08 February, 2021

Emergence of SARS-CoV-2 stains harbouring the signature mutations of both A2a and A3 clade -

SARS-CoV-2 strains with both high transmissibility and potential to cause asymptomatic infection is expected to gain selective advantage over other circulating strains having either high transmissibility or ability to trigger asymptomatic infection. The D614G mutation in spike glycoprotein, the characteristic mutation A2a clade, has been associated with high transmissibility, whereas the A3 clade specific mutation L37F in NSP6 protein has been linked with asymptomatic infection. In this study, we performed a comprehensive mutational analysis of 3,77,129 SARS-CoV-2 genomes collected during January, 2020 to December, 2020 from all across the world for the presence of D614G and L37F mutations. Out of 3,77,129 SARS-CoV-2 strains analysed, 14, 598 (3.87%) were found to harbour both the D614G and L37F mutations. Majority of these double mutant SARS-CoV-2 strains were identified in Europe (11097) followed by North America (1915), Asia (980), Oceania (242), Africa (219), and South America (145). Geographical root surveillance revealed their first emergence during February-March in all the six continents. Temporal prevalence analysis from February, 2020 to December, 2020 showed a gradual upsurge in their frequencies worldwide, which strongly demonstrated the adaptive selection of these double mutants. Evolutionary analysis depicted that these double mutants emerged as a new clade in the dendrogram (named as A2a/3), and were sub-divided into four distinct clusters (Cluster I, II, III and IV) according to different sets of coexisting mutations. The frequency distribution pattern showed the global predominance of cluster III (41.42%), followed by cluster IV (23.31%), cluster II (21.02%) and cluster I (14.25%). Overall, our study highlighted the emergence of a unique phylogenetic clade encompassing the double-mutant SARS-CoV-2 strains which may provide a fitness advantage during course of virus evolution.

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Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial -

Background Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. Methods We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Conclusion Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.

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Implementation of an in-house real-time reverse transcription-PCR assay for the rapid detection of the SARS-CoV-2 Marseille-4 variant -

Introduction. The SARS-CoV-2 pandemic has been associated with the occurrence since summer 2020 of several viral variants that overlapped or succeeded each other in time. Those of current concern harbor mutations within the spike receptor binding domain (RBD) that may be associated with viral escape to immune responses. In our geographical area a viral variant we named Marseille-4 harbors a S477N substitution in this RBD. Materials and methods. We aimed to implement an in-house one-step real-time reverse transcription-PCR (qPCR) assay with a hydrolysis probe that specifically detects the SARS-CoV-2 Marseille-4 variant. Results. All 6 cDNA samples from Marseille-4 variant strains identified in our institute by genome next-generation sequencing (NGS) tested positive using our Marseille-4 specific qPCR, whereas all 32 cDNA samples from other variants tested negative. In addition, 39/42 (93%) respiratory samples identified by NGS as containing a Marseille-4 variant strain and 0/26 samples identified as containing non-Marseille-4 variant strains were positive. Finally, 1,585/2,889 patients SARS-CoV-2-diagnosed in our institute, 10/277 (3.6%) respiratory samples collected in Algeria, and none of 207 respiratory samples collected in Senegal, Morocco, or Lebanon tested positive using our Marseille-4 specific qPCR. Discussion. Our in-house qPCR system was found reliable to detect specifically the Marseille-4 variant and allowed estimating it is involved in more than half of our SARS-CoV-2 diagnoses since December 2020. Such approach allows the real-time surveillance of SARS-CoV-2 variants, which is warranted to monitor and assess their epidemiological and clinical characterics based on comprehensive sets of data.

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SARS-CoV-2 Transmission Risk from sports Equipment (STRIKE) -

