27 May, 2021

Unpacking the black box: Empirical evidence to understand the human factor for effective rapid testing against SARS-CoV2 -

SARS-CoV-2 rapid antigen point-of-care (PoC) and home tests are available to laypeople. This raises questions regarding the drivers and barriers of people’s willingness to use tests, their understanding of test results and the psychological and behavioural consequences of positive and negative test results. Four cross-sectional data collections, including survey items, open text answers and three experiments, were therefore conducted between December 2020 and March 2021, involving 4,026 German participants. The majority was willing to use PoC or home tests. People will be more likely to use tests when they are inexpensive and easy to use or when they are a necessary (given low infection rates) for obtaining access to public and social life. However, people urgently need information about what a test result means and how they should behave. Recommendations based on the present findings could make rapid testing a successful pillar of pandemic management.

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Risk of Developing Posttraumatic Stress Disorder in Severe COVID-19 Survivors, their Families and Frontline Healthcare Workers: What Should Mental Health Specialists Prepare For? -

Given the high coronavirus disease 2019 (COVID-19) mortality, this disease may be a life-threatening event, especially for individuals at high risk of complications. Therefore, in the article we try to answer two questions that are relevant to public mental health: Can we define groups who are at higher risk of developing pandemic-related PTSD? How can health specialists prepare for it? Given the results of previous research on PTSD in epidemic (e.g. SARS) survivors, we suggest that mental health professionals in countries touched by the pandemic should prepare for an increase in the PTSD prevalence, specifically in: individuals who have had severe COVID-19; family members of these patients and of patients who have died; and frontline healthcare workers witnessing COVID-19 patients’ sudden deaths, or numerous life-threatening situations. We postulate that these groups at risk should be routinely screened for PTSD in primary medical and pediatric care. Mental health services should prepare for providing therapeutic interventions for individuals with PTSD in the vulnerable groups, and support to their families, especially children.

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Interpreting vaccine efficacy trial results for infection and transmission -

Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines9 effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness.

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Stillbirths in Germany: On the rise, but no additional increases during the first COVID-19 lockdown -

Abstract Background A growing body of studies on the indirect effect of the COVID-19 pandemic on stillbirths shows mixed and context-dependent evidence, even within high-income countries. We examined possible changes in the stillbirth rate in Germany during the first COVID-19 lockdown. Methods We used population-level data on live and stillbirths occurring between January 1995 and July 2020 and applied negative binomial regression to estimate the yearly and monthly stillbirth rate in this period. We compared the actual stillbirth rate to the expected figure for the first seven months of 2020, based on prediction intervals derived from the detected time trend. Findings We detected a steady increase in stillbirths in Germany since 2013, which was preceded by a declining (1995-2004), and then plateauing (2005-2012) stillbirth rate. The stillbirth rate for January 2020 through July 2020 (4·148) was slightly lower than the stillbirth rate in the same period in 2019 (4·242). Furthermore, all monthly stillbirth rates during the first half of 2020 lie inside the 95% prediction interval of expected stillbirth rates for this period. Thus, stillbirths in Germany have neither increased nor decreased during the country’s first COVID-19 lockdown period. Interpretation In contrast to other European countries, stillbirth rates have been on the rise in Germany in the last decade. However, stillbirth rates during the first seven months of 2020 were not higher than expected. Our results suggest that stillbirth rates have neither increased nor decreased during the first-wave COVID-19 lockdown in this high-income setting. Further studies on the causes of the increasing stillbirth trend in Germany are needed, however. Funding statement No external funding was received for this research.

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The human factor between airborne pollen concentrations and COVID-19 disease dynamics -

In their seminal paper, Damialis and colleagues (2021, PNAS) report that, in early 2020, higher airborne pollen concentrations were related to higher COVID-19 infection rates. As a mechanism, the authors propose that “pollen exposure weakens the immunity … by diminishing the antiviral interferon response.” Although they assume an effect for the whole population, they speculate that it could be stronger for those with allergies. As a limitation, they acknowledge that they did not account for the countries’ testing strategies. As allergic people may be more likely to show symptoms that may be mistaken for those of COVID-19 (runny nose, headache, increased temperature), we explored whether people with allergies were more prone to get a rapid SARS-CoV-2 antigen test. Moreover, we assessed whether the test result was more likely to be positive among those with allergies.

