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(searched for: doi:10.1093/infdis/jiab368)
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Weixu Feng, Yunru Xiang, Lianpeng Wu, Zhuo Chen, Qingfeng Li, Jun Chen, Yanru Guo, Dandan Xia, Na Chen, Lifang Zhang, et al.
Journal of Clinical Laboratory Analysis; https://doi.org/10.1002/jcla.24479

Adam Abdullahi, David Oladele, Steven A. Kemp, James Ayorinde, Abideen Salako, Fehintola Ige, Douglas Fink, Chika Onwuamah, Qosim Osuolale, Rufai Abubakar, et al.
Published: 5 May 2022
Abstract:
Background: There are no real world data on vaccine elicited neutralising antibody responses for the world’s most widely used vaccine, AZD1222, in African populations following scale up. Here, we measured i) baseline SARS-CoV-2 seroprevalence and levels of protective neutralizing antibodies prior to vaccination rollout using both flow cytometric based analysis of binding antibodies to nucleocapsid (N), coupled with virus neutralisation approaches and ii) neutralizing antibody responses to VOC prior to vaccination (January 2021) and after two-doses of AZD1222 vaccine administered between June and July 2021 in Lagos, Nigeria - a period when the Delta variant was circulating.Methods: Health workers at multiple sites in Lagos were recruited to the study. For binding antibody measurement, IgG antibodies against SARS-COV-2 Wuhan-1 receptor-binding domain (RBD), trimeric spike protein (S), nucleocapsid protein (N) and Omicron S1 were measured using the Luminex-based SARS-CoV-2-IgG assay by flow cytometry. For plasma neutralising antibody measurement, SARS-CoV-2 lentiviral pseudovirus (PV) were prepared by transfecting 293T cells with Wuhan-614G wild type (WT), B.1.617.2 (Delta) and BA.1 (Omicron) plasmids in conjunction with HIV-1 expression vectors and luciferase encoding genome flanked by LTRs. We performed serial plasma dilutions from each time point and mixed plasma with PV before infecting HeLa-ACE2 cell lines, reading out luminescence and calculating ID50 (reciprocal dilution of sera required to inhibit 50% of PV infection).Results: Our study population receiving at least one dose of vaccine comprised 140 participants with a median age of 40 (interquartile range: 33, 48). 62/140 (44%) participants were anti-N IgG positive prior to administration of first vaccine dose. 49 had plasma samples available at baseline prior to vaccination and at two follow-up timepoints post vaccination for neutralization assays. Half of the participants, 25/49 (51%) were IgG anti-N positive at baseline. Of the 24 individuals anti-N Ab negative at baseline, 12/24 had ID50 above the cut-off of 20. In these individuals, binding antibodies to S were also detectable, and neutralisation correlated with IgG anti-S, suggesting waning of N antibody after infection. Overall, neutralizing Ab titres to WT 1 month after second dose were 2579 and at 3 months post second-dose were 1695. As expected, lower levels of neutralization were observed against the Delta GMT 549 and Omicron variants 269 at 1 month. Positive anti-N IgG Ab status at baseline was associated with significantly higher titres of neutralizing antibodies following vaccination across all tested VOC. Those with anti-N Abs present at baseline did not experience waning of responses between months 1 and 3 post second dose. When data were analysed for negative anti-N IgG status at any timepoint, there was a significant decline in neutralization and binding antibodies between 1 month and 3 months post second-dose. The GMT in these individuals for Delta and Omicron was approximately 100, nearly a log lower in comparison to WT. We tested anti-N IgG in subjects who were anti-N IgG negative at baseline (n=78) and became positive between 1- and 3-months post second dose and found 7/49 (14%) with de-novo infection, with one additional participant demonstrating both reinfection and breakthrough infection to yield a total breakthrough rate of 8/49 (16%). Neutralising and binding Ab titres 1 month post vaccine, prior to breakthrough, were not associated with breakthrough