OBJECTIVES: To investigate the potential of shared sporting equipment as transmission vectors of SARS-CoV-2 during the reintroduction of sports such as soccer, rugby, cricket, tennis, golf and gymnastics. SETTING: Laboratory based live SARS-CoV-2 virus study. INTERVENTIONS: Ten different types of sporting equipment were inoculated with 40μl droplets containing clinically relevant high and low concentrations of live SARS-CoV-2 virus. Materials were then swabbed at time points relevant to sports (1, 5, 15, 30, 90 minutes). The amount of live SARS-CoV-2 recovered at each time point was enumerated using viral plaque assays, and viral decay and half-life was estimated through fitting linear models to log transformed data from each material. MAIN OUTCOME MEASURE: The primary outcome measure was quantification of retrievable SARS-CoV-2 virus from each piece of equipment at pre-determined time points. RESULTS: At one minute, SARS-CoV-2 virus was recovered in only seven of the ten types of equipment with the low dose inoculum, one at five minutes and none at 15 minutes. Retrievable virus dropped significantly for all materials tested using the high dose inoculum with mean recovery of virus falling to 0.74% at 1 minute, 0.39% at 15 minutes and 0.003% at 90 minutes. Viral recovery, predicted decay, and half-life varied between materials with porous surfaces limiting virus transmission. CONCLUSIONS: This study shows that there is an exponential reduction in SARS-CoV-2 recoverable from a range of sports equipment after a short time period, and virus is less transferrable from materials such as a tennis ball, red cricket ball and cricket glove. Given this rapid loss of viral load and the fact that transmission requires a significant inoculum to be transferred from equipment to the mucous membranes of another individual it seems unlikely that sports equipment is a major cause for transmission of SARS-CoV-2. These findings have important policy implications in the context of the pandemic and may promote other infection control measures in sports to reduce the risk of SARS-CoV-2 transmission and urge sports equipment manufacturers to identify surfaces that may or may not be likely to retain transferable virus.

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Conspiracy theories and their societal effects during the COVID-19 pandemic -

During COVID-19, conspiracy theories were intensely discussed in the media. Believing in specific conspiracy theories (i.e., explanations for events based on powerholders’ secret arrangements) as well as the general tendency to believe in conspiracy theories—a so-called conspiracy mentality—have been found to predict cognition and behavior with negative societal effects, such as low institutional trust. Accordingly, believing in conspiracy theories around COVID-19 should work against institutional trust, support of governmental regulations and their adoption, as well as societal engagement (e.g., helping members of risk groups). We tested these predictions in a national random sample, an experimental study, and a longitudinal study (Ntotal = 1,213; all studies preregistered). Indeed, believing in and being confronted with a COVID-19 conspiracy theory decreased institutional trust, support of governmental regulations, adoption of physical distancing, and—to some extent—social engagement. Findings underscore that conspiracy theories have severe societal effects in the context of COVID-19.

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Information Dissemination and the COVID-19 Pandemic: The Relationship between Different Information Sources and Symptoms of Psychopathology -

The 2020-2021 COVID-19 pandemic has added to the mental health strain on individuals and groups across the world. Viral mitigation protocols and viral spread affect millions every day, but to widely different degrees. How individuals gather information about the pandemic might have an effect on levels of mental distress in the population. In this cross-sectional and representative study of the adult population of Norway, findings suggest that information gathered through newspapers and social media are the information pathways with the strongest association to symptoms of anxiety, depression and health anxiety with small to medium effect sizes. However, avoiding information about the pandemic had larger effect sizes related to symptoms of psychopathology than acquiring information about the pandemic from any source. The results suggest that to reach those who avoid pandemic news is an important goal, both to ensure the population as a whole gets relevant information regarding current viral mitigation protocols, that may in turn alleviate stress, and thus reduce the likelihood of viral transmission. The spread of pandemic misinformation on social media and the internet must be buffered, and successful interventions against misinformation may affect the mental health of the population.

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Underweighting of rare events in social interactions and its implications to the design of voluntary health applications -

Research on small decisions from experience suggests that people often behave as if they underweight rare events and choose the options that are frequently better. In a pandemic, this tendency implies complacency and reckless behavior. Furthermore, behavioral contagion exacerbates this problem. In two pre-registered experiments (Ntotal = 312), we validate these predictions and highlight a potential solution. Groups of participants played a repeated social game in one of two versions. In the basic version, people clearly preferred the dangerous reckless behavior that was better most of the time over the safer responsible behavior. In the augmented version, we gave participants an additional alternative abstracting the use of an application that frequently saves time but can sometimes have high costs. This alternative was stochastically dominated by the option abstracting the responsible choice and was thus normatively “irrelevant” to the decision participants made. Nevertheless, most people chose the new (“irrelevant”) alternative, providing the first clear demonstration of underweighting of rare events in fully described social games. We discuss public policies that can make the responsible use of health applications better most of the time, thus helping them get traction despite being voluntary. In one field demonstration of this idea amid the COVID-19 pandemic, usage rates of a contact tracing application among nursing home employees more than tripled when using the app also started saving them little time on a daily basis, and the high usage rates sustained over at least four weeks.

