V2 Variant Research Articles

Unleashing the potential of nano-bainite bearing steels: Controllable selection of microstructure evolution enables concurrent improvement of toughness and hardness by pre-cold deformation

In the face of increasingly demanding service conditions for high-end bearings, the need for bearing steels that demonstrate superior mechanical properties, specifically a robust balance of strength and toughness, is growing. The adoption of near-net-shaped cold rolling methods has emerged as a leading international technology to enhance bearing performance. In this study, the effect mechanisms of pre-cold deformation on the phase transformation kinetics, microstructure evolution and mechanical properties of nano-bainite bearing steels are systematically studied. Results reveal that pre-cold deformation treatment effectively reduces the Ac1 temperature of the experimental steel, expedites nano-bainite transformation and promotes strong variant selection during bainite phase transformation. With the increase in pre-cold deformation from 0 % to 50 %, the size of the prior austenite grains decreases from 6.7 μm to 3.3 μm, and the size of carbides in specimens becomes more uniform, whilst the refinement of austenite grains can considerably reduce the thickness of bainitic ferrite plates. The decrease in grain size and the increase in V1–V2 variant pairs lead to an improvement in the toughness of the nano-bainite bearing steel from 64.9 J/cm2 to 114.3 J/cm2. A marginal increase in the hardness of the bearing steel is observed with the increase in pre-cold deformation. Furthermore, this study discusses the evolution mechanism of microstructure in the subsequent phase transformation by different microstructures in the early stage. Results show that pre-cold deformation leads to the transition of the martensite twin substructure in the specimens from {112} <111> twins to twinned variants. These insights offer critical understanding into the microstructural underpinning the enhanced performance of nano-bainite bearing steels subjected to pre-cold deformation treatment.

Abstract PO4-05-13: Expression of DLC1/STARD12 and variants in clinical breast cancer and implication in skeletal metastasis

Abstract Introduction: Deleted in Liver Cancer 1 Protein, DLC1, also known as StAR Related Lipid Transfer Domain Containing 12 (StarD12), is a known negative regulator of the Rho GTPases and at the cellular level regulates cell migration. DLC1 gene transcription produces multiple isoforms of the DLC1 protein. The present study examined the clinical and prognostic implications of DLC1 isoforms, DLC1/V1/V2/V3, in relationship with Rho GTPases in human breast cancer. Methods: Expression of three DLC1 isoforms was evaluated in a cohort of breast cancer tissues and against the clinical, pathological and clinical outcome of patients. DLC1 expression was also assessed and compared against Rho GTPases, including Rho and Rho GTP Dissociation Inhibitor (Rho GDI), in the same cohort. Results: DLC1/V3 had a significant impact on the overall survival of patients and high levels were linked to shorter survival (Hazard Ratio=3.551 (95%CI 1.332-9.471, p=0.011), a prediction that was independent of other factors in multivariate analysis. RUC analysis demonstrated a significant predictive value for bone metastasis with DLC1/V3 (RUC=0.714, p=0.020), showing a Hazard ratio of 9.0 (1.8-44.5, p=0.007). Similarly, high DLC1/V2 expression was also linked to a shorter overall survival (p=0.035). DLC1/V2 did not show a significant correlation with bone metastasis. In contrast to V3 and V2 variants, DLC1 had a marginal overall survival benefit for the patients, in that patients with high DLC1 had a longer survival (p=0.056). DLC1/V3 had a contrasting correlation with Rho-A (r=-0.203, p=0.015) and Rho-GDI-G (r=0.194, p=0.019) and the combined expression of DLC1/V3 and RhoA/Rho-GDI-G further identified patients with poorer clinical outcome. Conclusions: DLC1 and its variants have differing impacts on breast cancer; whereas DLC1 appears to be a tumour suppressive molecule, its variant isoform-3 was more oncogenic and a significant negative prognostic factor, together with its regulators Rho and Rho GDI. Citation Format: Binbin Cong, Jane Lane, Xiaoshan Cao, Tracey Martin, Robert E Mansel, Eleri Davies, Wen Jiang. Expression of DLC1/STARD12 and variants in clinical breast cancer and implication in skeletal metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-13.

