Covid19-Sources

The continuous emergence of highly immune evasive SARS-CoV-2 variants, like XBB.1.5 and XBB.1.16, highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by wildtype (WT)-based vaccination would compromise the antibody response to Omicron-based boosters. Vaccination strategies that can counter immune imprinting are critically needed. In this study, we investigated the degree and dynamics of immune imprinting in mouse models and human cohorts, especially focusing on the role of repeated Omicron stimulation. Our results show that in mice, the efficacy of single Omicron-boosting is heavily limited by immune imprinting, especially when using variants antigenically distinct from WT, like XBB, while the concerning situation could be largely mitigated by a second Omicron booster. Similarly, in humans, we found that repeated Omicron infections could also alleviate WT-vaccination-induced immune imprinting and generate high neutralizing titers against XBB.1.5 and XBB.1.16 in both plasma and nasal mucosa. By isolating 781 RBD-targeting mAbs from repeated Omicron infection cohorts, we revealed that double Omicron exposure alleviates immune imprinting by generating a large proportion of highly matured and potent Omicron-specific antibodies. Importantly, epitope characterization using deep mutational scanning (DMS) showed that these Omicron-specific antibodies target distinct RBD epitopes compared to WT-induced antibodies, and the bias towards non-neutralizing epitopes observed in single Omicron exposures due to imprinting was largely restored after repeated Omicron stimulation, together leading to a substantial neutralizing epitope shift. Based on the DMS profiles, we identified evolution hotspots of XBB.1.5 RBD and demonstrated the combinations of these mutations could further boost XBB.1.5's immune-evasion capability while maintaining high ACE2 binding affinity. Our findings suggest the WT component should be abandoned when updating COVID-19 vaccine antigen compositions to XBB lineages, and those who haven't been exposed to Omicron yet should receive two updated vaccine boosters. ### Competing Interest Statement X.S.X. and Y.C. are inventors on the provisional patent applications of BD series antibodies, which include BD55-5514 (SA55) and mAbs from Omicron infection convalescents. X.S.X. and Y.C. are founders of Singlomics Biopharmaceuticals. Other authors declare no competing interests.

Our findings also suggest the WT component should be abandoned when updating COVID-19 vaccine antigen compositions to XBB lineages, and those who haven't been exposed to Omicron yet should receive two updated vaccine boosters. 31/n— Yunlong Richard Cao (@yunlong_cao) May 3, 2023

The same letter to NEJM, for the receipt of the booster recently, VE against hospitalization after just 2 months (8 wks): estimated 30% (Supplementary Appendix)https://t.co/M5GK5Pe8HP pic.twitter.com/WtuvYRG503— Young Kos (@janko_js) April 12, 2023

This cross-sectional study evaluates IgG antibody levels in children and adolescents in Germany following SARS-CoV-2 infection.

Geruchs- und Geschmacksstörungen sind häufige Langzeitfolgen einer COVID-19-Erkrankung. Wie lange und bei wie vielen Betroffenen diese anhalten, wurde in einer Metaanalyse untersucht.

Six-month cardiac outcomes in children with multisystem inflammatory syndrome in children

