Human Antibody Neutralizes Severe Fever with Thrombocytopenia Syndrome Virus, an Emerging Hemorrhagic Fever Virus
Xiling GuoLi ZhangWenshuai ZhangYing ChiXiaoyan ZengXian LiXian QiJin QiuXiao ZhangMingming HuangHua WangYin ChenChangjun BaoJianli HuShuyi LiangLin BaoTao WuMinghao ZhouYongjun Jiao
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Abstract:
Severe fever with thrombocytopenia syndrome virus (SFTSV), a newly discovered member of the Bunyaviridae family, is the causative agent of an emerging hemorrhagic fever, SFTS, in China. Currently, there are no vaccines or effective therapies against SFTS. In this study, a combinatorial human antibody library was constructed from the peripheral lymphocytes of 5 patients who had recovered from SFTS. The library was screened against purified virions for the production of single-chain variable-region fragments (ScFv). Of the 6 positive clones, one clone (monoclonal antibody [MAb] 4-5) showed neutralizing activity against SFTSV infection in Vero cells. MAb 4-5 was found to effectively neutralize all of the clinical isolates of SFTSV tested, which were isolated from patients in China from 2010 to 2012. MAb 4-5 was found to bind a linear epitope in the ectodomain of glycoprotein Gn. Its neutralizing activity is attributed to blockage of the interactions between the Gn protein and the cellular receptor, indicating that inhibition of virus-cell attachment is its main mechanism. These data suggest that MAb 4-5 can be used as a promising candidate molecule for immunotherapy against SFTSV infection.Keywords:
Vero cell
Ectodomain
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a new virus (SFTS virus) reported to be endemic to central and northeastern parts of China. SFTS virus, which is classified into the genus Phlebovirus (the Bunyaviridae family), is suspected to be a tick-borne virus owing to evidence in two species of ticks: Haemaphysalis longicornis and Rhipicephalus microplus. SFTS virus is detected among many species of domestic animals in China. The clinical symptoms of SFTS include fever, thrombocytopenia, leucocytopenia, gastrointestinal symptoms, neural symptoms, bleeding tendency. The fatality rate of SFTS is 6-30%. Person-to-person transmission of SFTS virus is possible through blood contact. Clinical and epidemiological studies of SFTS, the cases of SFTS outside China, person-to-person transmission of SFTS virus, evolutionary and molecular analysis of the emergent SFTS virus, and risk assessment of human infection with a novel phlebovirus are considered in this review.Острая лихорадка с тромбоцитопеническим синдромом (SFTS) - новое инфекционное вирусное заболевание, эндемичное для центральной и северо-восточных частей Китайской Народной Республики. Природным хозяином вируса SFTS, который относится к роду Phlebovirus семейства Bunyaviridae, являются клещи видов Haemaphysalis longicornis и Rhipicephalus microplus. В КНР вирус SFTS обнаружен у многих видов домашних животных, у которых заболевание протекает инаппарантно. Заболевание характеризуется лихорадкой, тромбоцитопенией, лейкоцитопенией, синдромами поражения желудочно-кишечного тракта и нервной системы, проявлениями геморрагического синдрома. Летальность при SFTS составляет от 6 до 30%. Возможна передача вируса от человека к человеку вследствие контакта с кровью больного. В обзоре рассмотрены данные клинического и эпидемиологического изучения инфекции, эволюционный и молекулярно-биологический анализ возбудителя, случаи заболевания за пределами КНР, передача вируса SFTS от человека к человеку, факторы риска при заболевании, вызываемом новым флебовирусом.
Phlebovirus
Haemaphysalis longicornis
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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was discovered in China in 2010. The causative agent has been identified as a new member of the Phlebovirus genus in the family Bunyaviridae and has been designated severe fever with thrombocytopenia virus (SFTSV). SFTSV infection can be transmitted person-to-person, and the average case fatality rate is approximately 10% in humans. There is a high seroprevalence of SFTSV infection in a wide range of domesticated animals, including sheep, goats, cattle, pigs, dogs and chickens. Ticks are suspected to be the vector that transmits the virus to humans. Currently, the SFTS endemic area is expanding. Therefore, SFTSV infection is an increasingly important public health threat.
