Epitopes of an antibody that neutralizes a wide range of SARS-CoV-2 variants in a conserved subdomain 1 of the spike protein.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued, enabling the virus to escape from host immunity by changing its spike antigen, while biased toward the receptor-binding domain and N-terminal domain. Here, we isolated a novel pan-SARS-CoV-2 neutralizing antibody (which we named MO11) for even the recent dominators XBB.1.16 and EG.5.1, from a convalescent patient who had received three doses of an original mRNA COVID-19 vaccination. A cryo-electron microscopy analysis of the spike-MO11 complex at 2.3 Å atomic resolution revealed that it recognizes a conserved epitope hidden behind a glycan shield at N331 on subdomain 1 (SD1), holding both the N- and C-terminal segments comprising SD1. Our identification of MO11 unveiled the functional importance of SD1 for the spike's function, and we discuss the potential availability of a novel common epitope among the SARS-CoV-2 variants.IMPORTANCENovel severe acute respiratory syndrome coronavirus 2 variants with immune evasion ability are still repeatedly emerging, nonetheless, a part of immunity developed in responding to the antigen of earlier variants retains efficacy against recent variants irrespective of the numerous mutations. In exploration for the broadly effective antibodies, we identified a cross-neutralizing antibody, named MO11, from the B cells of the convalescent patient. MO11 targets a novel epitope in subdomain 1 (SD1) and was effective against all emerging variants including XBB.1.16 and EG.5.1. The neutralizing activity covering from D614G to EG.5.1 variants was explained by the conservation of the epitope, and it revealed the importance of the subdomain on regulating the function of the antigen for viral infection. Demonstrated identification of the neutralizing antibody that recognizes a conserved epitope implies basal contribution of such group of antibodies for prophylaxis against COVID-19.

Heterologous humoral immunity to human and zoonotic coronaviruses: Aiming for the achilles heel.

Coronaviruses are evolutionarily successful RNA viruses, common to multiple avian, amphibian and mammalian hosts. Despite their ubiquity and potential impact, knowledge of host immunity to coronaviruses remains incomplete, partly owing to the lack of overt pathogenicity of endemic human coronaviruses (HCoVs), which typically cause common colds. However, the need for deeper understanding became pressing with the zoonotic introduction of three novel coronaviruses in the past two decades, causing severe acute respiratory syndromes in humans, and the unfolding pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This renewed interest not only triggered the discovery of two of the four HCoVs, but also uncovered substantial cellular and humoral cross-reactivity with shared or related coronaviral antigens. Here, we review the evidence for cross-reactive B cell memory elicited by HCoVs and its potential impact on the puzzlingly variable outcome of SARS-CoV-2 infection. The available data indicate targeting of highly conserved regions primarily in the S2 subunits of the spike glycoproteins of HCoVs and SARS-CoV-2 by cross-reactive B cells and antibodies. Rare monoclonal antibodies reactive with conserved S2 epitopes and with potent virus neutralising activity have been cloned, underscoring the potential functional relevance of cross-reactivity. We discuss B cell and antibody cross-reactivity in the broader context of heterologous humoral immunity to coronaviruses, as well as the limits of protective immune memory against homologous re-infection. Given the bidirectional nature of cross-reactivity, the unprecedented current vaccination campaign against SARS-CoV-2 is expected to impact HCoVs, as well as future zoonotic coronaviruses attempting to cross the species barrier. However, emerging SARS-CoV-2 variants with resistance to neutralisation by vaccine-induced antibodies highlight a need for targeting more constrained, less mutable parts of the spike. The delineation of such cross-reactive areas, which humoral immunity can be trained to attack, may offer the key to permanently shifting the balance of our interaction with current and future coronaviruses in our favour.

Distinct motifs in the E protein are required for SARS-CoV-2 virus particle formation and lysosomal deacidification in host cells.

IMPORTANCE: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has caused a global public health crisis. The E protein, a structural protein found in this virus particle, is also known to be a viroporin. As such, it forms oligomeric ion channels or pores in the host cell membrane. However, the relationship between these two functions is poorly understood. In this study, we showed that the roles of E protein in virus particle and viroporin formation are distinct. This study contributes to the development of drugs that inhibit SARS-CoV-2 virus particle formation. Additionally, we designed a highly sensitive and high-throughput virus-like particle detection system using the HiBiT tag, which is a useful tool for studying the release of SARS-CoV-2.

