The reproduction rate of severe acute respiratory syndrome coronavirus 2 different variants recently circulated in human: a narrative review.

SARS-COV-2 is responsible for the current worldwide pandemic, which started on December 2019 in Wuhan, China. On March 2020 World Health Organization announced COVID-19 as the new pandemic. Some SARS-COV-2 variants have increased transmissibility, cause more severe disease (e.g., increased hospitalizations or deaths), are resistant to antibodies produced by the previous infection or vaccination, and there is more difficulty in treatment and diagnosis of them. World Health Organization considered them as SARS-CoV-2 variants of concern. The introductory reproduction rate (R0) is an epidemiologic index of the transmissibility of the virus, defined as the average number of persons infected by the virus after known contact with an infectious person in a susceptible population. An R0 > 1 means that the virus is spreading exponentially, and R0 < 1, means that the outbreak is subsiding. In various studies, the estimated R and VOC growth rates were reported to be greater than the ancestral strains. However, it was also a low level of concordance between the estimated Rt of the same variant in different studies. It is because the R of a variant not only dependent on the biological and intrinsic factors of the virus but also several parameters can affect the R0, including the duration of contagiousness and the likelihood of infection per contact. Evaluation of changes in SARS-CoV-2 has shown that the rate of human-to-human transmission of this virus has increased. Like other viruses with non-human sources which succeeded in surviving in the human population, SARS-CoV-2 has gradually adapted to the human population, and its ability to transmit from human to human has increased. Of course, due to the continuous changes in this virus, it is crucial to survey the rate of transmission of the virus over time.

Engineering viral genomics and nano-liposomes in microfluidic platforms for patient-specific analysis of SARS-CoV-2 variants.

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are continuing to spread globally, contributing to the persistence of the COVID-19 pandemic. Increasing resources have been focused on developing vaccines and therapeutics that target the Spike glycoprotein of SARS-CoV-2. Recent advances in microfluidics have the potential to recapitulate viral infection in the organ-specific platforms, known as organ-on-a-chip (OoC), in which binding of SARS-CoV-2 Spike protein to the angiotensin-converting enzyme 2 (ACE2) of the host cells occurs. As the COVID-19 pandemic lingers, there remains an unmet need to screen emerging mutations, to predict viral transmissibility and pathogenicity, and to assess the strength of neutralizing antibodies following vaccination or reinfection. Conventional detection of SARS-CoV-2 variants relies on two-dimensional (2-D) cell culture methods, whereas simulating the micro-environment requires three-dimensional (3-D) systems. To this end, analyzing SARS-CoV-2-mediated pathogenicity via microfluidic platforms minimizes the experimental cost, duration, and optimization needed for animal studies, and obviates the ethical concerns associated with the use of primates. In this context, this review highlights the state-of-the-art strategy to engineer the nano-liposomes that can be conjugated with SARS-CoV-2 Spike mutations or genomic sequences in the microfluidic platforms; thereby, allowing for screening the rising SARS-CoV-2 variants and predicting COVID-19-associated coagulation. Furthermore, introducing viral genomics to the patient-specific blood accelerates the discovery of therapeutic targets in the face of evolving viral variants, including B1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), c.37 (Lambda), and B.1.1.529 (Omicron). Thus, engineering nano-liposomes to encapsulate SARS-CoV-2 viral genomic sequences enables rapid detection of SARS-CoV-2 variants in the long COVID-19 era.

The Potential Protective Role of GS-441524, a Metabolite of the Prodrug Remdesivir, in Vaccine Breakthrough SARS-CoV-2 Infections.

Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe COVID-19. Remdesivir is a prodrug of the nucleoside analogue GS-441524 which is converted into the active nucleotide triphosphate to disrupt viral genome of the conserved non-structural proteins (NSPs) and thus block viral replication. GS-441524 exerts a number of pharmacological advantages over Remdesivir: (1) it needs fewer conversions for bioactivation to nucleotide triphosphate; (2) it requires only nucleoside kinase, while Remdesivir requires several hepato-renal enzymes, for bioactivation; (3) it is a smaller molecule and has a potency for aerosol and oral administration; (4) it is less toxic allowing higher pulmonary concentrations; (5) it is easier to be synthesized. The current article will focus on the discussion of interactions between GS-441524 and NSPs of VOCs to suggest potential application of GS-441524 in breakthrough SARS-CoV-2 infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s44231-022-00021-4.

Modular nanoarray vaccine for SARS-CoV-2.