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SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation -

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-{kappa}B activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-{kappa}B signaling. Nsp14 caused the nuclear translocation of NF-{kappa}B p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5’-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-{kappa}B signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-{kappa}B activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-{kappa}B signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-{kappa}B.

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Variable Induction of Pro-inflammatory Cytokines by Commercial SARS CoV-2 Spike Protein Reagents: Potential Impacts of LPS on In Vitro Modeling and Pathogenic Mechanisms In Vivo -

Proinflammatory cytokine production following infection with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is associated with poor clinical outcomes. Like SARS CoV-1, SARS CoV-2 enters host cells via its spike protein, which attaches to angiotensin-converting enzyme 2 (ACE2). As SARS CoV-1 spike protein is reported to induce cytokine production, we hypothesized that this pathway could be a shared mechanism underlying pathogenic immune responses. We herein compared the capabilities of Middle East Respiratory Syndrome (MERS), SARS CoV-1 and SARS CoV-2 spike proteins to induce cytokine expression in human peripheral blood mononuclear cells (PBMC). We observed that only specific commercial lots of SARS CoV-2 induce cytokine production. Surprisingly, recombinant SARS CoV-2 spike proteins from different vendors and batches exhibited different patterns of cytokine induction, and these activities were not inhibited by blockade of spike protein-ACE2 binding using either soluble ACE2 or neutralizing anti-S1 antibody. Moreover, commercial spike protein reagents contained varying levels of endotoxin, which correlated directly with their abilities to induce cytokine production. The lipopolysaccharide (LPS) inhibitor, polymyxin B, blocked this cytokine induction activity. In addition, SARS CoV-2 spike protein avidly bound soluble LPS in vitro, rendering it a cytokine inducer. These results not only suggest caution in monitoring the purity of SARS CoV-2 spike protein reagents, but they indicate the possibility that interactions of SARS CoV-2 spike protein with LPS from commensal bacteria in virally infected mucosal tissues could promote pathogenic inflammatory cytokine production.

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Evidence of neutralizing antibodies against SARS-CoV-2 in domestic cats living with owners with a history of COVID-19 in Lima, Peru -

SARS-CoV-2 can infect a variety of wild and domestic animals worldwide. Of these, domestic cats are highly susceptible species and potential viral reservoirs. As such, it is important to investigate disease exposure in areas with active community transmission and high disease prevalence. In this report we demonstrate the presence of serum neutralizing antibodies against the receptor binding-domain (RBD) of the SARS-CoV-2 in cats whose owners had been infected with SARS-CoV-2 in Lima, Peru, using a commercial competitive ELISA SARS-CoV-2 Surrogate Virus Neutralization Test. Out of 41 samples, 17.1% (7/41) and 31.7% (13/41) were positive, using the cut-off inhibition value of 30% and 20%, respectively. Not all cats living in a single house had detectable neutralizing antibodies showing that heterogenous exposure and immune among cohabiting animals. This is the first report of SARS-COV-2 exposure of domestic cats in Lima, Peru. Further studies are required to ascertain the prevalence of SARS-COV-2 exposure among domestic cats of Lima, Peru.

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Multi-level multi-state modelling applied to hospital admission in mexican patients with COVID-19 -

Since the beginning of the SARS-CoV 2 pandemic, healthcare authorities have made clear that it is crucial to track and identify COVID-19 symptoms and seek medical attention in the presence of the first warning signs, as immediate medical attention can improve the patient9s prognosis. Therefore the present work aims to analyze the risks associated with the time between the patient9s first symptoms and hospitalization followed by death. A cross-sectional study was performed among Mexican population diagnosed with COVID-19 and hospitalized from March to January 2021. Four different Bayesian models were developed to asses the risk associated with different patient trajectories: symptoms-hospitalization and hospitalization-death. Comorbidities that could worsen the patient outcome were included as linear predictions; these analyses were further broken down to the different states of the Mexican Republic and the healthcare providers within. Model III was chosen as the best performance through a validation of leaving one out (LOO). Increased risk for hospitalization was observed at the global population level for chronic renal disease, whereas for death such was the case for COPD and the interaction of diabetes:hypertension:obesity. Our results show that there are differences in mortality between the states without accounting for institution and it is related to the prompt time of death or viceversa. Regarding the 6 healthcare providers included in the analysis differences were also found. While state-managed hospitals and private sector showed lower risks, in contrast the IMSS seems to be the one with the highest risk. The proposed modelling can be helpful to improve healthcare assistance at a regional level, additionally it could inform statistical parameter inference in epidemiological models.

