Ribavirin for Lassa Fever Postexposure Prophylaxis

Hadi, Christiane; Goba, Augustine; Khan, Sheik Humarr; Bangura, James; Sankoh, Mbalu; Koroma, S B; Juana, Baindu; Bah, Alpha Oumar; Coulibaly, Mamadou B.; Bausch, Daniel G.

doi:10.3201/eid1612.100994

Cited by 47 publications

(26 citation statements)

References 7 publications

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“…Likewise, several arenaviruses pose credible biodefense threats (14). Concerns about human-pathogenic arenaviruses are exacerbated because there are no FDA-licensed arenavirus vaccines (15) and current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective (16)(17)(18). Therefore, it is important to develop novel antiviral strategies to combat human-pathogenic arenaviruses.…”

mentioning

confidence: 99%

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

Iwasaki

Cubitt

Sullivan

et al. 2016

J Virol

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Hemorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. We have recently shown that the noncoding intergenic region (IGR) present in each arenavirus genome segment, the S and L segments (S-IGR and L-IGR, respectively), plays important roles in the control of virus protein expression and that this knowledge could be harnessed for the development of live-attenuated vaccine strains to combat HFAs. In this study, we further investigated the sequence plasticity of the arenavirus IGR. We demonstrate that recombinants of the prototypic arenavirus lymphocytic choriomeningitis virus (rLCMVs), whose S-IGRs were replaced by the S-IGR of Lassa virus (LASV) or an entirely nonviral S-IGR-like sequence (Ssyn), are viable, indicating that the function of S-IGR tolerates a high degree of sequence plasticity. In addition, rLCMVs whose L-IGRs were replaced by Ssyn or S-IGRs of the very distantly related reptarenavirus Golden Gate virus (GGV) were viable and severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. Our findings indicate that replacement of L-IGR by a nonviral Ssyn could serve as a universal molecular determinant of arenavirus attenuation. IMPORTANCEHemorrhagic fever arenaviruses (HFAs) cause high rates of morbidity and mortality and pose important public health problems in regions where they are endemic. Implementation of live-attenuated vaccines (LAVs) will represent a major step to combat HFAs. Here we document that the arenavirus noncoding intergenic region (IGR) has a high degree of plasticity compatible with virus viability. This observation led us to generate recombinant LCMVs containing nonviral synthetic IGRs. These rLCMVs were severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. These nonviral synthetic IGRs can be used as universal molecular determinants of arenavirus attenuation for the rapid development of safe and effective, as well as stable, LAVs to combat HFA. H emorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic (1-3). Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, resulting in a high number of Lassa fever (LF) cases, which are associated with high rates of morbidity and significant mortality (4). Notably, increased travel has led to the importation of LF cases into metropolitan areas around the globe where the virus is not endemic (5, 6). Moreover, the regions where LASV is endemic are expanding (4), and the association of the recently identified arenavirus Lujo virus with a recent outbreak of hemorrhagic fever in South Africa (7, 8) has raised concerns about the emergence of novel HF...

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mentioning

confidence: 99%

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

Iwasaki

Cubitt

Sullivan

et al. 2016

J Virol

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“…Likewise, several arenaviruses, including LASV and LCMV, pose credible biodefense threats (14). Concerns about humanpathogenic arenaviruses are exacerbated because there are no FDA-licensed arenavirus vaccines (15), and current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective (16)(17)(18). Because live-attenuated vaccines (LAV) induce robust cellular and humoral immune responses following a single immunization, they represent the most feasible approach to control LASV in West Africa and other emergent HFA (19).…”

