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      Generation of therapeutic antisera for emerging viral infections

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          Abstract

          The recent Ebola virus outbreak has highlighted the therapeutic potential of antisera and renewed interest in this treatment approach. While human convalescent sera may not be readily available in the early stages of an outbreak, antisera of animal origin can be produced in a short time frame. Here, we compared adjuvanted virus-like particles (VLP) with recombinant modified vaccinia virus Ankara and vesicular stomatitis virus (VSV), both expressing the Ebola virus antigens. The neutralizing antibody titers of rabbits immunized with adjuvanted VLPs were similar to those immunized with the replication-competent VSV, indicating that presentation of the antigen in its native conformation rather than de novo antigen expression is essential for production of functional antibodies. This approach also yielded high-titer antisera against Nipah virus glycoproteins, illustrating that it is transferable to other virus families. Multiple-step immunoglobulin G purification using a two-step 20–40% ammonium sulfate precipitation followed by protein A affinity chromatography resulted in 90% recovery of functionality and sustained in vivo stability. Adjuvanted VLP-based immunization strategies are thus a promising approach for the rapid generation of therapeutic antisera against emerging infections.

          Anti-serum: Rapid generation for viral outbreaks

          Passive immunity through the transfer of anti-serum represents the earliest clinical application of antibodies and is still widely used to this day in the form of anti-venoms. Veronika von Messling and colleagues at the Paul Ehrlich Institute investigate the potential of generating neutralizing anti-serum to the emerging viruses Ebola and Nipah. The authors compare different vaccination platforms in mice and rabbits and find that following multiple vaccine challenges, neutralizing antibody titers equivalent to that seen in convalescent patients could be obtained. Purification of the IgG fraction and processing into F(ab’) 2 fragments has the potential to significantly reduce xeno-responses yet the authors find that neutralizing capacity is largely retained albeit at the cost of a shorter in vivo half-life. These findings offer the hope of rapidly generating large quantities of neutralizing anti-serum that could be used in a viral outbreak scenario.

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          Most cited references 68

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          Nipah virus: a recently emergent deadly paramyxovirus.

          A paramyxovirus virus termed Nipah virus has been identified as the etiologic agent of an outbreak of severe encephalitis in people with close contact exposure to pigs in Malaysia and Singapore. The outbreak was first noted in late September 1998 and by mid-June 1999, more than 265 encephalitis cases, including 105 deaths, had been reported in Malaysia, and 11 cases of encephalitis or respiratory illness with one death had been reported in Singapore. Electron microscopic, serologic, and genetic studies indicate that this virus belongs to the family Paramyxoviridae and is most closely related to the recently discovered Hendra virus. We suggest that these two viruses are representative of a new genus within the family Paramyxoviridae. Like Hendra virus, Nipah virus is unusual among the paramyxoviruses in its ability to infect and cause potentially fatal disease in a number of host species, including humans.
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            Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia.

            Between February and April, 1999, an outbreak of viral encephalitis occurred among pig-farmers in Malaysia. We report findings for the first three patients who died. Samples of tissue were taken at necropsy. Blood and cerebrospinal-fluid (CSF) samples taken before death were cultured for viruses, and tested for antibodies to viruses. The three pig-farmers presented with fever, headache, and altered level of consciousness. Myoclonus was present in two patients. There were signs of brainstem dysfunction with hypertension and tachycardia. Rapid deterioration led to irreversible hypotension and death. A virus causing syncytial formation of vero cells was cultured from the CSF of two patients after 5 days; the virus stained positively with antibodies against Hendra virus by indirect immunofluorescence. IgM capture ELISA showed that all three patients had IgM antibodies in CSF against Hendra viral antigens. Necropsy showed widespread microinfarction in the central nervous system and other organs resulting from vasculitis-induced thrombosis. There was no clinical evidence of pulmonary involvement. Inclusion bodies likely to be of viral origin were noted in neurons near vasculitic blood vessels. The causative agent was a previously undescribed paramyxovirus related to the Hendra virus. Close contact with infected pigs may be the source of the viral transmission. Clinically and epidemiologically the infection is distinct from infection by the Hendra virus. We propose that this Hendra-like virus was the cause of the outbreak of encephalitis in Malaysia.
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              Ebola haemorrhagic fever in Zaire, 1976.

