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(searched for: doi:10.1101/2021.05.08.443253)
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Tessa Prince, Xiaofeng Dong, Rebekah Penrice-Randal, Nadine Randle, Catherine Hartley, Hannah Goldswain, Benjamin Jones, Malcolm G. Semple, , Peter J. M. Openshaw, et al.
Published: 2 May 2022
Abstract:
SARS-CoV-2 is the causative agent of COVID-19. The virus has spread across the planet, causing a global pandemic.
Published: 20 April 2022
by MDPI
COVID, Volume 2, pp 513-531; https://doi.org/10.3390/covid2050038

Abstract:
SARS-CoV-2 is an RNA coronavirus responsible for Acute Respiratory Syndrome (COVID-19). In January 2021, the re-occurrence of COVID-19 infection was at its peak, considered the second wave of epidemics. In the initial stage, it was considered a double mutant strain due to two significant mutations observed in their Spike protein (E484Q and L452R). Although it was first detected in India later on, it was spread to several countries worldwide, causing high fatality due to this strain. In the present study, we investigated the spreading of B.1.617 strain worldwide through 822 genome sequences submitted in GISAID on 21 April 2021. All genome sequences were analyzed for variations in genome sequences based on their effects due to changes in nucleotides. At Allele frequency 0.05, there were a total of 47 variations in ORF1ab, 22 in Spike protein gene, 6 variations in N gene, 5 in ORF8 and M gene, four mutations in Orf7a, and one nucleotide substitution observed for ORF3a, ORF6 and ORF7b gene. The clustering for similar mutations mentioned B.1.617 sub-lineages. The outcome of this study established relative occurrence and spread worldwide. The study’s finding represented that “double mutant” strain is not only spread through traveling but it is also observed to evolve naturally with different mutations observed in B.1.617 lineage. The information extracted from the study helps to understand viral evolution and genome variations of B.1.617 lineage. The results support the need of separating B.1.617 into sub-lineages.
Published: 13 April 2022
by MDPI
Viruses, Volume 14; https://doi.org/10.3390/v14040803

Abstract:
Enhanced viral transmission and escape from vaccine–elicited neutralizing antibodies drive worldwide spread of SARS-CoV-2 variants and promote disease progression. However, the impact of specific spike mutations that are carried by different viral variants on viral infectivity and neutralization sensitivity has not been completely defined. Here, we use pseudoviruses to assess the contribution of spike mutations within the Receptor Binding Domain (RBD) and the Furin Cleavage Site (FCS), and appear in circulating viral variants, on viral infectivity and neutralization potential against sera that was drawn from fully vaccinated individuals. Our functional analysis demonstrates that single, P681H, P681R or A701V–FCS mutations do not play a role in viral infectivity and neutralization potential. However, when in conjunction with the RBD–N501Y mutation, viral infectivity is enhanced. Similarly, combining the E484K–RBD mutation to the spike that carries FCS mutations reduces neutralization sensitivity with no effects on viral infectivity. Employing a similar approach onto the spike from Delta or Lota SARS-CoV-2 variants further reveals that specific RBD mutations affect neutralization sensitivity or viral infectivity differently. Our results validate the efficacy of the Pfizer third dose vaccine against Delta and Lota SARS-CoV-2 variants, and outline the significance of distinct RBD mutations in promoting viral infectivity and neutralization sensitivity to post–vaccination sera.
Published: 22 March 2022
by MDPI
Viruses, Volume 14; https://doi.org/10.3390/v14040653

Abstract:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the coronavirus disease 2019 (COVID-19). The high rate of mutation of this virus is associated with a quick emergence of new viral variants that have been rapidly spreading worldwide. Several mutations have been documented in the receptor-binding domain (RBD) of the viral spike protein that increases the interaction between SARS-CoV-2 and its cellular receptor, the angiotensin-converting enzyme 2 (ACE2). Mutations in the spike can increase the viral spread rate, disease severity, and the ability of the virus to evade either the immune protective responses, monoclonal antibody treatments, or the efficacy of current licensed vaccines. This review aimed to highlight the functional virus classification used by the World Health Organization (WHO), Phylogenetic Assignment of Named Global Outbreak (PANGO), Global Initiative on Sharing All Influenza Data (GISAID), and Nextstrain, an open-source project to harness the scientific and public health potential of pathogen genome data, the chronological emergence of viral variants of concern (VOCs) and variants of interest (VOIs), the major findings related to the rate of spread, and the mutations in the spike protein that are involved in the evasion of the host immune responses elicited by prior SARS-CoV-2 infections and by the protection induced by vaccination.
Yifan Wang, Caixuan Liu, , Yanxing Wang, Qin Hong, Shiqi Xu, Zuyang Li, Yong Yang, ,
Published: 15 February 2022
Nature Communications, Volume 13, pp 1-12; https://doi.org/10.1038/s41467-022-28528-w

Abstract:
The SARS-CoV-2 Delta variant is currently the dominant circulating strain in the world. Uncovering the structural basis of the enhanced transmission and altered immune sensitivity of Delta is particularly important. Here we present cryo-EM structures revealing two conformational states of Delta spike and S/ACE2 complex in four states. Our cryo-EM analysis suggests that RBD destabilizations lead to population shift towards the more RBD-up and S1 destabilized fusion-prone state, beneficial for engagement with ACE2 and shedding of S1. Noteworthy, we find the Delta T478K substitution plays a vital role in stabilizing and reshaping the RBM loop473-490, enhancing interaction with ACE2. Collectively, increased propensity for more RBD-up states and the affinity-enhancing T478K substitution together contribute to increased ACE2 binding, providing structural basis of rapid spread of Delta. Moreover, we identify a previously generated MAb 8D3 as a cross-variant broadly neutralizing antibody and reveal that 8D3 binding induces a large K478 side-chain orientation change, suggesting 8D3 may use an “induced-fit” mechanism to tolerate Delta T478K mutation. We also find that all five RBD-targeting MAbs tested remain effective on Delta, suggesting that Delta well preserves the neutralizing antigenic landscape in RBD. Our findings shed new lights on the pathogenicity and antibody neutralization of Delta.
James W. Saville, Dhiraj Mannar, Xing Zhu, , Alison M. Berezuk, Jean-Philippe Demers, Steven Zhou, Katharine S. Tuttle, Inna Sekirov, Andrew Kim, et al.
Published: 8 February 2022
Nature Communications, Volume 13, pp 1-10; https://doi.org/10.1038/s41467-022-28324-6