The current vaccine development strategies for the COVID-19 pandemic utilize whole inactive or attenuated viruses, virus-like particles, recombinant proteins, and antigen-coding DNA and mRNA with various delivery strategies. While highly effective, these vaccine development strategies are time-consuming and often do not provide reliable protection for immunocompromised individuals, young children, and pregnant women. Here, we propose a novel modular vaccine platform to address these shortcomings using chemically synthesized peptides identified based on the validated bioinformatic data about the target. The vaccine is based on the rational design of an immunogen containing two defined B-cell epitopes from the spike glycoprotein of SARS-CoV-2 and the universal T-helper epitope PADRE. The epitopes were conjugated to short DNA probes and combined with a complementary scaffold strand, resulting in sequence-specific self-assembly. The immunogens were then formulated by conjugation to gold nanoparticles by three methods or by co-crystallization with epsilon inulin. BALB/C mice were immunized with each formulation, and the IgG immune responses and virus neutralizing titers were compared. The results demonstrate that this assembly is immunogenic and generates neutralizing antibodies against wildtype SARS-CoV-2 and the Delta variant.

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication.

We aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the necessary reactions to replicate SARS-CoV-2 in the lung as well as selected peripheral organs. Using this comprehensive host-virus model, we obtained the following key results: 1. The predicted maximal possible virus shedding rate was limited by isoleucine availability. 2. The supported initial viral load depended on the increase in CD4+ T-cells, consistent with the literature. 3. During viral infection, the whole-body metabolism changed including the blood metabolome, which agreed well with metabolomic studies from COVID-19 patients and healthy controls. 4. The virus shedding rate could be reduced by either inhibition of the guanylate kinase 1 or availability of amino acids, e.g., in the diet. 5. The virus variants differed in their maximal possible virus shedding rates, which could be inversely linked to isoleucine occurrences in the sequences. Taken together, this study presents the metabolic crosstalk between host and virus and emphasises the role of amino acid metabolism during SARS-CoV-2 infection, in particular of isoleucine. As such, it provides an example of how computational modelling can complement more canonical approaches to gain insight into host-virus crosstalk and to identify potential therapeutic strategies.

Immunogenicity and reactogenicity against the SARS-CoV-2 variants following heterologous primary series involving CoronaVac, ChAdox1 nCov-19 and BNT162b2 plus BNT162b2 booster vaccination: An open-label randomized study in healthy Thai adults.

We evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules involving BNT162b2 (Pfizer-BioNTech), ChAdOx1 nCoV-19 (AstraZeneca) and CoronaVac (Sinovac) in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. Participants were randomized to one of seven groups that received two-dose homologous BNT162b2 or heterologous combinations of CoronaVac, ChAdOx1 nCoV-19 and BNT162b2, with 4 weeks interval. A total of 210 participants were enrolled, 30 in each group. Median age of participants was 38 (19-60) years, and 108/210 (51.43%) were female. Overall adverse events after the second dose were mild to moderate. We found that groups that received BNT162b2 as second dose induced the highest anti-receptor binding domain IgG response against the ancestral strain [BNT162b2: geometric mean concentration (GMC) 2133-2249 BAU/mL; ChAdOx1 nCoV-19: 851-1201; CoronaVac: 137-225 BAU/mL], neutralizing antibodies (NAb) against Beta and Delta, and interferon gamma response. All groups induced low to negligible NAb against Omicron after second dose. A BNT162b2 booster (third dose) following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens induced >140-fold increase in NAb titers against Omicron. Our findings indicate that heterologous regimens using BNT162b2 as the second dose may be an alternative schedule to maximize immune response. While heterologous two-dose schedules induced low NAb against Omicron, the use of an mRNA vaccine booster dose substantially increased the Omicron response. These findings are relevant for low-income countries considering heterologous primary and booster COVID-19 vaccine schedules.

A Class of Shark-Derived Single-Domain Antibodies can Broadly Neutralize SARS-Related Coronaviruses and the Structural Basis of Neutralization and Omicron Escape.

The identification of a novel class of shark-derived single domain antibodies, named vnarbodies that show picomolar affinities binding to the receptor binding domain (RBD) of Wuhan and Alpha, Beta, Kappa, Delta, Delta-plus, and Lambda variants, is reported. Vnarbody 20G6 and 17F6 have broad neutralizing activities against all these SARS-CoV-2 viruses as well as other sarbecoviruses, including Pangolin coronavirus and Bat coronavirus. Intranasal administration of 20G6 effectively protects mice from the challenges of SARS-CoV-2 Wuhan and Beta variants. 20G6 and 17F6 contain a unique "WXGY" motif in the complementary determining region 3 that binds to a hidden epitope on RBD, which is highly conserved in sarbecoviruses through a novel ß-sheet interaction. It is found that the S375F mutation on Omicron RBD disrupts the structure of ß-strand, thus impair the binding with 20G6. The study demonstrates that shark-derived vnarbodies offer a prophylactic and therapeutic option against most SARS-CoV-2 variants and provide insights into antibody evasion by the Omicron variant.

