RESUMO
Tick-borne encephalitis virus (TBEV) infection may cause acute central nervous system inflammation varying in clinical manifestations and severity. A possible correlation of TBEV-specific antibody and cell-mediated immune responses, shortly after infection, with clinical manifestations, severity and long-term outcome has been poorly investigated. In a cohort of thirty early tick-borne encephalitis (TBE) patients, we assessed the magnitude, specificity and functional properties of TBEV-specific T-cell and antibody responses. These responses early during disease were assessed in view of clinical manifestations, severity and long-term outcome. TBEV-specific T-cell responses to C, E, NS1, and NS5 proteins were significantly lower in patients with severe acute illness than in patients with mild TBE. Lower T-cell responses to E, NS1, and NS5 proteins also correlated with the development of meningoencephalomyelitis. Virus-specific antibody titres early after infection did not correlate with disease severity, clinical manifestations, or long-term outcome in this study, possibly due to the small number of patients of which matching serum and peripheral blood mononuclear cells were available. The findings suggest that virus-specific T cells afford a certain degree of protection against the development of severe TBEV-induced disease.
Assuntos
Anticorpos Antivirais , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Linfócitos T , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Humanos , Linfócitos T/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Índice de Gravidade de Doença , Idoso , Proteínas não Estruturais Virais/imunologiaRESUMO
Hemorrhagic fever with renal syndrome (HFRS) and tick-borne encephalitis (TBE) are the most common viral diseases in Russia. HFRS is caused by six different types of hantaviruses: Hantaan, Amur, Seoul, Puumala, Kurkino, and Sochi, which are transmitted to humans through small mammals of the Muridae and Cricetidae families. TBE is caused by viruses belonging to five different phylogenetic subtypes. The similarities in the ecology of HFRS and TBE pathogens is presented here. Hantavirus-infected small mammals can transmit the virus to uninfected animals, and ticks can also transmit hantavirus to other ticks and mammals. Hantavirus transmission from ticks to humans is possible only hypothetically based on indirect data. Over the past 23 years, 164,582 cases of HFRS (4.9 per 105 people) and 71,579 cases of TBE (2.5 per 105 people) were registered in Russia. The mortality rate was 0.4% (668 cases) in HFRS and 1.6% deaths (1136 cases) in TBE. There were 4030 HFRS (2.5%) and 9414 TBE (13%) cases in children under 14 years old. HFRS and TBE cases were registered in 42 out of 85 Russian regions; in 18-only HFRS, in 13-only TBE, and 12 had no reported cases. The prospects of applying a combined vaccine for HFRS and TBE prevention are shown in this paper.
Assuntos
Encefalite Transmitida por Carrapatos , Febre Hemorrágica com Síndrome Renal , Vacinas Virais , Encefalite Transmitida por Carrapatos/prevenção & controle , Encefalite Transmitida por Carrapatos/epidemiologia , Encefalite Transmitida por Carrapatos/virologia , Encefalite Transmitida por Carrapatos/transmissão , Federação Russa/epidemiologia , Febre Hemorrágica com Síndrome Renal/epidemiologia , Febre Hemorrágica com Síndrome Renal/prevenção & controle , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Animais , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Orthohantavírus/imunologia , Orthohantavírus/genética , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/genética , Vacinas Combinadas/imunologia , Vacinas Combinadas/administração & dosagem , Carrapatos/virologiaRESUMO
