{"id":24405,"date":"2022-01-07T10:17:46","date_gmt":"2022-01-07T10:17:46","guid":{"rendered":"https:\/\/evaggelatos.com\/?p=24405"},"modified":"2022-01-07T10:31:25","modified_gmt":"2022-01-07T10:31:25","slug":"%ce%bf%ce%bb%cf%8c%ce%ba%ce%bb%ce%b7%cf%81%ce%b7-%ce%b7-%ce%b5%cf%81%ce%b3%ce%b1%cf%83%ce%af%ce%b1-%ce%b3%ce%b9%ce%b1-%cf%84%ce%b7%ce%bd-%cf%80%ce%b1%cf%81%ce%b1%ce%bb%ce%bb%ce%b1%ce%b3%ce%ae-%ce%ba","status":"publish","type":"post","link":"https:\/\/evaggelatos.com\/?p=24405","title":{"rendered":"\u039f\u03bb\u03cc\u03ba\u03bb\u03b7\u03c1\u03b7 \u03b7 \u03b5\u03c1\u03b3\u03b1\u03c3\u03af\u03b1 \u03b3\u03b9\u03b1 \u03c4\u03b7\u03bd \u03c0\u03b1\u03c1\u03b1\u03bb\u03bb\u03b1\u03b3\u03ae \u039a\u03b1\u03bc\u03b5\u03c1\u03bf\u03cd\u03bd \u03bc\u03b5 \u03c0\u03c1\u03c9\u03c4\u03b5\u03c1\u03b3\u03ac\u03c4\u03b5\u03c2 \u03c4\u03bf\u03c5\u03c2 Philippe COLSON \u03ba\u03b1\u03b9 \u03c4\u03bf\u03bd \u00a0Didier Raoult"},"content":{"rendered":"
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TITLE PAGE <\/span><\/div>\n
1 <\/span>2 <\/span><\/div>\n
Full-length title: <\/span><\/div>\n
3 <\/span><\/div>\n
Emergence in Southern France of a new SARS-CoV-2 variant of probably Cameroonian <\/span><\/div>\n
4 <\/span><\/div>\n
origin harbouring both substitutions N501Y and E484K in the spike protein<\/span><\/div>\n
\u00a0<\/span>5 <\/span>6 <\/span><\/div>\n
Short title (for the running head):<\/span><\/div>\n
\u00a0<\/span>7 <\/span><\/div>\n
A new SARS-CoV-2 variant with spike substitutions N501Y and E484K<\/span><\/div>\n
\u00a0<\/span>8 <\/span>9 <\/span><\/div>\n
Author list: Philippe COLSON<\/span><\/div>\n
1,2,3<\/span><\/div>\n
, J\u00e9r\u00e9my DELERCE<\/span><\/div>\n
1<\/span><\/div>\n
, Emilie BUREL<\/span><\/div>\n
1<\/span><\/div>\n
, Jordan <\/span><\/div>\n
10 <\/span><\/div>\n
DAHAN<\/span><\/div>\n
4<\/span><\/div>\n
, Agn\u00e8s JOUFFRET<\/span><\/div>\n
5<\/span><\/div>\n
, Florence FENOLLAR<\/span><\/div>\n
1,2,6<\/span><\/div>\n
, Nouara YAHI<\/span><\/div>\n
7<\/span><\/div>\n
, Jacques <\/span><\/div>\n
11 <\/span><\/div>\n
FANTINI<\/span><\/div>\n
7<\/span><\/div>\n
, Bernard LA SCOLA<\/span><\/div>\n
1,2,3<\/span><\/div>\n
, Didier RAOULT<\/span><\/div>\n
1,2 <\/span><\/div>\n
* <\/span><\/div>\n
12 <\/span><\/div>\n
Affiliations: <\/span><\/div>\n
1<\/span><\/div>\n
\u00a0IHU M\u00e9diterran\u00e9e Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, <\/span>13 <\/span>France; <\/span><\/div>\n
2 <\/span><\/div>\n
Aix-Marseille Univ., Institut de Recherche pour le D\u00e9veloppement (IRD), Microbes <\/span>14 <\/span>Evolution Phylogeny and Infections (MEPHI), 27 boulevard Jean Moulin, 13005 Marseille, <\/span>15 <\/span>France; <\/span><\/div>\n
3 <\/span><\/div>\n
Assistance Publique-H\u00f4pitaux de Marseille (AP-HM), 264 rue Saint-Pierre, 13005 <\/span><\/span>16 <\/span>Marseille, France; <\/span><\/div>\n
4<\/span><\/div>\n
\u00a0Laboratoire de Biologie M\u00e9dicale SYNLAB Provence Marseille, 25 rue <\/span>17 <\/span>Rabattu, 13015 Marseille, France; <\/span><\/div>\n
5<\/span><\/div>\n
\u00a0Laboratoire de Biologie M\u00e9dicale SYNLAB Provence <\/span>18 <\/span>Forcalquier, rue du Souvenir Fran\u00e7ais, 04300 Forcalquier, France; <\/span><\/span><\/div>\n
6<\/span><\/div>\n
\u00a0Aix-Marseille Univ., <\/span>19 <\/span>Institut de Recherche pour le D\u00e9veloppement (IRD), Vecteurs <\/span><\/span><\/div>\n
\u00a0\u2013\u00a0<\/span><\/div>\n
\u00a0Infections Tropicales et <\/span>20 <\/span>M\u00e9diterran\u00e9ennes (VITROME), 27 boulevard Jean Moulin, 13005 Marseille, France;<\/span><\/span><\/div>\n
\u00a07<\/span><\/div>\n
\u00a0Aix-<\/span>21 <\/span>Marseille Universit\u00e9, INSERM UMR S 1072, 51 boulevard Pierre Dramard, 13015 Marseille, <\/span>22 <\/span>France. <\/span>23 <\/span><\/div>\n
* Corresponding author:<\/span><\/div>\n
