D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

Weissman, Drew; Alameh, Mohamad-Gabriel; Silva, Thushan I. de; Collini, Paul; Hornsby, Hailey; Brown, Rebecca L.; LaBranche, Celia C.; Edwards, Robert J.; Sutherland, Laura L.; Santra, Sampa; Mansouri, Katayoun; Gobeil, S.; McDanal, Charlene; Pardi, Norbert; Hengartner, Nick; Lin, Paulo J.C.; Tam, Ying K.; Shaw, Pamela A.; Lewis, Mark G.; Boesler, Carsten; Şahin, Uğur; Acharya, Priyamvada; Haynes, Barton F.; Korber, Bette; Montefiori, David C.

doi:10.1016/j.chom.2020.11.012

Cited by 321 publications

(237 citation statements)

References 57 publications

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“…The greater conformational flexibility of the G614 spike explains how it more readily adopts the receptor-binding-competent conformation and suggests how the presently circulating strains of SARS-CoV-2 might have fitness advantage over the D614 variant and display higher infectivity. At the same time, the more open conformation may result in the exposure of epitopes for additional neutralizing antibodies; indeed, recent reports suggest that the D614G substitution increases the susceptibility of SARS-CoV-2 to neutralization ( 16 ). As a consequence, as populations become more exposed to SARS-CoV-2, and as more people acquire an immune reaction to the virus, it is likely that the G614 form will have less selective advantage.…”

Section: Discussionmentioning

confidence: 99%

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Benton

Wrobel

Roustan

et al. 2021

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

144

179

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The majority of currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses have mutant spike glycoproteins that contain the D614G substitution. Several studies have suggested that spikes with this substitution are associated with higher virus infectivity. We use cryo-electron microscopy to compare G614 and D614 spikes and show that the G614 mutant spike adopts a range of more open conformations that may facilitate binding to the SARS-CoV-2 receptor, ACE2, and the subsequent structural rearrangements required for viral membrane fusion.

show abstract

Section: Discussionmentioning

confidence: 99%

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Benton

Wrobel

Roustan

et al. 2021

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

144

179

View full text Add to dashboard Cite

show abstract

“…Moreover, IgG from elite neutralizers could efficiently block infection of 6 SARS-CoV-2 strains. Two of them (BavP1 and DRC94) contain the D614G mutation in the S protein 55 associated with higher infectivity 56 . Given the eminent risk of novel emerging CoVs and monoclonal antibody-resistant SARS-CoV-2 variants, developing antibodies with broader neutralization breadth would be critical.…”

Section: Discussionmentioning

confidence: 99%

Kinetics and correlates of the neutralizing antibody response to SARS-CoV-2

Vanshylla

Cristanziano

Kleipass

et al. 2021

Preprint

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A detailed understanding of antibody-based SARS-CoV-2 immunity has critical implications for overcoming the COVID-19 pandemic and for informing on vaccination strategies. In this study, we evaluated the dynamics of the SARS-CoV-2 antibody response in a cohort of 963 recovered individuals over a period of 10 months. Investigating a total of 2,146 samples, we detected an initial SARS-CoV-2 antibody response in 94.4% of individuals, with 82% and 79% exhibiting serum and IgG neutralization, respectively. Approximately 3% of recovered patients demonstrated exceptional SARS-CoV-2 neutralizing activity, defining them as ‘elite neutralizers’. These individuals also possessed effective cross-neutralizing IgG antibodies to SARS-CoV-1 without any known prior exposure to this virus. By applying multivariate statistical modeling, we found that sero-reactivity, age, time since disease onset, and fever are key factors predicting SARS-CoV-2 neutralizing activity in mild courses of COVID-19. Investigating longevity of the antibody response, we detected loss of anti-spike reactivity in 13% of individuals 10 months after infection. Moreover, neutralizing activity had an initial half-life of 6.7 weeks in serum versus 30.8 weeks in purified IgG samples indicating the presence of a more stable and long-term memory IgG B cell repertoire in the majority of individuals recovered from COVID-19. Our results demonstrate a broad spectrum of the initial SARS-CoV-2 neutralizing antibody response depending on clinical characteristics, with antibodies being maintained in the majority of individuals for the first 10 months after mild course of COVID-19.

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“…Neutralization assay evaluating the ability of sera from vaccinated animals to neutralize wildtype (with D614G in spike) versus the B.1.1.7 variant viruses were performed using a pseudotyped virus neutralization assay previously reported with minor modifications 35 . Briefly, mutations were introduced into a plasmid expressing codon-optimized Spike of the Wuhan-1 strain that contains the D614G mutation using site-directed mutagenesis.…”

Section: Methodsmentioning

confidence: 99%

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates

Arunachalam

Walls

Golden

et al. 2021

Preprint

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The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

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D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

Cited by 321 publications

References 57 publications

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Kinetics and correlates of the neutralizing antibody response to SARS-CoV-2

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates

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