Beta Variants Research Articles

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes. The spike glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) via its receptor binding domain (RBD) initiating the infection process. Attempting to understand the effect of RBD mutations in VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect the RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of four VOCs (Alpha, Beta, Delta, and Omicron). Our results show that the wt RBD presents two distinct conformations: an “open” conformation where it is free to bind ACE2; and a “closed” conformation, where the RBM ridge blocks the binding surface. The Alpha and Beta variants shift the open/closed equilibrium towards the open conformation by roughly 20%, likely increasing ACE2 binding affinity. Simulations of the Delta and Omicron variants showed extreme results, with the closed conformation being rarely observed. The Delta variant also differed substantially from the other variants, alternating between the open conformation and an alternative “reversed” one, with a significantly changed orientation of the RBM ridge. This alternate conformation could provide a fitness advantage due to increased availability for ACE2 binding, and by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the Omicron and Delta variants, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of Delta, may assist antibody escape.

No cardiac sequelae after COVID-19: results of the one year follow-up with echocardiography and biomarkers

Abstract Objective To evaluate the need for cardiac monitoring of unselected patients recovered from COVID-19 and to estimate the risk of heart failure development after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods During March 2020 and January 2021, 106 patients recovered from SARS-CoV-2 (alfa and beta variants) were enrolled in the prospective observational cohort study, CoSuBr (Covid Survivals in Brno). The diagnosis was established by reverse transcription polymerase chain reaction on swab test of the upper respiratory tract. Demographic parameters, patient history, clinical evaluation, cardiac biomarkers, ECG and echocardiography were recorded within three visits (V1 at least six weeks after infection, V2 three months later and V3 one year after V1). Results The study group (n=106) included 58% women, mean age was 46 years (range 18–77 years). Mean time interval between the onset of the infection and the follow-up visit was 107 days. One quarter (24.5%) of the patients required hospitalisation during the acute phase of the disease, the rest recovered at home. 74% suffered from mild form, 3.8% moderate, 18.3% severe and 2.9% of critical form of the disease. At the time of enrolment 63.5% of the patients were referring the ongoing symptoms, while more than half of the whole group (50.9%) mentioned at least one symptom of possible cardiac origin (breathing problems, palpitations, exercise intolerance, fatigue). During one year follow up after COVID-19 infection there was no decrease of left ventricle ejection fraction (V1: 62.1±5.26% to V3: 60.8±6.24%, p=0,150), no changes of troponin (4.8±3.41 to 4.7±3.31ng/L; p=0.417) and NT-proBNP (74.3±75.15 to 95.3±137.28pg/mL; p=0,315). There was a mild decrease of right ventricle end diastolic diameter (28.9±5.59 to 26.8±3.83mm, p<0.001), while no right ventricle dysfunction was detected. There was a very mild progress in a left ventricle diastolic diameter (47.9±6.34 to 49.3±4.21mm; p<0.001) between V1 a V3, a mild enlargement of left atrium (37.1±5.85 to 38.2±5.65mm; p=0,021) and non-significant trend to impairment of left ventricle diastolic dysfunction. There was a mild change of pulmonary artery systolic pressure (24.7±7.92 to 27.5±6.97mmHg; p=0,038). Conclusion Despite many information regarding cardiac impairment of SARS-CoV-2 our study does not suggest increased risk of development of heart failure during the one year follow-up. Based on our results the routine echocardiography and biomarkers collection is currently not recommended after COVID-19 recovery. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): MH CZ - DRO; MEYS - RI CZECRIN

Potent monoclonal antibodies neutralize Omicron sublineages and other SARS-CoV-2 variants.

The emergence and global spread of the SARS-CoV-2 Omicron variants, which carry an unprecedented number of mutations, raise serious concerns due to the reduced efficacy of current vaccines and resistance to therapeutic antibodies. Here, we report the generation and characterization of two potent human monoclonal antibodies, NA8 and NE12, against the receptor-binding domain of the SARS-CoV-2 spike protein. NA8 interacts with a highly conserved region and has a breadth of neutralization with picomolar potency against the Beta variant and the Omicron BA.1 and BA.2 sublineages and nanomolar potency against BA.2.12.1 and BA.4. Combination of NA8 and NE12 retains potent neutralizing activity against the major SARS-CoV-2 variants of concern. Cryo-EM analysis provides the structural basis for the broad and complementary neutralizing activity of these two antibodies. We confirm the in vivo protective and therapeutic efficacies of NA8 and NE12 in the hamster model. These results show that broad and potent human antibodies can overcome the continuous immune escape of evolving SARS-CoV-2 variants.