\u00a0Didier Raoult, IHU M\u00e9diterran\u00e9e Infection, 19-21 boulevard Jean <\/span>24 <\/span>Moulin, 13005 Marseille, France. Tel.: +33 413 732 401, Fax: +33 413 732 402; email: <\/span>25 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.<\/span><\/div>\n<\/div>\n<\/div>\n
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2 <\/span>didier.raoult@gmail.com <\/span>26 <\/span><\/p>\n

Keywords:<\/span><\/div>\n
\u00a0SARS-CoV-2, variant, emergence, travel, southern France <\/span><\/span>27 <\/span><\/div>\n
Word counts:<\/span><\/div>\n
\u00a0abstract, 198; text, 1,778 <\/span>28 <\/span><\/div>\n
Figure: <\/span><\/div>\n
1;<\/span><\/div>\n
\u00a0Table:<\/span><\/div>\n
\u00a01 <\/span><\/div>\n
References: <\/span><\/div>\n
23<\/span><\/div>\n
\u00a0<\/span><\/div>\n
29 <\/span><\/div>\n
Supplementary Material: Figure: <\/span><\/div>\n
1;<\/span><\/div>\n
\u00a0Tables:<\/span><\/div>\n
\u00a02; <\/span><\/div>\n
References: <\/span><\/div>\n
2 <\/span>30 <\/span>31 <\/span>32 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n
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3 <\/span><\/div>\n
ABSTRACT <\/span><\/div>\n
33 <\/span>34 <\/span>SARS-CoV-2 variants have become a major virological, epidemiological and clinical <\/span>35 <\/span>concern, particularly with regard to the risk of escape from vaccine-induced immunity. Here <\/span>36 <\/span>we describe the emergence of a new variant. For twelve SARS-CoV-positive patients living in <\/span>37 <\/span>the same geographical area of southeastern France, qPCR testing that screen for variant-<\/span>38 <\/span>associated mutations showed an atypical combination. The index case returned from a travel <\/span>39 <\/span>in Cameroon. The genomes were obtained by next-generation sequencing with Oxford <\/span>40 <\/span>\u00a0Nanopore Technologies on GridION instruments within <\/span><\/span><\/div>\n
\ue000<\/span><\/div>\n
8 h. Their analysis revealed 46 <\/span>41 <\/span>mutations and 37 deletions resulting in 30 amino acid substitutions and 12 deletions. Fourteen <\/span>42 <\/span>amino acid substitutions, including N501Y and E484K, and 9 deletions are located in the <\/span>43 <\/span>spike protein. This genotype pattern led to create a new Pangolin lineage named B.1.640.2, <\/span>44 <\/span>which is a phylogenetic sister group to the old B.1.640 lineage renamed B.1.640.1. Both <\/span>45 <\/span>lineages differ by 25 nucleotide substitutions and 33 deletions. The mutation set and <\/span>46 <\/span>\u00a0phylogenetic position of the genomes obtained here indicate based on our previous definition <\/span><\/span>47 <\/span>a new<\/span><\/div>\n
\u00a0<\/span><\/div>\n
variant we named \u201cIHU\u201d.<\/span><\/div>\n
\u00a0These data are another example of the unpredictability of the <\/span><\/span>48 <\/span>emergence of SARS-CoV-2 variants, and of their introduction in a given geographical area <\/span>49 <\/span>from abroad. <\/span>50 <\/span>51 <\/span>52 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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4 <\/span><\/div>\n
TEXT <\/span><\/div>\n
53 <\/span>54 <\/span>SARS-CoV-2 has emerged in China in December 2019 and has been declared a <\/span>55 <\/span>\u00a0pandemic 21 months ago [1]. We have shown since the summer of 2020 that several SARS-<\/span><\/span>56 <\/span>CoV-2 variants have emerged in our geographical area and caused distinct epidemics, either <\/span>57 <\/span>successive or superimposed [2,3]. In addition, we described that the origin of these variants <\/span><\/span>58 <\/span>was often their introduction from abroad but could also be mink. This was observed by <\/span>59 <\/span>genotyping, as of 09\/12\/2021, SARS-CoV-2 from almost 40,000 patients using next-<\/span>60 <\/span>generation sequencing (NGS) of complete genomes for more than 22,000 patients and <\/span><\/span>61 <\/span>implementing multiple