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Social Inequalities in Mobility During and Following the COVID-19 associated lockdown of the Madrid Metropolitan Area in Spain -

Spain has been one of the most affected regions by the COVID-19 worldwide, and Madrid its most affected city. In response to this, the Spanish government enacted a strict lockdown in late March, that was gradually eased until June. We explored differentials in mobility by area-level deprivation in the functional area of Madrid, before, during, and after the COVID-19 lockdown. We used cell phone-derived mobility indicators (% of the population leaving their area) from the National Institute of Statistics (INE), and a composite measure of deprivation from the Spanish Society of Epidemiology (SEE). We computed changes in mobility with respect to pre-pandemic levels, and explored spatial patterns and associations with deprivation. We found that levels of mobility before COVID-19 were slightly higher in areas with lower deprivation. The economic hibernation period resulted in very strong declines in mobility, most acutely in low deprivation areas. These differences weakened during the re-opening, and levels of mobility were similar by deprivation once the lockdown was lifted. Given the existence of important socioeconomic differentials in COVID-19 exposure, it is key to ensure that these interventions do not widen existing social inequalities.

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Mask-wearing and social distancing: Evidence from a video-observational and natural-experimental study of public space behavior during the COVID-19 pandemic -

Background: Face masks have been widely employed as a personal protective measure during the COVID-19 pandemic. However, concerns remain that masks create a false sense of security that reduces adherence to other public health measures, including social distancing. Purpose: This paper tested whether mask-wearing was negatively associated with social distancing compliance. Methods: In two studies, we combined video-observational records of public mask-wearing in two Dutch cities with a natural-experimental approach to evaluate the effect of an area-based mask mandate. Results: We found no observational evidence of an association between mask-wearing and social distancing (Study 1: p = .398; Study 2: p = .511), but found a positive link between crowding and social distancing violations (Study 1: p < .001; Study 2: p < .001). Our natural-experimental analysis showed that an area-based mask mandate did not significantly affect social distancing or crowding levels (Study 2: p = .781 and p = .126, respectively). Conclusions: Our results alleviate the concern that mask use reduces social distancing compliance or increases crowding levels. On the other hand, crowding reduction may be a viable strategy to mitigate social distancing violations.

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University Students’ Adherence to the COVID-19-guidelines: A Qualitative Study on Facilitators and Barriers -

Objective. This study aims to explore students’ adherence and reasons behind the (non)adherence to the COVID-19-regulations within a university setting. Methods. A total of 33 students participated in on-site and online focus group interviews (k=8). Discussed topics included the general COVID-19-guidelines of the university, including keeping ≥1.5 m distance, staying at home and getting tested when having symptoms, and wearing facemasks. Additionally, education and psychosocial wellbeing in the times of COVID-19 were discussed. We also conducted online interviews with stewards (2 focus group interviews and 1 individual interview) and security/crowd control officials (1 focus group interview) to learn more about students’ (non)adherence behaviors. Results. The findings of this study show that the interviewed students were willing to adhere to the guidelines within the university buildings. They mentioned several facilitators (e.g., the infrastructure of the buildings and staff) and barriers (e.g., being together with friends and difficulties with telling others to follow the regulations) for their compliance behaviors. Some students also stated that they are not afraid of COVID-19 because they are young, while others adhered to the regulations to protect vulnerable people. Conclusion. To create a safe environment within the university and alleviate the spread of the virus, future interventions require targeting the determinants of students’ non-adherence behaviors, such as lower risk perception (e.g., being young and no perceived threat/low vulnerability) and lower self-efficacy (e.g., for keeping distance, to determine symptoms for testing/isolating and to correct others).