Identification and Analysis of Monoclonal Antibodies with Neutralizing Activity against Diverse SARS-CoV-2 Variants.

We identified neutralizing monoclonal antibodies against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants (including Omicron variants BA.5 and BA.2.75) from individuals who received two doses of mRNA vaccination after they had been infected with the D614G virus. We named them MO1, MO2, and MO3. Among them, MO1 showed particularly high neutralizing activity against authentic variants: D614G, Delta, BA.1, BA.1.1, BA.2, BA.2.75, and BA.5. Furthermore, MO1 suppressed BA.5 infection in hamsters. A structural analysis revealed that MO1 binds to the conserved epitope of seven variants, including Omicron variants BA.5 and BA.2.75, in the receptor-binding domain of the spike protein. MO1 targets an epitope conserved among Omicron variants BA.1, BA.2, and BA.5 in a unique binding mode. Our findings confirm that D614G-derived vaccination can induce neutralizing antibodies that recognize the epitopes conserved among the SARS-CoV-2 variants. IMPORTANCE Omicron variants of SARS-CoV-2 acquired escape ability from host immunity and authorized antibody therapeutics and thereby have been spreading worldwide. We reported that patients infected with an early SARS-CoV-2 variant, D614G, and who received subsequent two-dose mRNA vaccination have high neutralizing antibody titer against Omicron lineages. It was speculated that the patients have neutralizing antibodies broadly effective against SARS-CoV-2 variants by targeting common epitopes. Here, we explored human monoclonal antibodies from B cells of the patients. One of the monoclonal antibodies, named MO1, showed high potency against broad SARS-CoV-2 variants including BA.2.75 and BA.5 variants. The results prove that monoclonal antibodies that have common neutralizing epitopes among several Omicrons were produced in patients infected with D614G and who received mRNA vaccination.

The association between probable post-COVID-19 condition and sleep-related parameters: a longitudinal study of non-hospitalised patients.

The long-term effects of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on sleep remain poorly known. We evaluated the association between probable post-COVID-19 condition and changes in sleep quality and quantity before and after SARS-CoV-2 infection in a consecutive sample of non-hospitalized adults. Individuals were identified with SARS-CoV-2 infection in 2020 at the central laboratory of a tertiary hospital in Porto and followed as outpatients. We included patients diagnosed with SARS-CoV-2 infection ≥3 months before this evaluation, with no missing data on key variables (n = 2445). Participants completed a questionnaire that included sociodemographic, clinical, and infection-related questions. We computed changes in sleep-related parameters referred to 1 month before diagnosis and 1 week before the questionnaire. Multinomial logistic regression models were fitted to compute crude and adjusted odds ratios and 95% confidence intervals (95% CIs). Compared to the pre-infection period, those with probable post-COVID-19 condition reported a greater decrease in hours of sleep, had a 2.60 (95% CI 2.02-3.34) higher adjusted odds of perceiving their sleep quality as worsened and experienced a significant increase in number of days with sleeping disturbances as defined according to multiple items. The association between post-COVID-19 condition and indicators of poor sleep health requires special attention from healthcare professionals and services. It is essential that appropriate multidisciplinary care is provided to mitigate the physical, psychological, social, and professional impact of sleeping problems in these already burdened patients.

Impacts of Vaccination and Severe Acute Respiratory Syndrome Coronavirus 2 Variants Alpha and Delta on Coronavirus Disease 2019 Transmission Dynamics in Four Metropolitan Areas of the United States.

To characterize Coronavirus Disease 2019 (COVID-19) transmission dynamics in each of the metropolitan statistical areas (MSAs) surrounding Dallas, Houston, New York City, and Phoenix in 2020 and 2021, we extended a previously reported compartmental model accounting for effects of multiple distinct periods of non-pharmaceutical interventions by adding consideration of vaccination and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants Alpha (lineage B.1.1.7) and Delta (lineage B.1.617.2). For each MSA, we found region-specific parameterizations of the model using daily reports of new COVID-19 cases available from January 21, 2020 to October 31, 2021. In the process, we obtained estimates of the relative infectiousness of Alpha and Delta as well as their takeoff times in each MSA (the times at which sustained transmission began). The estimated infectiousness of Alpha ranged from 1.1x to 1.4x that of viral strains circulating in 2020 and early 2021. The estimated relative infectiousness of Delta was higher in all cases, ranging from 1.6x to 2.1x. The estimated Alpha takeoff times ranged from February 1 to February 28, 2021. The estimated Delta takeoff times ranged from June 2 to June 26, 2021. Estimated takeoff times are consistent with genomic surveillance data.