An antibody cocktail with broadened mutational resistance and effective protection against SARS-CoV-2.

Neutralizing antibodies have been proven to be highly effective in treating mild and moderate COVID-19 patients, but continuous emergence of SARS-CoV-2 variants poses significant challenges. Antibody cocktail treatments reduce the risk of escape mutants and resistance. In this study, a new cocktail composed of two highly potent neutralizing antibodies (HB27 and H89Y) was developed, whose binding epitope is different from those cocktails that received emergency use authorization. This cocktail showed more potent and balanced neutralizing activities (IC50 0.9–11.3 ng mL−1) against a broad spectrum of SARS-CoV-2 variants over individual HB27 or H89Y antibodies. Furthermore, the cocktail conferred more effective protection against the SARS-CoV-2 Beta variant in an aged murine model than monotherapy. It was shown to prevent SARS-CoV-2 mutational escape in vitro and effectively neutralize 61 types of pseudoviruses harbouring single amino acid mutation originated from variants and escape strains of Bamlanivimab, Casirivimab and Imdevimab with IC50 of 0.6–65 ng mL−1. Despite its breadth of variant neutralization, the HB27+H89Y combo and EUA cocktails lost their potencies against Omicron variant. Our results provide important insights that new antibody cocktails covering different epitopes are valuable tools to counter virus mutation and escape, highlighting the need to search for more conserved epitopes to combat Omicron.Supporting InformationThe supporting information is available online at 10.1007/s11427-022-2166-y. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

Can high COVID-19 vaccination rates in adults help protect unvaccinated children? Evidence from a unique mass vaccination campaign, Schwaz/Austria, March 2021.

BackgroundAfter an outbreak of the SARS-CoV-2 Beta variant in the district of Schwaz/Austria, vaccination with Comirnaty vaccine (BNT162b2 mRNA, BioNTech-Pfizer) had been offered to all adult inhabitants (≥ 16 years) in March 2021. This made Schwaz one of the most vaccinated regions in Europe at that time (70% of the adult population took up the offer). In contrast, all other Austrian districts remained with low vaccine coverage.AimWe studied whether this rapid mass vaccination campaign provided indirect protection to unvaccinated individuals such as children (< 16 years) living in the same district.MethodsTo study the effect of the campaign we used two complementary approaches. We compared infection rates among the population of children (< 16 years) in Schwaz with (i) the child population from similar districts (using the synthetic control method), and (ii) with the child population from municipalities along the border of Schwaz not included in the campaign (using an event study approach).ResultsBefore the campaign, we observed very similar infection spread across the cohort of children in Schwaz and the control regions. After the campaign, we found a significant reduction of new cases among children of −64.5% (95%-CI: −82.0 to −30.2%) relative to adjacent border municipalities (using the event study model). Employing the synthetic control method, we observed a significant reduction of −42.8% in the same cohort.ConclusionOur results constitute novel evidence of an indirect protection effect from a group of vaccinated individuals to an unvaccinated group.

Biological, clinical features and modelling of heterozygous variants of glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes responsible for constitutional thrombocytopenia.

Constitutional thrombocytopenias are rare disorders, often difficult to discriminate from acquired thrombocytopenias. More than 80 genes have been described as being at the origin of these diseases. Among them, several variants of the glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes, coding for the GpIb-IX-V glycoprotein complex, have been reported in the literature. The study reported here aimed at describing newly identified monoallelic anomalies affecting the GP1BA and GP1BB genes on a clinical, biological and molecular level. In a cohort of nine patients with macrothrombocytopenia, eight heterozygous variants of the GP1BA or GP1BB genes were identified. Five of them had never been described in the heterozygous state. Computer modelling disclosed structure/function relationships of these five variants.