Abstract:
The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.
, Thoyaja Koritala, Saad Alhumaid, , Abeer N. Alshukairi, Mohamad-Hani Temsah, Abbas Al Mutair, Ali Rabaan, Raghavendra Tirupathi, Philippe Gautret
Published: 3 February 2022
The publisher has not yet granted permission to display this abstract.
Mostafa Salehi-Vaziri, Mehdi Fazlalipour, Seyed Mahmood Seyed Khorrami, Kayhan Azadmanesh, Mohammad Hassan Pouriayevali, Tahmineh Jalali, Zabihollah Shoja,
Published: 28 January 2022
Archives of Virology, Volume 167, pp 327-344; https://doi.org/10.1007/s00705-022-05365-2

The publisher has not yet granted permission to display this abstract.
Senem Merve Fred, Suvi Kuivanen, Hasan Ugurlu, Plinio Cabrera Casarotto, Lev Levanov, Kalle Saksela, Olli Vapalahti,
Published: 19 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.755600

Abstract:
Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our in vitro findings.
Published: 14 January 2022
by MDPI
Viruses, Volume 14; https://doi.org/10.3390/v14010144

Abstract:
The rapid emergence of SARS-CoV-2 variants is fueling the recent waves of the COVID-19 pandemic. Here, we assessed ACE2 binding and antigenicity of Mu (B.1.621) and A.2.5 Spikes. Both these variants carry some mutations shared by other emerging variants. Some of the pivotal mutations such as N501Y and E484K in the receptor-binding domain (RBD) detected in B.1.1.7 (Alpha), B.1.351 (Beta) and P.1 (Gamma) are now present within the Mu variant. Similarly, the L452R mutation of B.1.617.2 (Delta) variant is present in A.2.5. In this study, we observed that these Spike variants bound better to the ACE2 receptor in a temperature-dependent manner. Pseudoviral particles bearing the Spike of Mu were similarly neutralized by plasma from vaccinated individuals than those carrying the Beta (B.1.351) and Delta (B.1.617.2) Spikes. Altogether, our results indicate the importance of measuring critical parameters such as ACE2 interaction, plasma recognition and neutralization ability of each emerging variant.
Matthew McCallum, Alexandra C. Walls, Kaitlin R. Sprouse, John E. Bowen, Laura E. Rosen, , , Nicholas Franko, Sasha W. Tilles, , et al.
Science, Volume 374, pp 1621-1626; https://doi.org/10.1126/science.abl8506

Abstract:
How the Delta variant evades defenses: In the course of the COVID-19 epidemic, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, some of which evade immunity or increase transmission. In late 2020, the Delta and Kappa variants were detected, and the Delta variant became globally dominant by June 2021. McCallum et al . show that vaccine-elicited serum-neutralizing activity is reduced against these variants. Based on biochemistry and structural studies, the authors show that mutations in the domain that binds the ACE2 receptor abrogate binding to some monoclonal antibodies but do not improve ACE2 binding, suggesting that they emerged to escape immune recognition. Remodeling of the N-terminal domain allows the variants to escape recognition by most neutralizing antibodies that target it. The work could guide the development of next-generation vaccines and antibody therapies. —VV
Yifan Wang, Cong Xu, Yanxing Wang, Qin Hong, , Zuyang Li, Shiqi Xu, Qinyu Zuo, Caixuan Liu, , et al.
Published: 20 December 2021
Nature Communications, Volume 12, pp 1-13; https://doi.org/10.1038/s41467-021-27350-0

Abstract:
The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.
, , Gili Regev-Yochay, Yaniv Lustig, Ran D. Balicer
Published: 7 December 2021
Nature Reviews Immunology, Volume 22, pp 57-65; https://doi.org/10.1038/s41577-021-00662-4

The publisher has not yet granted permission to display this abstract.
Chuanqing Xu, Xiaotong Huang, ZongHao Zhang,
Published: 5 December 2021
Abstract:
In order to evaluate the decline in antibody levels and the impact of vaccination on the spread of the epidemic, we establish COVID-19 dynamic models that consider the decline in antibody levels and the effects of vaccination, and retrospectively evaluate the epidemic situation in England. Based on the epidemic data in England from September 1 to October 31, 2020, considering the continuous decline in the antibody level of COVID-19 recovers, an improved SEIR infectious disease dynamics model that considers the reinfection of recovers due to the decline in antibody levels is established. The kinetic parameters of the SEIR model are obtained by fitting. On this basis, a SEIRV infectious disease dynamic model with vaccination is established to study the impact of different vaccination rates and vaccine failure rates on the development of the epidemic in England. We obtain the lower the vaccine failure rate, the fewer new cases. When the vaccination rate is fixed at 0.005 (equivalent to 250000 people vaccinated every day), the peak of the epidemic will decrease with the decrease of vaccine failure rate. The peak value when the failure rate is 0.001 is 81.4% lower than the peak value when the failure rate is 0.01, and the peak value when the failure rate is 0.01 is 89.5% lower than the peak value when the failure rate is 0.02. When the failure rate is less than 0.01, the peak time will advance with the decrease of failure rate; when the failure rate is greater than 0.01, the peak time will be delayed with the decrease of failure rate; when the failure rate is 0.01, the peak time is 528 days later than that when the failure rate is 0.001 and 295 days later than that when the failure rate is 0.05. On the 60th day of vaccination, the vaccine failure rate of 0.002 decreases the number of cases by 5.8% compared with the vaccine failure rate of 0.01; on the 70th day of vaccination, the vaccine failure rate of 0.002 reduces the number of cases by 9.1% compared with the vaccine failure rate of 0.01. Therefore, with the extension of time, the vaccine with low failure rate has a more obvious effect on reducing the number of cases than the vaccine with high failure rate. When the vaccine failure rate is fixed at 0.005, we study the impact of different vaccination rates on the spread of the epidemic in England, the result shows that the peak of epidemic situation decreases with the increase of vaccination rate, and the peak time advance with the increase of vaccination rate, when the vaccination rate is 0.025, the peak decreases by 74.8% and the peak time was 114 days earlier than that when the vaccination rate is 0.005. Therefore, the higher the vaccine efficiency and vaccination rate, the lower the peak of the epidemic. On the basis of improving the effectiveness of vaccines, increasing the vaccination rate is of practical significance for controlling the spread of the epidemic.
, , Sujeet Kumar, , Chiman Kumari, Maheswari Kulandhasamy, Ravi K. Narayan, Rakesh K. Jha, , Pranav Prasoon, et al.
Published: 23 November 2021
Journal of Medical Virology, Volume 94, pp 1300-1314; https://doi.org/10.1002/jmv.27467