infection. Neutralizing titres were higher at the last time point in individuals who had experienced vaccine breakthrough infection (with no evidence of infection prior to vaccine), indicating a boosting effect of infection in addition to vaccine. The increase in titres against Delta PV observed in breakthrough was significantly greater than the increase for WT and Omicron PVs, coincident with in the Delta wave of infection during the sampling period.Conclusions: AZD1222 is immunogenic in this real world west African cohort with significant background seroprevalence and incidence of breakthrough infection over a short time period. Prior infection and breakthrough infection induced higher anti-SARS-CoV-2 Ab responses at 3 months post vaccine against all widely circulating VOC. However, responses to Omicron BA.1 were low at three months regardless of prior exposure or breakthrough infection. Booster doses after AZD1222 should be considered for those at high risk in the African setting, even after natural infection, as future variants may be more pathogenic as well as immune evasive in the context of waning immunity.
Daichi Yamasoba, Yusuke Kosugi, Izumi Kimura, Shigeru Fujita, Keiya Uriu, Jumpei Ito, , The Genotype to Phenotype Japan (G2P-Japan) Consortium
Published: 3 May 2022
Abstract:
As of May 2022, Omicron BA.2 variant is the most dominant variant in the world. Thereafter, Omicron subvariants have emerged and some of them began outcompeting BA.2 in multiple countries. For instance, Omicron BA.2.11, BA.2.12.1 and BA.4/5 subvariants are becoming dominant in France, the USA and South Africa, respectively. In this study, we evaluated the sensitivity of these new Omicron subvariants (BA.2.11, BA.2.12.1 and BA.4/5) to eight therapeutic monoclonal antibodies (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab and tixagevimab). Notably, we showed that although cilgavimab is antiviral against BA.2, BA.4/5 exhibits higher resistance to this antibody compared to BA.2. Since mutations are accumulated in the spike proteins of newly emerging SARS-CoV-2 variants, we suggest the importance of rapid evaluation of the efficiency of therapeutic monoclonal antibodies against novel SARS-CoV-2 variants.
Daichi Yamasoba, Izumi Kimura, Hesham Nasser, Yuhei Morioka, Naganori Nao, Jumpei Ito, Keiya Uriu, Masumi Tsuda, Jiri Zahradnik, Kotaro Shirakawa, et al.
Published: 1 May 2022
Izumi Kimura, Daichi Yamasoba, Hesham Nasser, Jiri Zahradnik, Yusuke Kosugi, Jiaqi Wu, Kayoko Nagata, Keiya Uriu, Yuri L Tanaka, Jumpei Ito, et al.
Published: 3 April 2022
Abstract:
Recent studies have revealed the unique virological characteristics of Omicron, the newest SARS-CoV-2 variant of concern, such as pronounced resistance to vaccine-induced neutralizing antibodies, less efficient cleavage of the spike protein, and poor fusogenicity. However, it remains unclear which mutation(s) in the spike protein determine the virological characteristics of Omicron. Here, we show that the representative characteristics of the Omicron spike are determined by its receptor-binding domain. Interestingly, the molecular phylogenetic analysis revealed that the acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidate that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue in another protomer in the spike trimer, which confers the attenuated spike cleavage efficiency and fusogenicity of Omicron. Our data shed light on the evolutionary events underlying Omicron emergence at the molecular level. Highlights Omicron spike receptor binding domain determines virological characteristics Spike S375F mutation results in the poor spike cleavage and fusogenicity in Omicron Acquisition of the spike S375F mutation triggered the explosive spread of Omicron F375-H505-mediated π-π interaction in the spike determines the phenotype of Omicron
, Safal Walia, Roma Rattan, Amol Kanampalliwar, Atimukta Jha, Shifu Aggarwal, Sana Fatma, Niyati Das, Nirupama Chayani, Punit Prasad, et al.
International Journal of Infectious Diseases, Volume 119, pp 111-113; https://doi.org/10.1016/j.ijid.2022.03.042