GSK3326595 is a promising drug to prevent SARS-CoV-2 Omicron and other variants infection by inhibiting ACE2-R671 di-methylation.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) caused COVID‐19 epidemic is worsening. Binding of the Spike1 protein of SARS‐CoV‐2 with the angiotensin‐converting enzyme 2 (ACE2) receptor mediates entry of the virus into host cells. Many reports show that protein arginine methylation by protein arginine methyltransferases (PRMTs) is important for the functions of these proteins, but it remains unclear whether ACE2 is methylated by PRMTs. Here, we show that PRMT5 catalyses ACE2 symmetric dimethylation at residue R671 (meR671‐ACE2). We indicate that PRMT5‐mediated meR671‐ACE2 promotes SARS‐CoV‐2 receptor‐binding domain (RBD) binding with ACE2 probably by enhancing ACE2 N‐glycosylation modification. We also reveal that the PRMT5‐specific inhibitor GSK3326595 is able to dramatically reduce ACE2 binding with RBD. Moreover, we discovered that meR671‐ACE2 plays an important role in ACE2 binding with Spike1 of the SARS‐CoV‐2 Omicron, Delta, and Beta variants; and we found that GSK3326595 strongly attenuates ACE2 interaction with Spike1 of the SARS‐CoV‐2 Omicron, Delta, and Beta variants. Finally, SARS‐CoV‐2 pseudovirus infection assays uncovered that PRMT5‐mediated meR671‐ACE2 is essential for SARS‐CoV‐2 infection in human cells, and pseudovirus infection experiments confirmed that GSK3326595 can strongly suppress SARS‐CoV‐2 infection of host cells. Our findings suggest that as a clinical phase II drug for several kinds of cancers, GSK3326595 is a promising candidate to decrease SARS‐CoV‐2 infection by inhibiting ACE2 methylation and ACE2‐Spike1 interaction.

The outbreak of SARS-CoV-2 Omicron lineages, immune escape, and vaccine effectivity.

As of November 2021, several SARS‐CoV‐2 variants appeared and became dominant epidemic strains in many countries, including five variants of concern (VOCs) Alpha, Beta, Gamma, Delta, and Omicron defined by the World Health Organization during the COVID‐19 pandemic. As of August 2022, Omicron is classified into five main lineages, BA.1, BA.2, BA.3, BA.4, BA.5 and some sublineages (BA.1.1, BA.2.12.1, BA.2.11, BA.2.75, BA.4.6) (https://www.gisaid.org/). Compared to the previous VOCs (Alpha, Beta, Gamma, and Delta), all the Omicron lineages have the most highly mutations in the spike protein, and with 50 mutations accumulated throughout the genome. Early data indicated that Omicron BA.2 sublineage had higher infectivity and more immune escape than the early wild‐type (WT) strain, the previous VOCs, and BA.1. Recently, global surveillance data suggest a higher transmissibility of BA.4/BA.5 than BA.1, BA.1.1 and BA.2, and BA.4/BA.5 is becoming dominant strain in many countries globally.

Variant-Specific Analysis Reveals a Novel Long-Range RNA-RNA Interaction in SARS-CoV-2 Orf1a.

Since the start of the COVID-19 pandemic, understanding the pathology of the SARS-CoV-2 RNA virus and its life cycle has been the priority of many researchers. Currently, new variants of the virus have emerged with various levels of pathogenicity and abundance within the human-host population. Although much of viral pathogenicity is attributed to the viral Spike protein’s binding affinity to human lung cells’ ACE2 receptor, comprehensive knowledge on the distinctive features of viral variants that might affect their life cycle and pathogenicity is yet to be attained. Recent in vivo studies into the RNA structure of the SARS-CoV-2 genome have revealed certain long-range RNA-RNA interactions. Using in silico predictions and a large population of SARS-CoV-2 sequences, we observed variant-specific evolutionary changes for certain long-range RRIs. We also found statistical evidence for the existence of one of the thermodynamic-based RRI predictions, namely Comp1, in the Beta variant sequences. A similar test that disregarded sequence variant information did not, however, lead to significant results. When performing population-based analyses, aggregate tests may fail to identify novel interactions due to variant-specific changes. Variant-specific analyses can result in de novo RRI identification.

