Variation of the Specificity of the Human Antibody Responses after Tick-Borne Encephalitis Virus Infection and Vaccination

Jarmer, Johanna; Zlatkovic, Jürgen; Tsouchnikas, Georgios; Vratskikh, Oksana; Strauß, Johannes; Aberle, Judith H.; Chmelík, V; Kundi, Michael; Stiasny, Karin; Heinz, Franz X.

doi:10.1128/jvi.02086-14

Cited by 78 publications

(77 citation statements)

References 81 publications

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“…Recombinant production of ZIKV sE protein. Recombinant Zika virus sE protein (strain H/PF/2013, GenBank accession number KJ776791) was produced with a tandem strep-tag in the Drosophila Expression System (Invitrogen) as described previously 29,30 . A chemically synthesized DNA fragment (GeneArt) containing the Zika sE sequence (amino acids 1-408) was cloned into the expression vector pT389 (ref.…”

Section: Methodsmentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

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Zika virus (ZIKV) is an arthropod-borne enveloped virus belonging to the Flavivirus genus in the family Flaviviridae, which also includes the human pathogenic yellow fever, dengue, West Nile and tick-borne encephalitis viruses 1 . Flaviviruses have two structural glycoproteins, prM and E (for precursor membrane and envelope proteins, respectively), which form a heterodimer in the endoplasmic reticulum (ER) of the infected cell and drive the budding of spiky immature virions into the ER lumen. These particles transit through the cellular secretory pathway, during which the trans-Golgi-resident protease furin cleaves prM. This processing is required for infectivity, and results in the loss of a large fragment of prM and reorganization of E on the virion surface. The mature particles have a smooth aspect, with 90 E dimers organized with icosahedral symmetry in a 'herringbone' pattern 2,3 .Three-dimensional cryo-electron microscopy (cryo-EM) structures of the mature ZIKV particles have recently been reported to near atomic resolution (3.8 Å) 4,5 , showing that the virus has essentially the same organization as the other flaviviruses of known structure, such as dengue virus (DENV) 3 and West Nile virus 6,7 . The E protein is about 500 amino acids long, with the 400 N-terminal residues forming the ectodomain essentially folded as β-sheets with three domains, named I, II and III, aligned in a row with domain I at the centre. The conserved fusion loop is at the distal end of the rod in domain II, buried at the E dimer interface. At the C terminus, the E ectodomain is followed by the 'stem' , featuring two α-helices lying flat on the viral membrane (the stem helices), which link to two C-terminal transmembrane α-helices. The main distinguishing feature of the ZIKV virion is an insertion within a glycosylated loop of E (the '150' loop), which protrudes from the mature virion surface 4,5 .Flaviviruses have been grouped into serocomplexes based on cross-neutralization studies with polyclonal immune sera 8 . The E protein is the main target of neutralizing antibodies, and is also the viral fusogen; cleavage of prM allows E to respond to the endosomal pH by undergoing a large-scale conformational change that catalyses membrane fusion and releases the viral genome into the cyotosol. Loss of the precursor fragment of prM lets the E protein fluctuate from its tight packing at the surface of the virion, transiently exposing otherwise buried surfaces. One surface exposed by this 'breathing' is the fusionloop epitope (FLE), which is a dominant cross-reactive antigenic site 9 . Although antibodies to this site can protect by complement-mediated mechanisms, as shown in a mouse model for West Nile virus 10 , they are poorly neutralizing and lead to antibody-dependent enhancement 11-15 , thereby aggravating Flavivirus pathogenesis and complicating the development of safe and effective vaccines.We recently reported the functional and structural characterization of a panel of antibodies isolated from patients with dengue disease 13,16 . ...