Ciclesonide Inhibits SARS-CoV-2 Papain-Like Protease in Vitro.

The emergence of coronavirus disease 2019 (COVID-19), a novel identified pneumonia resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has significantly impacted and posed significant challenges to human society. The papain-like protease (PLpro) found in the nonstructural protein 3 of SARS-CoV-2 plays a vital role in viral replication. Moreover, PLpro disrupts the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 from host proteins. Consequently, PLpro has emerged as a promising drug target against SARS-CoV-2 infection. Computational studies have reported that ciclesonide can bind to SARS-CoV-2 PLpro. However, the inhibitory effects of ciclenoside on the PLpro have not been experimentally evaluated. Here, we evaluated the inhibitory effects of synthetic glucocorticoids (sGCs), including ciclesonide, on SARS-CoV-2 PLpro in vitro assay. Ciclesonide significantly inhibited the enzymatic activity of PLpro, compared with other sGCs and its IC50 was 18.4 ± 1.89 µM. These findings provide insights into the development of PLpro inhibitors.

Current Status and Perspectives of Therapeutic Antibodies Targeting the Spike Protein S2 Subunit against SARS-CoV-2.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has devastated public health and the global economy. New variants are continually emerging because of amino acid mutations within the SARS-CoV-2 spike protein. Existing neutralizing antibodies (nAbs) that target the receptor-binding domain (RBD) within the spike protein have been shown to have reduced neutralizing activity against these variants. In particular, the recently expanding omicron subvariants BQ 1.1 and XBB are resistant to nAbs approved for emergency use by the United States Food and Drug Administration. Therefore, it is essential to develop broad nAbs to combat emerging variants. In contrast to the massive accumulation of mutations within the RBD, the S2 subunit remains highly conserved among variants. Therefore, nAbs targeting the S2 region may provide effective cross-protection against novel SARS-CoV-2 variants. Here, we provide a detailed summary of nAbs targeting the S2 subunit: the fusion peptide, stem helix, and heptad repeats 1 and 2. In addition, we provide prospects to solve problems such as the weak neutralizing potency of nAbs targeting the S2 subunit.

Inhibition Mechanism of SARS-CoV-2 Infection by a Cholesterol Derivative, Nat-20(S)-yne.

The coronavirus disease 2019 (COVID-19) is caused by the etiological agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19, with the recurrent epidemics of new variants of SARS-CoV-2, remains a global public health problem, and new antivirals are still required. Some cholesterol derivatives, such as 25-hydroxycholesterol, are known to have antiviral activity against a wide range of enveloped and non-enveloped viruses, including SARS-CoV-2. At the entry step of SARS-CoV-2 infection, the viral envelope fuses with the host membrane dependent of viral spike (S) glycoproteins. From the screening of cholesterol derivatives, we found a new compound 26,27-dinorcholest-5-en-24-yne-3ß,20-diol (Nat-20(S)-yne) that inhibited the SARS-CoV-2 S protein-dependent membrane fusion in a syncytium formation assay. Nat-20(S)-yne exhibited the inhibitory activities of SARS-CoV-2 pseudovirus entry and intact SARS-CoV-2 infection in a dose-dependent manner. Among the variants of SARS-CoV-2, inhibition of infection by Nat-20(S)-yne was stronger in delta and Wuhan strains, which predominantly invade into cells via fusion at the plasma membrane, than in omicron strains. The interaction between receptor-binding domain of S proteins and host receptor ACE2 was not affected by Nat-20(S)-yne. Unlike 25-hydroxycholesterol, which regulates various steps of cholesterol metabolism, Nat-20(S)-yne inhibited only de novo cholesterol biosynthesis. As a result, plasma membrane cholesterol content was substantially decreased in Nat-20(S)-yne-treated cells, leading to inhibition of SARS-CoV-2 infection. Nat-20(S)-yne having a new mechanism of action may be a potential therapeutic candidate for COVID-19.

The relation between proteinuria and the severity of COVID-19.

