Induction of humoral and cell-mediated immunity to the NS1 protein of TBEV with recombinant Influenza virus and MVA affords partial protection against lethal TBEV infection in mice

Kubinski, Mareike; Zdora, Isabel; Puff, Christina; Biermann, Jeannine; Gerlach, Thomas; Baumgärtner, Wolfgang; Sutter, Gerd; Osterhaus, Albert D. M. E.; Prajeeth, Chittappen Kandiyil; Rimmelzwaan, Guus F.

doi:10.3389/fimmu.2023.1177324

Cited by 4 publications

(26 citation statements)

References 83 publications

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“…Animal models have demonstrated that virus-specific antibodies contribute to protective immunity against TBEV infections [ 13 , 17–21 ]. Also in humans, TBEV-specific antibodies have been identified as a correlate of protection [ 6 ].…”

Section: Resultsmentioning

confidence: 99%

“…Upon infection with TBEV, stronger antibody responses to the E and NS1 proteins are induced than after vaccination [ 2 , 32 ]. We recently showed in mice that antibodies against TBEV E and NS1 proteins afford full or partial protection [ 13 , 18 ]. In the present study, we determined virus-specific IgG, IgM levels and antibody responses to the EDIII and NS1 protein and their neutralizing activity in view of disease severity and outcome.…”

Section: Discussionmentioning

confidence: 99%

“…The same holds true for the virus-specific antibody response. For example, it has been shown in a mouse model that in addition to virus-neutralizing antibodies, antibodies to non-structural protein 1 (NS1) contribute to protective immunity [ 13 , 14 ], but their role in human infections has not been conclusively demonstrated. We hypothesize that virus-specific cellular and possibly humoral responses induced early during TBEV infection determine clinical course of TBE, including its severity and long-term outcome.…”

Section: Introductionmentioning

confidence: 99%

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Poor virus-specific T-cell responses early after tick-borne encephalitis virus infection correlate with disease severity

Aregay,

Slunečko,

Bogovic

et al. 2024

Emerging Microbes & Infections

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Poor virus-specific T-cell responses early after tick-borne encephalitis virus infection correlate with disease severity

Aregay,

Slunečko,

Bogovic

et al. 2024

Emerging Microbes & Infections

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“…Recombinant MVA with integrated NS3 sequence in deletion site III (MVA-NS3) was generated by homologous and intragenomic homologous recombination using the modified standard protocol [ 37 ] ( Figure 1 A). MVA-NS3 was propagated in primary CEF cells and concentrated as described previously [ 35 , 36 ].…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we constructed and tested recombinant MVA candidate vaccines expressing the prM-E and NS1 TBEV proteins, respectively. With these recombinant MVAs, we were able to induce E- and NS1-specific antibody and T cell responses which afforded complete or partial protection, respectively, against lethal challenge infection in mice [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Immunity to Tick-Borne Encephalitis Virus NS3 Protein Induced with a Recombinant Modified Vaccinia Virus Ankara Fails to Afford Mice Protection against TBEV Infection

Kubinski,

Beicht,

Gerlach

et al. 2024

Vaccines

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Tick-borne encephalitis (TBE) is a serious neurological disease caused by TBE virus (TBEV). Because antiviral treatment options are not available, vaccination is the key prophylactic measure against TBEV infections. Despite the availability of effective vaccines, cases of vaccination breakthrough infections have been reported. The multienzymatic non-structural protein 3 (NS3) of orthoflaviviruses plays an important role in polyprotein processing and virus replication. In the present study, we evaluated NS3 of TBEV as a potential vaccine target for the induction of protective immunity. To this end, a recombinant modified vaccinia virus Ankara that drives the expression of the TBEV NS3 gene (MVA-NS3) was constructed. MVA-NS3 was used to immunize C57BL/6 mice. It induced NS3-specific immune responses, in particular T cell responses, especially against the helicase domain of NS3. However, MVA-NS3-immunized mice were not protected from subsequent challenge infection with a lethal dose of the TBEV strain Neudoerfl, indicating that in contrast to immunity to prME and NS1, NS3-specific immunity is not an independent correlate of protection against TBEV in this mouse model.