Energy Sustainability Indicators for the Use of Biomass as Fuel for the Sugar Industry

There are numerous analytical and/or computational tools for evaluating the energetic sustainability of biomass in the sugar industry. However, the simultaneous integration of the energetic–exergetic and emergetic criteria for such evaluation is still insufficient. The objective of the present work is to propose a range of indicators to evaluate the sustainability of the use of biomass as fuel in the sugar industry. For this purpose, energy, exergy, and emergy evaluation tools were theoretically used as sustainability indicators. They were validated in five variants of different biomass and their mixtures in two studies of technologies used in Cuba for the sugar industry. As a result, the energy method showed, for all variants, an increase in efficiency of about 5% in the VU-40 technology compared to the Retal technology. There is an increase in energy efficiency when considering AHRs of 2.8% or Marabu (Dichrostachys cinerea) (5.3%) compared to the V1 variant. Through the study of the exergetic efficiency, an increase of 2% was determined in both technologies for the case of the V1 variant, and an increase in efficiency is observed in the V2 variant of 5% and the V3 variant (5.6%) over the V1 variant. The emergetic method showed superior results for the VU-40 technology over the Retal technology due to higher fuel utilization. In the case of the V1 variant, there was a 7% increase in the renewability ratio and an 11.07% increase in the sustainability index. This is because more energy is produced per unit of environmental load.

Effect of refined multi-scale microstructures on the ultra-high impact toughness of bainitic steel austempered below Ms temperature

In this study, the multi-scale microstructures of bainitic steel were refined to different degrees by austempering below Ms (martensite start temperature). The influence of multi-scale microstructures and their boundaries on impact toughness was analyzed. The results revealed that the impact toughness of bainitic steel significantly improved as the austempering temperature decreased. The block structure and Bain groups are refined by austempering below Ms, thereby introducing high-density HAGBs (high-angle grain boundaries) and increasing crack propagation resistance. The proportion of V2, V3, and V5 variants increased and formed HAGBs with the V1 variant, which regulated phase transformation strain and delayed crack formation. The improvement in impact toughness can be attributed to the formation of more HAGBs. This is mainly caused by the refinement of the block structure. Therefore, the block structure can be considered as the dominating and effective controlling unit of impact toughness.

Microstructural evolution and ultra-high impact toughness of austempered lamellar bainitic steel far below Ms temperature

The present study investigated the effects of the austempering process far below Ms (martensite start temperature) on the microstructural evolution and impact toughness of bainitic steel with ultrahigh impact toughness and compared the results with the tempered martensitic steel. The results revealed that the lamellar bainitic steel composed of bainitic ferrite laths and retained austenite films is obtained by austempering far below Ms temperature. The obtained steel exhibited the Charpy V-notch impact absorbed energy of up to 131 ± 6 J, which was 2.7 times higher than that of the tempered martensitic steel (49 ± 1 J). The ultra-high impact toughness of bainitic steel was attributed to the deflection of the crack propagation direction by the refined bainitic ferrite laths and the passivation of the crack tip by the retained austenite films. Furthermore, the proportion of V2, V3, and V5 variants increased and formed HAGBs (high-angle grain boundaries) with the V1 variant in the austempered bainitic steel B-32. These HAGBs inhibited crack propagation effectively, thereby significantly improving the impact toughness of the austempered bainitic steel.

