Emergence of Drift Variants That May Affect COVID-19 Vaccine Development and Antibody Treatment

Koyama, Takahiko; Weeraratne, Dilhan; Snowdon, Jane L.; Parida, Laxmi

doi:10.20944/preprints202004.0024.v1

Cited by 118 publications

(120 citation statements)

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“…Four high frequency (> 25%), single, non-synonymous, nucleotide changes versus the SARS-CoV-2 Wash1 genome sequence were detected in the Munich S gene (Table 3). D614G (49,50) was present in all passages sequenced and has been suggested to increase the transmission efficiency of the virus (51). It has also recently been reported that the mutation allowed retrovirus pseudotypes to enter hACE2-expressing cells with greater efficiency (52).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients

Klimstra

Tilston-Lunel

Nambulli

et al. 2020

Preprint

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SARS-CoV-2, the causative agent of COVID-19, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients

Klimstra

Tilston-Lunel

Nambulli

et al. 2020

Preprint

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“…In-depth analysis of the genome cluster suggests a comparable rate of nucleotide substitutions with other predominant clades, though a gene-wise estimate of substitution suggests a distinct mode of evolution, driven by the Nucleocapsid (N) and Envelope (E) genes, and sparing of the Spike (S) gene in contrast to predominant diversity in the Spike (S) and Membrane protein (M) genes in A2a clade, the globally predominant clade. 34 However, it has not escaped our attention that host genetic factors could modulate the evolution of the virus genome, and without large-scale host-genomic studies, the causal relationships cannot be conclusively established.…”

Section: Discussionmentioning

confidence: 99%

A distinct phylogenetic cluster of Indian SARS-CoV-2 isolates

Banu

Jolly

Mukherjee

et al. 2020

Preprint

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From an isolated epidemic, COVID-19 has now emerged as a global pandemic. The availability of genomes in the public domain following the epidemic provides a unique opportunity to understand the evolution and spread of the SARS-CoV-2 virus across the globe. The availability of whole genomes from multiple states in India prompted us to analyse the phylogenetic clusters of genomes in India. We performed whole-genome sequencing for 64 genomes making a total of 361 genomes from India, followed by phylogenetic clustering, substitution analysis, and dating of the different phylogenetic clusters of viral genomes. We describe a distinct phylogenetic cluster (Clade I / A3i) of SARS-CoV-2 genomes from India, which encompasses 41% of all genomes sequenced and deposited in the public domain from multiple states in India. Globally 3.5% of genomes, which till date could not be mapped to any distinct known cluster fall in this newly defined clade. The cluster is characterized by a core set of shared genetic variants -C6312A (T2016K), C13730T (A88V/A97V), C23929T, and C28311T (P13L). Further, the cluster is also characterized by a nucleotide substitution rate of 1.4 x 10 -3 variants per site per year, lower than the prevalent A2a cluster, and predominantly driven by variants in the E and N genes and relative sparing of the S gene. Epidemiological assessments suggest that the common ancestor emerged in the month of February 2020 and possibly resulted in an outbreak followed by countrywide spread, as evidenced by the low divergence of the genomes from across the country. To the best of our knowledge, this is the first comprehensive study characterizing the distinct and predominant cluster of SARS-CoV-2 in India.

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“…Neutralizing antibodies are important for prevention of and possible recovery from viral infections. However, as viruses mutate during replication and spread, host neutralizing antibodies generated in the earlier phase of the infection may not be as effective later on 14,15 . To test whether D614G mutations could affect the neutralization sensitivity of the virus, the neutralization activity of serum samples from convalescent patients with COVID-19 against SARS-CoV-2 S-D614 and S-G614 pseudoviruses were evaluated.…”

Section: Neutralization Effect Of Convalescent Sera From Patients Witmentioning

confidence: 99%

D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity

Gao

et al. 2020

Preprint

150

141

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22Coronavirus disease 2019 is caused by severe acute respiratory 23 syndrome coronavirus 2 (SARS-CoV-2). The spike protein that mediates 24 SARS-CoV-2 entry into host cells, is one of the major targets for vaccines and 25 therapeutics. Thus, insights into the sequence variations of S protein are key to 26 understanding the infection and antigenicity of SARS-CoV-2. Here, we observed a 27 dominant mutational variant at the 614 position of S protein (aspartate to glycine, 28 D614G mutation). Using pseudovirus-based assay, we found that S-D614 and 29 S-G614 protein pseudotyped viruses share a common receptor, human 30 angiotensin-converting enzyme 2 (ACE2), which could be blocked by recombinant 31 ACE2 with the fused Fc region of human IgG1. However, S-D614 and S-G614 32 protein demonstrated functional differences. First, S-G614 protein could be cleaved 33 by serine protease elastase-2 more efficiently. Second, S-G614 pseudovirus 34 infected 293T-ACE2 cells significantly more efficiently than the S-D614 pseudovirus, 35 Moreover, 93% (38/41) sera from convalescent COVID-19 patients could neutralize 36 both S-D614 and S-G614 pseudotyped viruses with comparable efficiencies, but 37 about 7% (3/41) convalescent sera showed decreased neutralizing activity against 38 S-G614 pseudovirus. These findings have important implications for SARS-CoV-2 39 transmission and immune interventions.40 42 43 44 SARS-CoV-2 is a novel coronavirus reported in 2019 that caused the recent 45 outbreak of coronavirus disease-2019 (COVID-19) 1 . By June 17, 2020, the World 46 Health Organization (WHO) reported that 8.06 million people worldwide had been 47 infected with SARS-CoV-2, and 440,290 individuals died of COVID-19. This 48 pandemic had a significant adverse impact on international social and economic 49 activities. The RNA genome of SARS-CoV-2 was rapidly sequenced to facilitate 50 diagnostic testing, molecular epidemiologic source tracking, and development of 51 vaccines and therapeutic strategies 2 . Coronaviruses are enveloped, 52 positive-stranded RNA viruses that contain the largest known RNA genomes to 53 date. The mutation rate for RNA viruses is extremely high, which may contribute to 54 its transmission and virulence. The only significant variation in the SARS-CoV-2 55 spike (S) protein is a non-synonymous D614G (Aspartate (D) to Glycine (G)) 56 mutation 3 . Primary data showed that S-G614 is a more pathogenic strain of 57 SARS-CoV-2 with high transmission efficiency 3 , however whether D614G 58 conversion in S protein affect the viral entry and infectivity in cell model is still 59 unclear. 60 61The S protein of coronavirus, the major determinant of host and tissue tropism, is a 62 major target for vaccines, neutralizing antibodies, and viral entry inhibitors 4,5 . 63Similar to SARS-CoV, the cellular receptor of SARS-CoV-2 is 64 angiotensin-converting enzyme 2 (ACE2); however, the SARS-CoV-2 S protein has 65 a 10-to 20-fold higher affinity for ACE2 than the corresponding S protein of 66 SARS-CoV 6,7 . Coronaviruses use two d...

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Emergence of Drift Variants That May Affect COVID-19 Vaccine Development and Antibody Treatment

Cited by 118 publications

References 5 publications

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients

SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients

A distinct phylogenetic cluster of Indian SARS-CoV-2 isolates

D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity

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