Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein

McAuley, Alexander J.; Kuiper, Michael J.; Durr, Peter A.; Bruce, Matthew P.; Barr, Jennifer; Todd, Shawn; Au, Gough G.; Blasdell, Kim R.; Tachedjian, Mary; Lowther, Sue; Marsh, Glenn A.; Edwards, Sarah; Poole, Timothy; Layton, Rachel; Riddell, Sarah; Drew, Trevor W.; Druce, Julian; Smith, Trevor R.F.; Broderick, Kate E.; Vasan, Seshadri S.

doi:10.1038/s41541-020-00246-8

Cited by 63 publications

(82 citation statements)

References 26 publications

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“…In the hamster model, the D614G mutation significantly accelerated droplet transmission during the initial stages of infection [ 52 ], whilst in ferrets, it provided an advantage for viral replication and transmission but did not alter pathogenicity [ 53 ]. Cross-neutralization assays indicate that this mutation is not predicted to adversely impact vaccine efficacy [ 54 ]. Further work is needed to assess the impact of spike protein mutations on pathogenesis, host range and transmission of SARS-CoV-2 as well as on the host immune response.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection

Everett

Lean

Byrne

et al. 2021

Viruses

101

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Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.

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Section: Discussionmentioning

confidence: 99%

Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection

Everett

Lean

Byrne

et al. 2021

Viruses

101

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“…Serum samples used for neutralisation assays were generated and selected with the consent of the sponsor (Coalition for Epidemic Preparedness Innovations), as previously described 8 . In brief, four male and four female ferrets received two doses of INO-4800 via intramuscular administration of 1 mg plasmid DNA to the caudal thigh muscle, followed by electroporation split across two sites using the CELLECTRA® device.…”

Section: Methodsmentioning

confidence: 99%

“…We recently investigated the neutralisation of SARS-CoV-2 isolates containing either the ‘D614’ or the ‘G614’ variation of the Spike protein, using serum samples from ferrets vaccinated with INO-4800, a leading DNA vaccine candidate against SARS-CoV-2 8,9 , demonstrating the D614G mutation was unlikely to affect vaccine-induced antibody-mediated virus neutralisation. Given the interest around the 501Y.V1 and 501Y.V2 variants, we decided to follow up our previous study by comparing neutralisation titres of INO-4800-vaccinated ferret samples against representative SARS-CoV-2 isolates.…”

Section: Introductionmentioning

confidence: 99%

Live Virus Neutralisation of the 501Y.V1 and 501Y.V2 SARS-CoV-2 Variants following INO-4800 Vaccination of Ferrets

Riddell

Goldie

McAuley

et al. 2021

Preprint

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The ongoing COVID-19 pandemic has resulted in significant global morbidity and mortality on a scale similar to the influenza pandemic of 1918. Over the course of the last few months, a number of SARS-CoV-2 variants have been identified against which vaccine-induced immune responses may be less effective. These variants-of-concern have garnered significant attention in the media, with discussion around their impact on the future of the pandemic and the ability of leading COVID-19 vaccines to protect against them effectively. To address concerns about emerging SARS-CoV-2 variants affecting vaccine-induced immunity, we investigated the neutralisation of representative G614, 501Y.V1 and 501Y.V2 virus isolates using sera from ferrets that had received prime-boost doses of the DNA vaccine, INO-4800. Neutralisation titres against G614 and 501Y.V1 were comparable, but titres against the 501Y.V2 variant were approximately 4-fold lower, similar to results reported with other nucleic acid vaccines and supported by in silico biomolecular modelling. The results confirm that the vaccine-induced neutralising antibodies generated by INO-4800 remain effective against current variants-of-concern, albeit with lower neutralisation titres against 501Y.V2 similar to other leading nucleic acid-based vaccines.

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“…Similar neutralization or greater susceptibility of the S(G614) variant have been reproduced with live SARS-CoV-2 as well [ 47 , 48 ]. Several candidate vaccines have been evaluated in mouse, monkey, and ferret models and elicited antibodies with comparable neutralizing activity against S(D614) and S(G614) [ [79] , [80] , [81] ]. As underscored by these experimental data, single-residue mutations will not likely change viral sensitivity to neutralization unless they grossly alter S protein conformation.…”

Section: Introductionmentioning

confidence: 99%

Functional importance of the D614G mutation in the SARS-CoV-2 spike protein

Jackson

Zhang

Farzan

et al. 2021

Biochemical and Biophysical Research Communications

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped virus which binds its cellular receptor angiotensin-converting enzyme 2 (ACE2) and enters hosts cells through the action of its spike (S) glycoprotein displayed on the surface of the virion. Compared to the reference strain of SARS-CoV-2, the majority of currently circulating isolates possess an S protein variant characterized by an aspartic acid-to-glycine substitution at amino acid position 614 (D614G). Residue 614 lies outside the receptor binding domain (RBD) and the mutation does not alter the affinity of monomeric S protein for ACE2. However, S(G614), compared to S(D614), mediates more efficient ACE2-mediated transduction of cells by S-pseudotyped vectors and more efficient infection of cells and animals by live SARS-CoV-2. This review summarizes and synthesizes the epidemiological and functional observations of the D614G spike mutation, with focus on the biochemical and cell-biological impact of this mutation and its consequences for S protein function. We further discuss the significance of these recent findings in the context of the current global pandemic.

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Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein

Cited by 63 publications

References 26 publications

Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection

Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection

Live Virus Neutralisation of the 501Y.V1 and 501Y.V2 SARS-CoV-2 Variants following INO-4800 Vaccination of Ferrets

Functional importance of the D614G mutation in the SARS-CoV-2 spike protein

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