Powassan virus (POWV) is an emergent tick-borne flavivirus that causes fatal encephalitis in the elderly and long-term neurologic sequelae in survivors. How age contributes to severe POWV encephalitis remains an enigma, and no animal models have assessed age-dependent POWV neuropathology. Inoculating C57BL/6 mice with a POWV strain (LI9) currently circulating in Ixodes ticks resulted in age-dependent POWV lethality 10-20 dpi. POWV infection of 50-week-old mice was 82% fatal with lethality sequentially reduced by age to 7.1% in 10-week-old mice. POWV LI9 was neuroinvasive in mice of all ages, causing acute spongiform CNS pathology and reactive gliosis 5-15 dpi that persisted in survivors 30 dpi. High CNS viral loads were found in all mice 10 dpi. However, by 15 dpi, viral loads decreased by 2-4 logs in 10- to 40-week-old mice, while remaining at high levels in 50-week-old mice. Age-dependent differences in CNS viral loads 15 dpi occurred concomitantly with striking changes in CNS cytokine responses. In the CNS of 50-week-old mice, POWV induced Th1-type cytokines (IFNγ, IL-2, IL-12, IL-4, TNFα, IL-6), suggesting a neurodegenerative pro-inflammatory M1 microglial program. By contrast, in 10-week-old mice, POWV-induced Th2-type cytokines (IL-10, TGFß, IL-4) were consistent with a neuroprotective M2 microglial phenotype. These findings correlate age-dependent CNS cytokine responses and viral loads with POWV lethality and suggest potential neuroinflammatory therapeutic targets. Our results establish the age-dependent lethality of POWV in a murine model that mirrors human POWV severity and long-term CNS pathology in the elderly. IMPORTANCE: Powassan virus is an emerging tick-borne flavivirus causing lethal encephalitis in aged individuals. We reveal an age-dependent POWV murine model that mirrors human POWV encephalitis and long-term CNS damage in the elderly. We found that POWV is neuroinvasive and directs reactive gliosis in all age mice, but at acute stages selectively induces pro-inflammatory Th1 cytokine responses in 50-week-old mice and neuroprotective Th2 cytokine responses in 10-week-old mice. Our findings associate CNS viral loads and divergent cytokine responses with age-dependent POWV lethality and survival outcomes. Responses of young mice suggest potential therapeutic targets and approaches for preventing severe POWV encephalitis that may be broadly applicable to other neurodegenerative diseases. Our age-dependent murine POWV model permits analysis of vaccines that prevent POWV lethality, and therapeutics that resolve severe POWV encephalitis.
Assuntos
Citocinas , Modelos Animais de Doenças , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Camundongos Endogâmicos C57BL , Neuroglia , Carga Viral , Animais , Camundongos , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Encefalite Transmitida por Carrapatos/mortalidade , Encefalite Transmitida por Carrapatos/patologia , Citocinas/metabolismo , Citocinas/imunologia , Neuroglia/virologia , Neuroglia/imunologia , Neuroglia/patologia , Feminino , Fatores Etários , Ixodes/virologia , Ixodes/imunologia , Sistema Nervoso Central/virologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encéfalo/virologia , Encéfalo/patologia , Encéfalo/imunologiaRESUMO
Tick-borne encephalitis (TBE) virus is the most prevalent tick-transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA-based detection of specific antibodies in the patient serum. However, cross-reactivity between orthoflaviviruses complicates the diagnosis. Specificity issues may be mitigated by serum neutralization assays (SNT), although the handling of clinically relevant orthoflaviviruses requires biosafety level (BSL) 3 conditions and they have highly divergent viral kinetics and cell tropisms. In the present study, we established a reporter virus particle (RVP)-based SNT in which the infectivity is measured by luminescence and that can be performed under BSL-2 conditions. The RVP-based SNT for TBEV exhibited a highly significant correlation with the traditional virus-based SNT (R2 = 0.8637, p < 0.0001). The RVP-based assay demonstrated a sensitivity of 92.3% (95% CI: 79.7%-97.4%) and specificity of 100% (95% CI: 81.6%-100%). We also tested the cross-reactivity of serum samples in RVP-based assays against other orthoflaviviruses (yellow fever virus, dengue virus type 2, Zika virus, West Nile virus and Japanese encephalitis virus). Interestingly, all serum samples which had tested TBEV-positive by ELISA but negative by RVP-based SNT were reactive for antibodies against other orthoflaviviruses. Thus, the RVP-based seroneutralization assay provides an added value in clinical diagnostics as well as in epidemiological studies.