Objectives To determine the clinical sequelae of long covid for a year after infection in patients with mild disease and to evaluate its association with age, sex, SARS-CoV-2 variants, and vaccination status. Design Retrospective nationwide cohort study. Setting Electronic medical records from an Israeli nationwide healthcare organisation. Population 1 913 234 Maccabi Healthcare Services members of all ages who did a polymerase chain reaction test for SARS-CoV-2 between 1 March 2020 and 1 October 2021. Main outcome measures Risk of an evidence based list of 70 reported long covid outcomes in unvaccinated patients infected with SARS-CoV-2 matched to uninfected people, adjusted for age and sex and stratified by SARS-CoV-2 variants, and risk in patients with a breakthrough SARS-CoV-2 infection compared with unvaccinated infected controls. Risks were compared using hazard ratios and risk differences per 10 000 patients measured during the early (30-180 days) and late (180-360 days) time periods after infection. Results Covid-19 infection was significantly associated with increased risks in early and late periods for anosmia and dysgeusia (hazard ratio 4.59 (95% confidence interval 3.63 to 5.80), risk difference 19.6 (95% confidence interval 16.9 to 22.4) in early period; 2.96 (2.29 to 3.82), 11.0 (8.5 to 13.6) in late period), cognitive impairment (1.85 (1.58 to 2.17), 12.8, (9.6 to 16.1); 1.69 (1.45 to 1.96), 13.3 (9.4 to 17.3)), dyspnoea (1.79 (1.68 to 1.90), 85.7 (76.9 to 94.5); 1.30 (1.22 to 1.38), 35.4 (26.3 to 44.6)), weakness (1.78 (1.69 to 1.88), 108.5, 98.4 to 118.6; 1.30 (1.22 to 1.37), 50.2 (39.4 to 61.1)), and palpitations (1.49 (1.35 to 1.64), 22.1 (16.8 to 27.4); 1.16 (1.05 to 1.27), 8.3 (2.4 to 14.1)) and with significant but lower excess risk for streptococcal tonsillitis and dizziness. Hair loss, chest pain, cough, myalgia, and respiratory disorders were significantly increased only during the early phase. Male and female patients showed minor differences, and children had fewer outcomes than adults during the early phase of covid-19, which mostly resolved in the late period. Findings remained consistent across SARS-CoV-2 variants. Vaccinated patients with a breakthrough SARS-CoV-2 infection had a lower risk for dyspnoea and similar risk for other outcomes compared with unvaccinated infected patients. Conclusions This nationwide study suggests that patients with mild covid-19 are at risk for a small number of health outcomes, most of which are resolved within a year from diagnosis. Data supporting the findings of this study came from Maccabi Healthcare Services. Restrictions apply to the availability of these data, and they are therefore not publicly available. Owing to restrictions, these data can be accessed only by request to the authors and/or Maccabi Healthcare Services.

This case-control study aims to quantify 1-year outcomes among individuals meeting a post–COVID-19 condition definition compared with a control group of individuals without COVID-19.

The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site—the FCS, loop length, and glycosylation—are required for efficient SARS-CoV-2 replication and pathogenesis.

Patients with severe COVID-19 requiring mechanical ventilation are 16 times more likely to develop ventricular tachycardia within six months compared to their peers without severe infection, according to research presented at EHRA 2023, a scientific congress of the European Society of Cardiology.

Several teams have been publishing global estimates of excess deaths during the COVID-19 pandemic. Here, we examine potential flaws and underappreciated sources of uncertainty in global excess death calculations. Adjusting for changing population age structure is essential. Otherwise, excess deaths are markedly overestimated in countries with increasingly aging populations. Adjusting for changes in other high-risk indicators, such as residence in long-term facilities, may also make a difference. Death registration is highly incomplete in most countries; completeness corrections should allow for substantial uncertainty and consider that completeness may have changed during pandemic years. Excess death estimates have high sensitivity to modelling choice. Therefore different options should be considered and the full range of results should be shown for different choices of pre-pandemic reference periods and imposed models. Any post-modelling corrections in specific countries should be guided by pre-specified rules. Modelling of all-cause mortality (ACM) in countries that have ACM data and extrapolating these models to other countries is precarious; models may lack transportability. Existing global excess death estimates underestimate the overall uncertainty that is multiplicative across diverse sources of uncertainty. Informative excess death estimates require risk stratification, including age groups and ethnic/racial strata. Data to-date suggest a death deficit among children during the pandemic and marked socioeconomic differences in deaths, widening inequalities. Finally, causal explanations require great caution in disentangling SARS-CoV-2 deaths, indirect pandemic effects and effects from measures taken. We conclude that excess deaths have many uncertainties, but globally deaths from SARS-CoV-2 may be the minority of calculated excess deaths.

This paper examines how households adjusted their consumption behavior in response to COVID- 19 infection risk during the early phase of the pandemic. We use a monthly consumption survey specifically designed by the German Statistical Office covering the second wave of COVID-19 in- fections from September to November 2020. Households reduced their consumption expenditures on durables and social activities by, respectively, 24 percent and 36 percent in response to one hun- dred extra infections per one hundred thousand inhabitants per week. The effect was concentrated among the elderly, whose mortality risk from COVID-19 infection was arguably the highest.

This study monitored indoor environmental data in 144 classrooms in 31 schools in the Midwestern United States for two consecutive days every fall, wi…

David Needham, professor of mechanical engineering and materials science at Duke University, has demonstrated that a metabolic inhibiting drug called niclosamide, traditionally used to treat gut parasites, ...

Jeremy Nicholson is a world-leader in understanding how disease interacts with people’s genetic make-up. But when he got long COVID, he had a whole new level of insight.