South African (501Y.V2) and the United Kingdom (B.1.1.7) SARS-CoV-2 Spike (S) Protein Variants Demonstrate a Higher Binding Affinity to ACE2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the lower respiratory tract by binding to angiotensin-converting enzyme 2 (ACE2) via its S-protein. Recent emerging SARS-CoV-2 variants from the United Kingdom (B.1.1.7) and South Africa (501Y.V2) are spreading worldwide at an alarming rate. The new variants have manifested amino acid substitution K417N, E484K, and N501Y on the RBD domain that binds to ACE2. These mutations may influence the binding of the S-protein to ACE2 and affect viral entry into the host cell. In this study, we modelled the amino acid substitutions on the S-protein and utilised the HADDOCK server to assess the S-protein RBD domain binding with ACE2. Additionally, we calculated the binding affinity of ACE2 to S-protein WT, B.1.1.7 and 501Y.V2 variants using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA). We demonstrated that the S-protein of both variants possesses a higher binding affinity to ACE2 than WT, with the South African 501Y.V2 being more infective than the B.1.1.7 that originated in the United Kingdom. The South African 501Y.V2 variant presents three amino acid substitutions that changed the H-bonding network, resulting in a higher affinity to ACE2, indicating that the 501Y.V2 strain is more infective than the B.1.1.7 strain.

EVADR ceRNA transcript variants upregulate WNT and PI3K signaling pathways in SW480 and HCT116 cells by sponging miR-7 and miR-29b.

Long noncoding RNAs are cancer regulators and EVADR-lncRNA is highly upregulated in colorectal cancer (CRC). Accordingly, we aimed to functionally characterize the EVADR in CRC-originated cells. Firstly, during the amplification of EVADR full-length cDNA (named EVADR-v1), a novel/shorter variant (EVADR-v2) was discovered. Then, RT-qPCR analysis confirmed that EVADR is upregulated in tumors, consistent with RNA-seq analysis. Interestingly, bioinformatics analysis and dual-luciferase assay verified that EVADR sponges miR-7 and miR-29b. When both EVADR-v1/-v2 variants were overexpressed in SW480/HCT116 cells, miR-7 and miR-29b target genes (involved in the WNT/PI3K signaling) were upregulated. Furthermore, EVADR-v1/-v2 overexpression resulted in elevated PI3K activity (verified by western blotting and RT-qPCR) and upregulation of WNT signaling (confirmed by western blotting, TopFlash assay, and RT-qPCR). Consistently, overexpression of EVADR-v1/-v2 variants was followed by increased cell cycle progression, viability and migration aswell as reduced early/late apoptotic rate, and Bax/Bcl2 ratio of the CRC cells, detected by the cell cycle analysis, MTT,wound-healing, Annexin-V/PI, and RT-qPCR methods, respectively. Overall, we introduced two oncogenic transcript variants for EVADR that by sponging miR-7/miR-29b, upregulate WNT and PI3K signaling. Given the crucial role of these pathways in CRC, EVADR may present potential therapy use.

Functional characterization of two variants of mitochondrial topoisomerase TOP1MT that impact regulation of the mitochondrial genome

TOP1MT encodes a mitochondrial topoisomerase that is important for mtDNA regulation and is involved in mitochondrial replication, transcription, and translation. Two variants predicted to affect TOP1MT function (V1 - R198C and V2 - V338L) were identified by exome sequencing of a newborn with hypertrophic cardiomyopathy. As no pathogenic TOP1MT variants had been confirmed previously, we characterized these variants for their ability to rescue several TOP1MT functions in KO cells. Consistent with these TOP1MT variants contributing to the patient phenotype, our comprehensive characterization suggests that both variants had impaired activity. Critically, we determined neither variant was able to restore steady state levels of mitochondrial-encoded proteins nor to rescue oxidative phosphorylation when re-expressed in TOP1MT KO cells. However, we found the two variants behaved differently in some respects; while the V1 variant was more efficient in restoring transcript levels, the V2 variant showed better rescue of mtDNA copy number and replication. These findings suggest that the different TOP1MT variants affect distinct TOP1MT functions. Altogether, these findings begin to provide insight into the many roles that TOP1MT plays in the maintenance and expression of the mitochondrial genome and how impairments in this important protein may lead to human pathology.