Assuntos
Anticorpos Antivirais , Reações Cruzadas , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Ensaio de Imunoadsorção Enzimática , Testes de Neutralização , Sensibilidade e Especificidade , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Humanos , Anticorpos Antivirais/sangue , Testes de Neutralização/métodos , Encefalite Transmitida por Carrapatos/diagnóstico , Encefalite Transmitida por Carrapatos/virologia , Ensaio de Imunoadsorção Enzimática/métodos , Vírion/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , AnimaisRESUMO
Omsk hemorrhagic fever virus (OHFV) is a member of the tick-borne encephalitis virus (TBEV) complex of the Flaviviridae family. Currently, there are no data on the cross-reactivity of antibodies to the NS1 proteins of OHFV and TBEV. Such data are of major interest for monitoring viral encephalitis of unknown etiology due to the increasing geographical distribution of OHFV. In this study, a recombinant OHFV NS1 protein was produced using the Escherichia coli expression system and purified. The recombinant OHFV NS1 protein was recognized by specific mice immune ascetic fluids to the native OHFV NS1 protein. A Western blot analysis and ELISA of the recombinant NS1 proteins of OHFV and TBEV were used to study the cross-reactivity of antibodies from immune ascites fluid obtained from OHFV-infected mice and mAbs against TBEV NS1. Anti-TBEV NS1 mouse monoclonal antibodies (mAbs) have been shown to not be cross-reactive to the OHFV NS1 protein. Sera from patients with confirmed tick-borne encephalitis (TBE) were examined by ELISA using recombinant OHFV NS1 and TBEV NS1 proteins as antigens. It was shown for the first time that cross-reactive antibodies to the OHFV NS1 protein were not detected in the sera of TBE patients, whereas the sera contained antibodies to the TBEV NS1 protein.
Assuntos
Anticorpos Antivirais , Reações Cruzadas , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Proteínas Recombinantes , Proteínas não Estruturais Virais , Proteínas não Estruturais Virais/imunologia , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Encefalite Transmitida por Carrapatos/sangue , Reações Cruzadas/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Animais , Humanos , Camundongos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/genética , Ensaio de Imunoadsorção Enzimática , Escherichia coli/genética , Camundongos Endogâmicos BALB C , FemininoRESUMO
CONTEXT: Flaviviruses cause severe encephalitic or hemorrhagic diseases in humans. Its members, Kyasanur forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (ALKV), cause hemorrhagic fever and are prevalent in India and Saudi Arabia, respectively, while the tick-borne encephalitis virus (TBEV) causes a dangerous encephalitic infection in Europe and Asia. However, little information is available about the targets of immune responses for these deadly viruses. Here, we predict potential antigenic peptide epitopes of viral envelope protein for inducing a cell-mediated and humoral immune response. METHODS: Using the Immune Epitope Database and Analysis Resource (IEDB-AR), we identified 13 MHC-I and two MHC-II dominant conserved epitopes in KFDV and ALKV and six MHC-I and three MHC-II epitopes in TBEV envelope proteins. Parallelly, we also predicted B-cell linear and discontinuous envelope protein epitopes for these viruses. Interestingly, the epitopes are conserved in all three viral envelope proteins. Further, the discontinuous epitopes are structurally compared with the available DENV, ZIKV, WNV, TBEV, and LIV envelope protein antibody structures. Overall structural comparison analyses highlight (i) lateral ridge epitope in the ED-III domain of E protein, and (ii) envelope dimer epitope (EDE) could be targeted for developing potent vaccine candidates as well as therapeutic antibody production. Moreover, existing structural and biochemical functions of the same epitopes in homologous viruses are predicted to have a reduced antibody-dependent enhancement (ADE) effect on flaviviral infection.