The publisher has not yet granted permission to display this abstract.
Ting Y. Wong, , Brynnan P. Russ, Chengjin Ye, Katherine S. Lee, Michael T. Winters, Justin R. Bevere, Olivia A. Miller, Nathaniel A. Rader, Melissa Cooper, et al.
Journal of Virology, Volume 96; https://doi.org/10.1128/jvi.02184-21

Abstract:
SARS-CoV-2 variants of concern (VoC) are impacting responses to the COVID-19 pandemic. Here, we utilized passive immunization using human convalescent plasma (HCP) obtained from a critically ill COVID-19 patient in the early pandemic to study the efficacy of polyclonal antibodies generated to ancestral SARS-CoV-2 against the Alpha, Beta, and Delta VoC in the K18 human angiotensin converting enzyme 2 (hACE2) transgenic mouse model. HCP protected mice from challenge with the original WA-1 SARS-CoV-2 strain; however, only partially protected mice challenged with the Alpha VoC (60% survival) and failed to save Beta challenged mice from succumbing to disease. HCP treatment groups had elevated receptor binding domain (RBD) and nucleocapsid IgG titers in the serum; however, Beta VoC viral burden in the lung and brain was not decreased due to HCP treatment. While mice could be protected from WA-1 or Alpha challenge with a single dose of HCP, six doses of HCP could not decrease mortality of Delta challenged mice. Overall, these data demonstrate that VoC have enhanced immune evasion and this work underscores the need for in vivo models to evaluate future emerging strains. IMPORTANCE Emerging SARS-CoV-2 VoC are posing new problems regarding vaccine and monoclonal antibody efficacy. To better understand immune evasion tactics of the VoC, we utilized passive immunization to study the effect of early-pandemic SARS-CoV-2 HCP against, Alpha, Beta, and Delta VoC. We observed that HCP from a human infected with the original SARS-CoV-2 was unable to control lethality of Alpha, Beta, or Delta VoC in the K18-hACE2 transgenic mouse model of SARS-CoV-2 infection. Our findings demonstrate that passive immunization can be used as a model to evaluate immune evasion of emerging VoC strains.
Tarun Mishra, Rishikesh Dalavi, Garima Joshi, Atul Kumar, Pankaj Pandey, , Ram K Mishra,
Life Science Alliance, Volume 5; https://doi.org/10.26508/lsa.202201415

Abstract:
Breakthrough infections by emerging SARS-CoV-2 variants raise significant concerns. Here, we sequence-characterized the spike gene from breakthrough infections that corresponded to B.1.617 sublineage. Delineating the functional impact of spike mutations revealed that N-terminal domain (NTD)-specific E156G/Δ157-158 contributed to increased infectivity and reduced sensitivity to vaccine-induced 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 from cases concurrently screened, in addition to other circulating spike (S1) mutations such as T19R, T95I, L452R, E484Q, and D614G. Notably, E156G/Δ157-158 was present in more than 90% of the sequences reported from the USA and UK in October 2021. The spike-pseudotyped viruses bearing a combination of E156G/Δ157-158 and L452R exhibited higher infectivity and reduced sensitivity to neutralization. Notwithstanding, the post-recovery plasma robustly neutralized viral particles bearing the mutant spike. When the spike harbored E156G/Δ157-158 along with L452R and E484Q, increased cell-to-cell fusion was also observed, suggesting a combinatorial effect of these mutations. Our study underscores the importance of non-RBD changes in determining infectivity and immune escape.
Biswajit Biswas, Shagnik Chattopadhyay, Sayantee Hazra, Arman Kunwar Hansda,
Published: 15 March 2022
Inflammation Research, Volume 71, pp 377-396; https://doi.org/10.1007/s00011-022-01555-5

The publisher has not yet granted permission to display this abstract.
, Outi M. H. Salo-Ahen
Published: 10 March 2022
Abstract:
The ongoing pandemic caused by SARS-CoV-2 has gone through various phases. From the initial outbreak the virus has mutated several times, with some lineages showing even stronger infectivity and faster spread than the original virus. Among all the variants, beta, gamma, delta and the latest (omicron) are currently classified as variants of concern (VOC) while the remaining are labelled either as variants of interest (VOI) or variants under monitoring (VUM). In this work, we have focused on the mutations observed in important variants, particularly at the receptor-binding domain (RBD) of the spike protein that is responsible for the interactions with the host ACE2 receptor and binding of antibodies. Studying these mutations is particularly important for understanding the viral infectivity, spread of the disease and for tracking the escape routes of this virus from antibodies. Molecular dynamics (MD) based alchemical free energy calculations have been shown to be very accurate in predicting the free energy change due to a mutation that could have a deleterious or a stabilising effect on the protein itself or its binding affinity to another protein. Here, we investigated the significance of six commonly observed spike RBD mutations on the stability of the spike protein binding to ACE2 by free energy calculations using high throughput MD simulations. For comparison, we also used other (rigorous and non-rigorous) binding free energy prediction methods and compared our results with the experimental data if available. The alchemical free energy-based method consistently predicted the free-energy changes with an accuracy close to ±1.0 kcal/mol when compared with the available experimental values. As per our simulation data the most significant mutations responsible for stabilising the spike RBD interactions with human ACE2 are N501Y and L452R.
Published: 28 February 2022
by MDPI
Viruses, Volume 14; https://doi.org/10.3390/v14030504