Prognosis of patients with acute respiratory failure due to the SARS-CoV-2 501Y.V2 variant: a multicenter retrospective matched cohort study

The aim of this study was to compare the prognosis of patients with acute respiratory failure (ARF) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant 501Y.V2 to that of patients with ARF due to the original strain. This retrospective matched cohort study included all consecutive patients who were hospitalized for ARF due to SARS-CoV-2 in Reunion Island University Hospital between March 2020 and March 2021. Twenty-eight in hospital mortality was evaluated before and after matching. A total of 218 patients with ARF due to SARS-CoV-2 were enrolled in the study. Of these, 83 (38.1%) were infected with the 501Y.V2 variant. During intensive care unit stay, 104 (47.7%) patients received invasive mechanical ventilation and 20 (9.2%) patients were supported by venovenous extracorporeal membrane oxygenation. Patients infected with the 501Y.V2 variant were younger (58 [51–68] vs. 67 [56–74] years old, P = 0.003), had less hypertension (54.2% vs 68.1%, P = 0.04), and had less chronic kidney disease (13.3% vs. 31.9%, P = 0.002) than patients infected with the original strain. After controlling for confounding variables (62 matched patients in each group), 28-day mortality was higher in the group of patients infected with the 501Y.V2 variant (30.6%) than in the group of patients infected with the original strain (19.4%, P = 0.04). In Reunion Island, where SARS-CoV-2 incidence remained low until February 2021 and the health care system was never saturated, mortality was higher in patients with ARF infected with the 501Y.V2 variant than in patients infected with the original strain.

501Y.V2 spike protein resists the neutralizing antibody in atomistic simulations

SARS-CoV-2 outbreaks worldwide caused COVID-19 pandemic, which is related to several million deaths. In particular, SARS-CoV-2 Spike (S) protein is a major biological target for COVID-19 vaccine design. Unfortunately, recent reports indicated that Spike (S) protein mutations can lead to antibody resistance. However, understanding the process is limited, especially at the atomic scale. The structural change of S protein and neutralizing antibody fragment (FAb) complexes was thus probed using molecular dynamics (MD) simulations. In particular, the backbone RMSD of the 501Y.V2 complex was significantly larger than that of the wild-type one implying a large structural change of the mutation system. Moreover, the mean of Rg, CCS, and SASA are almost the same when compared two complexes, but the distributions of these values are absolutely different. Furthermore, the free energy landscape of the complexes was significantly changed when the 501Y.V2 variant was induced. The binding pose between S protein and FAb was thus altered. The FAb-binding affinity to S protein was thus reduced due to revealing over steered-MD (SMD) simulations. The observation is in good agreement with the respective experiment that the 501Y.V2 SARS-CoV-2 variant can escape from neutralizing antibody (NAb).

Genomic characterization of the dominating Beta, V2variant carrying vaccinated (Oxford-AstraZeneca) and nonvaccinated COVID-19 patient samples in Bangladesh: A metagenomics and whole-genome approach.

