key: cord-0685766-bhh7atgc authors: Focosi, Daniele; Maggi, Fabrizio title: Neutralising antibody escape of SARS‐CoV‐2 spike protein: Risk assessment for antibody‐based Covid‐19 therapeutics and vaccines date: 2021-03-16 journal: Rev Med Virol DOI: 10.1002/rmv.2231 sha: 9f395fc516c627b02e77587ee8f09c5d2a2ea2ce doc_id: 685766 cord_uid: bhh7atgc The Spike protein is the target of both antibody‐based therapeutics (convalescent plasma, polyclonal serum, monoclonal antibodies) and vaccines. Mutations in Spike could affect efficacy of those treatments. Hence, monitoring of mutations is necessary to forecast and readapt the inventory of therapeutics. Different phylogenetic nomenclatures have been used for the currently circulating SARS‐CoV‐2 clades. The Spike protein has different hotspots of mutation and deletion, the most dangerous for immune escape being the ones within the receptor binding domain (RBD), such as K417N/T, N439K, L452R, Y453F, S477N, E484K, and N501Y. Convergent evolution has led to different combinations of mutations among different clades. In this review we focus on the main variants of concern, that is, the so‐called UK (B.1.1.7), South African (B.1.351) and Brazilian (P.1) strains. follow. 12 All these antibody-based therapeutics and vaccines suffer from one major risk: mutational escape of the Spike protein. 13 Changes in Spike protein might also increase transmissibility, leading to increased re-infection rates and reduced efficacy of vaccine campaigns. 14 Please note that many of the references in this manuscript are preprints which have not yet been through the peer review process. Coronaviruses belong to the order Nidovirales, which is known for viruses with the longest RNA genome. 15 The genome of SARS-CoV-2 has 29,903 ribonucleotides, which encode 29 proteins. Although coronaviruses have a proof-reading apparatus, 16 their genomes remain subject to recombination as well as other copy-choice transcriptional errors. 17 Being a recent virus, the observed diversity is lower than for other RNA viruses. 18 Most SARS-CoV-2 proteins exhibit little mutational variability, the proteins with highest mutation rate (MR) being the Spike, NSP12 (RNA-dependent RNA polymerase [RdRp] ) and NSP9c. 19 The average MR of SARS-CoV-2 genome has been estimated from the related mouse hepatitis virus (MHV) at 10 −6 nucleotides per cycle, and the MR at 4.83 � 10 −4 subs/site/year, which is similar, or slightly lower, than what is observed for other RNA viruses. 20 Heterogeneous mutation patterns are mainly reflections of host antiviral mechanisms that are achieved through apolipoprotein B mRNA editing catalytic polypeptide-like proteins (APOBEC), adenosine deaminase acting on RNA proteins (ADAR) and ZAP proteins and probable adaptation against reactive oxygen species (ROS). 21 Two particular mutation types, G→U and C→U, possibly the result of APOBEC and ROS, cause the majority of mutations in the genome and occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasmic). 22 Nomenclature of genetic diversity within a given species is not regulated by the International Committee on Taxonomy of Viruses. Historically, genetic diversity is variably grouped in 'clades', 'subtypes', 'genotypes', 'groups' or 'lineages'. The main repositories for SARS-CoV-2 genomic sequences are listed in Table 2 . In April 2020, a preliminary work by the London School of Hy- 23 These findings were replicated by a Chinese study in June 2020 using only 103 isolates, which first introduced the L and S lineage nomenclature. 24 The Global Initiative on Sharing All Influenza Data (GISAID) repository contains more than 400,000 full SARS-CoV-2 proteome sequences (mostly from Europe, and in particular the UK) as of 20 December 2020, and classifies clades with progressive letters. In Winter 2020, the main clades were L, O, V and S. Later, clade G (with the associated D614G mutation in the Spike protein) emerged F I G U R E 1 Linearised representation of Single nucleotide polymorphisms (SNPs) and deletions commonly detected in the S1 and S2 domains of the Spike protein, with a focus on the receptor binding domain (RBD) and receptor binding motif (RBM). Circle size represents relative abundance of the mutation in worldwide genome repositories as of January 2021. Mutations within RBD are represented on grey background followed by the related GR and GH clades. 