BACKGROUND: The association between proteinuria, which is also an indicator of chronic kidney disease (CKD), and coronavirus disease 2019 (COVID-19) severity is unclear. METHODS: We selected 342 hospitalized patients with COVID-19 diagnosed via polymerase chain reaction testing between February 2020 and October 2022 and who had at least one urinalysis 14-365 days before admission. RESULTS: Proteinuria before admission was associated neither with oxygen administration nor developing pneumonia in multivariate analysis (odds ratio [OR] 1.03; 95% confidence interval (CI) 0.44-2.40, p = 0.95 and OR 1.01; 95% CI 0.47-2.17, p = 0.98, respectively). Proteinuria on admission was associated both with oxygen administration and developing pneumonia in multivariate analysis (OR 3.29; 95% CI 1.37-7.88, p < 0.01 and OR 3.81; 95% CI 1.68-8.62, p < 0.01, respectively). The percentage of patients with proteinuria on admission was significantly higher than those before admission (37.4% vs. 17.8%; p < 0.01). In the subgroup analysis, proteinuria on admission among patients with eGFR ≥ 60 mL/min/1.73 m2 was associated with both oxygen administration and developing pneumonia (OR 4.86; 95% CI 1.22-19.38, p = 0.03, OR 3.65; 95% CI 1.06-12.58, p = 0.04, respectively). In contrast, proteinuria on admission among patients with eGFR < 60 mL/min/1.73 m2 was associated with developing pneumonia (OR 6.45; 95%CI 1.78-23.35, p = 0.01), not with oxygen administration (OR 3.28; 95% CI 0.92-11.72, p = 0.07). CONCLUSIONS: Although underlying proteinuria before admission was not associated with COVID-19 severity, proteinuria on admission was associated with oxygen demand and developing pneumonia.

New onset of isolated adrenocorticotropin deficiency associated with encephalopathy following coronavirus disease 2019 in a healthy elderly man.

Coronavirus disease 2019 (COVID-19) due to a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can include various systemic organ disorders including endocrinopathies and neurological manifestations. We report the case of a 65-year-old Japanese man who developed isolated adrenocorticotropic hormone (ACTH) deficiency and encephalopathy following SARS-CoV-2 infection. Two weeks after his COVID-19 diagnosis, he was emergently admitted to our hospital because of subacute-onset delirium. On admission, he presented hyponatremia (128 mEq/L) and secondary adrenal insufficiency (ACTH <1.5 pg/mL, cortisol 0.53 µg/dL). Brain imaging and laboratory examinations including SARS-CoV-2 polymerase chain reaction testing in the cerebrospinal fluid revealed no abnormalities. His consciousness level worsened despite the amelioration of hyponatremia by intravenous hydrocortisone (100 mg/day), but his neurological presentations completely resolved after three consecutive days of high-dose (400 mg/day) hydrocortisone. His encephalopathy did not deteriorate during hydrocortisone tapering. He continued 15 mg/day hydrocortisone after discharge. His encephalopathy might have developed via a disturbance of the autoimmune system, or a metabolic effect associated with adrenal insufficiency, although the time lag between the hyponatremia's improvement and the patient's neurological response to the steroid was incompatible with common cases of delirium concurrent with adrenal insufficiency. At 13 months after his hospitalization, the patient's neurological symptoms have not recurred and he has no endocrinological dysfunctions other than the remaining ACTH deficiency. A thorough consideration of the immunological and metabolic characteristics of SARS-CoV-2 is advisable when clinicians treat patients during and even after their COVID-19 disease period.

Virucidal efficacy of hypochlorous acid water for aqueous phase and atomization against SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is an infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged at the end of 2019. SARS-CoV-2 can be transmitted through droplets, aerosols, and fomites. Disinfectants such as alcohol, quaternary ammonium salts, and chlorine-releasing agents, including hypochlorous acid, are used to prevent the spread of SARS-CoV-2 infection. In the present study, we investigated the efficacy of ionless hypochlorous acid water (HOCl) in suspension and by spraying to inactivate SARS-CoV-2. The virucidal efficacy of HOCl solution in tests against SARS-CoV-2 was evaluated as 50% tissue culture infectious dose. Although the presence of organic compounds influenced the virucidal efficacy, HOCl treatment for 20 s was significantly effective to inactivate Wuhan and Delta strains in the suspension test. HOCl atomization for several hours significantly reduced the SARS-CoV-2 attached to plastic plates. These results indicate that HOCl solution with elimination containing NaCl and other ions may have high virucidal efficacy against SARS-CoV-2. This study provides important information about the virucidal efficacy and use of HOCl solution.