qPCR specific of each variant for a more exhaustive assessment of <\/span><\/span>62 <\/span>their spread. Since then and with the emergence of the Alpha variant at the end of 2020, <\/span>63 <\/span>SARS-CoV-2 variants have become a major virological, epidemiological, and clinical <\/span>64 <\/span>concern, particularly with regard to the risk of escape from vaccine-induced immunity [4-7]. <\/span>65 <\/span>Here we describe the emergence in south-eastern France of a new variant of probably <\/span>66 <\/span>Cameroonian origin. <\/span>67 <\/span>68 <\/span>The index case was an adult first diagnosed as infected with SARS-CoV-2 by real-<\/span>69 <\/span>time reverse transcription PCR (qPCR) performed in a private medical biology laboratory on <\/span><\/span>70 <\/span>a nasopharyngeal sample collected mid-November 2021 (Table 1). He was vaccinated against <\/span><\/span>71 <\/span>SARS-CoV-2 and returned from a travel to Cameroon three days before. He developed mild <\/span>72 <\/span>respiratory symptoms the day before diagnosis. He lives in a small town of southeastern <\/span><\/span>73 <\/span>France. Subsequent detection by qPCR of three mutations in the spike gene to screen for <\/span><\/span>74 <\/span>variants, as systematically performed in France in case of SARS-CoV-2 positivity, revealed <\/span>75 <\/span>an atypical combination with L452R-negativity, E484K-positivity, and E484Q-negativity <\/span><\/span>76 <\/span>(Pentaplex assay, ID Solution, France) that did not correspond to the pattern of the Delta <\/span>77 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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5 <\/span>variant involved in almost all SARS-CoV-2 infections at that time (Table 1). Respiratory <\/span>78 <\/span>samples collected from seven other SARS-CoV-2-positive patients living in the same <\/span>79 <\/span>geographical area exhibited the same combination of mutations screened by qPCR. They were <\/span><\/span>80 <\/span>two adults and five children (<15 years of age) (Table 1). The respiratory samples from these <\/span>81 <\/span>eight patients were sent to university hospital institute M\u00e9diterran\u00e9e Infection for SARS-CoV-<\/span><\/span>82 <\/span>2 genome sequencing as recommended by French public health authorities. A rapid NGS <\/span><\/span>83 <\/span>\u00a0procedure was launched overnight. It allowed obtaining SARS-CoV-2 genotype identification <\/span><\/span><\/span>84 <\/span>in <\/span><\/p>\n

\ue000<\/span><\/div>\n
8 hours. Briefly, viral RNA was extracted from 200 \u00b5L of nasopharyngeal swab fluid <\/span>85 <\/span>using the KingFisher Flex system (Thermo Fisher Scientific, Waltham, MA, USA) following <\/span>86 <\/span><\/div>\n
the manufacturer\u2019s instructions<\/span><\/div>\n
. Extracted RNA was reverse-transcribed using SuperScript IV <\/span>87 <\/span>(Thermo Fisher Scientific) and cDNA second strand was synthesized with LunaScript RT <\/span>88 <\/span>SuperMix kit (New England Biolabs) then amplified using a multiplex PCR protocol <\/span>89 <\/span>according to the ARTIC procedure (https:\/\/artic.network\/) with ARTIC nCoV-2019 V3 panel <\/span><\/span>90 <\/span>of primers (IDT, Coralville, IA, USA). Finally, NGS was performed with the ligation <\/span>91 <\/span>sequencing kit and a GridION instrument of Oxford Nanopore Technologies (Oxford, UK) <\/span><\/span>92 <\/span>following <\/span><\/div>\n
manufacturer\u2019s instructions<\/span><\/div>\n