Assuntos
Flavivirus , Flavivirus/imunologia , Humanos , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/química , Biologia Computacional , Sequência de Aminoácidos , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/química , Homologia de Sequência de Aminoácidos , Epitopos/imunologia , Epitopos/química , Modelos Moleculares , Vírus da Encefalite Transmitidos por Carrapatos/imunologiaRESUMO
Background: Tick-borne encephalitis (TBE) is caused by the tick-borne encephalitis virus (TBEV). TBEV infection can cause symptoms of central nervous system (CNS) inflammation and result in severe consequences including death. TBE is an increasing health threat in the Czech Republic and elsewhere in Europe. In 2020, 23% of 3734 TBE cases reported to the European Centre for Disease Prevention and Control were from the Czech Republic. TBE vaccination is universally recommended in the Czech Republic, but a full analysis of TBE vaccine effectiveness (VE) in the Czech Republic has not been published. Methods: TBE is a notifiable disease in the Czech Republic with mandatory reporting of cases (i.e., laboratory-confirmed TBEV infected patient with symptoms of CNS inflammation) and vaccination history to public health authorities. TBE VE was estimated using the screening method utilizing public health surveillance data from 2018 to 2022 and online household surveys of the general population on TBE vaccine uptake conducted in 2019-2022. Results: In 2018-2022, 3648 TBE cases were reported in the Czech Republic; 98.1% (3105/3166) of TBE cases with known vaccination history were unvaccinated. Among 42,671 persons surveyed from the general population who had known TBE vaccination history, 66.5% were unvaccinated. VE against TBE was 97.6% (95% confidence interval 95.7-98.7). When stratified by age group, VE was 97.1% (88.4-99.3) in 1-15 years of age, 97.9% (95.3-99.0) in 16-59 years of age, and 96.9% (90.5-99.0) in ≥60 years of age. TBE vaccination averted an estimated 1020 TBE cases in the Czech Republic from 2018 to 2022. Conclusions: This first published study with a full analysis of TBE VE in the Czech Republic showed that vaccination was highly effective for the prevention of TBE including in children, an age group with increasing TBE disease burden. Vaccination averted hundreds of TBE cases and hospitalizations despite the relatively low compliance with TBE vaccine recommendations. To prevent additional TBE cases in the Czech Republic, enhanced efforts to increase TBE vaccine uptake are needed.
Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Vacinação , Vacinas Virais , Encefalite Transmitida por Carrapatos/prevenção & controle , Encefalite Transmitida por Carrapatos/epidemiologia , República Tcheca/epidemiologia , Humanos , Pessoa de Meia-Idade , Adolescente , Adulto , Criança , Adulto Jovem , Feminino , Masculino , Pré-Escolar , Vacinas Virais/administração & dosagem , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Idoso , LactenteRESUMO
Tick-borne encephalitis virus (TBEV) is a tick-borne flavivirus that induces severe central nervous system disorders. It has recently raised concerns due to an expanding geographical range and increasing infection rates. Existing vaccines, though effective, face low coverage rates in numerous TBEV endemic regions. Our previous work demonstrated the immunogenicity and full protection afforded by a TBEV vaccine based on virus-like particles (VLPs) produced in Leishmania tarentolae cells in immunization studies in a mouse model. In the present study, we explored the impact of adjuvants (AddaS03™, Alhydrogel®+MPLA) and administration routes (subcutaneous, intramuscular) on the immune response. Adjuvanted groups exhibited significantly enhanced antibody responses, higher avidity, and more balanced Th1/Th2 response. IFN-γ responses depended on the adjuvant type, while antibody levels were influenced by both adjuvant and administration routes. The combination of Leishmania-derived TBEV VLPs with Alhydrogel® and MPLA via intramuscular administration emerged as a highly promising prophylactic vaccine candidate, eliciting a robust, balanced immune response with substantial neutralization potential.