Clinical characteristics and outcomes of maintenance hemodialysis patients with COVID-19 during the Omicron wave of the pandemic in Beijing: a single center retrospective study.

BACKGROUND: The clinical manifestations and prognosis of hemodialysis patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) during the Omicron wave of the pandemic infection were still unclear. This study investigated the clinical characteristics of patients undergoing maintenance hemodialysis (MHD) infected with it. METHODS: This retrospective single-center study included 151 patients undergoing MHD. Healthcare workers were selected as control group were assessed from December 1, 2022 to March 31, 2023. Clinical data, laboratory test results, treatment protocols, and prognoses were collected and analyzed. RESULTS: The study population included 146 patients with MHD, 93 (63.7%) of whom were infected with SARS-CoV-2. The number of non-severe, severe, and critical cases was 84 (90.3%), 4 (4.3%), and 5 (5.3%), respectively. Six patients (6.5%) died during the study period. The main symptoms of SARS-CoV-2 infection, including fever, cough, and fatigue, were less common in patients with MHD than the controls. During SARS-CoV-2 infection, the C-reactive protein (2.9 vs. 11.8 mg/dl, p < 0.0001) and ferritin levels(257.7 vs. 537 ng/l, p < 0.0001) were elevated. The hemoglobin(113vs 111 g/L, p = 0.0001) and albumin levels(39.4 vs. 36.1 g/L, p < 0.0001) decreased. Generally, it took two months for the hemoglobin levels to recover. Positivity rate for SARS-COV-2 serum immunoglobin G (IgG) antibodies and IgG titers were lower in dialysis patients than the controls. Age was positively associated with disease severity, while age and hyponatremia were associated with death. CONCLUSIONS: Patients with MHD and COVID-19 were primarily classified as non-severe. SARS-CoV-2 infection would soon lead to the increase of inflammation related acute response protein in dialysis patients, and then lead to the decrease of hemoglobin and albumin. About 9.6% in HD patients were severe cases and had poor prognosis. Advanced age and hyponatremia were associated with disease severity and prognosis.

Anti-Inflammatory Cytokine Profiles in Thrombotic Thrombocytopenic Purpura-Differences Compared to COVID-19.

Thromboinflammation/immunothrombosis plays a role in several diseases including thrombotic thrombocytopenic purpura (TTP) and COVID-19. Unlike the extensive research that has been conducted on COVID-19 cytokine storms, the baseline and acute phase cytokine profiles of TTP are poorly characterized. Moreover, we compared the cytokine profiles of TTP and COVID-19 to identify the disease-specific/general characteristics of thromboinflammation/immunothrombosis. Plasma concentrations of 33 soluble mediators (SMs: cytokines, chemokines, soluble receptors, and growth factors) were measured by multiplex bead-based LEGENDplex™ immunoassay from 32 COVID-19 patients (32 non-vaccinated patients in three severity groups), 32 TTP patients (remission/acute phase pairs of 16 patients), and 15 control samples. Mainly, the levels of innate immunity-related SMs changed in both diseases. In TTP, ten SMs decreased in both remission and acute phases compared to the control, one decreased, and two increased only in the acute phase compared to remission, indicating mostly anti-inflammatory changes. In COVID-19, ten pro-inflammatory SMs increased, whereas one decreased with increasing severity compared to the control. In severe COVID-19, sixteen SMs exceeded acute TTP levels, with only one higher in TTP. PCA identified CXCL10, IL-1RA, and VEGF as the main discriminators among their cytokine profiles. The innate immune response is altered in both diseases. The cytokine profile of TTP suggests a distinct pathomechanism from COVID-19 and supports referring to TTP as thromboinflammatory rather than immunothrombotic, emphasizing thrombosis over inflammation as the driving force of the acute phase.

Remdesivir Resistance in Transplant Recipients With Persistent Coronavirus Disease 2019.

New mutations conferring resistance to SARS-CoV-2 therapeutics have important clinical implications. We describe the first cases of an independently acquired V792I RNA-dependent RNA polymerase mutation developing in renal transplant recipients after remdesivir exposure. Our work underscores the need for augmented efforts to identify concerning mutations and address their clinical implications.

