key: cord-0797034-h5xms8ez
authors: Boehm, Erik; Kronig, Ilona; Neher, Richard A.; Eckerle, Isabella; Vetter, Pauline; Kaiser, Laurent
title: Novel SARS-CoV-2 variants: the pandemics within the pandemic
date: 2021-05-17
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.05.022
sha: 00e4ab7411b97cde951b3aad2e20113c1953fadf
doc_id: 797034
cord_uid: h5xms8ez

BACKGROUND: Many new variants of SARS-CoV-2 have been termed Variants of Concern/Interest (VOC/I) because of their greater risk due to possibly: enhanced transmissibility and/or severity, immune escape, diagnostic and/or treatment failure, and reduced vaccine efficacy. OBJECTIVES: We sought to review current knowledge of emerging SARS-CoV-2 variants, particularly those deemed VOC/Is: B.1.351, B.1.1.7, and P.1. SOURCES: MEDLINE and BioRxiv databases, as well as the grey literature were searched for reports of SARS-CoV-2 variants since November 2020. Relevant articles and their references were screened. CONTENT: Mutations on the spike protein in particular may affect both affinity for the SARS-CoV-2 cell receptor ACEII or antibody binding. These VOC/Is often share similar mutation sets. The N501Y mutation is shared by the main three VOCs: B.1.1.7, first identified in the United Kingdom; P.1, originating from Brazil; and B.1.351, first described in South Africa. This mutation likely increases transmissibility, by increasing affinity for ACEII. The B.1.351 and P.1 variants also display the E484K mutation, which decreases binding of neutralizing antibodies, leading to partial immune escape, favoring reinfections, and decreased in vitro efficacy of some antibody therapies or vaccines. Those mutations may also have phenotypical repercussions of higher severity. Furthermore, the accumulation of mutations poses a diagnostic risk (lowered when using multiplex assays), as seen for some assays targeting the S-gene. With ongoing surveillance, many new VOC/Is have been identified. The emergence of the E484K mutation independently in different parts of the globe may reflect adaptation of SARS-CoV-2 to humans in a background of increasing immunity. IMPLICATIONS: These VOC/Is are increasing in frequency globally and pose challenges to any herd immunity approach of managing the pandemic. While vaccination is ongoing, vaccine updates may be prudent. The virus continues to adapt to transmission in humans, and further divergence from the initial Wuhan sequences is expected.

The evolutionary rate of SARS-CoV-2 is low (approximately 1 x10 -3 substitutions/site/year) thanks to its proof-44 reading RNA polymerase. This represents a fixation of 1 to 2 nucleotide changes per month per lineage, in the 45 30 ,000 base pairs of the virus [1] . These deletions, insertions or substitutions of nucleotides may either be 46 synonymous, with few or no repercussions to the virus, or non-synonymous, leading to a change in the amino- 

Early in the pandemic, the D614G mutation of S arose and is now found in nearly every sequence worldwide, 57 likely due to epidemiological factors and a transmission advantage. In summer 2020, a variant spreading in 58 minks accumulated numerous mutations, while retaining the potential to infect humans, which led to the 59 slaughtering of Danish mink populations [4] .

By the end of December 2020, new variants have emerged that have accumulated multiple mutations, called 61 "Variants of interest" (VOI) because they lead to phenotypic modifications, or have genomic mutations 62 suspected to lead to such modifications, and have been identified in multiple transmission events or in 63 multiple countries. "Variants of concern" (VOCs) have additionally been demonstrated to be associated with 64 increased transmissibility, increased virulence or changes in clinical disease presentation, or decreased We searched the MEDLINE and BioRxiv databases for reports of SARS-CoV-2 variants since November 71 2020. The grey literature, including Google database and Twitter was surveyed using the same keywords.

Search terms used in various combinations were as follows: "SARS-CoV-2", "variants", "variants of concern", 73 "VOC", "variants of interest", "VOI", "mutations", "evolution", "B.1.1.7", "B.1.351", "P.1", "B.1.148", "B.1.1.28", 74 "N501Y", "E484K", and "L452R". We screened all articles identified and relevant references cited in those 75 articles.

An overview of the new VOCs and VOIs is given in Table 1 . Lineage names, as determined by Pango 78 (https://cov-lineages.org/descriptions.html) and characterised by a combination of genetic and epidemiological 79 support, are commonly used; as are names given upon first identification [6] .

The number of new mutations accumulated by many of these VOCs and VOIs before detection is rather high.

For some, the apparent lack of intermediates suggests a long period of undetected replication and evolution, 82 which may be explainable by: intra-host-evolution during a long chronic infection, poor monitoring, 

A number of divergent sequences were identified in humans who had been in contact with minks [8] , and 92 attributed to adaptation to mink hosts, suggesting that the role of human to animal to human transmission 93 chains need to be carefully considered. Notably, some mink-associated variants resulted in partial escape 94 from neutralizing antibodies[9], emphasizing that the emergence of immune escape mutations does not 95 necessarily mean that emergence of these variants is due to selection pressure from human population-level 96 immunity. Transmission of these variants have been contained[10], likely due to efforts to culling mink 97 populations. Nonetheless, there remains a risk of further outbreaks from mink and other farmed or domestic 98 J o u r n a l P r e -p r o o f animals. It must be kept in mind that novel variants may be concerning not just for their effects in humans and 99 human to human transmissibility, but also their ability to establish animal reservoirs of SARS-CoV-2 and the 100 potentially elevated transmission due to a human-animal-human route [11] .

