Influenza Antigen Engineering Focuses Immune Responses to a Subdominant but Broadly Protective Viral Epitope

Bajic, Goran; Maron, Max J.; Adachi, Yu; Onodera, Taishi; McCarthy, K.; McGee, Charles E.; Sempowski, Gregory D.; Takahashi, Yoshimasa; Kelsoe, Garnett; Kuraoka, Masayuki; Schmidt, Aaron

doi:10.1016/j.chom.2019.04.003

Cited by 138 publications

(147 citation statements)

References 45 publications

(41 reference statements)

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“…Additionally, it may be that functional constraints, such as maintaining flexibility of the receptor binding domains, limit the accretion of glycans on coronavirus spikes, which would render it incapable of performing its primary functions, including receptor binding and membrane fusion. This phenomenon has been observed on other viral glycoproteins, including influenza HAs, where there is a limit to the accumulation of glycosylation sites that can be incorporated in vivo 64,65 , compared to in vitro 66 , with H3N2 and H1N1 HAs replacing existing PNGs rather than continually adding them upon the glycoprotein 26,65 .…”

Section: Comparison Of Viral Glycosylation Reveals Disparate Shieldinmentioning

confidence: 75%

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

Watanabe

Berndsen

Raghwani

et al. 2020

Preprint

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Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are zoonotic pathogens with high fatality rates and pandemic potential.Vaccine development has focussed on the principal target of the neutralizing humoral immune response, the spike (S) glycoprotein, which mediates receptor recognition and membrane fusion. Coronavirus S proteins are extensively glycosylated viral fusion proteins, encoding around 69-87 N-linked glycosylation sites per trimeric spike. Using a multifaceted structural approach, we reveal a specific area of high glycan density on MERS S that results in the formation of under-processed oligomannose-type glycan clusters, which was absent on SARS and HKU1 CoVs. We provide a comparison of the global glycan density of coronavirus spikes with other viral proteins including HIV-1 envelope, Lassa virus glycoprotein complex, and influenza hemagglutinin, where glycosylation plays a known role in shielding immunogenic epitopes. Consistent with the ability of the antibody-mediated immune response to effectively target and neutralize coronaviruses, we demonstrate that the glycans of coronavirus spikes are not able to form an efficacious high-density global shield to thwart the humoral immune response. Overall, our data reveal how differential organisation of viral glycosylation across class I viral fusion proteins influence not only individual glycan compositions but also the immunological pressure across the viral protein surface.

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Section: Comparison Of Viral Glycosylation Reveals Disparate Shieldinmentioning

confidence: 75%

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

Watanabe

Berndsen

Raghwani

et al. 2020

Preprint

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“…Overall, our study provides insight into how SARS-CoV-2 can be targeted by the humoral immune response and revealed a conserved, but cryptic epitope shared between SARS-CoV-2 and SARS-CoV. Recently, our group and others have identified a conserved epitope on influenza A virus hemagglutinin (HA) that is located in the trimeric interface and is only exposed through protein "breathing" (23)(24)(25), which is somewhat analogous to the epitope of CR3022. Antibodies to this influenza HA trimeric interface epitope do not exhibit in vitro neutralization activity but can confer in vivo protection.…”

mentioning

confidence: 73%

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

Yuan

Zhu

et al. 2020

Science

1,464

1,601

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I.A.W.)The outbreak of COVID-19 caused by SARS-CoV-2 virus has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein to 3.1 Å. CR3022 targets a highly conserved epitope, distal from the receptor-binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBD on the trimeric S protein are in the "up" conformation and slightly rotated. Overall, this study provides molecular insights into antibody recognition of SARS-CoV-2.

