Neutralizing and cross-reacting antibodies: implications for immunotherapy and SARS-CoV-2 vaccine development

Cohen, Samuel; Kellogg, Caitlyn; Equils, Ozlem

doi:10.1080/21645515.2020.1787074

Cited by 22 publications

(26 citation statements)

References 40 publications

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“…Furthermore, as previously reported by others (23)(24)(25), not all RBD-binding antibodies have neutralizing properties which is consistent with that reported herein regarding the RBD-based assays that do not have perfect concordance with VNT. Conversely, antibodies targeting a region other than the S protein may have functional activity, as previously reported (17,(26)(27)(28). In the present study, the Abbott and Bio-Rad assays directed against the N protein presented a substantial concordance with VNT.…”

Section: Discussionsupporting

confidence: 81%

Evaluation of high-throughput SARS-CoV-2 serological assays in a longitudinal cohort of mild COVID-19 patients: sensitivity, specificity and association with virus neutralization test

Bal

Pozzetto

Trabaud

et al. 2020

Preprint

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Objectives: We evaluated widely-used SARS-CoV-2 serological tests and their potential association with virus neutralization test (VNT) in a cohort of mild COVID-19 patients. Methods: A total of 439 specimens were longitudinally collected from 76 healthcare workers with RT-PCR-confirmed mild COVID-19. Nine serological assays developed by leading global companies (Abbott, DiaSorin, Siemens, Bio-Rad, Wantai, bioMerieux, Euroimmun) were assessed. For each test the sensitivity to detect SARS-CoV-2 antibodies was determined weekly after symptom onset. Correlation and concordance were assessed using the Spearman and Cohen Kappa coefficients, respectively. Positive percent agreement and negative percent agreement (NPA) with the VNT were also determined. Results: The Wantai Total Ab assay targeting the receptor binding domain (RBD) within the S protein presented the best sensitivity at different times during the course of disease. The best correlation between antibody level and neutralizing antibody titer was found with the Euroimmun S1-based IgA assay (Spearman coefficient [95%CI]: 0.71 [0.61-0.79]). A moderate concordance (Kappa [95%CI]: 0.43[0.23-0.63]) as well as the lowest NPA (33%) was found between the Wantai Total Ab assay and the VNT. Compared to the Wantai Total Ab assay, other total Ab or IgG assays targeting the S or the RBD (bioMerieux, DiaSorin, Siemens,) were more concordant with the VNT (Kappa>0.7 for the three tests) and had a higher NPA (range: 90% to 97%). Conclusions: Although some assays presented a better concordance with VNT than others, the present findings emphasize that commercialized serological tests including those targeting the RBD cannot substitute VNT for the assessment of functional antibody response.

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Section: Discussionsupporting

confidence: 81%

Evaluation of high-throughput SARS-CoV-2 serological assays in a longitudinal cohort of mild COVID-19 patients: sensitivity, specificity and association with virus neutralization test

Bal

Pozzetto

Trabaud

et al. 2020

Preprint

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“…Cross-reactive mAbs largely target the more conserved S2 subunit on S-proteins and we identified a SARS-CoV-2 cross-neutralizing epitope that could facilitate vaccine design and antibody-based intervention strategies. Indeed, studies have shown targeting of conserved S2 subunit neutralizing epitopes in SARS-CoV-2 infected donors and by SARS-CoV-1 nAbs that may potentially display activities against a broader range of human coronaviruses 27 – 30 Overall, our study highlights the need to understand fully the nature of pre-existing endemic HCoV immunity in large and diverse human cohorts as vaccination of hundreds of millions of people against COVID-19 is considered.…”

Section: Resultsmentioning

confidence: 85%

Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Song

Callaghan

et al. 2020

Preprint

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Pre-existing immune responses to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, either induced in natural infection or through vaccination. Such consequences are well established in the influenza and flavivirus fields. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. We compared serum antibody and memory B cell responses to coronavirus spike (S) proteins from pre-pandemic and SARS-CoV-2 convalescent donors using a series of binding and functional assays. We found weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we found stronger evidence of pre-existing cross-reactive memory B cells that were activated on SARS-CoV-2 infection. Monoclonal antibodies (mAbs) isolated from the donors showed varying degrees of cross-reactivity with betacoronaviruses, including SARS and endemic coronaviruses. None of the cross-reactive mAbs were neutralizing except for one that targeted the S2 subunit of the S protein. The results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2.

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“…It has been reported that antibodies from SARS-CoV-2 naïve donors who had reactivity to seasonal human coronavirus strains (such as OC43 and HKU1) were crossreactive against the nucleocapsid and S2 subunit on spike protein of SARS-CoV-2 50 . More studies have reported that cross-reactive mAbs largely target this more conserved S2 subunit on spike protein 51,52 . Conceptually, a number of S2 subunit-specific antibodies is non or weakly neutralizing, and potentially responsible for ADE.…”

Section: Discussionmentioning

confidence: 99%

One dose of COVID-19 nanoparticle vaccine REVC-128 provides protection against SARS-CoV-2 challenge at two weeks post immunization

Gu¹,

Torres

Greenhouse

et al. 2021

Preprint

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A COVID-19 vaccine with capability to induce early protection is needed to efficiently eliminate viral spread. Here, we demonstrate the development of a nanoparticle vaccine candidate, REVC-128, in which multiple trimeric spike ectodomain subunits with glycine (G) at position 614 were multimerized onto a nanoparticle. In-vitro characterization of this vaccine confirms its structural and antigenic integrity. In-vivo immunogenicity evaluation in mice indicates that a single dose of this vaccine induces potent serum neutralizing antibody titer at two weeks post immunization, which is significantly higher than titer induced by trimeric spike protein without nanoparticle presentation. The comparison of serum binding to spike subunits between animals immunized by spike with and without nanoparticle presentation indicates that nanoparticle prefers the display of spike RBD (Receptor-Binding Domain) over S2 subunit, likely resulting in a more neutralizing but less cross-reactive antibody response. Moreover, a Syrian golden hamster in-vivo model for SARS-CoV-2 virus challenge was implemented at two weeks post a single dose of REVC-128 immunization. The results show that vaccination protects hamsters against SARS-CoV-2 virus challenge with evidence of steady body weight, suppressed viral loads and alleviation of tissue damage (lung and nares) for protected animals, compared with ~10% weight loss, higher viral loads and tissue damage in unprotected animals. Furthermore, the data show that vaccine REVC-128 is thermostable at up to 37°C for at least 4 weeks. These findings, along with a long history of safety for protein vaccines, suggest that the REVC-128 is a safe, stable and efficacious single-shot vaccine candidate to induce the earliest protection against SARS-CoV-2 infection.

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Neutralizing and cross-reacting antibodies: implications for immunotherapy and SARS-CoV-2 vaccine development

Cited by 22 publications

References 40 publications

Evaluation of high-throughput SARS-CoV-2 serological assays in a longitudinal cohort of mild COVID-19 patients: sensitivity, specificity and association with virus neutralization test

Evaluation of high-throughput SARS-CoV-2 serological assays in a longitudinal cohort of mild COVID-19 patients: sensitivity, specificity and association with virus neutralization test

Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

One dose of COVID-19 nanoparticle vaccine REVC-128 provides protection against SARS-CoV-2 challenge at two weeks post immunization

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