Development of a thermostable SARS-CoV-2 variant-based bivalent protein vaccine with cross-neutralizing potency against Omicron subvariants

SARS-CoV-2 variants have posed significant challenges to the hopes of using ancestral strain-based vaccines to address the risk of breakthrough infection by variants. We designed and developed a bivalent vaccine based on SARS-CoV-2 Alpha and Beta variants (named SCTV01C). SCTV01C antigens were stable at 25 oC for at least 6 months. In the presence of a squalene-based oil-in-water adjuvant SCT-VA02B, SCTV01C showed significant protection efficacy against antigen-matched Beta variant, with favorable safety profiles in rodents. Notably, SCTV01C exhibited cross-neutralization capacity against Omicron subvariants (BA.1, BA.1.1, BA.2, BA.3, and BA.4/5) in mice, superior to a WT (D614G)-based vaccine, which reinforced our previously published findings that SCTV01C exhibited broad-spectrum neutralizing potencies against over a dozen pre-Omicron variants and the Omicron BA.1 variant. In summary, variant-based multivalent protein vaccine could be a platform approach to address the challenging issues of emerging variants, vaccine hesitancy and the needs of affordable and thermal stable vaccines.

SARS-CoV-2 Variants, Current Vaccines and Therapeutic Implications for COVID-19.

Over the past two years, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of infections, resulting in an unprecedented pandemic of coronavirus disease 2019 (COVID-19). As the virus spreads through the population, ongoing mutations and adaptations are being discovered. There is now substantial clinical evidence that demonstrates the SARS-CoV-2 variants have stronger transmissibility and higher virulence compared to the wild-type strain of SARS-CoV-2. Hence, development of vaccines against SARS-CoV-2 variants to boost individual immunity has become essential. However, current treatment options are limited for COVID-19 caused by the SARS-CoV-2 variants. In this review, we describe current distribution, variation, biology, and clinical features of COVID-19 caused by SARS-CoV-2 variants (including Alpha (B.1.1.7 Lineage) variant, Beta (B.1.351 Lineage) variant, Gamma (P.1 Lineage) variant, Delta (B.1.617.2 Lineage) variant, and Omicron (B.1.1.529 Lineage) variant and others. In addition, we review currently employed vaccines in clinical or preclinical phases as well as potential targeted therapies in an attempt to provide better preventive and treatment strategies for COVID-19 caused by different SARS-CoV-2 variants.

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in SARS-CoV-2 sequencing in Africa over the past year has led to a major increase in the number of sequences generated, now exceeding 100,000 genomes, used to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence domestically, and highlight that local sequencing enables faster turnaround time and more regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and shed light on the distinct dispersal dynamics of Variants of Concern, particularly Alpha, Beta, Delta, and Omicron, on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve, while the continent faces many emerging and re-emerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century.

When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy.

Accurate determination of binding free energy is pivotal for the study of many biological processes and has been applied in a number of theoretical investigations to compare the affinity of severe acute respiratory syndrome coronavirus 2 variants toward the host cell. Diversity of these variants challenges the development of effective general therapies, their transmissibility relying either on an increased affinity toward their dedicated human receptor, the angiotensin-converting enzyme 2 (ACE2), or on escaping the immune response. Now that robust structural data are available, we have determined with utmost accuracy the standard binding free energy of the receptor-binding domain to the most widespread variants, namely, Alpha, Beta, Delta, and Omicron BA.2, as well as the wild type (WT) in complex either with ACE2 or with antibodies, namely, S2E12 and H11-D4, using a rigorous theoretical framework that combines molecular dynamics and potential-of-mean-force calculations. Our results show that an appropriate starting structure is crucial to ensure appropriate reproduction of the binding affinity, allowing the variants to be compared. They also emphasize the necessity to apply the relevant methodology, bereft of any shortcut, to account for all the contributions to the standard binding free energy. Our estimates of the binding affinities support the view that while the Alpha and Beta variants lean on an increased affinity toward the host cell, the Delta and Omicron BA.2 variants choose immune escape. Moreover, the S2E12 antibody, already known to be active against the WT (Starr et al., 2021; Mlcochova et al., 2021), proved to be equally effective against the Delta variant. In stark contrast, H11-D4 retains a low affinity toward the WT compared to that of ACE2 for the latter. Assuming robust structural information, the methodology employed herein successfully addresses the challenging protein–protein binding problem in the context of coronavirus disease 2019 while offering promising perspectives for predictive studies of ever-emerging variants.