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Frailty variation models for susceptibility and exposure to SARS-CoV-2 -

Individual variation in susceptibility and exposure is subject to selection by force of infection, accelerating the natural acquisition of immunity, and reducing herd immunity thresholds and epidemic final sizes. This is a manifestation of a wider population phenomenon known as “frailty variation” in demography. Despite this theoretical understanding, public health policies continue to be guided by mathematical models that leave out most of the relevant variation and as a result inflate projected infection burdens. Here we focus on the trajectories of the coronavirus disease (COVID-19) pandemic in England and Scotland. We fit models to series of daily deaths and estimate relevant epidemiological parameters, including coefficients of variation which we find in agreement with direct measurements based on published contact surveys. Our estimates are robust to whether the data series encompass one or two pandemic waves. We conclude that herd immunity thresholds are being reached with a larger contribution of vaccination in Scotland than in England, where naturally acquired immunity is higher. These results are relevant to global vaccination policies.

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Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies -

SARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.

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Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence -

SARS-CoV-2 has infected over 160 million and caused more than 3 million deaths to date. Most individuals (>80%) have mild symptoms and recover in the outpatient setting, but detailed studies of immune responses have focused primarily on moderate to severe COVID-19. We deeply profiled the longitudinal immune response in individuals with mild COVID beginning with early time points post-infection (1-15 days) and proceeding through convalescence to >100 days after symptom onset. We correlated data from single cell analyses of peripheral blood cells, serum proteomics, virus-specific cellular and humoral immune responses, and clinical metadata. Acute infection was characterized by vigorous coordinated innate and adaptive activation, including an early cellular and proteomic signature that correlated with the amplitude of virus-specific humoral responses after day 30. We characterized signals associated with recovery and convalescence to define a new signature of inflammatory cytokines, gene expression, and chromatin accessibility that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC).

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Impaired function and delayed regeneration of dendritic cells in COVID-19 -

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DC) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute disease to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage- HLADR+ cells lacking DC markers. Increased frequency of the recently discovered CD163+ CD14+ DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of PD-L1 in conventional DC (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naive CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.

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REGEN-COV protects against viral escape in preclinical and human studies -

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in COVID-19 patients or identified from preclinical in vitro and in vivo studies. This study demonstrates that a combination of non-competing antibodies, REGEN-COV, not only provides full coverage against current variants of concern/interest but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

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Multispecific DARPin(R) therapeutics demonstrate very high potency against SARS-CoV-2 variants in vitro -

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has so far infected more than 160 million people globally, and continues to undergo genomic evolution. Emerging SARS-CoV-2 variants show increased infectivity and may lead to resistance against immune responses of previously immunized individuals or existing therapeutics, especially antibody-based therapies. Several monoclonal antibody therapeutics authorized for emergency use or in development have been shown to lose potency against some SARS-CoV-2 variants. Cocktails of two different monoclonal antibodies constitute a promising approach to protect against novel emerging variants as long as both antibodies are potent, but come with increased development complexity and therefore cost. As an alternative, we developed two multi-specific DARPin(R) therapeutics, each combining three independent DARPin(R) domains binding the SARS-CoV-2 spike protein in one molecule, to potently neutralize the virus and overcome virus escape. Here, we show in a panel of in vitro studies that the multispecific DARPin(R) therapeutic design incorporated in our clinical candidate ensovibep (MP0420) achieved high neutralization potencies against the circulating SARS-CoV-2 variants B.1.1.7 (UK variant), B.1.351 (South African variant), P.1 (Brazilian variant), B.1.429 (South Californian variant), B.1.526 (New York variant), R.1 (Japanese variant), A.23.1 (Ugandan variant), and B.1.617 (Indian variant), and there is strong evidence that ensovibep also potently neutralizes the Indian variant B.1.618 based on the analysis of the key point mutations in the spike protein of this variant. Additionally, viral passaging experiments show potent protection by ensovibep and MP0423 against development of escape mutations. Finally, we demonstrate that the cooperative binding of the individual modules in a multispecific DARPin(R) antiviral is key for potent virus inhibition and protection from escape variants. These results, combined with the relatively small size and high production yields of DARPin(R) molecules, suggest that ensovibep is a highly valuable alternative to monoclonal antibody cocktails for global supply and demonstrate the strength of the DARPin(R) platform for achieving potent and lasting virus inhibition for SARS-CoV-2 and possibly other viruses.

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Covid-19 Sentry

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