Abstract:
We describe a flight-associated infection scenario of seven individuals with a B.1.617.2 (Delta) lineage, harbouring an S:E484Q point mutation. In Sweden, at least 10% of all positive SARS-CoV-2 samples were sequenced in each county; the B.1.717.2 + S:E484Q combination was not detected in Sweden before and was imported within the scenario described in this report. The high transmission rate of the delta lineage combined with the S:E484Q mutation, associated with immune escape in other lineages, makes this specific genetic combination a possible threat to the global fight against the COVID-19 pandemic. Even within the Omicron wave, the B.1.617.2 + S:E484Q variant appeared in community samples in Sweden, as it seems that this combination has an evolutionary gain compared to other B.1.617.2 lineages. The here described genomic combination was not detectable with the common fasta file-based Pango-lineage analysis, hence increasing the probability of the true global prevalence to be higher.
Tsung-I Tsai, Jahan S. Khalili, Mark Gilchrist, Andrew B. Waight, Daniella Cohen, Shi Zhuo, Yong Zhang, Muran Ding, Hai Zhu, Amanda Nga-Sze Mak, et al.
Published: 28 February 2022
Antiviral Research, Volume 199; https://doi.org/10.1016/j.antiviral.2022.105271

The publisher has not yet granted permission to display this abstract.
Qi Xiang, Linhao Li, Jie Wu, Miao Tian,
Published: 16 February 2022
Microbiological Research, Volume 258; https://doi.org/10.1016/j.micres.2022.126993

The publisher has not yet granted permission to display this abstract.
Bo Meng, Adam Abdullahi, Isabella A. T. M. Ferreira, Niluka Goonawardane, Akatsuki Saito, Izumi Kimura, Daichi Yamasoba, Pehuén Pereyra Gerber, Saman Fatihi, Surabhi Rathore, et al.
Published: 1 February 2022
Nature, Volume 603, pp 706-714; https://doi.org/10.1038/s41586-022-04474-x

Abstract:
The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.
Kirill V. Kalnin, Timothy Plitnik, Michael Kishko, Dean Huang, Alice Raillard, Julie Piolat, , Timothy Tibbitts, Joshua DiNapoli, Shrirang Karve, et al.
Published: 31 January 2022
Vaccine, Volume 40, pp 1289-1298; https://doi.org/10.1016/j.vaccine.2022.01.021

The publisher has not yet granted permission to display this abstract.
Branislav Kovacech, Lubica Fialova, Peter Filipcik, Rostislav Skrabana, Monika Zilkova, Natalia Paulenka-Ivanovova, , Denisa Palova, Gabriela Paulikova Rolkova, Katarina Tomkova, et al.
Published: 21 January 2022
The publisher has not yet granted permission to display this abstract.
Bo-Seong Jeong, Jeong Seok Cha, Insu Hwang, Uijin Kim, Jared Adolf-Bryfogle, Brian Coventry, Hyun-Soo Cho, ,
Published: 14 January 2022
Abstract:
Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can “break-through” the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.
Published: 13 January 2022
by MDPI
International Journal of Molecular Sciences, Volume 23; https://doi.org/10.3390/ijms23020835

Abstract:
The global urgency to uncover medical countermeasures to combat the COVID-19 pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has revealed an unmet need for robust tissue culture models that faithfully recapitulate key features of human tissues and disease. Infection of the nose is considered the dominant initial site for SARS-CoV-2 infection and models that replicate this entry portal offer the greatest potential for examining and demonstrating the effectiveness of countermeasures designed to prevent or manage this highly communicable disease. Here, we test an air–liquid-interface (ALI) differentiated human nasal epithelium (HNE) culture system as a model of authentic SARS-CoV-2 infection. Progenitor cells (basal cells) were isolated from nasal turbinate brushings, expanded under conditionally reprogrammed cell (CRC) culture conditions and differentiated at ALI. Differentiated cells were inoculated with different SARS-CoV-2 clinical isolates. Infectious virus release into apical washes was determined by TCID50, while infected cells were visualized by immunofluorescence and confocal microscopy. We demonstrate robust, reproducible SARS-CoV-2 infection of ALI-HNE established from different donors. Viral entry and release occurred from the apical surface, and infection was primarily observed in ciliated cells. In contrast to the ancestral clinical isolate, the Delta variant caused considerable cell damage. Successful establishment of ALI-HNE is donor dependent. ALI-HNE recapitulate key features of human SARS-CoV-2 infection of the nose and can serve as a pre-clinical model without the need for invasive collection of human respiratory tissue samples.
, Klevia Dishnica, Alejandro Giorgetti
Published: 10 January 2022
The publisher has not yet granted permission to display this abstract.
Lei Lin, Juling Zhang, James Rogers, Allan Campbell, Jianjun Zhao, Doris Harding, Foday Sahr, , Isata Wurie
Published: 6 January 2022
Infection, Genetics and Evolution, Volume 98; https://doi.org/10.1016/j.meegid.2022.105208

