Mutations of SARS-CoV-2 spike protein: Implications on immune evasion and vaccine-induced immunity

Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7–2.4-fold more transmissible, and that previous (non-P.1) infection provides 54–79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

Download Full-text

Immune Evasion of SARS-CoV-2 Emerging Variants: What Have We Learnt So Far?

Viruses ◽

10.3390/v13071192 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1192

Author(s):

Ivana Lazarevic ◽

Vera Pravica ◽

Danijela Miljanovic ◽

Maja Cupic

Keyword(s):

Immune Evasion ◽

Human Population ◽

Evolutionary Rate ◽

Spike Protein ◽

Close Monitoring ◽

Global Level ◽

Therapeutic Application ◽

Neutralization Capacity ◽

Rapid Transmission ◽

Potential Impact

Despite the slow evolutionary rate of SARS-CoV-2 relative to other RNA viruses, its massive and rapid transmission during the COVID-19 pandemic has enabled it to acquire significant genetic diversity since it first entered the human population. This led to the emergence of numerous variants, some of them recently being labeled “variants of concern” (VOC), due to their potential impact on transmission, morbidity/mortality, and the evasion of neutralization by antibodies elicited by infection, vaccination, or therapeutic application. The potential to evade neutralization is the result of diversity of the target epitopes generated by the accumulation of mutations in the spike protein. While three globally recognized VOCs (Alpha or B.1.1.7, Beta or B.1.351, and Gamma or P.1) remain sensitive to neutralization albeit at reduced levels by the sera of convalescent individuals and recipients of several anti-COVID19 vaccines, the effect of spike variability is much more evident on the neutralization capacity of monoclonal antibodies. The newly recognized VOC Delta or lineage B.1.617.2, as well as locally accepted VOCs (Epsilon or B.1.427/29-US and B1.1.7 with the E484K-UK) are indicating the necessity of close monitoring of new variants on a global level. The VOCs characteristics, their mutational patterns, and the role mutations play in immune evasion are summarized in this review.

Download Full-text

ANALYSIS OF IMMUNE ESCAPE VARIANTS FROM ANTIBODY-BASED THERAPEUTICS AGAINST COVID-19.

10.1101/2021.11.11.21266207 ◽

2021 ◽

Author(s):

Daniele Focosi ◽

Fabrizio Maggi ◽

Massimo Franchini ◽

Scott McConnell ◽

Arturo Casadevall

Keyword(s):

Public Health ◽

Monoclonal Antibodies ◽

Immune Evasion ◽

Immune Escape ◽

Selective Pressure ◽

Neutralizing Antibody ◽

Spike Protein ◽

Single Amino Acid ◽

Receptor Binding Domain ◽

Amino Acid Mutations

Accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID19 convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), the few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of Spike protein (e.g, delHV69-70, delLGVY141-144 and delAL243-244). Continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and fitness of emerging variants.

Download Full-text

The Potential for SARS-CoV-2 to Evade Both Natural and Vaccine-induced Immunity

10.1101/2020.12.13.422567 ◽

2020 ◽

Cited By ~ 1

Author(s):

Emily Shang ◽

Paul Axelsen

Keyword(s):

Human Infection ◽

Antibody Binding ◽

Spike Protein ◽

Wild Type ◽

Binding Interface ◽

Naturally Occurring ◽

Binding Interfaces ◽

Induced Immunity ◽

Wild Type Form

SARS-CoV-2 attaches to the surface of susceptible cells through extensive interactions between the receptor binding domain (RBD) of its spike protein and angiotensin converting enzyme type 2 (ACE2) anchored in cell membranes. To investigate whether naturally occurring mutations in the spike protein are able to prevent antibody binding, yet while maintaining the ability to bind ACE2 and viral infectivity, mutations in the spike protein identified in cases of human infection were mapped to the crystallographically-determined interfaces between the spike protein and ACE2 (PDB entry 6M0J), antibody CC12.1 (PDB entry 6XC2), and antibody P2B-2F6 (PDB entry 7BWJ). Both antibody binding interfaces partially overlap with the ACE2 binding interface. Among 16 mutations that map to the RBD:CC12.1 interface, 11 are likely to disrupt CC12.1 binding but not ACE2 binding. Among 12 mutations that map to the RBD:P2B-2F6 interface, 8 are likely to disrupt P2B-2F6 binding but not ACE2 binding. As expected, none of the mutations observed to date appear likely to disrupt the RBD:ACE2 interface. We conclude that SARS-CoV-2 with mutated forms of the spike protein may retain the ability to bind ACE2 while evading recognition by antibodies that arise in response to the original wild-type form of the spike protein. It seems likely that immune evasion will be possible regardless of whether the spike protein was encountered in the form of infectious virus, or as the immunogen in a vaccine. Therefore, it also seems likely that reinfection with a variant strain of SARS-CoV-2 may occur among people who recover from Covid-19, and that vaccines with the ability to generate antibodies against multiple variant forms of the spike protein will be necessary to protect against variant forms of SARS-CoV-2 that are already circulating in the human population.