The publisher has not yet granted permission to display this abstract.
Published: 17 November 2021
by MDPI
Viruses, Volume 13; https://doi.org/10.3390/v13112295

Abstract:
The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these “variants of concern” has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (kappa and delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.
Published: 8 November 2021
by MDPI
Viruses, Volume 13; https://doi.org/10.3390/v13112238

Abstract:
The COVID-19 pandemic is a global challenge that impacted 200+ countries. India ranks in the second and third positions in terms of number of reported cases and deaths. Being a populous country with densely packed cities, SARS-CoV-2 spread exponentially. India sequenced ≈0.14% isolates from confirmed cases for pandemic surveillance and contributed ≈1.58% of complete genomes sequenced globally. This study was designed to map the circulating lineage diversity and to understand the evolution of SARS-CoV-2 in India using comparative genomics and population genetics approaches. Despite varied sequencing coverage across Indian States and Union Territories, isolates belonging to variants of concern (VoC) and variants of interest (VoI) circulated, persisted, and diversified during the first seventeen months of the pandemic. Delta and Kappa lineages emerged in India and spread globally. The phylogenetic tree shows lineage-wise monophyletic clusters of VoCs/VoIs and diversified tree topologies for non-VoC/VoI lineages designated as ‘Others’ in this study. Evolutionary dynamics analyses substantiate a lack of spatio-temporal clustering, which is indicative of multiple global and local introductions. Sites under positive selection and significant variations in spike protein corroborate with the constellation of mutations to be monitored for VoC/VoI as well as substitutions that are characteristic of functions with implications in virus–host interactions, differential glycosylation, immune evasion, and escape from neutralization.
Paroma Deb, Maruf Ahmed Molla, , Manik Chandra Das, Debashish Das
The Egyptian Journal of Bronchology, Volume 15, pp 1-14; https://doi.org/10.1186/s43168-021-00090-x

Abstract:
Background: After the first detection in November 2019, SARS-CoV-2 has spread rapidly over the continents and started the pandemic of the millennium. In addition to several novels and repurposed monoclonal antibodies (mAbs) as a therapeutic option against COVID-19, scientists from across the world have developed several candidate vaccines, developed mainly targeting the Wuhan strain, with very promising results to combat this pandemic. Unfortunately like any RNA viruses, SARS CoV-2 has also gone through the accumulation of hundreds and thousands of mutations in their genome lead to the development of several variants of concerns (VOC) and variants of interests (VOI), resulting in increased transmissibility and virulence of the virus, along with their capacity to escape cross-protection. Seemingly, the main hindrance of containing this pandemic right now is the effectiveness of currently available vaccines and mAbs against newly emerging variants. Therefore, it is important to monitor variants epidemiology, transmission dynamics, clinical characteristics, as well as their immune evasion capacity to implement appropriate vaccine strategy and other containment measures. Body: In this review, we tried to focus on variants characteristics and to what extent they can escape immunity, provided by both available vaccinated sera and convalescent sera. A stringent literature review was performed using various databases, mentioned in the methodology portion. The current geographical distribution of these variants of SARS CoV-2 has been presented using a heat map. Findings from published articles comparing these variants, in terms of genome epidemiology, transmissibility, viral load dynamics, and association with different waves have been described briefly. Due strength was given while describing variants neutralization potency against current vaccines, mAbs, and also against convalescent sera. Data from both clinical trials and in vitro/ex-vivo studies have been discussed here. Comparative findings from several articles were brought into one concise paper. After careful reviewing of all the available data, it was clear that, without hesitation, we should strengthen our vaccination strategy, because the severity of COVID 19 is reasonably lower, irrespective of variants and vaccine used. Conclusion: We hope that many falsified myths and beliefs regarding vaccine immunity and emerging variants will be clarified in light of this available evidence, which we summarized in our paper.
Deepali Gupta, Priyanka Sharma, Mandeep Singh, Mukesh Kumar, A. S. Ethayathulla,
Cellular and Molecular Life Sciences, Volume 78, pp 7967-7989; https://doi.org/10.1007/s00018-021-04008-0