. Subsequently, fastq files were processed using the <\/span>93 <\/span>ARTIC field bioinformatics pipeline (https:\/\/github.com\/artic-network\/fieldbioinformatics). <\/span><\/span><\/span>94 <\/span>\u00a0NGS reads were basecalled using Guppy (4.0.14) and aligned to the Wuhan-Hu-1 reference <\/span><\/span>95 <\/span>genome GenBank accession no. MN908947.3 using minimap2 (v2.17-r941) <\/span><\/span>96 <\/span>(https:\/\/github.com\/lh3\/minimap2) [8]. The ARTIC tool align_trim was used to softmask <\/span><\/span>97 <\/span>\u00a0primers from read alignment and to cap sequencing depth at a maximum of 400. The <\/span><\/span>98 <\/span>identification of consensus-level variant candidates was performed using the Medaka (0.11.5) <\/span>99 <\/span>workflow developed by ARTIC (https:\/\/github.com\/artic-network\/artic-ncov2019). This <\/span><\/span>100 <\/span>strategy allowed assemblying the complete genome from NGS reads obtained within 30 min <\/span>101 <\/span>of run for cycle threshold values (Ct) of qPCR comprised between 15 and 27. SARS-CoV-2 <\/span>102 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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6 <\/span>genomes were classified into Nextclade and Pangolin lineages using web applications <\/span>103 <\/span>(https:\/\/clades.nextstrain.org\/;https:\/\/cov-lineages.org\/pangolin.html) [10,11,13]. They were <\/span><\/span>104 <\/span>deposited in the GISAID sequence database (https:\/\/www.gisaid.org\/) [14] (Table 1). <\/span><\/span>105 <\/span>Phylogenies were reconstructed with the nextstrain\/ncov tool <\/span><\/span>106 <\/span>(https:\/\/github.com\/nextstrain\/ncov) then visualized with Auspice <\/span><\/span>107 <\/span>(https:\/\/docs.nextstrain.org\/projects\/auspice\/en\/stable\/). <\/span><\/span>108 <\/span>The analysis of viral genomes revealed the presence of 46 nucleotide substitutions and <\/span>109 <\/span>37 deletions, resulting in 30 amino acid substitutions and 12 deletions (Figure 1a; <\/span>110 <\/span>Supplementary Tables S1 and S2). Fourteen amino acid substitutions and 9 amino acid <\/span><\/span>111 <\/span>deletions are located in the spike protein. Substitutions N501Y and E484K are combined as in <\/span>112 <\/span>the Beta, Gamma, Theta and Omicron variants [5,15]. Substitution F490S is present as in the <\/span>113 <\/span>Lambda variant, and substitution P681H is present as in the Lambda and Omicron variants. In <\/span>114 <\/span>other structural proteins than the spike, amino acid changes include two substitutions in the <\/span>115 <\/span>nucleocapsid protein and one in the membrane protein. In non-structural proteins, amino acid <\/span><\/span>116 <\/span>changes include one substitution in proteins Nsp2, Nsp3, Nsp4, Nsp6, Nsp12 (RNA-<\/span>117 <\/span>dependent RNA polymerase), and Nsp13 (helicase); two substitutions in Nsp14 (<\/span><\/span><\/p>\n

3\u2019<\/span><\/div>\n
–<\/span>118 <\/span><\/div>\n
5\u2019exo<\/span><\/div>\n
nuclease); four substitutions in Nsp8 (which is part of the replication complex with <\/span>119 <\/span>\u00a0Nsp7 and Nsp12); and three deletions in Nsp6. Finally, in regulatory proteins, amino acid <\/span><\/span>120 <\/span>changes include four substitutions in ORF3a, one in ORF9b and one in ORF8. In addition, <\/span>121 <\/span>codon 27 of ORF8 gene is changed into a stop codon, as in the Alpha variant [16]; some <\/span>122 <\/span>members of the Marseille-4 variant (B.1.160) that predominated in our geographical area <\/span><\/span>123 <\/span>\u00a0between August 2020 and February 2021 also exhibit a stop codon in ORF8 gene but at <\/span><\/span>124 <\/span>another position [3]. <\/span>125 <\/span>\u00a0Nextclade identified a 20A lineage. Pangolin identified a B.1.640 lineage in primary <\/span><\/span><\/span>126 <\/span>analysis but a B.1 lineage with the -usher (Ultrafast Sample placement on Existing tRee; <\/span>127 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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7 <\/span>https:\/\/genome.ucsc.edu\/cgi-bin\/hgPhyloPlace) option, which showed the phylogenetic <\/span><\/span>128 <\/span>\u00a0placement of the genomes we obtained as an outgroup of the B.1.640 lineage and their <\/span><\/span>129 <\/span>clustering with a genome obtained late October in France (Ile-de-France) <\/span><\/span>130 <\/span>(EPI_ISL_5926666). The B.1.640 lineage corresponds to a variant first identified in France in <\/span><\/span>131 <\/span>April 2021, in Indonesia in August 2021, and in Republic of the Congo (Brazzaville) in <\/span>132 <\/span>September 2021, and it was involved in a cluster of cases in Brittany, France around mid-<\/span>133 <\/span>October 2021 [17]. As of 09\/12\/2021, 157 genomes were available from the GISAID database <\/span>134 <\/span>including 92 from France and 36 from the Republic of the Congo. The sets of spike mutations <\/span>135 <\/span>of the B.1.640 lineage and of genomes obtained here are similar, with 11 common nucleotide <\/span>136 <\/span>substitutions and 1 common deletion of 9 codons (Supplementary Figure S1, Tables S1-2). <\/span><\/span>137 <\/span>However, spike genes of both lineages differ by 7 mutations. In addition, 25 nucleotide <\/span>138 <\/span>substitutions and 33 nucleotide deletions located elsewhere in the genomes differ between the <\/span>139 <\/span>two genotypes. The pattern of mutations of present genomes hence indicates a new<\/span><\/p>\n

\u00a0<\/span><\/div>\n
variant, <\/span>140 <\/span><\/div>\n
which we named \u201cIHU\u201d (in reference to our institute)<\/span><\/div>\n
, based on our previous definition [3]. <\/span>141 <\/span>Phylogeny performed with nextstrain\/ncov tool (https:\/\/github.com\/nextstrain\/ncov) also <\/span><\/span>142 <\/span>showed that B.1.640 and IHU variants were most closely related between each other but <\/span>143 <\/span>comprised two divergent branches (Figure 1b). Their last common ancestor is estimated to <\/span><\/span>144 <\/span>date from January 2021 but no genome is currently available from GISAID that corresponds <\/span>145 <\/span>to it. Accordingly, a new Pangolin clade corresponding to the IHU variant was created on <\/span>146 <\/span>07\/12\/2021 that was named B.1.640.2, the old B.1.640 clade being renamed B.1.640.1 <\/span>147 <\/span>(https:\/\/github.com\/cov-lineages\/pango-designation\/issues\/362). It encompasses present <\/span><\/span>148 <\/span>genomes and three other genomes comprising a sister group including the one recovered late <\/span>149 <\/span>October 2021 in France (Ile-de-France) (EPI_ISL_5926666) and two additional genomes <\/span>150 <\/span>obtained from samples collected late November in England (EPI_ISL_7181977) and Wales <\/span>151 <\/span>(EPI_ISL_7402094). As the index case was probably infected with the IHU variant during his <\/span><\/span>152 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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8 <\/span>stay in Cameroon, we sought for this variant in GISAID among genomes from this country <\/span>153 <\/span>\u00a0but as of 09\/12\/2021 none of the 556 available genomes belong to the B.1.640.1 or B.1.640.2 <\/span><\/span>154 <\/span>lineages. <\/span>155 <\/span>We analyzed a complete structure of the spike protein of the IHU variant generated by <\/span>156 <\/span>incorporating its specific mutational profile to the original 20B SARS-CoV-2 (Wuhan-Hu-1 <\/span><\/span>157 <\/span>isolate with D614G substitution) [18] and fixing all gaps in the pdb file by incorporating the <\/span><\/span>158 <\/span>missing amino acids with the Robetta protein structure prediction tool <\/span>159 <\/span>[https:\/\/robetta.bakerlab.org\/], followed by energy minimization with the Polak-Ribi\u00e8re <\/span><\/span>160 <\/span>algorithm as previously reported (Figure 1c) [19]. In the N-terminal domain (NTD), the 134-<\/span>161 <\/span>145 amino acid deletion is predicted to significantly affect the neutralizing epitope. Other <\/span>162 <\/span>changes involve amino acids at positions 96 and 190: in Wuhan-Hu-1 isolate, E96 and R190 <\/span>163 <\/span>induce a turn in NTD secondary structure through electrostatic interactions between each <\/span>164 <\/span>other. This interaction is conserved between substituted amino acids 96Q and 190S, which <\/span>165 <\/span>suggests the co-evolution of these changes. In the receptor binding domain (RBD), aside the <\/span>166 <\/span>well-known substitutions N501Y and E484K, several changes were predicted to significantly <\/span>167 <\/span>affect the neutralizing epitopes. Particularly, P681H is located in the cleavage site of S1-S2 <\/span>168 <\/span>subunits of the spike and is observed in other variants including the recently emerging <\/span>169 <\/span>Omicron [15]. Besides, D1139H substitution implies an amino acid involved in the fusion <\/span>170 <\/span>\u00a0between the virus and the infected cell.Also, D614G is combined with T859N in the IHU <\/span><\/span>171 <\/span>variant. Interestingly, in the Wuhan-Hu-1 isolate, amino acids D614 and T859 from two <\/span>172 <\/span>subunits of the trimeric spike are face to face and lock the trimer in a closed conformation. <\/span>173 <\/span>Substitution D614G allows unlocking the trimer conformation, but this is predicted to be still <\/span>174 <\/span>easier in case of additional presence of substitution T859N. <\/span>175 <\/span>Respiratory samples collected until end of November 2021 from four other SARS-<\/span>176 <\/span>CoV-2 positive patients living in the same city or borough than the index case could be <\/span>177 <\/span><\/p>\n

. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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9 <\/span>identified as containing the IHU variant by NGS within 24 hours after their reception (Table <\/span>178 <\/span>1). All 12 IHU variant-positive samples showed the same combination of spike mutations as <\/span>179 <\/span>screened by real-time qPCR techniques: negativity for 452R and 484Q; positivity for 484K, <\/span>180 <\/span>501Y [20], and 681H [3]. We also used the TaqPath COVID-19 kit (Thermo Fisher Scientific, <\/span>181 <\/span>Waltham, USA) that provided positive signals for all three genes targeted (ORF1, S, and N). <\/span>182 <\/span>Thus, the IHU variant can be distinguished by screening with qPCR assays from the Delta <\/span><\/span>183 <\/span>(L452R-positive) and Omicron (L452R-negative and negative for S gene detection by the <\/span><\/span>184 <\/span>TaqPath COVID-19 assay) variants that currently co-circulate in our geographical area. <\/span>185 <\/span>Finally, scanning electron microscopy using a SUV 5000 microscope (Hitachi High-<\/span><\/span>186 <\/span>Technologies Corporation, Tokyo, Japan) [21] allowed a quick visualization of the virus from <\/span><\/span>187 <\/span>a respiratory sample (Figure 1d). <\/span>188 <\/span>189 <\/span>Overall, these observations show once again the unpredictability of the emergence of <\/span>190 <\/span>new SARS-CoV-2 variants and their introduction from abroad, and they exemplify the <\/span>191 <\/span>difficulty to control such introduction and subsequent spread. They also warrant the <\/span>192 <\/span>implementation of genomic surveillance of SARS-CoV-2 that we started from the very <\/span>193 <\/span>\u00a0beginning of the pandemic in our geographical area as soon as we diagnosed the first SARS-<\/span><\/span>194 <\/span>CoV-2 infection [21] and that we expanded during summer 2020 [2,3]. This surveillance has <\/span>195 <\/span>\u00a0been implemented at the country scale in 2021 through the French Emergen consortium <\/span><\/span>196 <\/span>(https:\/\/www.santepubliquefrance.fr\/dossiers\/coronavirus-covid-19\/consortium-emergen). It is <\/span><\/span>197 <\/span>too early to speculate on virological, epidemiological or clinical features of this IHU variant <\/span><\/span>198 <\/span>\u00a0based on these 12 cases. For this purpose, respiratory samples from infected patients were <\/span><\/span>199 <\/span>inoculated on Vero E6 cells as previously described [22] to be able assessing the sensibility to <\/span><\/span>200 <\/span>neutralization by anti-spike antibodies elicited by vaccine immunization, or by prior infection <\/span>201 <\/span>[23]. <\/span>202 <\/span><\/p>\n