Bangladesh is experiencing a second wave of COVID-19 since March 2021, despite the nationwide vaccination drive with ChAdOx1 (Oxford-AstraZeneca) vaccine from early February 2021. Here, we characterized 19 nasopharyngeal swab(NPS) samples from COVID-19 suspect patients using genomic and metagenomic approaches. Screening for SARS-CoV-2 by reverse transcriptase polymerase chain reactionand metagenomic sequencing revealed 17 samples of COVID-19 positive (vaccinated = 10, nonvaccinated = 7) and 2 samples of COVID-19 negative. We did not find any significant correlation between associated factors including vaccination status, age or sex of the patients, diversity or abundance of the coinfected organisms/pathogens, and the abundance of SARS-CoV-2. Though the first wave of the pandemic was dominated by clade 20B, Beta,V2 (South African variant) dominated the second wave (January 2021 to May 2021), while the third wave (May 2021 to September 2021) was responsible for Delta variants of the epidemic in Bangladesh including both vaccinated and unvaccinated infections. Noteworthily, the receptor binding domain (RBD) region of S protein of all the isolates harbored similar substitutions including K417N, E484K, and N501Y that signify the Beta, while D614G, D215G, D80A, A67V, L18F, and A701V substitutions were commonly found in the non-RBD region of Spike proteins. ORF7b and ORF3a genes underwent a positive selection (dN/dS ratio 1.77 and 1.24, respectively), while the overall S protein of the Bangladeshi SARS-CoV-2 isolates underwent negative selection pressure (dN/dS = 0.621). Furthermore, we found different bacterial coinfections like Streptococcus agalactiae, Neisseria meningitidis, Elizabethkingia anophelis, Stenotrophomonas maltophilia, Klebsiella pneumoniae, and Pseudomonas plecoglossicida, expressing a number of antibiotic resistance genes such as tetA and tetM. Overall, this approach provides valuable insights on the SARS-CoV-2 genomes and microbiome composition from both vaccinated and nonvaccinated patients in Bangladesh.

Emergency air evacuation of patients with acute respiratory failure due to SARS-CoV-2 from Mayotte to Reunion Island.

In February 2021, an explosion of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia overwhelmed the only hospital in Mayotte. To report a case series of patients with acute respiratory failure (ARF) due to SARS-CoV-2 who were evacuated by air from Mayotte to Reunion Island.This retrospective observational study evaluated all consecutive patients with ARF due to SARS-CoV-2 who were evacuated by air from Mayotte Hospital to the intensive care unit (ICU) of Félix Guyon University Hospital in Reunion Island between February 2, and March 5, 2021.A total of 43 patients with SARS-CoV-2 pneumonia were evacuated by air, for a total flight time of 2 hours and a total travel time of 6 hours. Of these, 38 patients (88.4%) with a median age of 55 (46–65) years presented with ARF and were hospitalized in our ICU. Fifteen patients were screened for the SARS-CoV-2 501Y.V2 variant, all of whom tested positive. Thirteen patients (34.2%) developed an episode of severe hypoxemia during air transport, and the median paO2/FiO2 ratio was lower on ICU admission (140 [102–192] mmHg) than on departure (165 [150–200], P = .022). Factors associated with severe hypoxemia during air transport was lack of treatment with curare (P = .012) and lack of invasive mechanical ventilation (P = .003). Nine patients (23.7%) received veno-venous extracorporeal membrane oxygenation support in our ICU. Seven deaths (18.4%) occurred in hospital.Emergency air evacuation of patients with ARF due to SARS-CoV-2 was associated with severe hypoxemia but remained feasible. In cases of ARF due to SARS-CoV-2 requiring emergency air evacuation, sedated patients receiving invasive mechanical ventilation and curare should be prioritized over nonintubated patients. It is noteworthy that patients with SARS-CoV-2 pneumonia related to the 501Y.V2 variant were very severe despite their young age.

Detection of SARS-CoV-2 variant 501Y.V2 in Comoros Islands in January 2021

Background. Genomic data is key in understanding the spread and evolution of SARS-CoV-2 pandemic and informing the design and evaluation of interventions. However, SARS-CoV-2 genomic data remains scarce across Africa, with no reports yet from the Indian Ocean islands. Methods. We genome sequenced six SARS-CoV-2 positive samples from the first major infection wave in the Union of Comoros in January 2021 and undertook detailed phylogenetic analysis. Results. All the recovered six genomes classified within the 501Y.V2 variant of concern (also known as lineage B.1.351) and appeared to be from 2 sub-clusters with the most recent common ancestor dated 30 th Oct-2020 (95% Credibility Interval: 06 th Sep-2020 to 10 th Dec-2020). Comparison of the Comoros genomes with those of 501Y.V2 variant of concern from other countries deposited into the GISAID database revealed their close association with viruses identified in France and Mayotte (part of the Comoros archipelago and a France, Overseas Department). Conclusions. The recovered genomes, albeit few, confirmed local transmission following probably multiple introductions of the SARS-CoV-2 501Y.V2 variant of concern during the Comoros’s first major COVID-19 wave. These findings demonstrate the importance of genomic surveillance and have implications for ongoing control strategies on the islands.