25 An eighth clade named GV has since been described in the following months. Nextstrain 26 sources data from public repositories such as NCBI, GISAID and ViPR, as well as GitHub repositories and other sources of genomic data. Nextstrain supports the year-letter dynamic Phylogenetic Assignment of Named Global Outbreak LINeages (PANGOLIN) lineage nomenclature 27 (https://github.com/nextstrain/ ncov/blob/master/docs/naming_clades.md). Clades originally needed a frequency of at least 20% globally for two or more months, and are named with the year it was first identified and the first available letter within the alphabet. The parent clade is reported with the '.' notation (e.g., 19A.20A.20C to indicate clade 20C). Then, in January 2021, it was acknowledged that lack of international travel made it slower for new clades to move past 20% global frequency, and consequently two alternative requirements were added: clade reaches more than 20% global frequency for two or more months: a clade reaches more than 30% regional frequency for two or more months, and a VOC ('variant of concern') is recognised. 28 All the above-mentioned different SARS-CoV-2 phylogenies are reconciled in Table 3 , which details the separating (barcoding) SNPs. Globally, Jacob et al. 29 Neutralising RBD I COVA2-16, COVA2-31, COVA2-23, COVA2-11, COVA3-06, COVA3-09, COVA2-29, COVA2-45, COVA1-18, COVA2-20 RdRp is under stronger overall negative selection in the mutant genomes, particularly during the early stages. 31 Single-nucleotide polymorphisms (SNP) and deletions, such as the ones reported in Table 3 45 Positive selection has been detected for 21 Spike signature mutations sites (convergent for 16 sites and nonconvergent for 5 sites) and 90 nonsignature mutation sites in these VOCs. 46 Given consistent convergent evolution, we will separately discuss individual mutations first, and will later focus on VOCs. year, without differences among clades. 50 The global frequencies of different immune escape variants has been assessed in several research articles. 51 It has been hypothesised that Spike protein mutations in novel SARS-CoV-2 'variants of concern' commonly occur in or near indels. 52 The residue D614 of the Spike protein began showing a D614G SNP missense mutation in January 2020 and showed an MR of 0.999 in October-November 2020, 19 meaning it is almost universal. In the quaternary structure, the D614 established a stabilising hydrogen bond with T859 of the adjacent monomer: D614G compromises such hydrogen bonds providing higher flexibility, potentially modifies glycosylation at close residues (such as N616 53 ), changes the inner motion of the RBD modifying its cross-connections with other domains, 54 affects the pH-dependent responsiveness of SARS-CoV-2 and enhances its lysosomal trafficking. 55 Clade G and its related strains GR and GH, are characterised by reduced S1 shedding, higher replication in nasopharynx and trachea 56 and increased infectivity 57 : it increases syncytium formation and viral transmission via enhanced furin-mediated Spike cleavage. 58 More D614 than G614 spike associates with the proteins UGGT1, calnexin, HSP7A and GRP78/BiP which ensure glycosylation and folding of proteins in the ER. In contrast to G614 spike, D614 spike is endoproteolytically cleaved and the N-terminal S1 domain is degraded in the ER even though C-terminal S2-only proteoforms remain present. D614 spike also binds more laminin than G614 spike, which suggests that extracellular laminins may function as cofactors for an alternative, S2-only dependent virus entry. 59 Interestingly, that particular mutation is not worrying for antibody-based therapeutics and vaccines since it actually increases the susceptibility to neutralisation. 60 The mutations A222V and L18F are far from the main D614G mutation and are found in the N-terminal domain of the S1 subunit, within areas defined as possible B-cell epitopes. 63 The A222V mutation (which characterises the 20A.EU1 clade 64 V367F has no effect 88 118 Modelling analysis showed that the N501Y mutation would allow a potential aromatic ring-ring interaction and an additional hydrogen bond between the RBD and ACE2. 112 Of interest N501 in SARS-CoV-2 corresponds to S487 in SARS-CoV, one of the residues whose mutations allowed the species jump from palm civet to humans. 119 It was selected in six passages in aged mice 120, 121 and increases transmissibility and virulence in a murine model. 122 (ACE2) and E484 (S)-K31 (ACE2). These two mutations may thus be more than compensating the attractive effect induced by N501Y, overall resulting in an ACE2-binding affinity comparable to that of the wild-type RBD. K417N and E484K abolish the salt bridges between Spike and selected mAbs, such as casirivimab (REGN10933), 160 BD23, H11_H4 and C105, 161 but not others, such as VH-Fc ab8. 162 The strain is fully resistant to bamlanivimab (also known as LY-CoV555), 160 K417N and N501Y mutations. Of concern, that area had a 76% seroprevalence at October 2020 after a largely unmitigated first wave, 170 but P.1 was able to cause a major second wave since January 2021. 