The publisher has not yet granted permission to display this abstract.
Zhenkui Hu, Xing Huang, Jianguo Zhang, Shixiang Fu, Daoyin Ding, Zhimin Tao
Published: 3 January 2022
Frontiers in Medicine, Volume 8; https://doi.org/10.3389/fmed.2021.792135

Abstract:
Background: As delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevailed in the current coronavirus disease 2019 (COVID-19) pandemic, its clinical characteristics with the difference from those of wild-type strains have been little studied.Methods: We reported one cohort of 341 wild-type patients with COVID-19 admitted at Wuhan, China in 2020 and the other cohort of 336 delta variant patients with COVID-19 admitted at Yangzhou, China in 2021, with comparisons of their demographic information, medical history, clinical manifestation, and hematological data. Furthermore, within the delta variant cohort, patients with none, partial, and full vaccination were also compared to assess vaccine effectiveness.Findings: For a total of 677 patients with COVID-19 included in this study, their median age was 53.0 years [interquartile range (IQR): 38.0–66.0] and 46.8% were men. No difference was found in age, gender, and percentage of patients with the leading comorbidity between wild-type and delta variant cohorts, but delta variant cohort showed a lessened time interval between disease onset to hospitalization, a reduced portion of patients with smoking history, and a lowered frequency of clinical symptoms. For hematological parameters, most values demonstrated significant differences between wild-type and delta variant cohorts, while full vaccination rather than partial vaccination alleviated the disease condition. This reflected the viremic effect of delta variant when vaccination succeeds or fails to protect.Interpretation: Delta variant of SARS-CoV-2 may cause severe disease profiles, but timely diagnosis and full vaccination could protect patients with COVID-19 from worsened disease progression.
Izumi Kimura, Yusuke Kosugi, Jiaqi Wu, , Daichi Yamasoba, Erika P. Butlertanaka, Yuri L. Tanaka, Keiya Uriu, Yafei Liu, Nanami Morizako, et al.
Published: 1 January 2022
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
Bo Meng, Isabella A.T.M Ferreira, Adam Abdullahi, Steven A. Kemp, Niluka Goonawardane, Guido Papa, Saman Fatihi, Oscar J. Charles, Dami Collier, CITIID-NIHR BioResource COVID-19 Collaboration, et al.
Published: 21 December 2021
Abstract:
The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.
Yusuke Matsui, Lin Li, Mary Prahl, Arianna G. Cassidy, Nida Ozarslan, Yarden Golan, Veronica J. Gonzalez, Christine Y. Lin, Unurzul Jigmeddagva, Megan A. Chidboy, et al.
Published: 11 December 2021
Abstract:
Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there is limited data comparing vaccine versus infection-induced nAb to COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines were matched with 30 naturally infected women by gestational age of exposure. Neutralization activity against the five SARS-CoV-2 Spike sequences was measured by a SARS-CoV-2 pseudotyped Spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared to wild type or Alpha variant Spike, these nAbs were less effective against the Kappa, Delta, and Mu Spike variants. Vaccination during the third trimester induced higher nAb levels at delivery than infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared to infection during the first trimester. The transfer ratio (cord nAb level/maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicit effective nAbs with differing neutralization kinetics that is impacted by gestational time of exposure. Vaccine induced neutralizing activity was reduced against the Delta, Mu, and Kappa variants.Graphic
Published: 10 December 2021
Siberian Research, Volume 6, pp 6-10; https://doi.org/10.33384/26587270.2021.06.02.01r

Abstract:
Обуздание Дельта-варианта SARS-Cov-2 в Японии, вероятно, запустило процесс угасания Дельта-варианта вируса и пандемии. Заменит ли Дельту Омикрон, вплоть до настоящего времени неизвестно. При испанке массовая смертность заболевших прекратилась через два года, но при вспышке испанки в Якутии в 1925 г. в некоторых наслегах умерло до 2% населения. Если Омикрон заменит Дельту, то, вероятно, Covid-19 может превратиться в сезонную инфекцию, если большинство населения в мире будет вакцинировано или перенесет инфекцию.
Published: 10 December 2021
Siberian Research, Volume 6, pp 26-30; https://doi.org/10.33384/26587270.2021.06.02.07e