Development of antibody resistance in emerging mutant strains of SARS CoV-2: Impediment for COVID-19 vaccines.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a highly infectious agent associated with unprecedented morbidity and mortality. A failure to stop growth of COVID-19-linked morbidity rates is caused by SARS-CoV-2 mutations and the emergence of new highly virulent SARS-CoV-2 strains. Several acquired SARS-CoV-2 mutations reflect viral adaptations to host immune defence. Mutations in the virus Spike-protein were associated with the lowered effectiveness of current preventive therapies, including vaccines. Recent in vitro studies detected diminished neutralisation capacity of vaccine-induced antibodies, which are targeted to bind Spike receptor-binding and N-terminal domains in the emerging strains. Lower than expected inhibitory activity of antibodies was reported against viruses with E484K Spike mutation, including B.1.1.7 (UK), P.1 (Brazil), B.1.351 (South African), and new Omicron variant (B.1.1.529) with E484A mutation. The vaccine effectiveness is yet to be examined against new mutant strains of SARS-CoV-2 originating in Europe, Nigeria, Brazil, South Africa, and India. To prevent the loss of anti-viral protection in vivo, often defined as antibody resistance, it is required to target highly conserved viral sequences (including Spike protein) and enhance the potency of antibody cocktails. In this review, we assess the reported mutation-acquiring potential of coronaviruses and compare efficacies of current COVID-19 vaccines against 'parent' and 'mutant' strains of SARS-CoV-2 (Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529)).

Rapid detection of SARS-CoV-2 variants using allele-specific PCR.

Tracking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants through whole genome sequencing (WGS) is vital for effective infection control and prevention (IPC) measures, but can be time-consuming and resource-heavy. We describe an in-house validation of an allele-specific polymerase chain reaction (ASP) variant assay to detect variants of concern (VOC). ASP sensitivity for detecting Delta, Alpha and Beta was 99.45 %, 100 %, and 66.67 %, respectively, compared with WGS. Specificity was 100 % in detecting all three VOC. ASP generated results 1.3 days faster compared with WGS. These findings suggest using variant assays such as ASP may enhance epidemiological surveillance and IPC measures.

The Disease Severity and Clinical Outcomes of the SARS-CoV-2 Variants of Concern.

With the continuation of the pandemic, many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have appeared around the world. Owing to a possible risk of increasing the transmissibility of the virus, severity of the infected individuals, and the ability to escape the antibody produced by the vaccines, the four SARS-CoV-2 variants of Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) have attracted the most widespread attention. At present, there is a unified conclusion that these four variants have increased the transmissibility of SARS-CoV-2, but the severity of the disease caused by them has not yet been determined. Studies from June 1, 2020 to October 15, 2021 were considered, and a meta-analysis was carried out to process the data. Alpha, Beta, Gamma, and Delta variants are all more serious than the wild-type virus in terms of hospitalization, ICU admission, and mortality, and the Beta and Delta variants have a higher risk than the Alpha and Gamma variants. Notably, the random effects of Beta variant to the wild-type virus with respect to hospitalization rate, severe illness rate, and mortality rate are 2.16 (95% CI: 1.19-3.14), 2.23 (95% CI: 1.31-3.15), and 1.50 (95% CI: 1.26-1.74), respectively, and the random effects of Delta variant to the wild-type virus are 2.08 (95% CI: 1.77-2.39), 3.35 (95% CI: 2.5-4.2), and 2.33 (95% CI: 1.45-3.21), respectively. Although, the emergence of vaccines may reduce the threat posed by SARS-CoV-2 variants, these are still very important, especially the Beta and Delta variants.

Molecular Level Dissection of Critical Spike Mutations in SARS-CoV-2 Variants of Concern (VOCs): A Simplified Review.

SARS-CoV-2 virus during its spread in the last one and half year has picked up critical changes in its genetic code i.e. mutations, which have leads to deleterious epidemiological characteristics. Due to critical role of spike protein in cell entry and pathogenesis, mutations in spike regions have been reported to enhance transmissibility, disease severity, possible escape from vaccine-induced immune response and reduced diagnostic sensitivity/specificity. Considering the structure-function impact of mutations, understanding the molecular details of these key mutations of newly emerged variants/lineages is of urgent concern. In this review, we have explored the literature on key spike mutations harbored by alpha, beta, gamma and delta 'variants of concern' (VOCs) and discussed their molecular consequences in the context of resultant virus biology. Commonly all these VOCs i.e. B.1.1.7, B.1.351, P.1 and B.1.617.2 lineages have decisive mutation in Receptor Binding Motif (RBM) region and/or region around Furin cleavage site (FCS) of spike protein. In general, mutation induced disruption of intra-molecular interaction enhances molecular flexibility leading to exposure of spike protein surface in these lineages to make it accessible for inter-molecular interaction with hACE2. A disruption of spike antigen-antibody inter-molecular interactions in epitope region due to the chemical nature of substituting amino acid hampers the neutralization efficacy. Simplified surveillance of mutation induced changes and their consequences at molecular level can contribute in rationalizing mutation's impact on virus biology. It is believed that molecular level dissection of these key spike mutation will assist the future investigations for a more resilient outcome against severity of COVID-19.