A highly attenuated vaccinia virus strain LC16m8-based vaccine for severe fever with thrombocytopenia syndrome

AbstractSevere fever with thrombocytopenia syndrome (SFTS) caused by Dabie bandavirus (formerly SFTS virus [SFTSV]) is an emerging hemorrhagic infectious disease with a high case-fatality rate. One of the best strategies for preventing SFTS is to develop a vaccine, which is expected to induce both humoral and cellular immunity. We applied a highly attenuated but still immunogenic vaccinia virus strain LC16m8 (m8) as a recombinant vaccine for SFTS. Recombinant m8s expressing SFTSV nucleoprotein (m8-N), envelope glycoprotein precursor (m8-GPC), and both N and GPC (m8-N+GPC) in the infected cells were generated. Both m8-GPC- and m8-N+GPC-infected cells were confirmed to produce SFTSV-like-particles (VLP) in vitro, and the N was incorporated in the VLP produced by the infection of cells with m8-N+GPC. Specific antibodies to SFTSV were induced in mice inoculated with each of the recombinant m8s, and the mice were fully protected from lethal challenge with SFTSV at both 103 TCID50 and 105 TCID50. In mice that had been immunized with vaccinia virus strain Lister in advance of m8-based SFTSV vaccine inoculation, protective immunity against the SFTSV challenge was also conferred. The pathological analysis revealed that mice immunized with m8-GPC or m8-N+GPC did not show any histopathological changes without any viral antigen-positive cells, whereas the control mice showed focal necrosis with inflammatory infiltration with SFTSV antigen-positive cells in tissues after SFTSV challenge. The passive serum transfer experiments revealed that sera collected from mice inoculated with m8-GPC or m8-N+GPC but not with m8-N conferred protective immunity against lethal SFTSV challenge in naïve mice. On the other hand, the depletion of CD8-positive cells in vivo did not abrogate the protective immunity conferred by m8-based SFTSV vaccines. Based on these results, the recombinant m8-GPC and m8-N+GPC were considered promising vaccine candidates for SFTS.Author SummarySevere fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with a high case-fatality rate (approximately 5% to >40%). Indigenous SFTS has been reported in China, Japan, South Korea, and Vietnam. Thus, the development of an effective vaccine for SFTS is urgently needed. Vaccinia virus (VAC) was previously used as a vaccine for smallpox. Unfortunately, after these strains, the so-called second generation of VAC used during the eradication campaign was associated with severe adverse events, and the third generation of VAC strains such as LC16m8 (m8) and modified vaccinia Ankara (MVA) was established. m8 is confirmed to be highly attenuated while still maintaining immunogenicity. m8 is licensed for use in healthy people in Japan. At the present time, approximately 100,000 people have undergone vaccination with m8 without experiencing any severe postvaccine complications. At present, third-generation VAC strains are attractive for a recombinant vaccine vector, especially for viral hemorrhagic infectious diseases, such as Ebola virus disease, Lassa fever, Crimean-Congo hemorrhagic fever, and SFTS. We investigated the practicality of an m8-based recombinant vaccine for SFTS as well as other promising recombinant VAC-based vaccines for viral hemorrhagic infectious diseases.

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A highly attenuated vaccinia virus strain LC16m8-based vaccine for severe fever with thrombocytopenia syndrome

PLoS Pathogens ◽

10.1371/journal.ppat.1008859 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1008859

Author(s):

Tomoki Yoshikawa ◽

Satoshi Taniguchi ◽

Hirofumi Kato ◽

Naoko Iwata-Yoshikawa ◽

Hideki Tani ◽

...

Keyword(s):