Assuntos
Adjuvantes Imunológicos , Anticorpos Antivirais , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Leishmania , Vacinas Sintéticas , Vacinas de Partículas Semelhantes a Vírus , Vacinas Virais , Animais , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Camundongos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/administração & dosagem , Encefalite Transmitida por Carrapatos/prevenção & controle , Encefalite Transmitida por Carrapatos/imunologia , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Leishmania/imunologia , Feminino , Adjuvantes de Vacinas/administração & dosagem , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Imunogenicidade da Vacina , Injeções Intramusculares , Camundongos Endogâmicos BALB C , Interferon gama/imunologia , Células Th1/imunologiaRESUMO
Tick-borne encephalitis (TBE) is usually diagnosed based on the presence of TBE virus (TBEV)-specific IgM and IgG antibodies in serum. However, antibodies induced by vaccination or cross-reactivity to previous flavivirus infections may result in false positive TBEV serology. Detection of TBEV RNA may be an alternative diagnostic approach to detect viral presence and circumvent the diagnostic difficulties present when using serology. Viral RNA in blood is commonly detectable only in the first viremic phase usually lasting up to two weeks, and not in the second neurologic phase, when the patients contact the health care system and undergo diagnostic work-up. TBEV RNA has previously been detected in urine in a few retrospective TBE cases in the neurologic phase, and furthermore RNA of other flaviviruses has been detected in patient saliva. In this study, blood, saliva and urine were collected from 31 hospitalised immunocompetent patients with pleocytosis and symptoms of aseptic meningitis and/or encephalitis, suspected to have TBE. We wanted to pursue if molecular testing of TBEV RNA in these patient materials may be useful in the diagnostics. Eleven of the 31 study patients were diagnosed with TBE based on ELISA detection of TBEV specific IgG and IgM antibodies. None of the study patients had TBEV RNA detectable in any of the collected patient material.
Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Imunoglobulina M , RNA Viral , Saliva , Humanos , Encefalite Transmitida por Carrapatos/diagnóstico , Encefalite Transmitida por Carrapatos/urina , Encefalite Transmitida por Carrapatos/sangue , Encefalite Transmitida por Carrapatos/virologia , Encefalite Transmitida por Carrapatos/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/isolamento & purificação , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/genética , Saliva/virologia , RNA Viral/urina , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Imunoglobulina M/sangue , Imunoglobulina M/urina , Imunoglobulina G/sangue , Imunoglobulina G/urina , Anticorpos Antivirais/sangue , Idoso de 80 Anos ou mais , Imunocompetência , HospitalizaçãoRESUMO
Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.
Assuntos
Anticorpos Neutralizantes , Humanos , Brasil , Anticorpos Neutralizantes/imunologia , México , Anticorpos Antivirais/imunologia , Animais , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Flavivirus/imunologia , Epitopos/imunologia , Anticorpos Monoclonais/imunologia , Carrapatos/virologia , Carrapatos/imunologia , Feminino , MasculinoRESUMO
BACKGROUND: Tick-borne encephalitis (TBE) is a severe human neuroinfection caused by TBE virus (TBEV). TBEV is transmitted by tick bites and by the consumption of unpasteurized dairy products from infected asymptomatic ruminants. In France, several food-borne transmission events have been reported since 2020, raising the question of the level of exposure of domestic ungulates to TBEV. In this study, our objectives were (i) to estimate TBEV seroprevalence and quantify antibodies titres in cattle in the historical endemic area of TBEV in France using the micro virus neutralisation test (MNT) and (ii) to compare the performance of two veterinary cELISA kits with MNT for detecting anti-TBEV antibodies in cattle in various epidemiological contexts. A total of 344 cattle sera from four grid cells of 100 km² in Alsace-Lorraine (endemic region) and 84 from western France, assumed to be TBEV-free, were investigated. RESULTS: In Alsace-Lorraine, cattle were exposed to the virus with an overall estimated seroprevalence of 57.6% (95% CI: 52.1-62.8%, n = 344), varying locally from 29.9% (95% CI: 21.0-40.0%) to 92.1% (95% CI: 84.5-96.8%). Seroprevalence did not increase with age, with one- to three-year-old cattle being as highly exposed as older ones, suggesting a short-life duration of antibodies. The proportion of sera with MNT titres lower than 1:40 per grid cell decreased with increased seroprevalence. Both cELISA kits showed high specificity (> 90%) and low sensitivity (less than 78.1%) compared with MNT. Sensitivity was lower for sera with neutralising antibodies titres below 1:40, suggesting that sensitivity of these tests varied with local virus circulation intensity. CONCLUSIONS: Our results highlight that cattle were highly exposed to TBEV. Screening strategy and serological tests should be carefully chosen according to the purpose of the serological study and with regard to the limitations of each method.