105 The clade has been later reported in many imported cases worldwide (https://cov-lineages.org/global_report_P.1. html). E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations induces conformational change greater than N501Y mutant alone. 171 P.1specific primer sets have been recently reported. 142 Based on similarity with cluster V RBD, it was predicted to highly resistant to both etesevimab (also known as LyCoV016, CB6 or JS016) and casirivimab (REGN10933) 102 : partial resistance to casirivimab 160 13, 78 Alternatively, in silico modelling can be used. The ddG represents the difference in protein-protein affinity upon mutation: it can be measured using the Rosetta Flex ddG method, and validated using surface plasmon resonance. 180 GRID-based pharmacophore model has been used to identify mutations in both Spike (N439K, L455F, G446V, G476S, S477I, S477N, E484Q and N501Y) and ACE2 that reciprocally affect binding and are recognised in sequence repositories. 181 As a third possibility, deep mutational scanning (DMS) captures a full range of consequences from single mutations within the RBD, ranging from protein expression, to ACE2 binding, and mAb binding. 110 The method was first deployed with yeast display libraries and applied to 10 human mAbs (nine neutralising and one cross-reactive nonneutralising mAb isolated from convalescents), 95 Lastly, mapping crystallographically determined interfaces between Spike mutants and nAb which do not disrupt ACE2 binding. 183 The 'Genome to Phenotype (G2P)'-UK National Virology Consortium will study how mutations in the virus affect key outcomes such as how transmissible it is, the severity of COVID-19 it causes, and the effectiveness of vaccines and treatments (https://www.ukri. org/news/national-consortium-to-study-threats-of-new-sars-cov-2variants/). Although within host SARS-CoV-2 mutation accumulation is typically very low, 186 In vitro, such mutant showed similar infectivity to wild type strain but resistance to many CCP donors. Without anti-Spike treatment for COVID19, Spike mutations are even rarer after immunosuppressive treatment. 188 have the potential to impact on antibody neutralisation. The common cold coronavirus HCoV-229E evolves antigenic variants that are comparatively resistant to the older sera but remain sensitive to contemporaneous sera. 194 Simulation results suggest prioritising SARS-CoV-2 vaccination by antibody status while doses of the vaccine remain in short supply is largely effective, 195, 196 but on the other side it is almost always better to use vaccines targeting the faster spreading SARS-CoV-2 strain, even when the initial prevalence of this variant is much lower. 197 Given the reported reduced neutralisation by vaccineelicited antibodies against single to triple K417N + E484K + N501Y mutants, 96 it is likely that vaccines may need to be updated periodically to avoid potential loss of clinical efficacy, and in this regard mRNA vaccines are likely the easiest to be remanufactured. Only a few of the commercial mAbs have been screened for their capacity to neutralise minor strains of SARS-CoV-2. mAb cocktails should reduce the opportunities for immune escape: nevertheless, novel mutants rapidly appear after treatment individual mAb, causing loss of neutralisation. While escape occurs when combining mAbs targeting overlapping regions of Spike, this does not happen when combining noncompeting antibodies. 198 Given the preserved affinity to ACE2 from Spike variants, ACE2-Ig proteins are broadly effective against SARS-CoV-2 variants. 102 Preparing to mutations first means adjusting the usage of CCP donations 199 : it has been formally proven that only a minority of convalescent samples lose all neutralising activity in contrast to mAbs from five different epitope clusters where neutralisation was completely abrogated by a single Spike mutation. While only a minority of sera from hospitalised individuals lose more than threefold potency against any individual mutant, more than half of the mild/asymptomatic serum samples showed a threefold drop in potency against at least one Spike mutant. 78 If the main strain changes among epidemic waves, hyperimmune serum, monoclonal antibody and vaccine stockpiles become ineffective, while CCP manufacturing can immediately restart restoring product efficacy. The unavoidable delay in retargeting mAbs and vaccines, with its detrimental consequences, should stimulate continuous research in genomic epidemiology. The authors declare that there are no conflict of interests. Daniele Focosi conceived the design and wrote the first draft. 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