Coronavirus Disease 19 (COVID-19) Vaccine Effectiveness Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Delta-Dominant and Omicron-Dominant Periods in Japan: A Multicenter Prospective Case-control Study (Factors Associated with SARS-CoV-2 Infection and the Effectiveness of COVID-19 Vaccines Study).

BACKGROUND: Although several coronavirus disease 2019 (COVID-19) vaccines initially showed high efficacy, there have been concerns because of waning immunity and the emergence of variants with immune escape capacity. METHODS: A test-negative design case-control study was conducted in 16 healthcare facilities in Japan during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic severe acute respiratory syndrome coronavirus 2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period compared with unvaccinated individuals. RESULTS: The analysis included 5795 individuals with 2595 (44.8%) cases. Among vaccinees, 2242 (55.8%) received BNT162b2 and 1624 (40.4%) received messenger RNA (mRNA)-1273 at manufacturer-recommended intervals. During the Delta-dominant period, VE was 88% (95% confidence interval [CI], 82-93) 14 days to 3 months after dose 2 and 87% (95% CI, 38-97) 3 to 6 months after dose 2. During the Omicron-dominant period, VE was 56% (95% CI, 37-70) 14 days to 3 months since dose 2, 52% (95% CI, 40-62) 3 to 6 months after dose 2, 49% (95% CI, 34-61) 6+ months after dose 2, and 74% (95% CI, 62-83) 14+ days after dose 3. Restricting to individuals at high risk of severe COVID-19 and additional adjustment for preventive measures (ie, mask wearing/high-risk behaviors) yielded similar estimates, respectively. CONCLUSIONS: In Japan, where most are infection-naïve, and strict prevention measures are maintained regardless of vaccination status, 2-dose mRNA vaccines provided high protection against symptomatic infection during the Delta-dominant period and moderate protection during the Omicron-dominant period. Among individuals who received an mRNA booster dose, VE recovered to a high level.

The therapeutic relevance of the Kallikrein-Kinin axis in SARS-cov-2-induced vascular pathology.

While coronavirus disease 2019 (COVID-19) begins as a respiratory infection, it progresses as a systemic disease involving multiorgan microthromboses that underly the pathology. SARS-CoV-2 enters host cells via attachment to the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is widely expressed in a multitude of tissues, including the lung (alveolar cells), heart, intestine, kidney, testis, gallbladder, vasculature (endothelial cells), and immune cells. Interference in ACE2 signaling could drive the aforementioned systemic pathologies, such as endothelial dysfunction, microthromboses, and systemic inflammation, that are typically seen in patients with severe COVID-19. ACE2 is a component of the renin-angiotensin system (RAS) and is intimately associated with the plasma kallikrein-kinin system (KKS). As many papers are published on the role of ACE and ACE2 in COVID-19, we will review the role of bradykinin, and more broadly the KSS, in SARS-CoV-2-induced vascular dysfunction. Furthermore, we will discuss the possible therapeutic interventions that are approved and in development for the following targets: coagulation factor XII (FXII), tissue kallikrein (KLK1), plasma kallikrein (KLKB1), bradykinin (BK), plasminogen activator inhibitor (PAI-1), bradykinin B1 receptor (BKB1R), bradykinin B2 receptor (BKB2R), ACE, furin, and the NLRP3 inflammasome. Understanding these targets may prove of value in the treatment of COVID-19 as well as in other virus-induced coagulopathies in the future.

Of vascular defense, hemostasis, cancer, and platelet biology: an evolutionary perspective.