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Section: Methodsmentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

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479

540

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“…In fact, once the beads are coated with a specific glycoprotein, they can be reused multiple times. Heinz et al (56,57) used a similar magnetic bead assay to dissect the Ab response of sera from people vaccinated against yellow fever virus or tick borne encephalitis virus. These researchers depleted the sera using subdomains of the surface glycoproteins and evaluated the residual neutralization response.…”

Section: Discussionmentioning

confidence: 99%

Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific

Cairns

Huang

Gallagher

et al. 2015

J Virol

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Herpes simplex virus 1 (HSV-1) and HSV-2 infect many humans and establish a latent infection in sensory ganglia. Although some infected people suffer periodic recurrences, others do not. Infected people mount both cell-mediated and humoral responses, including the production of virus-neutralizing antibodies (Abs) directed at viral entry glycoproteins. Previously, we examined IgGs from 10 HSV-seropositive individuals; all neutralized virus and were directed primarily against gD or gD؉gB. Here, we expand our studies and examine 32 additional sera from HSV-infected individuals, 23 of whom had no recurrent disease. Using an Octet RED96 system, we screened all 32 serum samples directly for both glycoprotein binding and competition with known neutralizing anti-gD and -gB monoclonal Abs (MAbs). On average, the recurrent cohort exhibited higher binding to gD and gB and had higher neutralization titers. There were similar trends in the blocking of MAbs to critical gD and gB epitopes. When we depleted six sera of Abs to specific glycoproteins, we found different types of responses, but always directed primarily at gD and/or gB. Interestingly, in one dual-infected person, the neutralizing response to HSV-2 was due to gD2 and gB2, whereas HSV-1 neutralization was due to gD1 and gB1. In another case, virus neutralization was HSV-1 specific, with the Ab response directed entirely at gB1, despite this serum blocking type-common anti-gD and -gB neutralizing MAbs. These data are pertinent in the design of future HSV vaccines since they demonstrate the importance of both serotypes of gD and gB as immunogens. IMPORTANCEWe previously showed that people infected with HSV produce neutralizing Abs directed against gD or a combination of gD؉gB (and in one case, gD؉gB؉gC, which was HSV-1 specific). In this more extensive study, we again found that gD or gD؉gB can account for the virus neutralizing response and critical epitopes of one or both of these proteins are represented in sera of naturally infected humans. However, we also found that some individuals produced a strong response against gB alone. In addition, we identified type-specific contributions to HSV neutralization from both gD and gB. Contributions from the other entry glycoproteins, gC and gH/gL, were minimal and limited to HSV-1 neutralization. Knowing the variations in how humans see and mount a response to HSV will be important to vaccine development. Herpes simplex virus 1 (HSV-1) and HSV-2 cause human diseases, ranging from benign cold sores to life-threatening infections such as encephalitis and neonatal HSV disease (1, 2). The hallmark of HSV infection is the ability of each serotype to establish a lifelong latent infection in sensory neurons. Reactivation can lead to clinical symptoms such as oral or genital lesions. Currently, 47% of the U.S. population is seropositive for HSV-1 and 16% are seropositive for HSV-2 (3). Many seropositive individuals are asymptomatic, although a number of people shed virus regardless of clinical signs of disease (4). However,...

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“…Recombinant TBE virus sE (amino acid [aa] 1 to 400), DI (aa 1 to 52 plus 8-Gly linker plus aa 137 to 192 plus 8-Gly linker plus aa 285 to 302), and DIDII (aa 1 to 302) proteins were derived from TBE virus strain Neudoerfl and WN virus sE (aa 1 to 400) protein from strain New York 99 (GenBank accession number AF196835). All antigens were expressed in Schneider 2 (S2) cells with an enterokinase cleavage site and a double Strep (Trp-Ser-His-ProGln-Phe-Glu-Lys) tag, using the pT389 vector (kindly provided by T. Krey and F. Rey, Institut Pasteur, France), as described previously (15,16,46). All Strep-tagged proteins were affinity purified using StrepTactin columns (IBA), according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…In our mouse immunization study, we therefore combined knowledge of the atomic structure of the TBE virus sE protein and of the binding sites of MAbs to obtain information on epitopespecific effects in the induction of antibodies upon IC immunization in a structurally defined system. For dissecting the specificities of antibody populations induced, we exploited previously established immunoassays using recombinant domains and domain combinations of E protein as well as a heterologous flavivirus E protein that allowed us to quantify distinct antibody subsets in polyclonal sera (15,46). Using ICs with MAbs specific for each of the three E domains, we found neither an enhancing nor a decreasing effect on the overall response but demonstrated a specific modulation of the fine specificity of antibodies induced by two of the ICs.…”