The publisher has not yet granted permission to display this abstract.
Zohreh Fattahi, Marzieh Mohseni, Maryam Beheshtian, Ali Jafarpour, Khadijeh Jalalvand, Fatemeh Keshavarzi, Hanieh Behravan, Fatemeh Ghodratpour, Farzane Zare Ashrafi, Marzieh Kalhor, et al.
Published: 25 October 2021
Abstract:
SARS-CoV-2 genome surveillance projects provide a good measure of transmission and monitor the circulating SARS-CoV-2 variants at regional and global scales. Iran is one of the most affected countries still involved with the virus circulating in at least five significant disease waves, as of September 2021. Complete genome sequencing of 50 viral isolates in an early phase of outbreak in Iran, shed light on the origins and circulating lineages at that time. As part of a genomic surveillance program, we provided an additional 319 complete genomes from October 2020 onwards. The current study is the report of complete SARS-CoV-2 genome sequences of Iran in the March 2020-May 2021 time interval. We aimed to characterize the genetic diversity of SARS-CoV-2 in Iran over one year. Overall, 35 different lineages and 8 clades were detected. Temporal dynamics of the prominent SARS-CoV-2 clades/lineages circulating in Iran is comparable to the global perspective and introduces the 19A clade (B.4) dominating the first disease wave, followed by 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7) clades, dominating second, third and fourth disease waves, respectively. We observed a mixture of circulating 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7) clades in winter 2021, paralleled in a diminishing manner for 20A/20B and a growing rise for 20I, eventually prompting the 4th outbreak peak. Furthermore, our study provides evidence on the entry of the Delta variant in April 2021, leading to the 5th disease wave in summer 2021. Three lineages are highlighted as hallmarks of SARS-CoV-2 outbreak in Iran; B4, dominating early periods of the epidemic, B.1.1.413 (specific B.1.1 lineage carrying a combination of [D138Y-S477N-D614G] spike mutations) in October 2020-February 2021, and the co-occurrence of [I100T-L699I] spike mutations in half of B.1.1.7 sequences mediating the fourth peak. Continuous monthly monitoring of SARS-CoV-2 genome mutations led to the detection of 1577 distinct nucleotide mutations, in which the top recurrent mutations were D614G, P323L, R203K/G204R, 3037C>T, and 241C>T; the renowned combination of mutations in G and GH clades. The most frequent spike mutation is D614G followed by 13 other frequent mutations based on the prominent circulating lineages; B.1.1.7 (H69_V70del, Y144del, N501Y, A570D, P681H, T716I, S982A, D1118H, I100T, and L699I), B.1.1.413 (D138Y, S477N) and B.1.36 (I210del). In brief, mutation surveillance in this study provided a real-time comprehensive picture of the SARS-CoV-2 mutation profile in Iran, which is beneficial for evaluating the magnitude of the epidemic and assessment of vaccine and therapeutic efficiency in this population.
, Geetanjali Lal, Sonu Kumar, Chandan J. Das, Anoop Saraya, Shalimar
Frontiers in Cellular and Infection Microbiology, Volume 11; https://doi.org/10.3389/fcimb.2021.753249

Abstract:
Novel coronavirus SARS-CoV2 is evolving continuously with emergence of several variants of increasing transmission capabilities and pandemic potential. Generation of variants occurs through accumulation of mutations due to the RNA nature of viral genome, which is further enhanced by variable selection pressures of this ongoing pandemic. COVID-19 presentations of SARS-CoV2 are mainly pulmonary manifestations with or without mild gastrointestinal (GI) and hepatic symptoms. However, the virus has evolved beyond pulmonary manifestations to multisystem disorder due to systemic inflammation and cytokine storm. Definitive cause of acute or late onset of inflammation, infection in various organs, and host response to emerging variants lacks clarity and needs elucidation. Several studies have reported underlying diseases including diabetes, hypertension, obesity, cardio- and cerebrovascular disorders, and immunocompromised conditions as significant risk factors for severe form of COVID-19. Pre-existing liver and GI diseases are also highly predominant in the population, which can alter COVID-19 outcome due to altered immune status and host response. We aim to review the emerging variants of SARS-CoV2 and host response in patients with pre-existing liver and GI diseases. In this review, we have elucidated the emergence and characteristic features of new SARS-CoV2 variants, mechanisms of infection and host immune response, GI and hepatic manifestation with radiologic features of COVID-19, and outcomes in pre-existing liver and GI diseases. Emerging variants of concern (VOC) have shown increased transmissibility and virulence with severe COVID-19 presentation and mortality. There is a drastic swift of variants from the first wave to the next wave of infections with predominated major VOC including alpha (B.1.1.7, UK), beta (B.1.351, South Africa), gamma (B.1.1.28.1, Brazil), and delta (B1.1.617, India) variants. The mutations in the spike protein of VOC are implicated for increased receptor binding (N501Y, P681R) and immune escape (L452R, E484K/Q, T478K/R) to host response. Pre-existing liver and GI diseases not only have altered tissue expression and distribution of viral entry ACE2 receptor but also host protease TMPRSS2, which is required for both spike protein binding and cleavage to initiate infection. Altered immune status due to pre-existing conditions results in delayed virus clearance or prolonged viremia. Even though GI and hepatic manifestations of SARS-CoV2 are less severe, the detection of virus in patient’s stool indicates GI tropism, replication, and shedding from the GI tract. COVID-19-induced liver injury, acute hepatic decompensation, and incidences of acute-on-chronic liver failure may change the disease outcomes. The changes in the spike protein of emerging variants, immunomodulation by viral proteins, and altered expression of host viral entry receptor in pre-existing diseases are the key determinants of host response to SARS-CoV2 and its disease outcome.
Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, Meng Yuan, Mary Peterson, Janie Liang, , , Yu Cong, Elena Postnikova, et al.
Science Translational Medicine, Volume 13; https://doi.org/10.1126/scitranslmed.abj5413

Abstract:
Bispecific antibodies targeting multiple regions of the SARS-CoV-2 spike protein comparably neutralize variants of concern and wild-type virus.
Harald S. Vöhringer, Theo Sanderson, Matthew Sinnott, Nicola De Maio, Thuy Nguyen, , Frank Schwach, Ian Harrison, , Cristina V. Ariani, et al.
Published: 14 October 2021
Nature, Volume 600, pp 506-511; https://doi.org/10.1038/s41586-021-04069-y

Abstract:
The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.
Chen Bai, Junlin Wang, Geng Chen, Honghui Zhang, , Peiyi Xu, Yang Du, , , Aoxuan Zhang, et al.
Journal of the American Chemical Society, Volume 143, pp 17646-17654; https://doi.org/10.1021/jacs.1c07965

The publisher has not yet granted permission to display this abstract.
, Satinder Kaur, Karashdeep Kaur, Ramanpreet Kaur, Jaspreet Kaur Boparai, Ritika Ghai, Tanveer Kaur, AmritPal Kaur, Jaspreet Kaur, Kajal Verma, et al.
Journal of Pure and Applied Microbiology, Volume 15, pp 1864-1872; https://doi.org/10.22207/jpam.15.4.07

