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      Development of a New Vaccine for the Prevention of Lassa Fever

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          Abstract

          Background

          Recent importation of Lassa fever into Germany, the Netherlands, the United Kingdom, and the United States by travelers on commercial airlines from Africa underscores the public health challenge of emerging viruses. Currently, there are no licensed vaccines for Lassa fever, and no experimental vaccine has completely protected nonhuman primates against a lethal challenge.

          Methods and Findings

          We developed a replication-competent vaccine against Lassa virus based on attenuated recombinant vesicular stomatitis virus vectors expressing the Lassa viral glycoprotein. A single intramuscular vaccination of the Lassa vaccine elicited a protective immune response in nonhuman primates against a lethal Lassa virus challenge. Vaccine shedding was not detected in the monkeys, and none of the animals developed fever or other symptoms of illness associated with vaccination. The Lassa vaccine induced strong humoral and cellular immune responses in the four vaccinated and challenged monkeys. Despite a transient Lassa viremia in vaccinated animals 7 d after challenge, the vaccinated animals showed no evidence of clinical disease. In contrast, the two control animals developed severe symptoms including rashes, facial edema, and elevated liver enzymes, and ultimately succumbed to the Lassa infection.

          Conclusion

          Our data suggest that the Lassa vaccine candidate based on recombinant vesicular stomatitis virus is safe and highly efficacious in a relevant animal model that faithfully reproduces human disease.

          Abstract

          A replication-competent vaccine based on attenuated recombinant vesicular stomatitis virus vector protects non- human primates.

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          Most cited references39

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          Hemorrhagic fever viruses as biological weapons: medical and public health management.

          To develop consensus-based recommendations for measures to be taken by medical and public health professionals if hemorrhagic fever viruses (HFVs) are used as biological weapons against a civilian population. The Working Group on Civilian Biodefense included 26 representatives from academic medical centers, public health, military services, governmental agencies, and other emergency management institutions. MEDLINE was searched from January 1966 to January 2002. Retrieved references, relevant material published prior to 1966, and additional sources identified by participants were reviewed. Three formal drafts of the statement that synthesized information obtained in the evidence-gathering process were reviewed by the working group. Each draft incorporated comments and judgments of the members. All members approved the final draft. Weapons disseminating a number of HFVs could cause an outbreak of an undifferentiated febrile illness 2 to 21 days later, associated with clinical manifestations that could include rash, hemorrhagic diathesis, and shock. The mode of transmission and clinical course would vary depending on the specific pathogen. Diagnosis may be delayed given clinicians' unfamiliarity with these diseases, heterogeneous clinical presentation within an infected cohort, and lack of widely available diagnostic tests. Initiation of ribavirin therapy in the early phases of illness may be useful in treatment of some of these viruses, although extensive experience is lacking. There are no licensed vaccines to treat the diseases caused by HFVs.
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            Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates

            Containment of highly lethal Ebola virus outbreaks poses a serious public health challenge. Although an experimental vaccine has successfully protected non-human primates against disease 1 , more than six months was required to complete the immunizations, making it impractical to limit an acute epidemic. Here, we report the development of accelerated vaccination against Ebola virus in non-human primates. The antibody response to immunization with an adenoviral (ADV) vector encoding the Ebola glycoprotein (GP) was induced more rapidly than with DNA priming and ADV boosting, but it was of lower magnitude. To determine whether this earlier immune response could nonetheless protect against disease, cynomolgus macaques were challenged with Ebola virus after vaccination with ADV–GP and nucleoprotein (NP) vectors. Protection was highly effective and correlated with the generation of Ebola-specific CD8+ T-cell and antibody responses. Even when animals were immunized once with ADV–GP/NP and challenged 28 days later, they remained resistant to challenge with either low or high doses of virus. This accelerated vaccine provides an intervention that may help to limit the epidemic spread of Ebola, and is applicable to other viruses. Supplementary information The online version of this article (doi:10.1038/nature01876) contains supplementary material, which is available to authorized users.
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              The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P.

              The surface glycoprotein of the Lassa virus, a member of the arenaviridae family, is synthesized as a 76-kDa precursor (GP-C) that is posttranslationally cleaved into an N-terminal 44-kDa subunit and a C-terminal membrane-anchored 36-kDa subunit. Cleavage occurs at the C-terminal end of the unusual recognition motif R-R-L-L. We show here that GP-C is cleaved in the endoplasmic reticulum by the cellular subtilase SKI-1/S1P, an enzyme that has so far been observed to be involved in cholesterol metabolism. Furthermore, we present evidence that only cleaved glycoprotein is incorporated into virions and that this is necessary for the formation of infectious virus. To our knowledge, there have been no previous reports of this type of viral glycoprotein processing, one that may be an interesting target for antiviral therapy.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                June 2005
                28 June 2005
                : 2
                : 6
                : e183
                Affiliations
                [1] 1Virology Division, United States Army Medical Research Institute of Infectious Diseases Fort Detrick, MarylandUnited States of America
                [2] 2Department of Pathology, Uniformed Services University of the Health Sciences Bethesda, MarylandUnited States of America
                [3] 3Special Pathogens Program, National Microbiology Laboratory Public Health Agency of Canada, Winnipeg, ManitobaCanada
                [4] 4Department of Immunology, University of Manitoba Winnipeg, ManitobaCanada
                [5] 5Department of Medical Microbiology, University of Manitoba Winnipeg, ManitobaCanada
                [6] 6Department of Biological Sciences, California State University San Marcos, CaliforniaUnited States of America
                [7] 7Pathology Division, United States Army Medical Research Institute of Infectious Diseases Fort Detrick, MarylandUnited States of America
                [8] 8Headquarters, United States Army Medical Research Institute of Infectious Diseases Fort Detrick, MarylandUnited States of America
                University of Bonn Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author Contributions: Please see acknowledgements section

                *To whom correspondence should be addressed. E-mail: tom.geisbert@ 123456amedd.army.mil
                Article
                10.1371/journal.pmed.0020183
                1160587
                15971954
                9319c565-b591-40d9-8da3-ec63bf0e0c93
                Copyright: © 2005 Geisbert et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
                History
                : 23 February 2005
                : 2 May 2005
                Categories
                Research Article
                Infectious Diseases
                Virology
                Epidemiology/Public Health
                Women's Health
                Vaccines
                Infectious Diseases
                Global Health
                Immunology and Allergy
                Travel Medicine

                Medicine
                Medicine

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