An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity

Motozono, Chihiro; Toyoda, Mako; Zahradník, Jiří; Ikeda, Terumasa; Saito, Akatsuki; Tan, Toong Seng; Ngare, Isaac; Nasser, Hesham; Kimura, Izumi; Uriu, Keiya; Kosugi, Yusuke; Torii, Shiho; Yonekawa, Akiko; Shimono, Nobuyuki; Nagasaki, Yoji; Minami, Ryoji; Toya, Takashi; Sekiya, Noritaka; Fukuhara, Takasuke; Matsuura, Yoshiharu; Schreiber, Gideon; Nakagawa, So; Ueno, Takamasa; Sato, Kei

doi:10.1101/2021.04.02.438288

Cited by 84 publications

(104 citation statements)

References 94 publications

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“…The vaccine sera data presented are consistent with emerging data from observational studies on vaccine efficacy (VE) in the UK, showing that VE is lower for the Delta versus the Alpha variant following both first and second doses of vaccine (PHE Technical Briefing 16). Although we did not map the mutations responsible, previous work with shows that L452R and T478K in the RBD are likely to have contributed 23 , as well as NTD mutations such as T19R.…”

Section: Discussionmentioning

confidence: 89%

SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

Mlčochová¹,

Kemp²,

Dhar

et al. 2021

Preprint

112

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The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and has spread throughout India, displacing the B.1.1.7 (Alpha) variant and other pre-existing lineages. Mathematical modelling indicates that the growth advantage is most likely explained by a combination of increased transmissibility and immune evasion. Indeed in vitro, the delta variant is less sensitive to neutralising antibodies in sera from recovered individuals, with higher replication efficiency as compared to the Alpha variant. In an analysis of vaccine breakthrough in over 100 healthcare workers across three centres in India, the Delta variant not only dominates vaccine-breakthrough infections with higher respiratory viral loads compared to non-delta infections (Ct value of 16.5 versus 19), but also generates greater transmission between HCW as compared to B.1.1.7 or B.1.617.1 (p=0.02). In vitro, the Delta variant shows 8 fold approximately reduced sensitivity to vaccine-elicited antibodies compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against the SARS-CoV-2 Delta variant were significantly lower in participants vaccinated with ChadOx-1 as compared to BNT162b2 (GMT 3372 versus 654, p<0001). These combined epidemiological and in vitro data indicate that the dominance of the Delta variant in India has been most likely driven by a combination of evasion of neutralising antibodies in previously infected individuals and increased virus infectivity. Whilst severe disease in fully vaccinated HCW was rare, breakthrough transmission clusters in hospitals associated with the Delta variant are concerning and indicate that infection control measures need continue in the post-vaccination era.

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Section: Discussionmentioning

confidence: 89%

SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

Mlčochová¹,

Kemp²,

Dhar

et al. 2021

Preprint

112

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“…This may explain why L452R emerged independently in the Indian B.1.617 variant (Table 1). The L452R mutation increases hAce2 affinity only slightly but results in much higher viral replication in non-human veroE6 cells [65] suggesting a role for this site in animal reservoirs like the mink [66]. This is supported by the mutation of Y453 in the Danish B.1.1.298 strain that transferred reversibly between humans and mink.…”

Section: The D614g Mutation In Spike Facilitates Sars-cov-2 Evolutionmentioning

confidence: 95%

The Spike of Concern—The Novel Variants of SARS-CoV-2

Winger

Caspari

2021

Viruses

107

116

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The high sequence identity of the first SARS-CoV-2 samples collected in December 2019 at Wuhan did not foretell the emergence of novel variants in the United Kingdom, North and South America, India, or South Africa that drive the current waves of the pandemic. The viral spike receptor possesses two surface areas of high mutagenic plasticity: the supersite in its N-terminal domain (NTD) that is recognised by all anti-NTD antibodies and its receptor binding domain (RBD) where 17 residues make contact with the human Ace2 protein (angiotensin I converting enzyme 2) and many neutralising antibodies bind. While NTD mutations appear at first glance very diverse, they converge on the structure of the supersite. The mutations within the RBD, on the other hand, hone in on only a small number of key sites (K417, L452, E484, N501) that are allosteric control points enabling spike to escape neutralising antibodies while maintaining or even gaining Ace2-binding activity. The D614G mutation is the hallmark of all variants, as it promotes viral spread by increasing the number of open spike protomers in the homo-trimeric receptor complex. This review discusses the recent spike mutations as well as their evolution.

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“…L452R was observed in the California variant and is associated with increase in viral load and around 20% increased transmissibility 9 . It was also associated with increased ACE2 binding, increased infectivity 10 and 3-6 fold loss of neutralisation sensitivity to vaccine elicited sera in experiments with pseudotyped virus (PV) particles 10,11 . Little is known about E484Q though E484K is a defining feature of two VOCs, B.1.351 12 and P.1 13 .…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 B.1.617.2 Delta variant replication, sensitivity to neutralising antibodies and vaccine breakthrough

Mlčochová¹,

Kemp²,

Dhar³

et al. 2021

Preprint

Self Cite

106

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The B.1.617 variant emerged in the Indian state of Maharashtra in late 2020 and has spread throughout India and to at least 40 countries. There have been fears that two key mutations seen in the receptor binding domain L452R and E484Q would have additive effects on evasion of neutralising antibodies. Here we delineate the phylogenetics of B.1.617 and spike mutation frequencies, in the context of others bearing L452R. The defining mutations in B.1.617.1 spike are L452R and E484Q in the RBD that interacts with ACE2 and is the target of neutralising antibodies. All B.1.617 viruses have the P681R mutation in the polybasic cleavage site region in spike. We report that B.1.617.1 spike bearing L452R, E484Q and P681R mediates entry into cells with slightly reduced efficiency compared to Wuhan-1. This spike confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies that is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. Furthermore we show that the P681R mutation significantly augments syncytium formation upon the B.1.617.1 spike protein, potentially contributing to increased pathogenesis observed in hamsters and infection growth rates observed in humans.

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An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity

Cited by 84 publications

References 94 publications

SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

The Spike of Concern—The Novel Variants of SARS-CoV-2

SARS-CoV-2 B.1.617.2 Delta variant replication, sensitivity to neutralising antibodies and vaccine breakthrough

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