102 Several combined mutations define each new lineage (Table 2) . When occurring on S and especially on its 103 RBD, these mutations may affect receptor or antibody binding. The following mutations are particularly 104 noteworthy:

The N501Y mutation, within the RBD of S, results in greater affinity for human ACE2 receptor[12], which may 106 increase transmissibility.

The E484K mutation, also in the RBD of S, is associated with immune escape[13] and increased ACE2 108 affinity [14] . Notably, a similar mutation, E484Q, was also associated with immune escape [13] . with mutations in S are a concern for various antibody mediated therapies such as etesivimab (LY-CoV016), 126 bamlanivimab, casirivimab(REGN10933) [17, 22] . Resistance to specific monoclonal antibodies or resistance 127 due to a single mutation is unlikely to significantly affect neutralizing activity of polyclonal sera, while multiple 128 mutations may have more substantial effects; which is supported by studies using vaccine sera and 129 pseudovirus (PsV) [23] . No single mutation identified so far would be sufficient to abolish neutralizing activity, 130 so we can expect that current vaccines and exposure to other variants will still provide some degree of 131 protection. Notably, neutralization studies give no indication on the effectiveness of cell-mediated immunity 132 elicited after vaccination, which also contributes to protection against COVID-19. Indeed, the vast majority of 

Immune escape concerns: This variant contains a few mutations linked with potential immune escape (Table   152 2) and convalescent plasma or vaccine sera show reductions in neutralizing antibody titers; although 153 J o u r n a l P r e -p r o o f neutralization generally remains robust (Supplemental Table 1 ). There is no evidence of elevated reinfection 154 rates [30] , and current vaccines largely retain their effectiveness against it (Table 3) (Table 4 ). Furthermore, 189 serology and epidemiological studies indicated that 1/3 of the population had previously been exposed to Table 1 ). Preliminary data showed a complete escape from neutralization by 

Immune escape concerns: Sera neutralization is reportedly decreased (Supplemental Table 1 ), and the 229 L452R mutation has been reported to escape neutralization by bamlanivimab. 

D253G mutation is also notable, and believed to play a role in immune escape.

Diagnostic Impact: No data, but no issues are expected. 

Immune escape concerns: Both the E484Q and L452R mutations are a cause for concern of immune escape.

Diagnostic Impact: No data, likely unaffected.

The presence of the E484K mutation by itself should be enough to qualify a variant for VOI status, and the 260 known instances of variants with the E484K are too numerous to list here, but include: P.2, P.3, some isolates 261 of A. 23.1 and B.1.111, B.1.525, B.1.619, N.9, N.10, and A. VOI.V2. Data on these variants are scarce, but the 262 presence of the E484K mutation raises concerns of immune escape. Many of these variants are temporally 263 linked to a surge in cases, but their emergence may be an effect rather than a cause of such surges.

J o u r n a l P r e -p r o o f P.3 is also notable for containing the N501Y mutation that is found in the 3 variants classified as 265 VOCs by the WHO, which has been linked to increased ACEII affinity/transmissibility, ability to use rat and New variants, sharing some common mutations, emerged independently across the world in a background of 295 increasing population immunity, and rapidly spread in the area where they were identified. In many ways this 296 mirrors the early independent emergence and spread of D614G mutations. Their mutations likely render them 297 more transmissible (e.g. N501Y), with some ability to escape previous immunity (e.g. E484K), and may be 298 able to effectively establish infections in animals that are routinely in close proximity to humans. This was to 299 be expected given the number of infections across the world, and that the virus has only been adapting to 300 human transmission for a short time. While vaccination strategies aim to reduce the burden of COVID-19, the 301 efficacy of the vaccines may be reduced by the emergence of these new mutations, but two doses may still 302 protect against severe COVID-19.

With the increase of worldwide genome sequencing surveillance, the number of new identified variants is 304 expected to increase. Surveillance of all new identified variants has to be closely monitored, in order to be 305 able to take necessary countermeasures as soon as possible.

Acknowledgments 307 We thank Manuel Schibler and Samuel Cordey for their meaningful advice. (Unk E)  --------+  ------T19R, G142D, E154K, E156G, ∆157-158, V382L, N440T, 950N,  Q1071H, H1101D, D1153Y: Unk E   --------------+/-T20N, P26S, D138Y, R190S, T1027I: Unk E  --+  ------------S31F, S50L, P384L, A1070S: Unk E  -------------+/--Q52R, F888L: Unk E  ------+  --------H66D, G142V, G669S, Q949R, N1187D: Unk E  -----------+ I210N, ∆211, ∆247-249, W258L, R346K, Q957H : J o u r n a l P r e -p r o o f

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