Dissection of Antibody Specificities Induced by Yellow Fever Vaccination

Vratskikh, Oksana; Stiasny, Karin; Zlatkovic, Jürgen; Tsouchnikas, Georgios; Jarmer, Johanna; Karrer, Urs; Roggendorf, Michael; Roggendorf, Hedwig; Allwinn, Regina; Heinz, Franz X.

doi:10.1371/journal.ppat.1003458

Cited by 63 publications

(72 citation statements)

References 58 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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481

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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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481

540

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“…These findings are supported by genetic approaches demonstrating that mutations in DIII epitopes do not result in a significant reduction in the neutralization potency of flavivirus immune human sera (227,236). Most of the serum neutralizing activity following YFV or DENV infection or vaccination is not affected by the depletion by soluble E protein, suggesting that quaternary epitopes may be important targets for NAbs (227,245), as discussed below. In general, most studies characterizing antiflavivirus NAb specificities in human polyclonal sera have largely ruled out the importance of particular epitopes, such as those in DIII (227,236,249).…”

Section: Neutralizing Antibodies Target a Limited Number Of Specificimentioning

confidence: 74%

“…One approach is to compare the neutralizing activity of sera preincubated with soluble recombinant antigens representing various E protein domains to that of untreated sera. Such serum depletion studies have shown that DIII is not a major target of human NAbs following vaccination or natural infection with DENV (227), WNV (236), YFV (245), and TBEV (246) despite being the target of very potent murine neutralizing MAbs (50-52, 55, 59, 247, 248). These findings are supported by genetic approaches demonstrating that mutations in DIII epitopes do not result in a significant reduction in the neutralization potency of flavivirus immune human sera (227,236).…”

Section: Neutralizing Antibodies Target a Limited Number Of Specificimentioning

confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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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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Dissection of Antibody Specificities Induced by Yellow Fever Vaccination

Cited by 63 publications

References 58 publications

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

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

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

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

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