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CD4+ T Cell Depletion Before Primary Dengue and/or Secondary Zika Infection Reveals Mechanistic Correlates of Antibody Functionality in Rhesus Macaques

Serrano-Collazo,

Miranda,

Cruz

et al. 2024

Preprint

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Dengue (DENV) virus and Zika virus (ZIKV) are two flaviviruses of major public health concern. One drawback designing effective vaccines is our limited understanding of the mechanisms ruling protection or harm among DENV serotypes, or between DENV and ZIKV. Here, we depleted rhesus macaques of CD4+T cellsin vivobefore primary DENV infection and/or secondary ZIKV challenge to recreate a sub-optimal priming of the humoral immune response. Our results support that CD4+T cells are needed to induce a quantitative and type-specific effective humoral immune response against primary DENV, but also against secondary ZIKV in DENV-experimented subjects. Our results also indicate a limited contribution of the DENV-Memory B cells to anti-ZIKV response. Furthermore, our results suggest that a suboptimal B cell priming during a primary DENV infection does differentially impact different antibody (Abs) properties. While binding or neutralization of ZIKV or DENV during a subsequent exposure to ZIKV is not affected by the lack of CD4+T - B cells interaction during a primary DENV infection, that interaction is critical to guarantee the Abs specificity. Also, we found that depleting CD4+T cells before DENV primary infection but not before ZIKV challenge significantly increases Abs cross-reactivity against DENV-EDIII domain and DENV-NS1 protein but not against ZIKV-EDIII domain or NS1 protein. Furthermore, there was more cross-reactivity among the DENV-NS1 proteins than against DENV-EDIII domains, suggesting that during a primary DENV infection CD4+T cells have a different weight in the responses against EDIII domain and NS1 protein. The proper Abs binding and neutralization with increased cross-reactivity profile was associated with limited frequency of circulating peripheral T helper cells (pTfh) with T helper 1 phenotype (CD4+/CXCR5+/CXCR3+) and expressing markers related to B cell activation (CXCR5+/CXCR3+/PD-1+/ICOS+) in the group depleted of CD4+T cells only before primary DENV infection. However, memory B cells – but not Antibody Secreting Cells (ASC) activation 7 days after the infection – positively correlate with those two populations of pTfh. Finally, when Abs cross-reactivity values were incorporated in a Principal Component Analysis (PCA), the DENV-CD4+T depleted group separates from the other two groups with similar Abs binding and neutralization profiles. Our result strongly suggests that during a heterologous sequential DENV/ZIKV infections Abs binding, and neutralization, may be regulated by different factors than their specificity. Before, the induction of cross-neutralizing Abs has been described in the context of secondary DENV infection. Here, for the first time, we are reproducing the experimental conditions leading to the generation of such Abs populationin vivo. In summary, we show that suboptimal immune priming during a primary flavivirus infection has functional consequences during a secondary heterologous infection. These results have huge implications understanding the immune response to DENV vaccines (and maybe ZIKV), including why an optimal vaccine or natural-induced neutralizing response not necessarily protects or enhances pathogenesis during a subsequent natural heterologous exposure.

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Induction of humoral and cell-mediated immunity to the NS1 protein of TBEV with recombinant Influenza virus and MVA affords partial protection against lethal TBEV infection in mice

Cited by 4 publications

References 83 publications

Poor virus-specific T-cell responses early after tick-borne encephalitis virus infection correlate with disease severity

Poor virus-specific T-cell responses early after tick-borne encephalitis virus infection correlate with disease severity

Immunity to Tick-Borne Encephalitis Virus NS3 Protein Induced with a Recombinant Modified Vaccinia Virus Ankara Fails to Afford Mice Protection against TBEV Infection

CD4+ T Cell Depletion Before Primary Dengue and/or Secondary Zika Infection Reveals Mechanistic Correlates of Antibody Functionality in Rhesus Macaques

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