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(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n
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(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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14 <\/span>12. Garrison E, Marth G (2012). Haplotype-based variant detection from short-read <\/span><\/span><\/span><\/span><\/span><\/span>289 <\/span>sequencing. arXiv.org. https:\/\/arxiv.org\/abs\/1207.3907 (accessed 10 December 2021). <\/span><\/span>290 <\/span>13. Rambaut A, Holmes EC, O’Toole \u00c3, Hill V, McCrone JT, Ruis C, du Plessis L, Pybus <\/span><\/span><\/span><\/span><\/span>291 <\/span>OG (2020). A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist <\/span><\/span>292 <\/span>genomic epidemiology. Nat. Microbiol 5: 1403-1407. <\/span>293 <\/span>14. Alm E, Broberg EK, Connor T, Hodcroft EB, Komissarov AB, Maurer-Stroh S, <\/span><\/span><\/span><\/span>294 <\/span>Melidou A, Neher RA, O’Toole A, Pereyaslov D, WHO European Region sequencing <\/span>295 <\/span>laboratories and GISAID EpiCoV group; WHO European Region sequencing <\/span><\/span>296 <\/span>laboratories and GISAID EpiCoV group (2020) Geographical and temporal distribution <\/span><\/span>297 <\/span>of SARS-CoV-2 clades in the WHO European Region, January to June 2020. Euro. <\/span>298 <\/span>Surveill 25: 2001410. <\/span>299 <\/span>15. Karim SSA, Karim QA (2021) Omicron SARS-CoV-2 variant: a new chapter in the <\/span><\/span><\/span><\/span>300 <\/span>COVID-19 pandemic. Lancet 398: 2126-2128. <\/span>301 <\/span>16. Rambaut A, Loman N, Pybus O, Barclay W, Barrett J, Carabelli A, Connor T, Peacock <\/span><\/span><\/span>302 <\/span>T, Robertson DL, Volz E, on behalf of COVID-19 Genomics Consortium UK (CoG-<\/span>303 <\/span>UK) (2020) Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage <\/span>304 <\/span>in the UK defined by a novel set of spike mutations. Virological Pre-print. <\/span>305 <\/span>https:\/\/virological.org\/t\/preliminary-genomic-characterisation-of-an-emergent-sars-cov-<\/span><\/span>306 <\/span>2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations\/563 <\/span><\/span>307 <\/span>17. Le Page M (2021) New variant gains ground. New Sci 252: 8. <\/span><\/span><\/span><\/span><\/span>308 <\/span>18. Benton DJ, Wrobel AG, Roustan C, Borg A, Xu P, Martin SR, Rosenthal PB, Skehel JJ, <\/span><\/span><\/span>309 <\/span>Gamblin SJ (2021). The effect of the D614G substitution on the structure of the spike <\/span>310 <\/span>glycoprotein of SARS-CoV-2. Proc. Natl. Acad. Sci. U S A. 118:e2022586118. <\/span><\/span>311 <\/span><\/p>\n

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(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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10 <\/span>203 <\/span>204 <\/span><\/p>\n

Acknowledgments <\/span><\/div>\n
205 <\/span>We are thankful to the Emergen French consortium <\/span><\/span>206 <\/span>(https:\/\/www.santepubliquefrance.fr\/dossiers\/coronavirus-covid-19\/consortium-emergen). We <\/span><\/span>207 <\/span>are also grateful to Laurence Thomas, Claudia Andrieu, Ludivine Brechard, Mamadou Beye, <\/span>208 <\/span>Marielle Bedotto, Elsa Prudent, Sofiane Bakour, Jacques Bou Khalil, and Clio Grimaldier for <\/span>209 <\/span>their technical help. <\/span>210 <\/span>211 <\/span><\/div>\n
Author contributions <\/span><\/div>\n