Abstract:
SARS-CoV-2 variants rapid emergence has posed critical challenge of higher transmission and immune escape causing serious threats to control the pandemic. The present study was carried out in confirmed cases of SARS-CoV-2 patients to elucidate the prevalence of SARS-CoV-2 variant strain. We performed RT-PCR using extracted RNA from the nasopharyngeal swabs of suspected Covid-19 patients. Confirmed positive cases with CT<25 were subjected to whole-genome sequencing to track the prevalence of the virus in the Malwa region of Punjab. The presence of B.1, B.1.1.7, B.1.351, B.1.617.1, B.1.617.2, AY.1 and other unidentified variants of SARS-CoV-2 was found in the studied population. Among all the variants, B.1.1.7 (UK variant) and B.1.617.2 (delta-Indian variant) was found to be the most dominant variant in the population and was found majorly in Patiala followed by Ludhiana, SBS Nagar, Mansa and Sangrur. In addition to this, sequencing results also observed that the dominant trait was more prevalent in male population and age group 21-40 years. The B.1.1.7 and B.1.617.2 variant of SARS-CoV-2 is replacing the wild type (Wuhan Strain) and emerging as the dominant variant in Punjab.
Tarun Mishra, Garima Joshi, Atul Kumar, Rishikesh Dalavi, Pankaj Pandey, Sanjeev Shukla, Ram Kumar Mishra,
Published: 5 October 2021
Abstract:
SARS CoV-2 variants raise significant concerns due to their ability to cause vaccine breakthrough infections. Here, we sequence-characterized the spike gene, isolated from a breakthrough infection, that corresponded to B.1.617.3 lineage. Delineating the functional impact of spike mutations using reporter pseudoviruses (PV) revealed that N-terminal domain (NTD)-specific E156G/Δ157-158 contributed to increased infectivity and reduced sensitivity to ChAdOx1 nCoV-19 vaccine (Covishield™)-elicited neutralizing antibodies. A six-nucleotide deletion (467-472) in the spike coding region introduced this change in the NTD. We confirmed the presence of E156G/Δ157-158 in the RT-PCR-positive cases concurrently screened, in addition to other circulating spike (S1) mutations like T19R, T95I, L452R, E484Q, and D614G. Notably, E156G/Δ157-158 was present in more than 85% of the sequences reported from the USA, UK, and India in August 2021. The spike PV bearing combination of E156G/Δ157-158 and L452R further promoted infectivity and conferred immune evasion. Additionally, increased cell-to-cell fusion was observed when spike harbored E156G/Δ157-158, L452R, and E484Q, suggesting a combinatorial effect of these mutations. Notwithstanding, the plasma from a recovered individual robustly inhibited mutant spike PV, indicating the increased breadth of neutralization post-recovery. Our data highlights the importance of spike NTD-specific changes in determining infectivity and immune escape of variants.
, , Behnam Subin, Silke Müller, Martina Sombetzki, Emil C. Reisinger,
Published: 21 September 2021
Abstract:
While vaccination programs against SARS-CoV-2 are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness. In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell and antibody dynamics. AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein specific effector T cells which were dominated by Th1 responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA. Our results suggest that the strategy for spike antigen delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.
, Ankit Tripathi, Naveen Kumar, Nirmal Kumar Ganguly
Frontiers in Cellular and Infection Microbiology, Volume 11; https://doi.org/10.3389/fcimb.2021.744903

Abstract:
The outbreak of COVID-19 has proven to be an unprecedented disaster for the whole world. The virus has inflicted billion of lives across the globe in all aspects—physically, psychologically, as well as socially. Compared to the previous strains of β-CoV genera- MERS and SARS, SARS-CoV-2 has significantly higher transmissibility and worst post-recovery implications. A frequent mutation in the initial SARS-CoV-2 strain has been a major cause of mortalities (approx. 3 million deaths) and uncontrolled virulence (approx. 1 billion positive cases). As far as clinical manifestations are concerned, this particular virus has exhibited deleterious impacts on systems other than the respiratory system (primary target organ), such as the brain, hematological system, liver, kidneys, endocrine system, etc. with no promising curatives to date. Lack of emergency treatments and shortage of life-saving drugs has promoted the repurposing of existing therapeutics along with the emergence of vaccines with the combined efforts of scientists and industrial experts in this short span. This review summarizes every detail on COVID-19 and emphasizes undermining the future approaches to minimize its prevalence to the remaining lives.
Tzu-Jing Yang, Pei-Yu Yu, Yuan-Chih Chang, Ning-En Chang, Yu-Xi Tsai, Kang-Hao Liang, Piotr Draczkowski, Bertina Lin, Yong-Sheng Wang, Yu-Chun Chien, et al.
Published: 13 September 2021
Abstract:
The surge of COVID-19 infection cases is spurred by emerging SARS-CoV-2 variants such as B.1.617. Here we report 38 cryo-EM structures, corresponding to the spike protein of the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Kappa (B.1.617.1) variants in different functional states with and without its receptor, ACE2. Mutations on the N-terminal domain not only alter the conformation of the highly antigenic supersite of the Delta variant, but also remodel the glycan shield by deleting or adding N-glycans of the Delta and Gamma variants, respectively. Substantially enhanced ACE2 binding was observed for all variants, whose mutations on the receptor binding domain modulate the electrostatics of the binding interfaces. Despite their abilities to escape host immunity, all variants can be potently neutralized by three unique antibodies.
Published: 5 September 2021
by MDPI
Viruses, Volume 13; https://doi.org/10.3390/v13091773

Abstract:
B.1.617 is becoming a dominant Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) lineage worldwide with many sublineages, of which B.1.617.2 is designated as a variant of concern. The pathogenicity of B.1.617.2 (Delta) and B.1.617.3 lineage of SARS-CoV-2 was evaluated and compared with that of B.1, an early virus isolate with D614G mutation in a Syrian hamster model. Viral load, antibody response, and lung disease were studied. There was no significant difference in the virus shedding pattern among these variants. High levels of SARS-CoV-2 sub genomic RNA were detected in the respiratory tract of hamsters infected with the Delta variant for 14 days, which warrants further transmission studies. The Delta variant induced lung disease of moderate severity in about 40% of infected animals, which supports the attributed disease severity of the variant. Cross neutralizing antibodies were detected in animals infected with B.1, Delta, and B.1.617.3 variant, but neutralizing capacity was significantly lower with B.1.351 (Beta variant).
Published: 31 August 2021
by MDPI
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests a broad spectrum of clinical presentations, varying in severity from asymptomatic to mortality. As the viral infection spread, it evolved and developed into many variants of concern. Understanding the impact of mutations in the SARS-CoV-2 genome on the clinical phenotype and associated co-morbidities is important for treatment and preventionas the pandemic progresses. Based on the mild, moderate, and severe clinical phenotypes, we analyzed the possible association between both, the clinical sub-phenotypes and genomic mutations with respect to the severity and outcome of the patients. We found a significant association between the requirement of respiratory support and co-morbidities. We also identified six SARS-CoV-2 genome mutations that were significantly correlated with severity and mortality in our cohort. We examined structural alterations at the RNA and protein levels as a result of three of these mutations: A26194T, T28854T, and C25611A, present in the Orf3a and N protein. The RNA secondary structure change due to the above mutations can be one of the modulators of the disease outcome. Our findings highlight the importance of integrative analysis in which clinical and genetic components of the disease are co-analyzed. In combination with genomic surveillance, the clinical outcome-associated mutations could help identify individuals for priority medical support.
Sandrine M. Soh, Yeongjun Kim, Chanwoo Kim, Ui Soon Jang,
Published: 27 August 2021
Journal of Microbiology, Volume 59, pp 807-818; https://doi.org/10.1007/s12275-021-1348-5