              Between 1 September and 24 October 1976, 318 cases of acute viral haemorrhagic fever occurred in northern Zaire. The outbreak was centred in the Bumba Zone of the Equateur Region and most of the cases were recorded within a radius of 70 km of Yambuku, although a few patients sought medical attention in Bumba, Abumombazi, and the capital city of Kinshasa, where individual secondary and tertiary cases occurred. There were 280 deaths, and only 38 serologically confirmed survivors.The index case in this outbreak had onset of symptoms on 1 September 1976, five days after receiving an injection of chloroquine for presumptive malaria at the outpatient clinic at Yambuku Mission Hospital (YMH). He had a clinical remission of his malaria symptoms. Within one week several other persons who had received injections at YMH also suffered from Ebola haemorrhagic fever, and almost all subsequent cases had either received injections at the hospital or had had close contact with another case. Most of these occurred during the first four weeks of the epidemic, after which time the hospital was closed, 11 of the 17 staff members having died of the disease. All ages and both sexes were affected, but women 15-29 years of age had the highest incidence of disease, a phenomenon strongly related to attendance at prenatal and outpatient clinics at the hospital where they received injections. The overall secondary attack rate was about 5%, although it ranged to 20% among close relatives such as spouses, parent or child, and brother or sister.Active surveillance disclosed that cases occurred in 55 of some 550 villages which were examined house-by-house. The disease was hitherto unknown to the people of the affected region. Intensive search for cases in the area of north-eastern Zaire between the Bumba Zone and the Sudan frontier near Nzara and Maridi failed to detect definite evidence of a link between an epidemic of the disease in that country and the outbreak near Bumba. Nevertheless it was established that people can and do make the trip between Nzara and Bumba in not more than four days: thus it was regarded as quite possible that an infected person had travelled from Sudan to Yambuku and transferred the virus to a needle of the hospital while receiving an injection at the outpatient clinic.Both the incubation period, and the duration of the clinical disease averaged about one week. After 3-4 days of non-specific symptoms and signs, patients typically experienced progressively severe sore throat, developed a maculopapular rash, had intractable abdominal pain, and began to bleed from multiple sites, principally the gastrointestinal tract. Although laboratory determinations were limited and not conclusive, it was concluded that pathogenesis of the disease included non-icteric hepatitis and possibly acute pancreatitis as well as disseminated intravascular coagulation.This syndrome was caused by a virus morphologically similar to Marburg virus, but immunologically distinct. It was named Ebola virus. The agent was isolated from the blood of 8 of 10 suspected cases using Vero cell cultures. Titrations of serial specimens obtained from one patient disclosed persistent viraemia of 10(6.5)-10(4.5) infectious units from the third day of illness until death on the eighth day. Ebola virus particles were found in formalin-
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                Author and article information

                Contributors
                +49 6103 777400 , veronika.vonmessling@pei.de
                Journal
                NPJ Vaccines
                NPJ Vaccines
                NPJ Vaccines
                Nature Publishing Group UK (London )
                2059-0105
                5 October 2018
                5 October 2018
                2018
                : 3
                Affiliations
                [1 ]ISNI 0000 0001 1019 0926, GRID grid.425396.f, Veterinary Medicine Division, , Paul-Ehrlich-Institut, ; Langen, Germany
                [2 ]GRID grid.452463.2, Thematic Translational Unit Emerging Infections, , German Center of Infection Research (DZIF), ; Marburg - Langen - Munich, Germany
                [3 ]ISNI 0000 0004 1936 9756, GRID grid.10253.35, Institute of Virology, , Philipps University Marburg, ; Marburg, Germany
                [4 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Institute for Infectious Diseases and Zoonoses, , Ludwig-Maximilians-University, ; Munich, Germany
                Article
                82
                10.1038/s41541-018-0082-4
                6173733
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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