Abstract:
Curbing the SARS-CoV-2 Delta variant in Japan has probably initiated extinction of the Delta variant and the pandemic. Whether Omicron will replace Delta has been unknown so far. In case of Spanish flu, mass mortality reached an end two years later, although up to 2% of the population died in some villages at the Spanish flu outbreak in Yakutia in 1925 [23]. If Omicron replaces Delta, COVID-19 may probably turn into a seasonal infection, provided that the majority of the world population gets vaccinated or get sick.
Rakesh Sarkar, Mahadeb Lo, Ritubrita Saha, Shanta Dutta,
Published: 5 December 2021
Abstract:
On the backdrop of ongoing Delta variant infection and vaccine-induced immunity, the emergence of the new Variant of Concern, the Omicron, has again fuelled the fears of COVID-19 around the world. Currently, very little information is available about the S glycoprotein mutations, transmissibility, severity, and immune evasion behaviour of the Omicron variant. In the present study, we have performed a comprehensive analysis of the S glycoprotein mutations of 309 strains of the Omicron variant and also discussed the probable effects of observed mutations on several aspects of virus biology based on known available knowledge of mutational effects on S glycoprotein structure, function, and immune evasion characteristics.
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.
Petra Mlcochova, Steven A. Kemp, Mahesh Shanker Dhar, Guido Papa, Bo Meng, Isabella A. T. M. Ferreira, Rawlings Datir, Dami A. Collier, Anna Albecka, Sujeet Singh, et al.
Published: 6 September 2021
Nature, Volume 599, pp 114-119; https://doi.org/10.1038/s41586-021-03944-y

Abstract:
The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
Arup Ghosh, Safal Walia, Roma Rattan, Amol Kanampalliwar, Atimukta Jha, Shifu Aggarwal, Sana Fatma, Niyati Das, Nirupama Chayani, Punit Prasad, et al.
Published: 20 August 2021
Abstract:
Vaccine breakthrough infections pose a vast challenge in the eradication of the COVID pandemic situation. Emerging SARS-CoV-2 variants of concern infecting the immunized individuals indicate an ongoing battle between host immunity and natural selection of the pathogen. Our report sheds light on the prominent SARS-CoV-2 variations observed in the isolates from AZD1222/Covishield and BBV152/Covaxin vaccinated subjects.
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.
Ming-Shao Tsai, Yao-Hsu Yang, Yu-Shih Lin, Geng-He Chang, Cheng-Ming Hsu, Reming-Albert Yeh, Li-Hsin Shu, Yu-Ching Cheng, Hung-Te Liu, Yu-Huei Wu, et al.
Published: 5 August 2021
Biomedicine & Pharmacotherapy, Volume 142, pp 112011-112011; https://doi.org/10.1016/j.biopha.2021.112011

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Isabella Ferreira, Rawlings Datir, Guido Papa, Steven Kemp, Bo Meng, Partha Rakshit, Sujeet Singh, Rajesh Pandey, Kalaiarasan Ponnusamy, Venkatraman Srinivasan Radhakrishnan, et al.
Published: 9 May 2021
Abstract:
The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha). In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
, Klevia Dishnica,
Published: 19 April 2021
Abstract:
Tracking the evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through genomic surveillance programs is undoubtedly one of the key priorities in the current pandemic situation. Although the genome of SARS-CoV-2 acquires mutations at a slower rate compared with other RNA viruses, evolutionary pressures derived from the widespread circulation of SARS-CoV-2 in the human population have progressively favored the global emergence, though natural selection, of several variants of concern that carry multiple non-synonymous mutations in the spike glycoprotein. These are often placed in key sites within major antibody epitopes and may therefore confer resistance to neutralizing antibodies, leading to partial immune escape, or otherwise compensate infectivity deficits associated with other non-synonymous substitutions. As previously shown by other authors, several emerging variants carry recurrent deletion regions (RDRs) that display a partial overlap with antibody epitopes located in the spike N-terminal domain (NTD). Comparatively, very little attention has been directed towards spike insertion mutations prior to the emergence of the B.1.1.529 (omicron) lineage. This manuscript describes a single recurrent insertion region (RIR1) in the N-terminal domain of SARS-CoV-2 spike protein, characterized by at least 41 independent acquisitions of 1-8 additional codons between Val213 and Leu216 in different viral lineages. Even though RIR1 is unlikely to confer antibody escape, its association with two distinct formerly widespread lineages (A.2.5 and B.1.214.2), with the quickly spreading omicron and with other VOCs and VOIs warrants further investigation concerning its effects on spike structure and viral infectivity.
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