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International Journal of Molecular Sciences, Volume 22; https://doi.org/10.3390/ijms22179131

Abstract:
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.
Matthew McCallum, Alexandra C. Walls, Kaitlin R. Sprouse, John E. Bowen, Laura Rosen, Ha V. Dang, Anna Demarco, Nicholas Franko, Sasha W Tilles, Jennifer Logue, et al.
Published: 11 August 2021
Abstract:
Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.
, Hua Wu, Kristi A Egland, Eddie J Sullivan, Christoph L Bausch
Published: 9 August 2021
Abstract:
SAB-185 is a fully human polyclonal anti-SARS-CoV-2 immunoglobulin produced from the plasma of transchromosomic bovines that are hyperimmunized with recombinant SARS-CoV-2 Wuhan-Hu-1 Spike protein. SAB-185 is being evaluated for efficacy in aphase 3 clinical trial. The World Health Organization (WHO) has identified multiple Variants-of-Concern and Variants-of-Interest (VOC/VOI) that have mutations in their Spike protein that appear to increase transmissibility and/or reduce the effectiveness of therapeutics and vaccines, among other parameters of concern. SAB-185 was evaluated using lentiviral-based pseudovirus assays performed in a BSL2 environment that incorporates stable or transient cell lines that express human angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). The results indicate that SAB-185 retained neutralization potency against multiple SARS-CoV-2 pseudovirus variants, including the Delta, Kappa, Lambda and Omicron variants, that have or are supplanting other VOC/VOI in many countries and regions around the world.
, , Juliana Cuervo-Rojas, Hernando Díaz, Manuel González-Mayorga,
Published: 7 August 2021
Abstract:
Background In Bogotá by August 1st, more than 27,000 COVID-19 deaths have been reported, while complete and partial vaccination coverage reached 30% and 37%, respectively. Although reported cases are decreasing, the potential impact of new variants is uncertain. Methods We used an agent-based model of COVID-19 calibrated to local data. Variants and vaccination strategies were included. We estimated the impact of vaccination and modelled scenarios of early and delayed introduction of the delta variant, along with changes in mobility, social contact, and vaccine uptake over the next months. Findings By mid-July, vaccination may have prevented 17,800 (95% CrI: 16,000 - 19,000) deaths in Bogotá. We found that delta could lead to a fourth wave of magnitude and timing dependent on social mixing, vaccination strategy, and delta dominance. In scenarios of early dominance of delta by mid-July, age prioritization and maintaining the interval between doses were important factors to avert deaths. However, if delta dominance occurred after mid-September, age prioritization would be less relevant, and the magnitude of a four wave would be smaller. In all scenarios, higher social mixing increased the magnitude of the fourth wave. Increasing vaccination rates from 50,000/day to 100,000/day reduced the impact of a fourth wave due to delta. Interpretation The magnitude and timing of a potential fourth wave in Bogotá caused by delta would depend on social mixing and the timing of dominance. Rapidly increasing vaccination coverage with non-delayed second doses could reduce the burden of a new wave. Funding NSF RAPID DEB 2027718. HERMES 50419. Medical Research Council. MR/R024855/1 Research in Context Evidence before this study The impact of vaccination strategies in the context of emerging SARS-CoV-2 variants and increasing social mixing in Colombia had not been previously evaluated through mathematical modelling. We searched PubMed for modelling studies using the terms “COVID-19 vaccine AND model AND variant AND Colombia” or “SARS-CoV-2 AND vaccine AND model AND variant AND Colombia” (From 2021/1/1 to 2021/07/31). We did not find studies addressing this question. However, we found a model describing the evolution of the epidemic in the country during the first year, and research on the emergence of alpha, gamma, and B.1.621 variants in Colombia. We extended a previous version of our SARS-CoV-2 agent-based model for Bogotá to include the potential effect of vaccination and variants. This model simulates transmission of SARS-CoV-2 based on daily activity patterns of a synthetic population, representing demographic and geographic characteristics of the total population of the city. Added value of this study First, our study provides a preliminary estimate of the impact of the vaccination program in Bogotá in terms of the number of deaths prevented. The second major finding is the indication that due to the introduction of the delta variant in the city, and based on the current knowledge of its biology, there is a risk of a fourth epidemic wave, whose time of occurrence and magnitude would depend mainly on three factors: when delta becomes dominant, the intensity of social contact, and vaccination roll-out strategy and coverage. Implications of all the available evidence We estimate that by mid-July, vaccination may have already prevented 17,800 (95% CrI: 16,000 - 19,000) deaths in Bogotá. The delta variant could become dominant and lead to a fourth wave later in the year, but its timing will depend on the date of introduction, social mixing patterns, and vaccination strategy. In all scenarios, higher social mixing is associated with a fourth wave of considerable magnitude. If an early delta introduction occurred (dominance by mid-July), a new wave may occur in August/September and in such case, age prioritization of vaccination and maintaining the 21-day interval between doses of the Pfizer-BioNTech BNT162b2 are more important. However, if introduction occurred one or two months later (with dominance by mid-August/September) a fourth wave would be of smaller magnitude, the age-prioritization is less relevant, but maintaining the dose scheme without postponement is more important. In all scenarios we found that increasing the vaccination rate from the current average of 50,000/day to 100,000/day reduces the impact of a potential fourth wave due to the delta variant. Our study indicates that given the possibility of a fourth wave in the city, it is necessary to continue maintaining adherence to non-pharmacological interventions, such as the use of face masks and physical distancing, to be cautious with the intensification of social activities, and that it is essential to increase the current pace of vaccinations to rapidly reach high vaccination coverage in the population of the city.
, Lavanya Khullar,
Published: 28 July 2021
Environmental Microbiology; https://doi.org/10.1111/1462-2920.15687