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“…This notion is also supported by our recent study, which showed that the cross-reactive antibody CR3022 could not neutralize SARS-CoV-2 despite its strong binding (Yuan et al, 2020). Future studies need to investigate whether these non-neutralizing antibody responses can confer in vivo protections despite the lack of in vitro neutralization activity, which have been observed in some non-neutralizing antibodies to other viruses (Bajic et al, 2019; Bangaru et al, 2019; Bootz et al, 2017; Burke et al, 2018; Dreyfus et al, 2012; Henchal et al, 1988; Lee et al, 2016; Petro et al, 2015; Watanabe et al, 2019). On the contrary, non-neutralizing antibody responses can also lead to antibody-dependent enhancement (ADE) of infection as reported in other coronaviruses (Tseng et al, 2012; Wang et al, 2014; Weiss and Scott, 1981).…”

Section: Discussionmentioning

confidence: 99%

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Tsang

et al. 2020

Preprint

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26The World Health Organization has recently declared the ongoing outbreak of COVID-27 19, which is caused by a novel coronavirus SARS-CoV-2, as pandemic. There is 28 currently a lack of knowledge in the antibody response elicited from SARS-CoV-2 29 infection. One major immunological question is concerning the antigenic differences 30 between SARS-CoV-2 and SARS-CoV. We address this question by using plasma from 31 patients infected by SARS-CoV-2 or SARS-CoV, and plasma obtained from infected or 32 immunized mice. Our results show that while cross-reactivity in antibody binding to the 33 spike protein is common, cross-neutralization of the live viruses is rare, indicating the 34 presence of non-neutralizing antibody response to conserved epitopes in the spike. 35Whether these non-neutralizing antibody responses will lead to antibody-dependent 36 disease enhancement needs to be addressed in the future. Overall, this study not only 37 addresses a fundamental question regarding the antigenicity differences between 38 SARS-CoV-2 and SARS-CoV, but also has important implications in vaccine 39 development. : bioRxiv preprint 4 polyclonal human sera from patients to evaluate the antibody response elicited by 67 SARS-CoV-2 infection and to determine whether cross-reactive antibody responses 68 between SARS-CoV-2 and SARS-CoV can be generated. In this study, we examined the 69 antibody responses in 15 patients from Hong Kong who were infected by SARS-CoV-2, 70 and seven by SARS-CoV. Mice infected or immunized with SARS-CoV-2 or SARS-CoV 71 were also used to investigate cross-reactivity of antibody responses between SARS-72 CoV-2 and SARS-CoV. 73 74 Results 75 Patient samples show cross-reactivity in binding 76 Fifteen heparin anticoagulated plasma samples (from day 2 to 22 post-symptom onset) 77 from SARS-CoV-2 infected patients were analyzed (Table S1). Binding of plasma to the 78 S ectodomain and RBD of both SARS-CoV-2 and SARS-CoV (see Methods) was 79 measured by ELISA ( Figure 1B, Figure S1). Plasma samples from healthy donors 80 collected from the Hong Kong Red Cross served as controls. As compared to the 81 plasma from healthy donors, plasma from patients from day 10 post-symptom onward 82 reacted strongly in ELISA binding assays to the S ectodomain (p-value < 2e-16, two-83 tailed t-test) and RBD (p-value = 2e-13, two-tailed t-test) of SARS-CoV-2. Interestingly, 84 the plasma from SARS-CoV-2-infected patients could also cross-react, although less 85 strongly, with the SARS-CoV S ectodomain (p-value = 8e-06, two-tailed t-test) and the 86 SARS-CoV RBD (p-value = 0.048, two-tailed t-test) ( Figure 1B). Nevertheless, only five 87 of the samples from the SARS-CoV-2-infected patients had convincing antibody binding 88 responses to the SARS-CoV RBD. The other plasma reacted more weakly or not at all 89 with the SARS-CoV RBD ( Figure 1B). This result indicates that the cross-reactive 90 antibody response to the S protein after SARS-CoV-2 infection mostly targets non-RBD 91 regions. Consistent with that observation, reactivi...

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Influenza Antigen Engineering Focuses Immune Responses to a Subdominant but Broadly Protective Viral Epitope

Cited by 138 publications

References 45 publications

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

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