Assuntos
Anticorpos Antivirais , Doenças dos Bovinos , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Animais , Bovinos , Encefalite Transmitida por Carrapatos/epidemiologia , Encefalite Transmitida por Carrapatos/veterinária , Encefalite Transmitida por Carrapatos/virologia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/isolamento & purificação , França/epidemiologia , Estudos Soroepidemiológicos , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/virologia , Anticorpos Antivirais/sangue , Feminino , Masculino , Testes de Neutralização/veterinária , Doenças Endêmicas/veterináriaRESUMO
BackgroundTick-borne encephalitis (TBE) is a severe, vaccine-preventable viral infection of the central nervous system. Symptoms are generally milder in children and adolescents than in adults, though severe disease does occur. A better understanding of the disease burden and duration of vaccine-mediated protection is important for vaccination recommendations.AimTo estimate TBE vaccination coverage, disease severity and vaccine effectiveness (VE) among individuals aged 0-17â¯years in Switzerland.MethodsVaccination coverage between 2005 and 2022 was estimated using the Swiss National Vaccination Coverage Survey (SNVCS), a nationwide, repeated cross-sectional study assessing vaccine uptake. Incidence and severity of TBE between 2005 and 2022 were determined using data from the Swiss disease surveillance system and VE was calculated using a case-control analysis, matching TBE cases with SNVCS controls.ResultsOver the study period, vaccination coverage increased substantially, from 4.8% (95% confidence interval (CI): 4.1-5.5%) to 50.1% (95% CI: 48.3-52.0%). Reported clinical symptoms in TBE cases were similar irrespective of age. Neurological involvement was less likely in incompletely (1-2 doses) and completely (≥â¯3 doses) vaccinated cases compared with unvaccinated ones. For incomplete vaccination, VE was 66.2% (95% CI: 42.3-80.2), whereas VE for complete vaccination was 90.8% (95% CI: 87.7-96.4). Vaccine effectiveness remained high, 83.9% (95% CI: 69.0-91.7) up to 10â¯years since last vaccination.ConclusionsEven children younger than 5â¯years can experience severe TBE. Incomplete and complete vaccination protect against neurological manifestations of the disease. Complete vaccination offers durable protection up to 10â¯years against TBE.
Assuntos
Encefalite Transmitida por Carrapatos , Cobertura Vacinal , Vacinação , Vacinas Virais , Humanos , Encefalite Transmitida por Carrapatos/prevenção & controle , Encefalite Transmitida por Carrapatos/epidemiologia , Adolescente , Estudos de Casos e Controles , Suíça/epidemiologia , Criança , Estudos Transversais , Masculino , Feminino , Pré-Escolar , Lactente , Vacinação/estatística & dados numéricos , Cobertura Vacinal/estatística & dados numéricos , Vacinas Virais/administração & dosagem , Incidência , Eficácia de Vacinas/estatística & dados numéricos , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Recém-Nascido , Vigilância da PopulaçãoRESUMO
BACKGROUND: Tick-borne encephalitis (TBE) virus infects the central nervous system and may lead to severe neurological complications or death. This study assessed immunogenicity, safety, and tolerability of TBE vaccine in Japanese participants 1 year of age and older. METHODS: This phase 3, multicenter, single-arm, open-label study was conducted in Japanese adult (≥ 16 years) and pediatric (1-< 16 years) populations. Participants received a single 0.5-mL (adult) or 0.25-mL (pediatric) dose of TBE vaccine at each of 3 visits. The primary endpoint was the proportion of participants who were seropositive (neutralization test [NT] titer ≥ 1:10) 4 weeks after Dose 3. Secondary and exploratory endpoints included NT seropositivity rates 4 weeks after Dose 2, immunoglobulin G (IgG) seropositivity 4 weeks after Doses 2 and 3, NT geometric mean titers (GMTs), IgG geometric mean concentrations (GMCs), and geometric mean fold rises. Primary safety endpoints were frequencies of local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Among 100 adult and 65 pediatric participants, 99.0 % and 100.0 % completed the study, respectively. NT seropositivity was achieved in 98.0 % adult and 100.0 % pediatric participants after Dose 3; seropositivity after Dose 2 was 93.0 % and 92.3 %, respectively. In both age groups, IgG seropositivity was ≥ 90.0 % and ≥ 96.0 % after Doses 2 and 3, respectively; GMTs and GMCs were highest 4 weeks after Dose 3. Reactogenicity events were generally mild to moderate in severity and short-lived. AEs were reported by 15.0 % (adult) and 43.1 % (pediatric) of participants. No life-threatening AEs, AEs leading to discontinuation, immediate AEs, related AEs, or deaths were reported. No serious AEs were considered related to TBE vaccine. CONCLUSIONS: TBE vaccine elicited robust immune responses in Japanese participants 1 year of age and older. The 3-dose regimen was safe and well tolerated, and findings were consistent with the known safety profile of this TBE vaccine. CLINICALTRIALS: gov: NCT04648241.