Phlebovirus
Orthobunyavirus
Emerging infectious disease
Zoonosis
Seroprevalence
Case fatality rate
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(1) Background: Our aim is the evaluation of the neutralizing activity of BNT162b2 mRNA vaccine-induced antibodies in different in vitro cellular models, as this still represents one of the surrogates of protection against SARS-CoV-2 viral variants. (2) Methods: The entry mechanisms of SARS-CoV-2 in three cell lines (Vero E6, Vero E6/TMPRSS2 and Calu-3) were evaluated with both pseudoviruses and whole virus particles. The neutralizing capability of sera collected from vaccinated subjects was characterized through cytopathic effects and Real-Time RT PCR. (3) Results: In contrast to Vero E6 and Vero E6/TMPRSS2, Calu-3 allowed the evaluation of both viral entry mechanisms, resembling what occurs during natural infection. The choice of an appropriate cellular model can decisively influence the determination of the neutralizing activity of antibodies against SARS-CoV-2 variants. Indeed, the lack of correlation between neutralizing data in Calu-3 and Vero E6 demonstrated that testing the antibody inhibitory activity by using a single cell model possibly results in an inaccurate characterization. (4) Conclusions: Cellular systems allowing only one of the two viral entry pathways may not fully reflect the neutralizing activity of vaccine-induced antibodies moving increasingly further away from possible correlates of protection from SARS-CoV-2 infection.
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Objective
To develop a micro-neutralization test for determination of neutralizing antibody against ZIKA virus (ZIKV) in human sera and to verify the acute and convalescent serum samples of 10 ZIKA virus-infected cases diagnosed by nucleic acid detection and/or virus isolation.
Methods
ZIKV isolated from ZIKA cases was used to determine micro-neutralization antibody. The virus solution was prepared by infecting BHK21, VERO and VERO-E6 cell lines and viral titer was tested; 100 TCID50 viral solution and 4 times diluted sera which were inactivated at 56 ℃ for 30 min were neutralized, then added the cell suspension and incubated in 5% CO2 incubator at 37 ℃ for 7 d. The CPE was observed every day.
Results
The sensitivity of BHK21, VERO and VERO-E6 was different after infection with ZIKA virus. VERO cell line was the most sensitive and showed typical CPE. VERO cell line was used to establish a micro-neutralization test for determination of neutralizing antibody against ZIKA virus in sera.
Conclusions
The neutralizing antibody test for zika virus in sera is a special and usefulmethod to diagnose human infection of ZIKV and to conduct population based epidemiological investigation.
Key words:
Neutralizing antibody; ZIKA virus; VERO cell line
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Zika Virus
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To observe the safety and efficacy of lyophilized purified human rabies vaccine CTN-Vero RV, CTN strain produced in Vero cells.450 healthy volunteers were divided into two groups, with 300 of them receiving CTN-Vero-RV (rabies vaccine for human use made in Vero cells with CTN strain) while 150 of them receiving PVRV to serve as control group. All the subjects were immunized on days 0, 3, 7, 14 and 28 at deltoid muscle respectively. Local and systemic reactions were observed and sera were collected for neutralizing antibody testing using RFFIT. 365 and 730 days after the first dose, sera from the 212 and 176 subjects of the studied group while 97 and 80 subjects from the control group were collected to test for neutralizing antibody.No severe local or systemic reactions were observed after immunization was performed in the two groups. On days 3, 7, 14, 28 and 365 after the first dose, the antibody positive rates appeared to be 2.35%, 80.78%, 100.00%, 100.00%, 98.58% and 73.30% in the study group and 4.00%, 87.20%, 100.00%, 100.00%, 97.94% and 76.25% in the controls respectively. On day 0, 3, 7, 14, 28, 365 and 730, GMT of the neutralizing antibody level were 0.12, 1.01, 9.83, 12.61, 3.68 and 2.81 IU/ml in the study group while 0.13, 1.18, 10.24, 11.61, 4.18 and 1.92 IU/ml were seen in the control group respectively. There were no significant differences in both antibody positive rates and GMT between the two groups on days 3, 7, 14, 28, 365 or 730 (P > 0.05).CTN-Vero-RV was safe and effective as well as could generate a persistent immune response.