212 <\/span>Conceived and designed the experiments: PC, DR, JF, BLS. Contributed materials\/analysis <\/span><\/span>213 <\/span>tools: PC, JDe, EB, JDa, AJ, FF, NY, JF. Analyzed the data: PC, DR, BLS, JD, EB, JF, NY. <\/span>214 <\/span>Wrote the paper: PC, JF, DR. All authors approved the last version of the manuscript. <\/span>215 <\/span>216 <\/span><\/div>\n
Funding <\/span><\/div>\n
217 <\/span><\/div>\n
This work was supported by the French Government under the \u201cInvestments for the Future\u201d <\/span><\/div>\n
218 <\/span>\u00a0program managed by the National Agency for Research (ANR), M\u00e9diterran\u00e9e-Infection 10-<\/span><\/span><\/span>219 <\/span>IAHU-03 and was also supported by R\u00e9gion Provence Alpes C\u00f4te <\/span><\/div>\n
d\u2019Azur and European <\/span><\/div>\n
220 <\/span>funding FEDER PRIMMI (Fonds Europ\u00e9en de D\u00e9veloppement R\u00e9gional-Plateformes de <\/span>221 <\/span>Recherche et d’Innovation Mutualis\u00e9es M\u00e9diterran\u00e9e Infection), FEDER PA 0000320 <\/span>222 <\/span>PRIMMI, and by Hitachi High-Technologies Corporation, Tokyo, Japan. <\/span><\/span>223 <\/span>224 <\/span><\/div>\n
Conflicts of interest <\/span><\/div>\n
225 <\/span>DR has a conflict of interest being a consultant for Hitachi High-Technologies Corporation, <\/span>226 <\/span>Tokyo, Japan from 2018 to 2020. All other authors have no conflicts of interest to declare. <\/span>227 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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11 <\/span>Funding sources had no role in the design and conduct of the study; collection, management, <\/span>228 <\/span>analysis, and interpretation of the data; and preparation, review, or approval of the <\/span>229 <\/span>manuscript. <\/span>230 <\/span>231 <\/span><\/div>\n
Ethics <\/span><\/div>\n
232 <\/span>This study has been approved by the ethics committee of University Hospital Institute (IHU) <\/span>233 <\/span>M\u00e9diterran\u00e9e Infection (N\u00b02021-<\/span><\/div>\n
029). Access to the patients\u2019 biological and registry data <\/span><\/div>\n
234 <\/span>issued from the hospital information system was approved by the data protection committee <\/span>235 <\/span>of Assistance Publique-H\u00f4pitaux de Marseille (APHM) and was recorded in the European <\/span>236 <\/span>General Data Protection Regulation registry under number RGPD\/APHM 2019-73. <\/span>237 <\/span>238 <\/span>239 <\/span><\/div>\n
. <\/span>CC-BY 4.0 International license<\/a><\/span>It is made available under a<\/span>\u00a0<\/a><\/span><\/span> per<\/span>petuity. <\/a><\/span>is the author\/funder, who has granted medRxiv a license to display the preprint in<\/span><\/div>\n
(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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12 <\/span><\/p>\n

REFERENCES<\/strong> <\/span><\/div>\n
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(which was not certified by peer review)<\/span><\/div>\n
preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n<\/div>\n<\/div>\n
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preprint <\/span>The copyright holder for this<\/span>this version posted December 29, 2021. <\/span>;<\/a><\/span>\u00a0<\/span>https:\/\/doi.org\/10.1101\/2021.12.24.21268174<\/a><\/span>doi:<\/span>\u00a0<\/a><\/span>medRxiv preprint <\/span><\/span><\/div>\n
<\/div>\n
Source:https:\/\/www.zerohedge.com\/medical\/new-variant-46-mutations-discovered-southern-france<\/div>\n<\/div>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

TITLE PAGE 1 2 Full-length title: 3 Emergence in Southern France of a new SARS-CoV-2 variant of probably Cameroonian 4 origin harbouring both substitutions N501Y and E484K in the spike protein \u00a05 6 Short title (for the running head): \u00a07 A new SARS-CoV-2 variant with spike substitutions N501Y and E484K \u00a08 9 Author list: Philippe … <\/p>\n

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