Lassa/genética , Filogeografía , Factores de Riesgo , Roedores
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