Study on the Relationship between High Temperature Mechanical Properties and Precipitates Evolution of 7085 Al Alloy after Long Time Thermal Exposures

The requirement for 7085 Al alloy as large airframe parts has been increasing due to its low quenching sensitivity and high strength. However, the relationship between high temperature mechanical properties and the evolution of precipitates in hot environments is still unclear. In this work, thermal exposure followed by tensile tests were conducted on the 7085 Al alloy at various temperatures (100 °C, 125 °C, 150 °C and 175 °C). Variations of hardness, electrical conductivity and tensile properties were investigated. The evolution of the nano scale precipitates was also quantitatively characterized by transmission electron microscopy (TEM). The results show that the hardness and electrical conductivity of the alloy are more sensitive to the temperature than to the time. The strength decreases continuously with the increase of temperature due to the transformation from η′ to η phase during the process. Furthermore, the main η phase in the alloy transformed from V3 and V4 to V1 and V2 variants when the temperature was 125 °C. Additionally, with increasing the temperature, the average precipitate radius increased, meanwhile the volume fraction and number density of the precipitates decreased. The strengthening effect of nano scale precipitates on tensile properties of the alloy was calculated and analyzed.

Transient acquisition of cross-species infectivity during the evolution of SARS-CoV-2.

Summary The emergence and global spread of SARS-CoV-2 variants has caused global concerns about increased virulence and decreased efficacy of medical countermeasures. Herein, we demonstrate that the newly emerged 501Y.V2 variant (also called the beta variant) is capable of infecting standard laboratory mice after intranasal instillation, unlike the earlier isolates. However, the infectivity in mice demonstrated in the laboratory may not occur in nature; indeed, there is no evidence of natural transmission of 501Y.V2 in mice to date. Most interestingly, the 501Y.V2 variant was quickly replaced by another variant—the delta variant—in the human population. Our results indicate that circulating SARS-CoV-2 has been evolving rapidly and that transient acquisition of cross-species infectivity in animals may occur. This phenomenon creates new challenges as well as opportunities in studying SARS-CoV-2 circulation and evolution.

SARS-CoV-2 Variants: Surveillance, Evaluation, and Challenges

SARS-CoV-2 Variants: Surveillance, Evaluation, and Challenges

Evolution, Mode of Transmission, and Mutational Landscape of Newly Emerging SARS-CoV-2 Variants.

ABSTRACTThe recent emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant concern for public health worldwide. New variants have been classified either as variants of concern (VOCs) or variants of interest (VOIs) by the CDC (USA) and WHO. The VOCs include lineages such as B.1.1.7 (20I/501Y.V1 variant), P.1 (20J/501Y.V3 variant), B.1.351 (20H/501Y.V2 variant), and B.1.617.2. In contrast, the VOI category includes B.1.525, B.1.526, P.2, and B.1.427/B.1.429. The WHO provided the alert for last two variants (P.2 and B.1.427/B.1.429) and labeled them for further monitoring. As per the WHO, these variants can be reclassified due to their status at a particular time. At the same time, the CDC (USA) has marked these two variants as VOIs up through today. This article analyzes the evolutionary patterns of all these emerging variants, as well as their geographical distributions and transmission patterns, including the circulating frequency, entropy diversity, and mutational event diversity throughout the genomes of all SARS-CoV-2 lineages. The transmission pattern was observed highest in the B.1.1.7 lineage. Our frequency evaluation found that this lineage achieved 100% frequency in early October 2020. We also critically evaluated the above emerging variants mutational landscape and significant spike protein mutations (E484K, K417T/N, N501Y, and D614G) impacting public health. Finally, the effectiveness of vaccines against newly SARS-CoV-2 variants was also analyzed.