Assuntos
Anticorpos Antivirais , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Imunoglobulina G , Vacinas Virais , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , População do Leste Asiático , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/prevenção & controle , Encefalite Transmitida por Carrapatos/imunologia , Voluntários Saudáveis , Imunogenicidade da Vacina , Imunoglobulina G/sangue , Japão , Testes de Neutralização , Vacinas Virais/imunologia , Vacinas Virais/efeitos adversos , Vacinas Virais/administração & dosagem , Idoso de 80 Anos ou maisAssuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Células de Langerhans , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Humanos , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Animais , Células de Langerhans/imunologia , Células de Langerhans/virologia , Diferenciação Celular , Células-Tronco/virologia , Células-Tronco/imunologiaRESUMO
PURPOSE: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection. METHODS: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls. RESULTS: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV. CONCLUSION: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.
Assuntos
Agamaglobulinemia , Anticorpos Antivirais , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Doenças Genéticas Ligadas ao Cromossomo X , Imunoglobulina G , Linfócitos T , Humanos , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/diagnóstico , Encefalite Transmitida por Carrapatos/terapia , Masculino , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Anticorpos Antivirais/sangue , Linfócitos T/imunologia , Resultado do Tratamento , Adulto , Imunização Passiva/métodosRESUMO
Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.
Assuntos
Alelos , DNA Polimerase gama , Vírus da Encefalite Transmitidos por Carrapatos , Herpesvirus Humano 1 , Tolerância Imunológica , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Camundongos , Idade de Início , COVID-19/imunologia , COVID-19/virologia , COVID-19/genética , DNA Polimerase gama/genética , DNA Polimerase gama/imunologia , DNA Polimerase gama/metabolismo , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Mutação , RNA Mitocondrial/imunologia , RNA Mitocondrial/metabolismo , SARS-CoV-2/imunologiaRESUMO
Tick-borne encephalitis virus (TBEV) is an important human arthropod-borne virus that causes tick-borne encephalitis (TBE) in humans. TBEV acutely infects the central nervous system (CNS), leading to neurological symptoms of various severity. No therapeutics are currently available for TBEV-associated disease. Virus strains of various pathogenicity have been described, although the basis of their diverse clinical outcome remains undefined. Work with infectious TBEV requires high-level biocontainment, meaning model systems that can recapitulate the virus life cycle are highly sought. Here, we report the generation of a self-replicating, noninfectious TBEV replicon used to study properties of high (Hypr) and low (Vs) pathogenic TBEV isolates. Using a Spinach2 RNA aptamer and luciferase reporter system, we perform the first direct comparison of Hypr and Vs in cell culture. Infectious wild-type (WT) viruses and chimeras of the nonstructural proteins 3 (NS3) and 5 (NS5) were investigated in parallel to validate the replicon data. We show that Hypr replicates to higher levels than Vs in mammalian cells, but not in arthropod cells, and that the basis of these differences map to the NS5 region, encoding the methyltransferase and RNA polymerase. For both Hypr and Vs strains, NS5 and the viral genome localized to intracellular structures typical of positive-strand RNA viruses. Hypr was associated with significant activation of IRF-3, caspase-3, and caspase-8, while Vs activated Akt, affording protection against caspase-mediated apoptosis. Higher activation of stress-granule proteins TIAR and G3BPI were an additional early feature of Vs but not for Hypr. These findings highlight novel host cell responses driven by NS5 that may