Abstract:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging respiratory virus responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic. More than a year into this pandemic, the COVID-19 fatigue is still escalating and takes hold of the entire world population. Driven by the ongoing geographical expansion and upcoming mutations, the COVID-19 pandemic has taken a new shape in the form of emerging SARS-CoV-2 variants. These mutations in the viral spike (S) protein enhance the virulence of SARS-CoV-2 variants by improving viral infectivity, transmissibility, and immune evasion abilities. Such variants have resulted in cluster outbreaks and fresh infection waves in various parts of the world with increased disease severity and poor clinical outcomes. Hence, the variants of SARS-CoV-2 pose a threat to human health and public safety. This review enlists the most recent updates regarding the presently characterized variants of SARS-CoV-2 recognized by the global regulatory health authorities (WHO, CDC). Based on the slender literature on SARS-CoV-2 variants, we collate information on the biological implications of these mutations on virus pathology. We also shed light on the efficacy of therapeutics and COVID-19 vaccines against the emerging SARS-CoV-2 variants.
Randall J. Olsen, Paul A. Christensen, , Sishir Subedi, Parsa Hodjat, Robert Olson, Marcus Nguyen, James J. Davis, Prasanti Yerramilli, , et al.
The American Journal of Pathology, Volume 191, pp 1754-1773; https://doi.org/10.1016/j.ajpath.2021.07.002

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Jérémie Prévost, Jonathan Richard, Romain Gasser, Shilei Ding, Clément Fage, Sai Priya Anand, Damien Adam, Natasha Gupta Vergara, Alexandra Tauzin, Mehdi Benlarbi, et al.
Published: 9 July 2021
Abstract:
The seasonal nature in the outbreaks of respiratory viral infections with increased transmission during low temperatures has been well established. The current COVID-19 pandemic makes no exception, and temperature has been suggested to play a role on the viability and transmissibility of SARS-CoV-2. The receptor binding domain (RBD) of the Spike glycoprotein binds to the angiotensin-converting enzyme 2 (ACE2) to initiate viral fusion. Studying the effect of temperature on the receptor-Spike interaction, we observed a significant and stepwise increase in RBD-ACE2 affinity at low temperatures, resulting in slower dissociation kinetics. This translated into enhanced interaction of the full Spike to ACE2 receptor and higher viral attachment at low temperatures. Interestingly, the RBD N501Y mutation, present in emerging variants of concern (VOCs) that are fueling the pandemic worldwide, bypassed this requirement. This data suggests that the acquisition of N501Y reflects an adaptation to warmer climates, a hypothesis that remains to be tested.
Quentin Moyon, Delphine Sterlin, Makoto Miyara, François Anna, Alexis Mathian, Raphael Lhote, Pascale Ghillani-Dalbin, Paul Breillat, Sasi Mudumba, Sophia de Alba, et al.
Published: 8 July 2021
Abstract:
Objectives Our aims were to evaluate Systemic Lupus Erythematosus (SLE) disease activity and SARS-CoV-2 specific immune responses after BNT162b2 vaccination. Methods In this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine, until day 15 after the second dose in 126 SLE patients. SARS-CoV-2 antibody responses were measured against wild-type spike antigen while serum-neutralizing activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T-cell responses were quantified by Interferon (IFN)-γ release assay after the second dose. Results BNT162b2 was well tolerated and no statistically significant variations of BILAG and SLEDAI scores were observed throughout the study in SLE patients with active and inactive disease at baseline. Mycophenolate Mofetil (MMF) and Methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody-response (β=-78; p=0.007, β=-122; p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total IgG serum levels, naïve B cell frequencies (β=2; p=0.018, β=2.5; p=0.003) and SARS-CoV-2-specific T cell response (r=0.462; p=0.003). In responders, serum neutralization activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients. Conclusion MMF, MTX and poor baseline humoral immune status, particularly: low naïve B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating SLE patients who might need adapted vaccine regimens and follow-up. KEY MESSAGES What is already known about this subject? BNT162b2 efficacy and safety has been described in studies mixing different RMDs What does this study add? No serious adverse effects, nor SLE flares have been documented after BNT162b2 in SLE patients. Not only MMF and MTX, but also a poor humoral immune status at baseline impair vaccine antibody response Albeit decreased, serum neutralizing activity against VOCs is conferred to vaccine-responders. How might this impact on clinical practice or future developments? These parameters could be helpful for physicians to delineate which patients should have antibody measurement after full BNT162b2 vaccination and should be proposed a third injection of BNT162b2 vaccine.
Delphine Planas, David Veyer, , Isabelle Staropoli, Florence Guivel-Benhassine, , Cyril Planchais, Françoise Porrot, Nicolas Robillard, Julien Puech, et al.
Published: 8 July 2021
Nature, Volume 596, pp 276-280; https://doi.org/10.1038/s41586-021-03777-9

The publisher has not yet granted permission to display this abstract.
Published: 23 June 2021
by MDPI
Viruses, Volume 13; https://doi.org/10.3390/v13071211

Abstract:
We summarize here in vitro evidences of efficacy for convalescent plasma, currently approved vaccines and monoclonal antibodies against SARS-CoV-2 variants of concern (VOC: B.1.1.7, B.1.351, P.1, and B.1.617.2), variants of interest (VOI: B.1.427/B.1.429, P.2, B.1.525, P.3, B.1.526, and B.1.671.1), and other strains (B.1.1.298 and B.1.258delta). While waiting from real world clinical efficacy, these data provide guidance for the treating physician.
Published: 22 June 2021
by MDPI
Viruses, Volume 13; https://doi.org/10.3390/v13071192