Published evidence indicates that Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection causes endothelial cell (EC) injury in the Coronavirus Disease 2019 (COVID-19). Endothelial junctions (EJ) are crucial to maintain EC integrity and normal microvascular functions due to the adhesive properties of Vascular endothelial (VE)-cadherin to glue EC together. Here we report studies in vitro and in vivo that indicate VE-cadherin to be a target for cleavage by ACE2. We have identified that the extracellular domain of VE-cadherin contains these two amino acid sequences at the positions 256P-F257 and 321PMKP-325L for ACE2 substrate recognition. Incubation of purified sVE with ACE2 revealed a dose-dependent loss of immunoreactivity detected with an antibody directed against the Extracellular domain 1 (EC1) domain of sVE. We confirmed the presence of ACE2 on ECs using immunofluorescence studies, and by western blotting on ECs extracts. We also present evidence from patients with severe COVID-19 disease for a circulating form of ACE2. Its apparent molecular weight of 70 kDa is in agreement with a previously described extracellular form of ACE2 bearing the catalytic site of the ectopeptidase. Consistent with the experimental evidence for our hypothesis, the level of circulating soluble VE-cadherin fragments was increased in the blood of patients with severe COVID-19 disease. Further studies are needed to determine if increased circulating fragments of ACE2 and VE-cadherin may contribute to the future development of post-acute COVID-19 syndrome characterized by vascular endothelial injury, hypoxia, and inflammatory state. Impact Statement SARS-CoV-2 infection promotes vascular dysfunction but the processes are not completely understood. The vascular endothelium is composed of a monolayer of endothelial cells (ECs) that exclusively express VE-cadherin at adherens junctions (AJs). The published structure of VE-cadherin has revealed crucial residues in the domains EC1-2 for ECs adhesiveness. In this report, we demonstrate for the first time that VE-cadherin is a target for ACE2 ectoenzyme in the domains EC2-3. In addition, in COVID-19 patients’ blood, we identify truncated forms of ACE2 and VE-cadherin that are correlated with severe SARS-CoV-2 infection. Because the turnover rate of ECs is very low, this could provide part of the explanation for Long CoVID-19 disease. These exciting results highlight the role of proteases and AJs, and the need for continuing efforts to elucidate whether these circulating proteins might be of prime significance for clinicians to facilitate personalized medicine. ### Competing Interest Statement The authors have declared no competing interest.

Scientific Reports - Cognitive impairment in young adults with post COVID-19 syndrome

Stillbirth is a recognized complication of COVID-19 in pregnant women that has recently been demonstrated to be caused by SARS-CoV-2 infection of the placenta. Multiple global studies have found that the placental pathology present in cases of stillbirth consists of a combination of concurrent destructive findings that include increased fibrin deposition that typically reaches the level of massive perivillous fibrin deposition, chronic histiocytic intervillositis, and trophoblast necrosis. These 3 pathologic lesions, collectively termed SARS-CoV-2 placentitis, can cause severe and diffuse placental parenchymal destruction that can affect 75% of the placenta, effectively rendering it incapable of performing its function of oxygenating the fetus and leading to stillbirth and neonatal death via malperfusion and placental insufficiency. Placental infection and destruction can occur in the absence of demonstrable fetal infection. Development of SARS-CoV-2 placentitis is a complex process that may have both an infectious and immunologic basis. An important observation is that in all reported cases of SARS-CoV-2 placentitis causing stillbirth and neonatal death, the mothers were unvaccinated. SARS-CoV-2 placentitis is likely the result of an episode of SARS-CoV-2 viremia at some time during the pregnancy. This article discusses clinical and pathologic aspects of the relationship between maternal COVID-19 vaccination, SARS-CoV-2 placentitis, and perinatal death.

This cohort study describes trends in severe outcomes among patients hospitalized with COVID-19 from March 2020 to May 2022 in the Canadian Nosocomial Infection Surveillance Program.