Detection of SARS-CoV-2 variant 501Y.V2 in Comoros Islands in January 2021.

Background. Genomic data is key in understanding the spread and evolution of SARS-CoV-2 pandemic and informing the design and evaluation of interventions. However, SARS-CoV-2 genomic data remains scarce across Africa, with no reports yet from the Indian Ocean islands. Methods. We genome sequenced six SARS-CoV-2 positive samples from the first major infection wave in the Union of Comoros in January 2021 and undertook detailed phylogenetic analysis. Results. All the recovered six genomes classified within the 501Y.V2 variant of concern (also known as lineage B.1.351) and appeared to be from 2 sub-clusters with the most recent common ancestor dated 30 th Oct-2020 (95% Credibility Interval: 06 th Sep-2020 to 10 th Dec-2020). Comparison of the Comoros genomes with those of 501Y.V2 variant of concern from other countries deposited into the GISAID database revealed their close association with viruses identified in France and Mayotte (part of the Comoros archipelago and a France, Overseas Department). Conclusions. The recovered genomes, albeit few, confirmed local transmission following probably multiple introductions of the SARS-CoV-2 501Y.V2 variant of concern during the Comoros's first major COVID-19 wave. These findings demonstrate the importance of genomic surveillance and have implications for ongoing control strategies on the islands.

A Possible Role of Remdesivir and Plasma Therapy in the Selective Sweep and Emergence of New SARS-CoV-2 Variants.

Since summer 2020, SARS-CoV-2 strains at the origin of the COVID-19 pandemic have suddenly been replaced by new SARS-CoV-2 variants, some of which are highly transmissible and spread at a high rate. These variants include the Marseille-4 lineage (Nextclade 20A.EU2) in Europe, the 20I/501Y.V1 variant first detected in the UK, the 20H/501Y.V2 variant first detected in South Africa, and the 20J/501Y.V3 variant first detected in Brazil. These variants are characterized by multiple mutations in the viral spike protein that is targeted by neutralizing antibodies elicited in response to infection or vaccine immunization. The usual coronavirus mutation rate through genetic drift alone cannot account for such rapid changes. Recent reports of the occurrence of such mutations in immunocompromised patients who received remdesivir and/or convalescent plasma or monoclonal antibodies to treat prolonged SARS-CoV-2 infections led us to hypothesize that experimental therapies that fail to cure the patients from COVID-19 could favor the emergence of immune escape SARS-CoV-2 variants. We review here the data that support this hypothesis and urge physicians and clinical trial promoters to systematically monitor viral mutations by whole-genome sequencing for patients who are administered these treatments.

Live Virus Neutralisation of the 501Y.V1 and 501Y.V2 SARS-CoV-2 Variants following INO-4800 Vaccination of Ferrets.

The ongoing COVID-19 pandemic has resulted in significant global morbidity and mortality on a scale similar to the influenza pandemic of 1918. Over the course of the last few months, a number of SARS-CoV-2 variants have been identified against which vaccine-induced immune responses may be less effective. These “variants-of-concern” have garnered significant attention in the media, with discussion around their impact on the future of the pandemic and the ability of leading COVID-19 vaccines to protect against them effectively. To address concerns about emerging SARS-CoV-2 variants affecting vaccine-induced immunity, we investigated the neutralisation of representative ‘G614’, ‘501Y.V1’ and ‘501Y.V2’ virus isolates using sera from ferrets that had received prime-boost doses of the DNA vaccine, INO-4800. Neutralisation titres against G614 and 501Y.V1 were comparable, but titres against the 501Y.V2 variant were approximately 4-fold lower, similar to results reported with other nucleic acid vaccines and supported by in silico biomolecular modelling. The results confirm that the vaccine-induced neutralising antibodies generated by INO-4800 remain effective against current variants-of-concern, albeit with lower neutralisation titres against 501Y.V2 similar to other leading nucleic acid-based vaccines.