Abstract:
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.
Félix Rey
Comptes Rendus. Biologies, Volume 344, pp 77-110; https://doi.org/10.5802/crbiol.53

Abstract:
This review covers the main features of the severe acquired respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, its interaction with the main entry receptor, the human angiotensin converting enzyme 2 (ACE2), and the subsequent membrane fusion step. The focus is on the structural organization of these proteins and mechanistic aspects of their interactions that lead to cytoplasmic release of the viral genome. The most potently neutralizing antibodies against SARS-CoV-2 were shown to interfere with the spike/ACE2 interaction. I thus also review the location and the potential impact of mutations in the spike protein observed in the variants of concern that emerged concomitantly with acquired immunity in the population after one year of virus circulation. Understanding how these interactions affect the spike/ACE2 interactions and the subsequent spike-protein-induced membrane fusion reaction is important to stay one step ahead of the virus evolution and develop efficient countermeasures.
, , Prakhar Dwivedi, Gopichand Kumar, Ravi K. Narayan, Rakesh K. Jha, Rakesh Parashar, Chetan Sahni, Sada N. Pandey
Published: 12 June 2021
Abstract:
India recently witnessed a devastating second wave of COVID-19, which peaked by the end of the first week of May 2021. We aimed to understand formation and spread of the second wave in the country. We analyzed time series distribution of the genomic sequence data for SARS-CoV-2 and correlated that with the epidemiological data for new cases and deaths, for the corresponding period of the second wave. Further we analyzed the phylodynamics of the circulating SARS-CoV-2 variants in the Indian population in the period of study. Our analysis shows that the first indications of arrival of the second wave were observable by the end of January 2021, and by the end of March, 2021 it was clearly indicated. B.1.617 lineage variants drove the wave, particularly B.1.617.2 (a.k.a. delta variant). Based on the observations of this study, we propose that genomic surveillance of the SARS-CoV-2 variants augmented with epidemiological data can be a promising tool for forecasting imminent COVID-19 waves.
, David Veyer, Artem Baidaliuk, Isabelle Staropoli, Florence Guivel-Benhassine, Maaran Michael Rajah, Cyril Planchais, Françoise Porrot, Nicolas Robillard, Julien Puech, et al.
Published: 27 May 2021
Abstract:
The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India1–6. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1.617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1.617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1.617.2, relative to B.1.1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1.617.2. Thus, B.1.617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.
, Ritubrita Saha, Pratik Mallick, Ranjana Sharma, Amandeep Kaur, Shanta Dutta,
Published: 26 May 2021
Abstract:
India is currently facing the devastating second wave of COVID-19 pandemic resulting in approximately 4000 deaths per day. To control this pandemic continuous mutational surveillance and genomic epidemiology of circulating strains is very important. In this study, we performed mutational analysis of the protein coding genes of SARS-CoV-2 strains (n=2000) collected during January 2021 to March 2021. Our data revealed the emergence of a new variant in West Bengal, India, which is characterized by the presence of 11 co-existing mutations including D614G, P681H and V1230L in S-glycoprotein. This new variant was identified in 70 out of 412 sequences submitted from West Bengal. Interestingly, among these 70 sequences, 16 sequences also harbored E484K in the S glycoprotein. Phylogenetic analysis revealed strains of this new variant emerged from GR clade (B.1.1) and formed a new cluster. We propose to name this variant as GRL or lineage B.1.1/S:V1230L due to the presence of V1230L in S glycoprotein along with GR clade specific mutations. Co-occurrence of P681H, previously observed in UK variant, and E484K, previously observed in South African variant and California variant, demonstrates the convergent evolution of SARS-CoV-2 mutation. V1230L, present within the transmembrane domain of S2 subunit of S glycoprotein, has not yet been reported from any country. Substitution of valine with more hydrophobic amino acid leucine at position 1230 of the transmembrane domain, having role in S protein binding to the viral envelope, could strengthen the interaction of S protein with the viral envelope and also increase the deposition of S protein to the viral envelope, and thus positively regulate virus infection. P618H and E484K mutation have already been demonstrated in favor of increased infectivity and immune invasion respectively. Therefore, the new variant having G614G, P618H, P1230L and E484K is expected to have better infectivity, transmissibility and immune invasion characteristics, which may pose additional threat along with B.1.617 in the ongoing COVID-19 pandemic in India.
, , Matthew Sinnott, , Thuy Nguyen, Richard Goater, , Ian Harrison, , Cristina Ariani, et al.
Published: 26 May 2021
Abstract:
The evolution of the SARS-CoV-2 pandemic continuously produces new variants, which warrant timely epidemiological characterisation. Here we use the dense genomic surveillance generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of sub-epidemics that peaked in the early autumn of 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. Alpha grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed Alpha and eliminated nearly all other lineages in early 2021. However, a series of variants (mostly containing the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. Accounting for sustained introductions, however, indicates that their transmissibility is unlikely to have exceeded that of Alpha. Finally, B.1.617.2/Delta was repeatedly introduced to England and grew rapidly in the early summer of 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on June 26.
Randall James Olsen, Paul Christensen, , Sishir Subedi, Parsa Hodjat, Robert Olson, Marcus Nguyen, James Davis, Prasanti Yerramilli, Matthew Ojeda-Saavedra, et al.
Published: 23 May 2021
Abstract:
Genetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 India variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex.
Ralf Salzer, , Marina Vaysburd, Veronica T. Chang, Anna Albecka, , , Andres Gonzalez Llamazares, , , et al.
Published: 18 May 2021
Abstract:
The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. So far, several different types of vaccines have shown strong efficacy. However, both the emergence of new SARS-CoV-2 variants and the need to vaccinate a large fraction of the world’s population necessitate the development of alternative vaccines, especially those that are simple and easy to store, transport and administer. Here, we showed that ferritin-like Dps protein from hyperthermophilic Sulfolobus islandicus can be covalently coupled with different SARS-CoV-2 antigens via the SpyCatcher system, to form extremely stable and defined multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) shows particular promise as it elicited a higher antibody titre and an enhanced neutralising antibody response compared to the monomeric RBD. Furthermore, we showed that a single immunisation with the multivalent RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to efficient viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.
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