We have established considerable expertise in studying the role of platelets in cancer biology. From this expertise, we were keen to recognize the numerous venous-, arterial-, microvascular-, and macrovascular thrombotic events and immunologic disorders are caused by severe, acute-respiratory-syndrome coronavirus 2 (SARS-CoV-2) infections. With this offering, we explore the evolutionary connections that place platelets at the center of hemostasis, immunity, and adaptive phylogeny. Coevolutionary changes have also occurred in vertebrate viruses and their vertebrate hosts that reflect their respective evolutionary interactions. As mammals adapted from aquatic to terrestrial life and the heavy blood loss associated with placentalization-based live birth, platelets evolved phylogenetically from thrombocytes toward higher megakaryocyte-blebbing-based production rates and the lack of nuclei. With no nuclei and robust RNA synthesis, this adaptation may have influenced viral replication to become less efficient after virus particles are engulfed. Human platelets express numerous receptors that bind viral particles, which developed from archetypal origins to initiate aggregation and exocytic-release of thrombo-, immuno-, angiogenic-, growth-, and repair-stimulatory granule contents. Whether by direct, evolutionary, selective pressure, or not, these responses may help to contain virus spread, attract immune cells for eradication, and stimulate angiogenesis, growth, and wound repair after viral damage. Because mammalian and marsupial platelets became smaller and more plate-like their biophysical properties improved in function, which facilitated distribution near vessel walls in fluid-shear fields. This adaptation increased the probability that platelets could then interact with and engulf shedding virus particles. Platelets also generate circulating microvesicles that increase membrane surface-area encounters and mark viral targets. In order to match virus-production rates, billions of platelets are generated and turned over per day to continually provide active defenses and adaptation to suppress the spectrum of evolving threats like SARS-CoV-2.

Rate of COVID-19 vaccination among patients with cancer who tested positive for severe acute respiratory syndrome-coronavirus 2: Analysis of the American Society of Clinical Oncology Registry.

BACKGROUND: The availability of safe and effective COVID-19 vaccines has enabled protections against serious COVID-19 outcomes, which are particularly important for patients with cancer. The American Society of Clinical Oncology Registry enabled the study of COVID-19 vaccine uptake in patients with cancer who were positive for severe acute respiratory syndrome-coronavirus 2. METHODS: Medical oncology practices entered data on patients who were in cancer treatment. The cohort included patients who had severe acute respiratory syndrome-coronavirus 2 infection in 2020 and had visits and vaccine data after December 31, 2020. The primary end point was the time to first vaccination from January 1, 2021. Cumulative incidence estimates and Cox regression with death as a competing risk were used to describe the time to vaccine uptake and factors associated with vaccine receipt. RESULTS: The cohort included 1155 patients from 56 practices. Among 690 patients who received the first vaccine dose, 92% received the second dose. The median time to vaccine was 99 days. After adjustment, older patients were associated with a higher likelihood of vaccination compared with patients younger than 50 years in January through March 2021, and age exhibited a linear effect, with older patients showing higher rates of vaccination. Metastatic solid tumors (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73-0.98) or non-B-cell hematologic malignancies (HR, 0.71; 95% CI, 0.54-0.93) compared with nonmetastatic solid tumors, and any comorbidity (HR, 0.83; 95% CI, 0.73-0.95) compared with no comorbidity, were associated with lower vaccination rates. Area-level social determinants of health (lower education attainment and higher unemployment rates) were associated with lower vaccination rates. CONCLUSIONS: Patient age, cancer type, comorbidity, area-level education attainment, and unemployment rates were associated with differential vaccine uptake rates. These findings should inform strategies to communicate about vaccine safety and efficacy to patients with cancer.

Augmented humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 after breakthrough infection in kidney transplant recipients who received 3 doses of coronavirus disease 2019 vaccine.

Diminished immune response to coronavirus disease 2019 (COVID-19) vaccines and breakthrough infection (BI) is a major concern for solid organ transplant recipients. Humoral and cellular immune responses of kidney transplant (KT) recipients after a third COVID-19 vaccination were investigated compared to matched health care workers. Anti-severe acute respiratory syndrome coronavirus 2 spike protein antibody and severe acute respiratory syndrome coronavirus 2 specific interferon-gamma releasing assay (IGRA) were assessed. A total of 38 KT recipients, including 20 BI and 18 noninfection, were evaluated. In the KT BI group, antibody titers were significantly increased (median 5 to 724, binding antibody units/mL (P = 0.002) after the third vaccination, but IGRA responses were negligible. After BI, antibody titers increased (median 11 355 binding antibody unit/mL; P < 0.001) and there was a significant increase of IGRA responses to spike proteins (Spike1-Nil, median 0.05 to 0.41 IU/mL; P = 0.009). Antibody titers and IGRA responses were significantly higher in the BI than in the noninfection group after 6 months. Immune responses were stronger in the health care worker than in the KT cohort, but the gap became narrower after BI. In conclusion, KT recipients who experienced BI after 3 COVID-19 vaccinations acquired augmented humoral and cellular immune responses.