SARS-CoV-2 variants from COVID-19 positive cases in the Free State province, South Africa from July 2020 to December 2021

Since the COVID-19 outbreak emerged, SARS-CoV-2 has continuously evolved into variants with underlying mutations associated with increased transmissibility, potential escape from neutralizing antibodies, and disease severity. The SARS-CoV-2 pandemic in South Africa has been characterized by periods of infections with four major epidemic waves. To determine whether the variants driving the epidemic waves at the national level were also driving the epidemic waves at the local level, we performed analysis of a total of 1287 samples from qPCR confirmed SARS-CoV-2 positive individuals. The samples were subjected to viral RNA extraction, genomic amplification, and sequencing. Variant assignment of the viral sequences and mutation identification were conducted using PANGOLIN and SARS-CoV-2 genome annotator, respectively. Our analysis revealed that during the initial part of the first wave, B.1, B.1.1, B.1.1.53, B.1.1.448 and B.1.237 circulated in the Free State province, followed by Beta variant, B.1.351 later in the wave. Although most of the initially detected variants disappeared during the second wave, the Beta variant, B.1.351, persisted. Early in the third wave, the Beta variant, B.1.351, predominated but was replaced by the Delta sub-lineage, AY.45. The fourth wave was characterized by unique emergence of the Omicron sub-variant, BA.1. The data further indicates that SARS-CoV-2 variants driving the epidemic waves in the Free State at the local level correlated with the ones driving the epidemic waves at the national level. Findings from this study highlight the importance of continued genomic surveillance and monitoring of the circulating SARS-CoV-2 variants to inform public health efforts and ensure adequate control of the ongoing pandemic.

Susceptibility of Domestic Goat (Capra aegagrus hircus) to Experimental Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) B.1.351/Beta Variant.

A wide range of animal species are susceptible to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Natural and/or experimental infections have been reported in pet, zoo, farmed and wild animals. Interestingly, some SARS-CoV-2 variants, such as B.1.1.7/Alpha, B.1.351/Beta, and B.1.1.529/Omicron, were demonstrated to infect some animal species not susceptible to classical viral variants. The present study aimed to elucidate if goats (Capra aegagrus hircus) are susceptible to the B.1.351/Beta variant. First, an in silico approach was used to predict the affinity between the receptor-binding domain of the spike protein of SARS-CoV-2 B.1.351/Beta variant and angiotensin-converting enzyme 2 from goats. Moreover, we performed an experimental inoculation with this variant in domestic goat and showed evidence of infection. SARS-CoV-2 was detected in nasal swabs and tissues by RT-qPCR and/or immunohistochemistry, and seroneutralisation was confirmed via ELISA and live virus neutralisation assays. However, the viral amount and tissue distribution suggest a low susceptibility of goats to the B.1.351/Beta variant. Therefore, although monitoring livestock is advisable, it is unlikely that goats play a role as SARS-CoV-2 reservoir species, and they are not useful surrogates to study SARS-CoV-2 infection in farmed animals.

Comparison of COVID-19 Pandemic Waves in 10 Countries in Southern Africa, 2020-2021.

We used publicly available data to describe epidemiology, genomic surveillance, and public health and social measures from the first 3 COVID-19 pandemic waves in southern Africa during April 6, 2020-September 19, 2021. South Africa detected regional waves on average 7.2 weeks before other countries. Average testing volume 244 tests/million/day) increased across waves and was highest in upper-middle-income countries. Across the 3 waves, average reported regional incidence increased (17.4, 51.9, 123.3 cases/1 million population/day), as did positivity of diagnostic tests (8.8%, 12.2%, 14.5%); mortality (0.3, 1.5, 2.7 deaths/1 million populaiton/day); and case-fatality ratios (1.9%, 2.1%, 2.5%). Beta variant (B.1.351) drove the second wave and Delta (B.1.617.2) the third. Stringent implementation of safety measures declined across waves. As of September 19, 2021, completed vaccination coverage remained low (8.1% of total population). Our findings highlight opportunities for strengthening surveillance, health systems, and access to realistically available therapeutics, and scaling up risk-based vaccination.