Vaccinia Virus ◽

Virus Strain ◽

Protective Immunity ◽

Case Fatality ◽

Glycoprotein Precursor ◽

Lethal Challenge ◽

Inflammatory Infiltration ◽

Infected Cells ◽

Vaccinia Virus Strain ◽

Severe Fever

Severe fever with thrombocytopenia syndrome (SFTS) caused by a species Dabie bandavirus (formerly SFTS virus [SFTSV]) is an emerging hemorrhagic infectious disease with a high case-fatality rate. One of the best strategies for preventing SFTS is to develop a vaccine, which is expected to induce both humoral and cellular immunity. We applied a highly attenuated but still immunogenic vaccinia virus strain LC16m8 (m8) as a recombinant vaccine for SFTS. Recombinant m8s expressing SFTSV nucleoprotein (m8-N), envelope glycoprotein precursor (m8-GPC), and both N and GPC (m8-N+GPC) in the infected cells were generated. Both m8-GPC- and m8-N+GPC-infected cells were confirmed to produce SFTSV-like-particles (VLP) in vitro, and the N was incorporated in the VLP produced by the infection of cells with m8-N+GPC. Specific antibodies to SFTSV were induced in mice inoculated with each of the recombinant m8s, and the mice were fully protected from lethal challenge with SFTSV at both 103 TCID50 and 105 TCID50. In mice that had been immunized with vaccinia virus strain Lister in advance of m8-based SFTSV vaccine inoculation, protective immunity against the SFTSV challenge was also conferred. The pathological analysis revealed that mice immunized with m8-GPC or m8-N+GPC did not show any histopathological changes without any viral antigen-positive cells, whereas the control mice showed focal necrosis with inflammatory infiltration with SFTSV antigen-positive cells in tissues after SFTSV challenge. The passive serum transfer experiments revealed that sera collected from mice inoculated with m8-GPC or m8-N+GPC but not with m8-N conferred protective immunity against lethal SFTSV challenge in naïve mice. On the other hand, the depletion of CD8-positive cells in vivo did not abrogate the protective immunity conferred by m8-based SFTSV vaccines. Based on these results, the recombinant m8-GPC and m8-N+GPC were considered promising vaccine candidates for SFTS.

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Characterization of Glycoprotein-Mediated Entry of Severe Fever with Thrombocytopenia Syndrome Virus

Journal of Virology ◽

10.1128/jvi.00110-16 ◽

2016 ◽

Vol 90 (11) ◽

pp. 5292-5301 ◽

Cited By ~ 37

Author(s):

Hideki Tani ◽

Masayuki Shimojima ◽

Shuetsu Fukushi ◽

Tomoki Yoshikawa ◽

Aiko Fukuma ◽

...

Keyword(s):

Host Cell ◽

Cell Lines ◽

Case Fatality Rate ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Cell Entry ◽

Fatality Rate ◽

High Case Fatality Rate ◽

Ph Dependent ◽

Severe Fever

ABSTRACTSevere fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with a high case fatality rate caused by SFTS virus (SFTSV). Effective vaccines and specific therapies for SFTS are urgently sought, and investigation into virus-host cell interactions is expected to contribute to the development of antiviral strategies. In this study, we have developed a pseudotype vesicular stomatitis virus (VSV) bearing the unmodified Gn/Gc glycoproteins (GPs) of SFTSV (SFTSVpv). We have analyzed the host cell entry of this pseudotype virus and native SFTSV. Both SFTSVpv and SFTSV exhibited high infectivity in various mammalian cell lines. The use of lysosomotropic agents indicated that virus entry occurred via pH-dependent endocytosis. SFTSVpv and SFTSV infectivity was neutralized by serial dilutions of convalescent-phase patient sera. Entry of SFTSVpv and growth of SFTSV were increased in Raji cells expressing not only the C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) but also DC-SIGN-related (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin). 25-Hydroxycholesterol (25HC), a soluble oxysterol metabolite, inhibited the cell entry of SFTSVpv and the membrane fusion of SFTSV. These results indicate that pH-dependent endocytosis of SFTSVpv and SFTSV is enhanced by attachment to certain C-type lectins. SFTSVpv is an appropriate model for the investigation of SFTSV-GP-mediated cell entry and virus neutralization at lower biosafety levels. Furthermore, 25HC may represent a potential antiviral agent against SFTS.IMPORTANCESFTSV is a recently discovered bunyavirus associated with SFTS, a viral hemorrhagic fever with a high case fatality rate endemic to China, South Korea, and Japan. Because little is known about the characteristics of the envelope protein and entry mechanisms of SFTSV, further studies will be required for the development of a vaccine or effective therapies. In this study, we investigated the mechanism of SFTSV cell entry using SFTSVpv and the native virus. SFTSV can grow in nonsusceptible cell lines in the presence of certain C-type lectins. Moreover, 25HC, an oxysterol metabolite, may represent a potential therapeutic inhibitor of SFTSV infection.