dictate the differential clinical characteristics of TBEV strains. This highlights the utility of the TBEV replicons for further virological characterization and antiviral drug screening. IMPORTANCE Tick-borne encephalitis virus (TBEV) is an emerging virus of the flavivirus family that is spread by ticks and causes neurological disease of various severity. No specific therapeutic treatments are available for TBE, and control in areas of endemicity is limited to vaccination. The pathology of TBEV ranges from mild to fatal, depending on the virus genotype. Characterization of TBEV isolates is challenging due to the requirement for high-containment facilities. Here, we described the construction of novel TBEV replicons that permit a molecular comparison of TBEV isolates of high and low pathogenicity.
Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Interações entre Hospedeiro e Microrganismos , Animais , Caspase 3/metabolismo , Caspase 8/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/imunologia , Ativação Enzimática , Fator Regulador 3 de Interferon/genética , Metiltransferases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas não Estruturais Virais/imunologiaRESUMO
Powassan virus (POWV) is a tick-borne pathogen for which humans are an incidental host. POWV infection can be fatal or result in long-term neurological sequelae; however, there are no approved vaccinations for POWV. Integral to efficacious vaccine development is the identification of correlates of protection, which we accomplished in this study by utilizing a murine model of POWV infection. Using POWV lethal and sub-lethal challenge models, we show that (1) robust B and T cell responses are necessary for immune protection, (2) POWV lethality can be attributed to both viral- and host-mediated drivers of disease, and (3) knowledge of the immune correlates of protection against POWV can be applied in a virus-like particle (VLP)-based vaccination approach that provides protection from lethal POWV challenge. Identification of these immune protection factors is significant as it will aid in the rational design of POWV vaccines.
Assuntos
Linfócitos B/imunologia , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/prevenção & controle , Linfócitos T/imunologia , Vacinação , Vírion/imunologia , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Especificidade de Anticorpos/imunologia , Modelos Animais de Doenças , Encefalite Transmitida por Carrapatos/virologia , Interações Hospedeiro-Patógeno/imunologia , Camundongos Endogâmicos C57BLRESUMO
There is evidence that flaviviral NS1 glycoprotein plays an important role in the pathology of tick-borne encephalitis (TBE) and NS1-specific antibodies are detected in the blood of patients with TBE. This makes NS1 a good target for the development of therapeutic inhibitors and NS1 could be an important biomarker for the early diagnosis of TBE in vaccinated individuals. Eukaryotic expression systems are mainly used to produce recombinant tick-borne encephalitis virus (TBEV) NS1. The expression of TBEV NS1 proteins in eukaryotic cells was successful, but there were some limitations. Several attempts have also been made to obtain the NS1 protein in Escherichia coli cells; however, they were unsuccessful due to the low solubility of the recombinant protein and improper folding. In this study, using Trx-tag as a fusion partner, soluble Trx-fused TBEV NS1 protein was first produced in the E. coli BL21 strain. In addition, insoluble Trx-fused TBEV NS1 protein was obtained when cultivation conditions were changed to increase the productivity. The insoluble TBEV NS1 obtained from inclusion bodies was solubilized using chaotropic reagents and successfully refolded using dialysis. Both soluble variant and successfully refolded from inclusion bodies variant showed immunological properties similar to the native TBEV NS1 protein and were recognized by specific monoclonal antibodies (mAbs), immune ascetic fluid in ELISA, western blot, and competitive analysis.