Background and Objectives: Post-COVID condition (PCC) is common and often involves neuropsychiatric symptoms. This study aimed to use blood-oxygenation-level-dependent functional MRI (BOLD-fMRI) to assess whether participants with PCC had abnormal brain activation during working memory (WM), and whether the abnormal brain activation could predict cognitive performance, motor function or psychiatric symptoms. Methods: The PCC participants had documented COVID-19 at least 6 weeks prior to enrollment. Healthy control participants had no prior history of COVID-19 and negative tests for SARS-CoV-2. Participants were assessed using three NIH-Toolbox (NIHTB) batteries for Cognition (NIHTB-CB), Emotion (NIHTB-EB) and Motor function (NIHTB-MB), as well as selected tests from the Patient-Reported Outcomes Measurement Information System (PROMIS). Each had BOLD-fMRI at 3 Tesla, during WM (N-back) tasks with increasing attentional/WM load. Results: 169 participants were screened; 50 fulfilled the study criteria and had complete and usable datasets for this cross-sectional cohort study. 29 PCC participants were diagnosed with COVID-19 242±156 days earlier, had similar ages (42±12 vs. 41±12 years), gender proportion (65% vs. 57%), racial/ethnic distribution, handedness, education, and socioeconomic status, as the 21 uninfected healthy controls. Despite the high prevalence of memory (79%) and concentration (93%) complaints, the PCC group had similar and normal performance on the NIHTB-CB as the controls. However, PCC participants had greater brain activation than the controls across the network (p-FDR-corrected=0.003, T-max=4.17), with greater activation in the right superior frontal gyrus (p=0.009, Cohen’s- d =0.81, 95%CI [0.15-1.46]) but lesser deactivation in the default mode regions (p=0.001, d =1.03, 95%CI [0.61-1.99]). Compared to controls, PCC participants also had poorer dexterity and endurance on the NIHTB-MB, higher T-scores for negative affect and perceived stress, but lower T-scores for psychological well-being on the NIHTB-EB, as well as more pain symptoms and poorer mental and physical health on measures from PROMIS. Greater brain activation also predicted poorer scores on measures that were abnormal on the NIHTB-EB. Discussion: PCC participants with neuropsychiatric symptoms demonstrated compensatory neural processes with greater usage of alternate brain regions, and reorganized networks, to maintain normal performance during WM tasks. BOLD-fMRI was sensitive for detecting brain abnormalities that correlated with various quantitative neuropsychiatric symptoms.

SARS-CoV-2 Omicron variants emerged in 2022 with 30 novel amino acid mutations in the spike protein alone. While most studies focus on the impact of receptor binding domain changes, mutations in the C-terminal of S1 (CTS1), adjacent to the furin cleavage site, have largely been ignored. In this study, we examined three Omicron mutations in CTS1: H655Y, N679K, and P681H. Generating a SARS-CoV-2 triple mutant (YKH), we found that the mutant increased spike processing, consistent with prior reports for H655Y and P681H individually. Next, we generated a single N679K mutant, finding reduced viral replication in vitro and less disease in vivo . Mechanistically, the N679K mutant had reduced spike protein in purified virions compared to wild-type; spike protein decreases were further exacerbated in infected cell lysates. Importantly, exogenous spike expression also revealed that N679K reduced overall spike protein yield independent of infection. Together, the data show that N679K is a loss-of-function mutation reducing overall spike levels during omicron infection, which may have important implications for disease severity, immunity, and vaccine efficacy. One Sentence Summary Spike substitution N679K attenuates SARS-CoV-2 Omicron variants by decreasing spike protein and has potential implications for immunity and vaccine efficacy. ### Competing Interest Statement VDM has filed a patent on the reverse genetic system and reporter SARS-CoV-2. MNV and VDM have filed a provisional patent on a stabilized SARS-CoV-2 spike protein. Other authors declare no competing interests.

Nature Immunology - Phetsouphanh and colleagues show that individuals with long COVID have persistent activation of the innate and adaptive immune system at 8 months after infection and define a...

@JadeKhalife: Damage to the immune system has been an ongoing debate throughout this pandemic. Very few warned of this early on (& some abused!). But it was logical to avoid finding out (preventing infection). There...…

1/7 SARS-CoV-2 upregulates endogenous opioids& influences behaviorIt upregulates OPRPN, which encodes opiorphinOpiorphin?https://t.co/8fxVdYGobX* painkilling effect greater than morphine* anti-depressant* shown to be antipanic agent (panicolytic)https://t.co/4StXu0lBMT— 🔴 tohmes (@tohmes1) March 31, 2023

Human-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interaction can have an array of various outcomes-it could be mortal, morbid or merely carrying minor health consequences. The very rapid global spread has raised the issue whether there are further multi-dimensional consequences of …

Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavi …

Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million ind…

COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent mes…

Background: Post-acute sequelae of COVID, termed “Long COVID”, is an emerging chronic illness potentially affecting ~10% of those with COVID-19. We so

We assessed effectiveness of the BNT162b2 vaccine against infection with the B.1.1.529 (Omicron) variant (mostly BA.1 subvariant), among children 5-11 years of age in Israel. Using a matched case-control design, we matched SARS-CoV-2-positive children (cases) and SARS-CoV-2-negative children (contro …