Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy to protect the vulnerable, and can be established through immunity from past infection or vaccination. Whether SARS-CoV-2 infection results in the development of a reservoir of resilient memory cells is under investigation. Vaccines have been developed at an unprecedented rate and 7 408 870 760 vaccine doses have been administered worldwide. Recently emerged SARS-CoV-2 variants are more transmissible with a reduced sensitivity to immune mechanisms. This is due to the presence of amino acid substitutions in the spike protein, which confer a selective advantage. The emergence of variants therefore poses a risk for vaccine effectiveness and long-term immunity, and it is crucial therefore to determine the effectiveness of vaccines against currently circulating variants. Here we review both SARS-CoV-2-induced host immune activation and vaccine-induced immune responses, highlighting the responses of immune memory cells that are key indicators of host immunity. We further discuss how variants emerge and the currently circulating variants of concern (VOC), with particular focus on implications for vaccine effectiveness. Finally, we describe new antibody treatments and future vaccine approaches that will be important as we navigate through the COVID-19 pandemic.

SARS-CoV-2 Variants, Vaccines, and Host Immunity

The highly contagious Delta variant of SARS‐CoV‐2 has become a prevalent strain globally and poses a public health challenge around the world. While there has been extensive focus on understanding the amino acid mutations in the Delta variant’s Spike protein, the mutational landscape of the rest of the SARS‐CoV‐2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS‐CoV‐2 proteins from nearly 2 million SARS‐CoV‐2 genomes from 176 countries/territories. Six highly prevalent missense mutations in the viral life cycle‐associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, and Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant. Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of amino acid mutations in the Delta variant’s proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.15252/msb.202110673

High diversity in Delta variant across countries revealed by genome‐wide analysis of SARS‐CoV‐2 beyond the Spike protein

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compelled the scientific community to search for an effective drug that can cure or a vaccine that can prevent the disease. Alternatively, symptomatic treatment and traditional immunity boosters are prescribed. Holy Tulsi (Ocimum sanctum) has been known as an ancient remedy for cure of common cold and respiratory ailment. Several reports have come on virtual screening of phytochemicals including those of Tulsi against various enzymes of the virus. We undertook in silico analysis of the ethanol extracted phytochemicals of Tulsi as inhibitors of SARS-CoV-2 (2019-nCoV) main protease with an approach to look into the possibility of covalent ligand binding with the catalytic residue Cys145, which makes the report unique. The results suggest that the flavonoids and polyphenolic compounds of Tulsi, have potential to covalently bind to the catalytic residue Cys145 of main protease and irreversibly inhibit the viral enzyme. Luteolin-7-O-glucuronide is specially considered for its optimum properties, namely, low toxicity (LD50 5000 mg/kg body weight), high drug-likeness score (0.71), the active site binding free energy (ΔGbind) -19.19 kcal/mol by GBSA method and covalent binding energy -24.23 kcal/mol. Further experimental validations are required to establish the theoretical findings.Communicated by Ramaswamy H. Sarma.

In silico screening and covalent binding of phytochemicals of Ocimum sanctum against SARS-CoV-2 (COVID 19) main protease.

Emergence of unique SARS-CoV-2 ORF10 variants and their impact on protein structure and function

Emerging variants of concern (VOCs) drive the SARS-CoV-2 pandemic. We assessed VOC B.1.1.7, now prevalent in several countries, and VOC B.1.351, representing the greatest threat to populations with immunity to the early SARS-CoV-2 progenitors. B.1.1.7 showed a clear fitness advantage over the progenitor variant (wt-S614G) in ferrets and two mouse models, where the substitutions in the spike glycoprotein were major drivers for fitness advantage. In the “superspreader” hamster model, B.1.1.7 and wt-S614G had comparable fitness, whereas B.1.351 was outcompeted. The VOCs had similar replication kinetics as compared to wt-S614G in human airway epithelial cultures. Our study highlights the importance of using multiple models for complete fitness characterization of VOCs and demonstrates adaptation of B.1.1.7 towards increased upper respiratory tract replication and enhanced transmission in vivo. Summary sentence B.1.1.7 VOC outcompetes progenitor SARS-CoV-2 in upper respiratory tract replication competition in vivo.