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Vaccinia virus strain differences in cell attachment and entry

Virology ◽

10.1016/j.virol.2009.04.012 ◽

2009 ◽

Vol 389 (1-2) ◽

pp. 132-140 ◽

Cited By ~ 66

Author(s):

Zain Bengali ◽

Alan C. Townsley ◽

Bernard Moss

Keyword(s):

Vaccinia Virus ◽

Virus Strain ◽

Cell Attachment ◽

Strain Differences ◽

Vaccinia Virus Strain

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Notes on Transient Host Range Selection for Engineering Vaccinia Virus Strain MVA

BioTechniques ◽

10.2144/02331dd01 ◽

2002 ◽

Vol 33 (1) ◽

pp. 186-188 ◽

Cited By ~ 2

Author(s):

David C. Tscharke ◽

Geoffrey L. Smith

Keyword(s):

Vaccinia Virus ◽

Host Range ◽

Virus Strain ◽

Selection For ◽

Vaccinia Virus Strain ◽

Range Selection

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Crimean-Congo hemorrhagic fever-induced liver injury: a systematic review and meta-analysis

10.22541/au.161962547.79756407/v1 ◽

2021 ◽

Author(s):

Sawai Singh Rathore ◽

Ade Harrison Manju ◽

Qingqing Wen ◽

Manush Sondhi ◽

Reshma Pydi ◽

...

Keyword(s):

Liver Injury ◽

Case Fatality Rate ◽

Meta Analysis ◽

Case Series ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Fatality Rate ◽

High Case Fatality Rate ◽

Crimean Congo Hemorrhagic Fever ◽

Pooled Prevalence

Background: Crimean-Congo hemorrhagic fever (CCHF) is a fatal acute tick-borne viral infection and a substantial emerging global public health threat. This illness has a high case fatality rate of up to 40%. The liver is one of the important target organs of the CCHF virus. Objective: The aim of this meta-analysis to evaluate the correlation between CCHF and liver injury and draw more generalized inferences about the abnormal serum markers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) in CCHF patients. Methods: A literature search was accomplished for published eligible articles with MEDLINE/PubMed and Embase databases. All eligible observational studies and case series were included from around the world. The inclusion criteria were articles describing liver injury biomarkers AST and ALT amongst patients diagnosed with CCHF. Results: Data from 18 studies, consisting of 1238 patients with CCHF were included in this meta-analysis. The overall pooled prevalence of at least one raised liver injury biomarker was 77.95% (95% CI, I2 = 88.50%, p < 0.0001). Similarly, pooled prevalence of elevated AST and ALT was 85.92% (95% CI, I2 = 85.27%, p < 0.0001) and 64.30% (95% CI, I2 = 88.32%, p < 0.0001) respectively. Both Egger and Begg-Mazumdar’s tests detected no apparent publication bias in all three meta-analyses(p > 0.05). Conclusion: These elevated liver injury biomarkers have been identified as significant prognostic factors. Hence, Physicians must recognize and continuously monitor these biomarkers, since these aid early stratification of prognosis and the prevention of severe outcomes in infection with such a high case fatality rate.

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KEPADATAN NYAMUK DEWASA Aedes Sp DI KELURAHAN MALALAYANG I KECAMATAN MALALAYANG MANADO PERIODE JANUARI – PEBRUARI 2010

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.3.3.2011.874 ◽

2013 ◽

Vol 3 (3) ◽

Author(s):

Janno B. B. Bernadus ◽

Victor D. Pijoh ◽

Venny Kareth

Keyword(s):