Abstract P253: Delta And Omicron Variants Of SARS-Cov-2 Do Not Stimulate ACE2 Conversion Of Ang II To Ang-(1-7)

The Spike domain of SARS-COV-2 binds ACE2 and induces peptidase internalization removing a key regulatory site within the renin-angiotensin system that may exacerbate the effects of SARS-COV-2. However, a recent study finds that an early Beta variant (D614G) of the SARS-COV-2 Spike protein and its receptor-binding domain (RBD) markedly stimulated ACE2 activity using fluorescent substrates. The more dominant forms of SARS-COV-2 include the Delta and Omicron variants and we determined whether these new variants activate ACE2. Delta (B.1.617.1) and Omicron (B.1.1.529) RBDs, and Beta Spike (B1.351) were incubated with human soluble ACE2 for 10 mins at 37°C followed by Ang II [2 μM] and 125I-Ang II [0.5 nM] for up to 20 mins, and the Ang-(1-7)/Ang II ratio quantified by HPLC-γ detection. Ang-(1-7)/Ang II increased linearly over time and doubled with 10 ng of ACE2 (*P&lt;0.01 vs 5 ng; N=4); however, the Delta or Omicron RBD proteins (1 μM) failed to stimulate ACE2 activity at any time point (A). Varying concentrations of the Delta or Omicron RBDs, as well as Spike protein also failed to stimulate ACE2 activity (5 ng), although 200 nM Omicron RBD was inhibitory (B). The newer Spike variants may not activate ACE2; however, the Spike D614G variant also failed to activate ACE2, which questions whether SARS-COV-2 enhances ACE2 activity to metabolize Ang II. We conclude that Delta and Omicron variants do not stimulate the metabolism of Ang II to Ang-(1-7). Moreover, alterations in circulating ACE2 activity in COVID-19 patients likely reflect changes in protein content through shedding of the peptidase, although the interaction of ACE2 autoantibodies to influence peptidase activity is also possible.

COVID-19 hospital admissions and mortality among healthcare workers in South Africa, 2020–2021

This study describes the characteristics of admitted HCWs reported to the DATCOV surveillance system, and the factors associated with in-hospital mortality in South African HCWs. Data from March 5, 2020 to April 30, 2021 were obtained from DATCOV, a national hospital surveillance system monitoring COVID-19 admissions in South Africa. Characteristics of HCWs were compared with those of non-HCWs. Furthermore, a logistic regression model was used to assess factors associated with in-hospital mortality among HCWs. In total, there were 169678 confirmed COVID-19 admissions, of which 6364 (3.8%) were HCWs. More of these HCW admissions were accounted for in wave 1 (48.6%; n = 3095) than in wave 2 (32.0%; n = 2036). Admitted HCWs were less likely to be male (28.2%; n = 1791) (aOR 0.3; 95% CI 0.3-0.4), in the 50-59 age group (33.1%; n = 2103) (aOR 1.4; 95% CI 1.1-1.8), or accessing the private health sector (63.3%; n = 4030) (aOR 1.3; 95% CI 1.1-1.5). Age, comorbidities, race, wave, province, and sector were significant risk factors for COVID-19-related mortality. The trends in cases showed a decline in HCW admissions in wave 2 compared with wave 1. Acquired SARS-COV-2 immunity from prior infection may have been a reason for reduced admissions and mortality of HCWs despite the more transmissible and more severe beta variant in wave 2.

Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy: a cross-sectional study.

Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant's disease severity in other settings, particularly in an African context, and when compared to the Beta variant. Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene Allplex TM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status. Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95% confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95%CI: 0.11-0.92) as was vaccination (aOR [95%CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]). Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.