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confidence: 99%

“…In human dengue virus infections, for instance, cross-reactive antibodies directed to the conserved fusion peptide (FP) (Fig. 1) make up a substantial portion of the total antibody response (13,14), whereas this site is not comparably dominant in the response to TBE virus infection or to TBE and YF virus vaccination (15,16). Differences in the stability of E complexes at the virion surface, the extent of proteolytic maturation cleavage of the second envelope glycoprotein (prM) present in immature virions (reviewed in ref- erence 17), and the dynamics of epitope exposure by viral "breathing" phenomena (18-23) may be responsible for such effects.…”

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confidence: 99%

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Immunization with Immune Complexes Modulates the Fine Specificity of Antibody Responses to a Flavivirus Antigen

Tsouchnikas

Zlatkovic

Jarmer

et al. 2015

J Virol

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The antibody response to proteins may be modulated by the presence of preexisting antigen-specific antibodies and the formation of immune complexes (ICs). Effects such as a general increase or decrease of the response as well as epitope-specific phenomena have been described. In this study, we investigated influences of IC immunization on the fine specificity of antibody responses in a structurally well-defined system, using the envelope (E) protein of tick-borne encephalitis (TBE) virus as an immunogen. TBE virus occurs in Europe and Asia and-together with the yellow fever, dengue, West Nile, and Japanese encephalitis viruses-represents one of the major human-pathogenic flaviviruses. Mice were immunized with a dimeric soluble form of E (sE) alone or in complex with monoclonal antibodies specific for each of the three domains of E, and the antibody response induced by these ICs was compared to that seen after immunization with sE alone. Immunoassays using recombinant domains and domain combinations of TBE virus sE as well as the distantly related West Nile virus sE allowed the dissection and quantification of antibody subsets present in postimmunization sera, thus generating fine-specificity patterns of the polyclonal responses. There were substantially different responses with two of the ICs, and the differences could be mechanistically related to (i) epitope shielding and (ii) antibody-mediated structural changes leading to dissociation of the sE dimer. The phenomena described may also be relevant for polyclonal responses upon secondary infections and/or booster immunizations and may affect antibody responses in an individual-specific way. IMPORTANCEInfections with flaviviruses such as yellow fever, dengue, Japanese encephalitis, West Nile, and tick-borne encephalitis (TBE) viruses pose substantial public health problems in different parts of the world. Antibodies to viral envelope protein E induced by natural infection or vaccination were shown to confer protection from disease. Such antibodies can target different epitopes in E protein, and the fine specificities of polyclonal responses can differ between individuals. We conducted a mouse immunization study with TBE E protein alone or complexed to monoclonal antibodies specific for each of the three protein domains. We demonstrated that phenomena such as epitope shielding and antibody-induced structural changes can profoundly influence the fine specificity of antibody responses to the same immunogen. The study thus provided important new information on the potential immunomodulatory role of preexisting antibodies in a flavivirus system that can be relevant for understanding individual-specific factors influencing antibody responses in sequential flavivirus infections and/or immunizations. Several mosquito-and tick-transmitted flaviviruses are important human pathogens and have a substantial public health impact in countries of endemicity (1). These include the yellow fever (YF), dengue (DEN), West Nile (WN), Japanese encephalitis (JE), and tick-borne...

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Variation of the Specificity of the Human Antibody Responses after Tick-Borne Encephalitis Virus Infection and Vaccination

Cited by 78 publications

References 81 publications

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific

Immunization with Immune Complexes Modulates the Fine Specificity of Antibody Responses to a Flavivirus Antigen

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