Download Full-text

Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229e

eLife ◽

10.7554/elife.64509 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 4

Author(s):

Kathryn E Kistler ◽

Trevor Bedford

Keyword(s):

Adaptive Evolution ◽

Immune Evasion ◽

Human Population ◽

Seasonal Influenza ◽

Respiratory Infections ◽

Antigenic Drift ◽

Spike Protein ◽

Immune Memory ◽

Receptor Binding Domain ◽

Genetic Changes

Seasonal coronaviruses (OC43, 229E, NL63, and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.

Download Full-text

Structural analysis of the Spike of the Omicron SARS-COV-2 variant by Cryo-EM and implications for immune evasion

10.1101/2021.12.27.474250 ◽

2021 ◽

Author(s):

Dongchun Ni ◽

Kelvin Lau ◽

Priscilla Turelli ◽

Charlene Raclot ◽

Bertrand Beckert ◽

...

Keyword(s):

South Africa ◽

United Kingdom ◽

Structural Analysis ◽

High Resolution ◽

Immune Evasion ◽

Spike Protein ◽

Spike Glycoprotein ◽

The United Kingdom ◽

New Variant ◽

Structural Insights

The Omicron (B.1.1.529) SARS-COV-2 was reported on November 24, 2021 and declared a variant of concern a couple of days later. With its constellation of mutations acquired by this variant on its Spike glycoprotein and the speed at which this new variant has replaced the previously dominant variant Delta in South Africa and the United Kingdom, it is crucial to have atomic structural insights to reveal the mechanism of its rapid proliferation. Here we present a high-resolution cryo-EM structure of the Spike protein of the Omicron variant.

Download Full-text

Age-Dependent Reduction in Neutralization against Alpha and Beta Variants of BNT162b2 SARS-CoV-2 Vaccine-Induced Immunity

Microbiology Spectrum ◽

10.1128/spectrum.00561-21 ◽

2021 ◽

Author(s):

Hitoshi Kawasuji ◽

Yoshitomo Morinaga ◽

Hideki Tani ◽

Yumiko Saga ◽

Makito Kaneda ◽

...

Keyword(s):

Age Groups ◽

Older Age ◽

Spike Protein ◽

Wild Type Virus ◽

Type Virus ◽

Wild Type ◽

Neutralizing Activity ◽

Age Dependent ◽

Induced Immunity

Since mRNA vaccines utilize wild-type SARS-CoV-2 spike protein as an antigen, there are potential concerns about acquiring immunity to variants of this virus. The neutralizing activity in BNT162b2-vaccinated individuals was higher against the wild-type virus than against its variants; this effect was more apparent in older age groups.

Download Full-text

Mutation-induced Changes in the Receptor-binding Interface of the SARS-CoV-2 Delta Variant B.1.617.2 and Implications for Immune Evasion

10.1101/2021.07.17.452576 ◽

2021 ◽

Author(s):

Prabin Baral ◽

Nisha Bhattarai ◽

Md Lokman Hossen ◽

Vitalii Stebliankin ◽

Bernard Gerstman ◽

...

Keyword(s):

Receptor Binding ◽

Immune Evasion ◽

Genetic Variants ◽

Neutralizing Antibodies ◽

Structural Changes ◽

Spike Protein ◽

Sharp Rise ◽

Stable Conformation ◽

Binding Interface ◽

Induced Changes

While the vaccination efforts against SARS-CoV-2 infections are ongoing worldwide, new genetic variants of the virus are emerging and spreading. Following the initial surges of the Alpha (B.1.1.7) and the Beta (B.1.351) variants, a more infectious Delta variant (B.1.617.2) is now surging, further deepening the health crises caused by the pandemic. The sharp rise in cases attributed to the Delta variant has made it especially disturbing and is a variant of concern. Fortunately, current vaccines offer protection against known variants of concern, including the Delta variant. However, the Delta variant has exhibited some ability to dodge the immune system as it is found that neutralizing antibodies from prior infections or vaccines are less receptive to binding with the Delta spike protein. Here, we investigated the structural changes caused by the mutations in the Delta variant's receptor-binding interface and explored the effects on binding with the ACE2 receptor as well as with neutralizing antibodies. We find that the receptor-binding beta-loop-beta motif adopts an altered but stable conformation causing separation in some of the antibody binding epitopes. Our study shows reduced binding of neutralizing antibodies and provides a possible mechanism for the immune evasion exhibited by the Delta variant.