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Self-assembling SARS-CoV-2 nanoparticle vaccines targeting the S protein induces protective immunity in mice -

The spike (S), a homotrimer glycoprotein, is the most important antigen target in the research and development of SARS-CoV-2 vaccine. There is no doubt that fully simulating the advanced structure of this homotrimer in the subunit vaccine development strategy is the most likely way to improve the immune protective effect of the vaccine. In this study, the preparation strategies of S protein receptor-binding domain (RBD) trimer, S1 region trimer, and ectodomain (ECD) trimer nanoparticles were designed based on ferritin nanoparticle self-assembly technology. The Bombyx mori baculovirus expression system was used to prepare these three nanoparticle vaccines with high expression levels in the silkworm. The immune results of mice show that the nanoparticle vaccine prepared by this strategy can not only induce an immune response by subcutaneous administration but also effective by oral administration. Given the stability of these ferritin-based nanoparticles vaccine, easy-to-use and low-cost oral immunization strategy can make up for the vaccination blind areas caused by the shortage of ultralow-temperature equipment and medical resources in underdeveloped areas. And the oral vaccine is also a very potential candidate to cut off the spread of SARS-CoV-2 in domestic and farmed animals, especially in stray and wild animals.

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SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability -

COVID-19 patients may exhibit neuropsychiatric and neurological symptoms. Here we found that anxiety and cognitive impairment are manifested by 28-56% of COVID-19 convalescent individuals with mild respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 25% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. We also found that neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons and in the biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and consequently leads to neuronal death or dysfunction. These processes are likely to contribute to the structural and functional alterations in the brain of COVID-19 patients.

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Insights on SARS-CoV-2’s Mutations for Evading Human Antibodies: Sacrifice and Survival -

Recent mutations on the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein have been manifested as the major cause of the wide and rapid spread of the virus. Especially, the variant B.1.351 in South Africa with the hallmark of triple mutations (N501Y, K417N and E484K) is worrisome. Quickly after the outbreak of this new variant, several studies showed that both N501Y and E484K can enhance the binding between RBD and the human ACE2 receptor. However, the mutation K417N seems to be unfavorable because it removes one interfacial salt-bridge. So far, it is still not well understood why the K417N mutation is selected in the viral evolution. Here, we show that despite the loss in the binding affinity (1.48 kcal/mol) between RBD and ACE2 the K417N mutation abolishes a buried interfacial salt-bridge between RBD and the neutralizing antibody CB6 and thus substantially reduces their binding energy by 9.59 kcal/mol, facilitating the variants to efficiently elude CB6 (as well as many other antibodies). Thus, when proliferating from person to person the virus might have adapted to the human immune system through evasive mutations. Taking into account limited and relevant experimental works in the field, we show that our theoretical predictions are consistent with existing experimental findings. By harnessing the revealed molecular mechanism for variants, it becomes feasible to redesign therapeutic antibodies accordingly to make them more efficacious.

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The local topological free energy of the SARS-CoV-2 Spike protein -

The novel coronavirus SARS-CoV-2 infects human cells using a mechanism that involves binding and structural rearrangement of its spike protein. Understanding protein rearrangement and identifying specific residues where mutations affect protein rearrangement has attracted a lot of attention for drug development. We use a mathematical method introduced in (Baldwin2021) to associate a local topological/geometrical free energy along the SARS-CoV-2 spike protein backbone. Our results show that the total local topological free energy of the SARS-CoV-2 spike protein monotonically decreases from pre-to post-fusion and that its distribution along the protein domains is related to their activity in protein rearrangement. By using density functional theory (DFT) calculations with inclusion of solvent effects, we show that high local topological free energy conformations are unstable compared to those of low topological free energy. By comparing to experimental data, we find that the high local topological free energy conformations in the spike protein are associated with mutations which have the largest experimentally observed effect to protein rearrangement.

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Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection -

The newly emerged SARS-CoV-2 caused a global pandemic with astonishing mortality and morbidity. The mechanisms underpinning its highly infectious nature remain poorly understood. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. Screening a SARS-CoV-2 expression library identified ORF7b and ORF8 that suppressed IFN induction via inducing the deamidation of interferon regulatory factor 3 (IRF3). Deamidated IRF3 fails to bind the promoters of classic IRF3-responsible genes, thus muting IFN induction. Conversely, a shRNA-mediated screen focused on cellular glutamine amidotransferases corroborated that CTPS1 deamidates IRF3 to inhibit IFN induction. Functionally, ORF7b and ORF8 activate CTPS1 to promote de novo CTP synthesis while shutting down IFN induction. De novo synthesis of small-molecule inhibitors of CTPS1 enabled CTP depletion and IFN induction in SARS-CoV-2 infection, thus impeding SARS-CoV-2 replication. Our work uncovers a strategy that a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means for developing antiviral therapy that would be resistant to SARS-CoV-2 mutation.

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Covid-19 Sentry

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