mentioning

confidence: 99%

General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

Iwasaki

Ngo

Cubitt

et al. 2015

J Virol

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Hemorrhagic fever arenaviruses (HFA) pose important public health problems in regions where they are endemic. Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, causing a large number of Lassa fever cases associated with high morbidity and mortality. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. The Mopeia virus (MOPV)/LASV reassortant (ML29) is a LASV candidate live-attenuated vaccine (LAV) that has shown promising results in animal models. Nevertheless, the mechanism of ML29 attenuation remains unknown, which raises concerns about the phenotypic stability of ML29 in response to additional mutations. Development of LAVs based on well-defined molecular mechanisms of attenuation will represent a major step in combatting HFA. We used the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) to develop a general molecular strategy for arenavirus attenuation. Our approach involved replacement of the noncoding intergenic region (IGR) of the L genome segment with the IGR of the S genome segment to generate a recombinant LCMV, rLCMV(IGR/S-S), that was highly attenuated in vivo but induced protection against a lethal challenge with wild-type LCMV. Attenuation of rLCMV(IGR/S-S) was associated with a stable reorganization of the control of viral gene expression. This strategy can facilitate the rapid development of LAVs with the antigenic composition of the parental HFA and a mechanism of attenuation that minimizes concerns about increased virulence that could be caused by genetic changes in the LAV. IMPORTANCEHemorrhagic fever arenaviruses (HFA) cause high morbidity and mortality, and pose important public health problems in the regions where they are endemic. Implementation of live-attenuated vaccines (LAV) will represent a major step in combatting HFA. Here we have used the prototypic arenavirus LCMV to document a general molecular strategy for arenavirus attenuation that can facilitate the rapid development of safe and effective, as well as stable, LAV to combat HFA. Hemorrhagic fever arenaviruses (HFA) pose important public health problems in the regions where they are endemic (1-3). Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, resulting in a high number of Lassa fever (LF) cases associated with high morbidity and significant mortality (4). Notably, increased traveling has led to the importation of LF cases into metropolitan areas around the globe where the virus is not endemic (5, 6). Moreover, regions of LASV endemicity are expanding (4), and the association of the recently identified arenavirus Lujo with a recent outbreak of HF in southern Africa (7,8) has raised concerns about the emergence of novel HFA. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis vi...

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“…Of 20 LF cases hospitalized in developed countries, secondary transmission of disease has not been confirmed in over 1,000 persons with various degrees of contact with the index cases (Crowcroft et al, 2004;Haas et al, 2003;Hadi et al, 2010;Holmes et al, 1990;Johnson et al, 1990;Macher et al, 2006;Tarantola et al, 2007). The absence of secondary cases has been primarlily attributed to barrier infection control measures, but many individuals with high-risk exposure to LF virus had also received postexposure prophylaxis with oral ribavirin.…”

Section: Ribavirin Postexposure Prophylaxis For Lassa Fevermentioning

confidence: 99%

Experience with Ribavirin for Treatment and Postexposure Prophylaxis of Hemorrhagic Fever Viruses: Crimean Congo Hemorrhagic Fever, Lassa Fever, and Hantaviruses

Rusnak

2011

Appl Biosaf.

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The increase in research laboratories with biosafety level-4 (BSL-4) capabilities may be associated with increased research with hemorrhagic fever (HF) viruses. The yellow fever vaccine and an investigational formalin-inactivated Rift Valley fever vaccine are the only vaccines for at-risk laboratory workers available in the United States against HF viruses. Ribavirin is a nucleoside analogue that has been demonstrated to have antiviral activity against a wide range of viruses, including many HF viruses. While intravenous (IV) ribavirin is not FDA-approved and oral ribavirin is approved only for treatment of hepatitis C in the United States, ribavirin has been used for treatment and postexposure prophylaxis for Crimean Congo hemorrhagic fever (CCHF), Lassa fever (LF), and hantaviruses, based mainly on in vitro sensitivity testing and efficacy studies in animals, but only on a limited number of studies and/or anecdotal experience in humans.The literature on both IV and oral ribavirin for treatment and postexposure prophylaxis for CCHF, LF, and hantaviruses is reviewed to aid occupational healthcare providers in the evaluation and recommendation of ribavirin to laboratory workers with exposures or illness from these HF viruses, which are associated with a significant morbidity and mortality.

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Ribavirin for Lassa Fever Postexposure Prophylaxis

Cited by 47 publications

References 7 publications

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

Experience with Ribavirin for Treatment and Postexposure Prophylaxis of Hemorrhagic Fever Viruses: Crimean Congo Hemorrhagic Fever, Lassa Fever, and Hantaviruses

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