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Enhanced fitness of SARS-CoV-2 variant of concern B.1.1.7, but not B.1.351, in animal models

Scientists and the public were alarmed at the first large viral variant of SARS-CoV-2 reported in December 2020. We have followed the time course of emerging viral mutants and variants during the SARS-CoV-2 pandemic in ten countries on four continents. We examined > 383,500 complete SARS-CoV-2 nucleotide sequences in GISAID (Global Initiative of Sharing All Influenza Data) with sampling dates extending until April 05, 2021. These sequences originated from ten different countries: United Kingdom, South Africa, Brazil, United States, India, Russia, France, Spain, Germany, and China. Among the 77 to 100 novel mutations, some previously reported mutations waned and some of them increased in prevalence over time. VUI2012/01 (B.1.1.7) and 501Y.V2 (B.1.351), the so-called UK and South Africa variants, respectively, and two variants from Brazil, 484K.V2, now called P.1 and P.2, increased in prevalence. Despite lockdowns, worldwide active replication in genetically and socio-economically diverse populations facilitated selection of new mutations. The data on mutant and variant SARS-CoV-2 strains provided here comprise a global resource for easy access to the myriad mutations and variants detected to date globally. Rapidly evolving new variant and mutant strains might give rise to escape variants, capable of limiting the efficacy of vaccines, therapies, and diagnostic tests.

https://www.medrxiv.org/content/medrxiv/early/2021/02/06/2021.02.04.21251111.full.pdf

SARS-CoV-2 worldwide replication drives rapid rise and selection of mutations across the viral genome: a time-course study - potential challenge for vaccines and therapies.

Scientists and the public were alarmed at the first large viral variant of SARS-CoV2 reported in December 2020. We have followed the time course of emerging viral mutants and variants during the SARS-CoV-2 pandemic in ten countries on four continents. We examined complete SARS-CoV-2 nucleotide sequences in GISAID, (Global Initiative of Sharing All Influenza Data) with sampling dates extending until January 20, 2021. These sequences originated from ten different countries: United Kingdom, South Africa, Brazil, USA, India, Russia, France, Spain, Germany, and China. Among the novel mutations, some previously reported mutations waned and some of them increased in prevalence over time. VUI2012/01 (B.1.1.7) and 501Y.V2 (B.1.351), the so-called UK and South Africa variants, respectively, and two variants from Brazil, 484K.V2, now called P.1 and P.2, increased in prevalence. Despite lockdowns, worldwide active replication in genetically and socio-economically diverse populations facilitated selection of new mutations. The data on mutant and variant SARS-CoV-2 strains provided here comprise a global resource for easy access to the myriad mutations and variants detected to date globally. Rapidly evolving new variant and mutant strains might give rise to escape variants, capable of limiting the efficacy of vaccines, therapies, and diagnostic tests. Significance and New Aspects of Study - SynopsisO_LIWe examine the time course of emerging mutations in the SARS-CoV-2 genome that have rapidly been selected in the worlds populations through the beginning of 2021. A study of the prevalence of viral mutations in the GISAID database in ten different countries - United Kingdom, South Africa, Brazil, US, India, Russia, France, Spain, Germany, and China - revealed widespread mutations along the genome. C_LIO_LIWe previously identified about 10 hotspot mutations in the SARS-CoV-2 genome that became prevalent in many of the countries studied1. Since the beginning of February, many new mutations arose in the ten countries (and worldwide). The preponderance of variants and mutations correlated with the increased spread of Covid-19. C_LIO_LIThere was a temporal progression from about 10 predominant mutants shared by several countries up to the end of May 2020, followed by a consistent and rapid increase in the number of new mutations between June and December along with the emergence of variants of concern, first reported in December 2020. C_LIO_LIWe examine the relative frequencies of mutations, along with variants of interest, in 10 countries up until January 20, 2021. Investigations on the pathogenic properties of individual SARS-CoV-2 mutations will be urgently needed to understand the kaleidoscopic patterns of worldwide Covid-19 outbreaks and symptoms. Monitoring the frequency and speed of mutant selection have direct relevance to diagnostic testing, vaccines and therapeutics. C_LIO_LIAs an explanation for efficient viral mutagenesis, we hypothesize that the viral spike protein - as documented - facilitates viral entry via the cells ACE receptor2. This in turn interacts with the APOBEC polypeptide, an m-RNA editing function. The actually observed frequent C to U (T) transitions and other base exchanges are thus effected. Hence, as one of the earliest steps upon viral entry, active mutagenesis commences, since SARS-CoV-2 exploits one of the cells defenses against viral infections. C_LI

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SARS-CoV-2 Worldwide Replication Drives Rapid Rise and Selection of Mutations across the Viral Genome: A Time-Course Study Potential Challenge for Vaccines and Therapies

Barbara Weiser

Papers

SARS-CoV-2 worldwide replication drives rapid rise and selection of mutations across the viral genome: a time-course study - potential challenge for vaccines and therapies.

SARS-CoV-2 Worldwide Replication Drives Rapid Rise and Selection of Mutations across the Viral Genome: A Time-Course Study Potential Challenge for Vaccines and Therapies