Aedes Aegypti ◽

Aedes Albopictus ◽

Case Fatality Rate ◽

Case Fatality ◽

Public Health Problem ◽

Hemorrhagic Fever ◽

Adult Mosquito ◽

Fatality Rate ◽

North Sulawesi ◽

Culex Sp

Abstract: Dengue Hemorrhagic Fever (DHF) has become a public health problem in Indonesia because of its high prevalence and ability to spread more widely. In North Sulawesi itself Case Fatality Rate of carrying dengue is increasing from year to year. The local village Malalayang has a high potential for spreading this disease. The result of an entomology survey on adult mosquitos showed that Aedes sp was found in 40 houses of 80 house samples. From these 40 houses we got 71 mosquito samples. From these 71 samples tested and identified, we found three species: Aedes aegypti (30 samples, 42.25%), Aedes albopictus (22 samples, 30.99%), and Culex sp (19 samples, 26.76%). Mosquito density can be seen from the indices of the resting rates, which were 0.375 for Aedes aegypti, 0.275 for Aedes albopictus, and 0.65 for Aedes sp. Key words: density, adult mosquito, Aedes sp., resting rate. Abstrak: Demam Berdarah Dengue (DBD) merupakan penyakit yang menjadi masalah kesehatan masyarakat di Indonesia karena prevalensinya yang tinggi dan penyebarannya semakin luas. Di Sulawesi Utara, Case Fatality Rate penyakit DBD tercatat terus meningkat dari tahun ke tahun. Kelurahan Malalayang I merupakan daerah yang potensial sebagai daerah penyebaran DBD. Survei entomologi terhadap nyamuk dewasa Aedes sp pada 80 rumah memperlihatkan bahwa 40 diantaranya terdapat 71 sampel nyamuk. Setelah diperiksa dan diidentifikasi ternyata ditemukan tiga spesies yaitu Aedes aegypti 30 sampel (42,25%), Aedes albopictus 22 sampel (30,99%) dan Culex sp 19 (26,76%). Kepadatan nyamuk dapat dilihat dari angka indeks pada resting rate yaitu Aedes aegypti = 0,375 , Aedes albopictus = 0,275 dan Aedes sp.= 0,65. Kata kunci: kepadatan, nyamuk dewasa, Aedes sp., resting rate.

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Decline of notified dengue infections in Indonesia in 2017: Discussion of the possible determinants

Narra J ◽

10.52225/narraj.v1i1.23 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Pandji Wibawa Dhewantara ◽

Kurnia F. Jamil ◽

Jonny Karunia Fajar ◽

Panji Probo Saktianggi ◽

Roy Nusa ◽

...

Keyword(s):

Disease Surveillance ◽

Protective Immunity ◽

Case Fatality Rate ◽

Southern Oscillation ◽

Case Fatality ◽

Annual Incidence Rate ◽

Percent Change ◽

Vector Management ◽

Notification Data

This study was conducted to quantify the trend in dengue notifications in the country in 2017 and to explore the possible determinants. Annual nation-wide dengue notification data were obtained from the National Disease Surveillance of Ministry of Health of Indonesia. Annual incidence rate (IR) and case fatality rate (CFR) in 2017 and the previous years were quantified and compared. Correlations between annual larva free index (LFI), implementation coverage of integrated vector management (IVM), El Niño Southern Oscillation (Niño3.4), Dipole Mode Index (DMI), Zika virus seropositivity and the percent change in IR and CFR of dengue were examined. The change of dengue IR and CFRs were mapped. In 2017, dengue IR was declined by 71% (22.55 per 100,000 population) compared to 2016 (77.96 per 100,000 population) while the CFR was slightly reduced from 0.79% to 0.75%. Reduction in IR and CFR occurred in 94.1% and 70.1% out of 34 provinces, respectively. The trend of dengue IR seems to be influenced by Niño3.4 but there is no clear evidence that Niño3.4 is the main reason for dengue reduction in 2017. It is difficult to elucidate that the reduction of dengue in 2017 was associated with previous Zika outbreaks. In conclusion, there was a significant reduction on dengue notifications in Indonesia in 2017. Further investigation is needed to look at the role of climate on the decline of dengue IR at finer temporal scale. In addition, study on the role of cross-protective immunity generated by Zika infection on dengue incidence is also warranted.

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Complete Genome Sequence of Vaccinia Virus Strain L-IVP

Genome Announcements ◽

10.1128/genomea.00372-16 ◽

2016 ◽

Vol 4 (3) ◽

Cited By ~ 2

Author(s):

Alexander N. Shvalov ◽

Galina F. Sivolobova ◽

Elena V. Kuligina ◽

Galina V. Kochneva

Keyword(s):

Vaccinia Virus ◽

Genome Sequence ◽

Virus Strain ◽

Complete Genome Sequence ◽

Complete Genome ◽

Sequence Similarity ◽

Consensus Sequence ◽

Live Vaccine ◽

Eradication Programme ◽

Vaccinia Virus Strain

Most of the live vaccine doses of vaccinia virus donated to the Intensified Smallpox Eradication Programme after 1971 were prepared using the L-IVP strain. A mixture of three clones of the L-IVP strain was sequenced using MySEQ. Consensus sequence similarity with the vaccinia virus Lister strain is 99.5%.

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