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Heightened surveillance of acute febrile illness in China since 2009 has led to the identification of a severe fever with thrombocytopenia syndrome (SFTS) with an unknown cause. Infection with Anaplasma phagocytophilum has been suggested as a cause, but the pathogen has not been detected in most patients on laboratory testing.We obtained blood samples from patients with the case definition of SFTS in six provinces in China. The blood samples were used to isolate the causal pathogen by inoculation of cell culture and for detection of viral RNA on polymerase-chain-reaction assay. The pathogen was characterized on electron microscopy and nucleic acid sequencing. We used enzyme-linked immunosorbent assay, indirect immunofluorescence assay, and neutralization testing to analyze the level of virus-specific antibody in patients' serum samples.We isolated a novel virus, designated SFTS bunyavirus, from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA sequence analysis revealed that the virus was a newly identified member of the genus phlebovirus in the Bunyaviridae family. Electron-microscopical examination revealed virions with the morphologic characteristics of a bunyavirus. The presence of the virus was confirmed in 171 patients with SFTS from six provinces by detection of viral RNA, specific antibodies to the virus in blood, or both. Serologic assays showed a virus-specific immune response in all 35 pairs of serum samples collected from patients during the acute and convalescent phases of the illness.A novel phlebovirus was identified in patients with a life-threatening illness associated with fever and thrombocytopenia in China. (Funded by the China Mega-Project for Infectious Diseases and others.).
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Bunyaviruses are becoming increasingly important as ecological changes modulate vector dynamics and humans become targets.1Walter C.T. Barr J.N. Recent advances in the molecular and cellular biology of bunyaviruses.J Gen Virol. 2011; 92: 2467-2484Crossref PubMed Scopus (154) Google Scholar, 2Elliott R.M. Bunyaviruses and climate change.Clin Microbiol Infect. 2009; 15: 510-517Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar A novel Phlebovirus in the Bunyaviridae family, designated as severe fever with thrombocytopenia syndrome bunyavirus (SFTSV), was confirmed to be associated with the SFTS reported in rural areas of Hubei and Henan provinces in central China.3Yu X.J. Liang M.F. Zhang S.Y. Liu Y. Li J.D. Sun Y.L. et al.Fever with thrombocytopenia associated with a novel bunyavirus in China.N Engl J Med. 2011; 364: 1523-1532Crossref PubMed Scopus (1061) Google Scholar Sporadic cases infected by SFTSV have also been found in other non-epidemic regions of China.4Li S.B. Xue C. Fu Y.F. Wang J.L. Ding X.J. Liu R.D. et al.Sporadic case infected by severe fever with thrombocytopenia syndrome bunyavirus in a non-epidemic region of China.Biosci Trends. 2011; 5: 273-276Crossref PubMed Scopus (31) Google Scholar According to recent studies, SFTSV can be transmitted from person to person through blood contact.5Gai Z. Liang M. Zhang Y. Zhang S. Jin C. Wang S.W. et al.Person-to-person transmission of severe fever with thrombocytopenia syndrome bunyavirus through blood contact.Clin Infect Dis. 2012; 54: 249-252Crossref PubMed Scopus (179) Google Scholar, 6Bao C.J. Guo X.L. Qi X. Hu J.L. Zhou M.H. Varma J.K. et al.A family cluster of infections by a newly recognized bunyavirus in eastern China, 2007: further evidence of person-to-person transmission.Clin Infect Dis. 2011; 53: 1208-1214Crossref PubMed Scopus (212) Google Scholar As a result, enhanced surveillance has been implemented for the effective control and prevention of SFTSV infections in epidemic regions. During these years, patients with hemorrhagic fever-like illnesses of unknown etiology have also been found in Zhejiang Province, which borders the epidemic regions for SFTS disease (Anhui and Jiangsu). However, infections of SFTSV in Zhejiang Province have not been investigated before. In this study, blood specimens were collected from suspected patients during the acute phase, and serum samples were used for SFTSV detection. In accordance with the diagnostic criteria, SFTSV RNA was detected through real-time reverse transcriptase PCR (RT-PCR).7Sun Y. Liang M. Qu J. Jin C. Zhang Q. Li J. et al.Early diagnosis of novel SFTS bunyavirus infection by quantitative real-time RT-PCR assay.J Clin Virol. 