Structural Mimicry of the Dengue Virus Envelope Glycoprotein Revealed by the Crystallographic Study of an Idiotype–Anti-idiotype Fab Complex

Wong, Yee Hwa; Goh, Boon Chong; Lim, She Yah; Teo, En Wei; Lim, Angeline; Dedon, Pete C.; Hanson, Brendon J.; MacAry, Paul A.; Lescar, Julien

doi:10.1128/jvi.00406-17

Cited by 6 publications

(5 citation statements)

References 29 publications

(40 reference statements)

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“…The same could be explored to develop therapeutics ( 164 ). E1 was able to detect HM14c10- and HM14c10-like antibodies in the sera of patients who recovered from DENV infection ( 165 ), which suggested that it is a common idiotype and could be further tailored to obtain the desired results, including broader neutralization capability and diminished ADE.…”

Section: Fab Antibodiesmentioning

confidence: 99%

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

et al. 2018

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Antibody-dependent enhancement (ADE) is a phenomenon in which preexisting poorly neutralizing antibodies leads to enhanced infection. It is a serious concern with mosquito-borne flaviviruses such as Dengue virus (DENV) and Zika virus (ZIKV). In vitro experimental evidences have indicated the preventive, as well as a pathogenicity-enhancing role, of preexisting DENV antibodies in ZIKV infections. ADE has been confirmed in DENV but not ZIKV infections. Principally, the Fc region of the anti-DENV antibody binds with the fragment crystallizable gamma receptor (FcγR), and subsequent C1q interactions and immune effector functions are responsible for the ADE. In contrast to normal DENV infections, with ADE in DENV infections, inhibition of STAT1 phosphorylation and a reduction in IRF-1 gene expression, NOS2 levels, and RIG-1 and MDA-5 expression levels occurs. FcγRIIA is the most permissive FcγR for DENV-ADE, and under hypoxic conditions, hypoxia-inducible factor-1 alpha transcriptionally enhances expression levels of FcγRIIA, which further enhances ADE. To produce therapeutic antibodies with broad reactivity to different DENV serotypes, as well as to ZIKV, bispecific antibodies, Fc region mutants, modified Fc regions, and anti-idiotypic antibodies may be engineered. An in-depth understanding of the immunological and molecular mechanisms of DENV-ADE of ZIKV pathogenicity will be useful for the design of common and safe therapeutics and prophylactics against both viral pathogens. The present review discusses the role of DENV antibodies in modulating DENV/ZIKV pathogenicity/infection and strategies to counter ADE to protect against Zika infection.

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Section: Fab Antibodiesmentioning

confidence: 99%

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

et al. 2018

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“…Using hen egg lysozyme (HEL) as a model antigen, structural immunologists discovered that both the anti-HEL antibody (D1.3) and its anti-idiotypic antibody (E5.2) could bind to the D1.3 combining site ( 54 ). A previous study also documented that an anti-idiotype Fab E1 can partially mimic the E protein of Dengue virus ( 55 ). Few reports have confirmed that anti-idiotype antibodies completely mimic the antigen in structure and function ( 56 ).…”

Section: Discussionmentioning

confidence: 81%

A novel strategy for an anti-idiotype vaccine: nanobody mimicking neutralization epitope of porcine circovirus type 2

Deng,

Sheng,

Zhang

et al. 2024

J Virol

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Vaccination is the most effective method to protect humans and animals from diseases. Anti-idiotype vaccines are safer due to their absence of pathogens. However, the commercial production of traditional anti-idiotype vaccines using monoclonal and polyclonal antibodies (mAb and pAb) is complex and has a high failure rate. The present study designed a novel, simple, low-cost strategy for developing anti-idiotype vaccines with nanobody technology. We used porcine circovirus type 2 (PCV2) as a viral model, which can result in serious economic loss in the pig industry. The neutralizing mAb-1E7 (Ab1) against PCV2 capsid protein (PCV2-Cap) was immunized in the camel. And 12 nanobodies against mAb-1E7 were screened. Among them, Nb61 (Ab2) targeted the idiotype epitope of mAb-1E7 and blocked mAb-1E7’s binding to PCV2-Cap. Additionally, a high-dose Nb61 vaccination can also protect mice and pigs from PCV2 infection. Epitope mapping showed that mAb-1E7 recognized the 75 NINDFL 80 of PCV2-Cap and 101 NYNDFLG 107 of Nb61. Subsequently, the mAb-3G4 (Ab3) against Nb61 was produced and can neutralize PCV2 infection in the PK-15 cells. Structure analysis showed that the amino acids of mAb-1E7 and mAb-3G4 respective binding to PCV2-Cap and Nb61 were also similar on the amino acids sequences and spatial conformation. Collectively, our study first provided a strategy for producing nanobody-based anti-idiotype vaccines and identified that anti-idiotype nanobodies could mimic the antigen on amino acids and structures. Importantly, as more and more neutralization mAbs against different pathogens are prepared, anti-idiotype nanobody vaccines can be easily produced against the disease with our strategy, especially for dangerous pathogens. IMPORTANCE Anti-idiotype vaccines utilize idiotype-anti-idiotype network theory, eliminating the need for external antigens as vaccine candidates. Especially for dangerous pathogens, they were safer because they did not contact the live pathogenic microorganisms. However, developing anti-idiotype vaccines with traditional monoclonal and polyclonal antibodies is complex and has a high failure rate. We present a novel, universal, simple, low-cost strategy for producing anti-idiotype vaccines with nanobody technology. Using a neutralization antibody against PCV2-Cap, a nanobody (Ab2) was successfully produced and could mimic the neutralizing epitope of PCV2-Cap. The nanobody can induce protective immune responses against PCV2 infection in mice and pigs. It highlighted that the anti-idiotype vaccine using nanobody has a very good application in the future, especially for dangerous pathogens.

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“…In contrast, E5.2 and lysozyme, which both bind D1.3 with similar affinities, share 13 contact residues, indicating that E5.2 is a good structural mimic for lysozyme. More recently, Wong and co-workers identified the antiidiotype Fab E1 to be a partial structural mimic for Dengue virus E protein 53 . These studies support the idea of structural mimicry, which originated purely from the observed binding properties of antibodies 35,36 .…”

Section: Discussionmentioning

confidence: 99%

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design

et al. 2021

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HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

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Structural Mimicry of the Dengue Virus Envelope Glycoprotein Revealed by the Crystallographic Study of an Idiotype–Anti-idiotype Fab Complex

Cited by 6 publications

References 29 publications

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

A novel strategy for an anti-idiotype vaccine: nanobody mimicking neutralization epitope of porcine circovirus type 2

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design

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