Double Lock of a Human Neutralizing and Protective Monoclonal Antibody Targeting the Yellow Fever Virus Envelope

Lu, Xinghua; Xiao, Hui; Li, S.; Pang, Xiaobing; Jiang, Song; Liu, S.; Cheng, Hong; Li, Yan; Wang, X.; Changming, Huang; Guo, Tong; Meulen, Jan ter; Daffis, Stéphane; Yan, Jinghua; Dai, Lianpan; Rao, Z.; Klenk, Hans‐Dieter; Qi, Jianxun; Shi, Yi; Gao, George F.

doi:10.1016/j.celrep.2018.12.065

Cited by 49 publications

(55 citation statements)

References 53 publications

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“…The relatively high abundance of these two germline genes (VH4-4 and VL1-51) in the naïve B cell repertoire perhaps provides a molecular explanation for how the YFV-17D vaccine is able to induce protective neutralizing Ab responses in such an extraordinarily high proportion of individuals (>95%) (42,43). Furthermore, a subset of these nAbs displayed exceptionally potent neutralizing activity, with IC 50 s that were about 10 times lower than previously described YFV mAbs (13,14). Given the recent YFV outbreaks in Brazil and the Democratic Republic of…”

Section: Discussionmentioning

confidence: 92%

“…Our work provides key insights into the B cell response underlying the efficacy of the YFV-17D vaccine, which may facilitate the design of vaccines for more refractory pathogens, such as malaria and HIV. mAbs described to date target overlapping epitopes within DII of the E protein (13,14).…”

Section: Significancementioning

confidence: 99%

“…S16); 4G2 is a pan-flavivirus mAb that targets the fusion loop (FL) (23), whereas 5A is a YFV E-specific mAb that binds to a FL-proximal epitope overlapping the proposed prM association region (Fig. 5A) (13). Competition experiments were performed using high-throughput surface plasmon resonance on a Carterra LSA instrument (24).…”

Section: The Majority Of Mbc-derived Mabs Target Epitopes Within Ormentioning

confidence: 99%

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Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

Wec

Haslwanter

Abdiche

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+and atypical IgM+and IgD+MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.

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Section: Discussionmentioning

confidence: 92%

Section: Significancementioning

confidence: 99%

Section: The Majority Of Mbc-derived Mabs Target Epitopes Within Ormentioning

confidence: 99%

See 1 more Smart Citation

Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

Wec

Haslwanter

Abdiche

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Sequence alignment revealed that DIII is the most variable domain among the flavivirus E proteins (Fig. 3A), and thus, antibodies targeting DIII are more likely to be species specific (21 (38,(40)(41)(42)(43)(44)(45)(46) (Fig. 3).…”

mentioning

confidence: 99%

Molecular Basis of a Protective/Neutralizing Monoclonal Antibody Targeting Envelope Proteins of both Tick-Borne Encephalitis Virus and Louping Ill Virus

Peng

et al. 2019

J Virol

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Tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are members of the tick-borne flaviviruses (TBFVs) in the family Flaviviridae which cause encephalomeningitis and encephalitis in humans and other animals. Although vaccines against TBEV and LIV are available, infection rates are rising due to the low vaccination coverage. To date, no specific therapeutics have been licensed. Several neutralizing monoclonal antibodies (MAbs) show promising effectiveness in the control of TBFVs, but the underlying molecular mechanisms are yet to be characterized. Here, we determined the crystal structures of the LIV envelope (E) protein and report the comparative structural analysis of a TBFV broadly neutralizing murine MAb (MAb 4.2) in complex with either the LIV or TBEV E protein. The structures reveal that MAb 4.2 binds to the lateral ridge of domain III of the E protein (EDIII) of LIV or TBEV, an epitope also reported for other potently neutralizing MAbs against mosquito-borne flaviviruses (MBFVs), but adopts a unique binding orientation. Further structural analysis suggested that MAb 4.2 may neutralize flavivirus infection by preventing the structural rearrangement required for membrane fusion during virus entry. These findings extend our understanding of the vulnerability of TBFVs and other flaviviruses (including MBFVs) and provide an avenue for antibody-based TBFV antiviral development.IMPORTANCE Understanding the mechanism of antibody neutralization/protection against a virus is crucial for antiviral countermeasure development. Tickborne encephalitis virus (TBEV) and louping ill virus (LIV) are tick-borne flaviviruses (TBFVs) in the family Flaviviridae. They cause encephalomeningitis and encephalitis in humans and other animals. Although vaccines for both viruses are available, infection rates are rising due to low vaccination coverage. In this study, we solved the crystal structures of the LIV envelope protein (E) and a broadly neutralizing/protective TBFV MAb, MAb 4.2, in complex with E from either TBEV or LIV. Key structural features shared by TBFV E proteins were analyzed. The structures of E-antibody complexes showed that MAb 4.2 targets the lateral ridge of both the TBEV and LIV E proteins, a vulnerable site in flaviviruses for other potent neutralizing MAbs. Thus, this site represents a promising target for TBFV antiviral development. Further, these structures provide important information for understanding TBFV antigenicity. KEYWORDS louping ill virus (LIV), crystal structure, envelope protein (E), monoclonal neutralizing/protective antibody, tick-borne encephalitis virus (TBEV), tick-borne flaviviruses (TBFVs)

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“…Thus, MAb 5A prevents both virus attachment and fusion. As the fusion loop is a highly conserved antigen, there is a high possibility that 5A neutralizes other flaviviruses [76]. In the same way, Wu et al [77] identified a panel of human MAbs that target DIII of the ZIKV envelope protein from a large Phage Display naïve antibody library.…”

Section: Application Of Phage Display In the Context Of Denv And Othementioning

confidence: 99%

Phage Display as a Strategy to Obtain Anti-flavivirus Monoclonal Antibodies

Silva¹,

França²,

Silva³

et al. 2020

Dengue Fever in a One Health Perspective

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Arbovirus of the Flaviviridae family represents an issue worldwide, particularly because it can lead to serious illness and death in some countries. There is still a great complexity in obtaining effective therapies and specific and sensitive diagnostic tests, due to the high antigenic similarity between them. This similarity may account for antibodies cross reactivity which has positive and negative consequences for the course of infectious diseases. Among dengue virus (DENV) serotype infections, the cross-reactivity can increase virus replication and the risk of a severe disease by a mechanism known as an antibody-dependent enhancement (ADE). The search for serological biomarkers through monoclonal antibodies (MAbs) that identify unique viral regions can assist in the differential detection, whereas the development of recombinant antibodies with a neutralizing potential can lead to the establishment of efficacious treatments. The Phage Display methodology emerged as one of the main alternatives for the selection of human MAbs with high affinity for a specific target. Therefore, this technology can be a faster alternative for the development of specific diagnostic platforms and efficient and safe treatments for flavivirus infections. In this context, we propose for this chapter a discussion about Phage Display as a strategy to obtain MAbs for DENV and other flaviviruses.

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Double Lock of a Human Neutralizing and Protective Monoclonal Antibody Targeting the Yellow Fever Virus Envelope

Abstract: Highlights d The crystal structures of YFV-E in both pre-and post-fusion states are determined d A neutralizing monoclonal antibody engages YFV-E in both states as a double lock d This monoclonal antibody inhibits YFV infection at multiple steps of virus entry

Cited by 49 publications

References 53 publications

Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

Molecular Basis of a Protective/Neutralizing Monoclonal Antibody Targeting Envelope Proteins of both Tick-Borne Encephalitis Virus and Louping Ill Virus

Phage Display as a Strategy to Obtain Anti-flavivirus Monoclonal Antibodies

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