2012; 53: 48-53Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Positive serum samples were inoculated into Vero cells for SFTSV isolation. Samples from 30 suspected cases were subjected to RT-PCR for the detection of SFTSV RNA and 12 cases were identified as SFTSV infection. SFTSV was isolated and successfully cultured, and a phylogenic analysis was performed based on the nucleocapsid gene sequence (Figure 1). Results showed 88.1% identical ratios of all the nucleocapsid gene sequences from the different isolates. From the phylogenetic tree, it is interesting to observe that the SFTSV isolates from Zhejiang are present in an independent branch to that of the isolates from the epidemic regions. In this study, symptom onset among patients with confirmed or clinically diagnosed SFTSV occurred mainly from May to July. All age groups were affected, but most infections occurred among persons over 50 years of age; nine (75%) were women, and almost all the patients were peasants. This is the first time that SFTSV has been detected in Zhejiang Province, East China. It is also the first time that SFTSV infections have been found in insular areas. SFTSV could be an important cause of the hemorrhagic fever-like disease here. Clinical vigilance and strong epidemiologic and laboratory surveillance are essential for the control of this disease in Zhejiang. This work was supported by the grant from Zhejiang Provincial CDC (4-10k035-25). Conflict of interest: We declare that we have no competing interests.
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Severe fever with thrombocytopenia syndrome (SFTS) was detected for the first time in China in 2011. Since then, human cases have been reported in endemic regions, including Japan. To investigate the presence of tick-borne pathogens in Tokyo, 551 ticks (266 samples) were collected from October 2015 to October 2016. Although the SFTS virus was not detected by RT-PCR, a novel phlebovirus was detected in one sample. In a phylogenetic analysis based on the partial nucleotide sequences of the L and S segments of the virus, the virus clustered with Lesvos virus (Greece), Yongjia tick virus, and Dabieshan tick virus (China). Further studies involving virus isolation are required to characterize this novel phlebovirus and to expand the epidemiological knowledge of related pathogens.
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Severe fever with thrombocytopenia syndrome (SFTS) is a newly recognized hemorrhagic fever disease found throughout Asia with a case fatality rate between 12% and 30%. Since 2009, SFTS has been reported in China throughout 14 Chinese Provinces. In addition, SFTS has been recognized in South Korea and Japan with the first confirmed cases reported in 2012. A similar disease, caused by the closely related Heartland virus, was also reported in the United States in 2009. SFTS is caused by SFTS virus, a novel tick-borne virus in the family Bunyaviridae, genus Phlebovirus. Unlike other mosquito- and sandfly-borne bunyaviruses, SFTS virus has not been extensively studied due to its recent emergence and many unknowns regarding its pathogenesis, life cycle, transmission, and options for therapeutics remains. In this review, we report the most current findings in SFTS virus research.
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