Download Full-text

Cryo-EM structure of porcine delta coronavirus spike protein in the pre-fusion state

Journal of Virology ◽

10.1128/jvi.01556-17 ◽

2017 ◽

pp. JVI.01556-17 ◽

Cited By ~ 19

Author(s):

Jian Shang ◽

Yuan Zheng ◽

Yang Yang ◽

Chang Liu ◽

Qibin Geng ◽

...

Keyword(s):

Membrane Fusion ◽

Receptor Binding ◽

Immune Evasion ◽

Amino Acid Sequences ◽

Spike Protein ◽

Structural Elements ◽

Compact Structure ◽

Terminal Domain ◽

Receptor Recognition ◽

Spike Proteins

Coronavirus spike proteins from different genera are divergent, although they all mediate coronavirus entry into cells by binding to host receptors and fusing viral and cell membranes. Here we determined the cryo-EM structure of porcine delta coronavirus (PdCoV) spike protein at 3.3-angstrom resolution. The trimeric protein contains three receptor-binding S1 subunits that tightly pack into a crown-like structure and three membrane-fusion S2 subunits that form a stalk. Each S1 subunit contains two domains, N-terminal domain (S1-NTD) and C-terminal domain (S1-CTD). PdCoV S1-NTD has the same structural fold as alpha- and beta-coronavirus S1-NTDs as well as host galectins, and it recognizes sugar as its potential receptor. PdCoV S1-CTD has the same structural fold as alpha-coronavirus S1-CTDs, but its structure differs from that of beta-coronavirus S1-CTDs. PdCoV S1-CTD binds to an unidentified receptor on host cell surfaces. PdCoV S2 is locked in the pre-fusion conformation by structural restraint of S1 from a different monomeric subunit. PdCoV spike possesses several structural features that may facilitate immune evasion by the virus, such as its compact structure, concealed receptor-binding sites, and shielded critical epitopes. Overall, this study reveals that delta-coronavirus spikes are structurally and evolutionally more closely related to alpha-coronavirus spikes than to beta-coronavirus spikes; it also has implications for the receptor recognition, membrane fusion, and immune evasion by delta-coronaviruses as well as coronaviruses in general.SIGNIFICANCEIn this study we determined the cryo-EM structure of porcine delta coronavirus (PdCoV) spike protein at 3.3 angstrom. This is the first atomic structure of a spike protein from the delta coronavirus genus, which is divergent in amino acid sequences from the well-studied alpha- and beta-coronavirus spike proteins. In the current study, we described the overall structure of the PdCoV spike and the detailed structure of each of its structural elements. Moreover, we analyzed the functions of each of the structural elements. Based on the structures and functions of these structural elements, we discussed the evolution of PdCoV spike protein in relation to the spike proteins from other coronavirus genera. This study combines the structure, function, and evolution of coronavirus spike proteins, and provides many insights into the receptor recognition, membrane fusion, immune evasion, and evolution of PdCoV spike protein.

Download Full-text

Neutralization and Stability of SARS-CoV-2 Omicron Variant

10.1101/2021.12.16.472934 ◽

2021 ◽

Author(s):

Zeng Cong ◽

John P Evans ◽

Panke Qu ◽

Julia Faraone ◽

Yi-Min Zheng ◽

...

Keyword(s):

Receptor Binding ◽

Immune Evasion ◽

Receptor Binding Domain ◽

S Protein ◽

Booster Vaccine ◽

Mechanistic Insight ◽

Vaccine Booster ◽

Induced Immunity ◽

Insight Into ◽

Binding Cell

The SARS-CoV-2 B.1.1.529/Omicron variant was first characterized in South Africa and was swiftly designated a variant of concern. Of great concern is its high number of mutations, including 30-40 mutations in the virus spike (S) protein compared to 7-10 for other variants. Some of these mutations have been shown to enhance escape from vaccine-induced immunity, while others remain uncharacterized. Additionally, reports of increasing frequencies of the Omicron variant may indicate a higher rate of transmission compared to other variants. However, the transmissibility of Omicron and its degree of resistance to vaccine-induced immunity remain unclear. Here we show that Omicron exhibits significant immune evasion compared to other variants, but antibody neutralization is largely restored by mRNA vaccine booster doses. Additionally, the Omicron spike exhibits reduced receptor binding, cell-cell fusion, S1 subunit shedding, but increased cell-to-cell transmission, and homology modeling indicates a more stable closed S structure. These findings suggest dual immune evasion strategies for Omicron, due to altered epitopes and reduced exposure of the S receptor binding domain, coupled with enhanced transmissibility due to enhanced S protein stability. These results highlight the importance of booster vaccine doses for maintaining protection against the Omicron variant, and provide mechanistic insight into the altered functionality of the Omicron spike protein.

Download Full-text