Nasal spray of an IgM-like ACE2 fusion protein HH-120 accelerates SARS-CoV-2 clearance: A single-center propensity score-matched cohort study.

HH-120, a recently developed IgM-like ACE2 fusion protein with broad-spectrum neutralizing activity against all ACE2-utilizing coronaviruses, has been developed as a nasal spray for use as an early treatment agent to reduce disease progression and airborne transmission. The objective of this study was to evaluate the safety and efficacy of the HH-120 nasal spray in SARS-CoV-2-infected subjects. Eligible symptomatic or asymptomatic SARS-CoV-2-infected participants were enrolled in a single-arm trial to receive the HH-120 nasal spray for no longer than 6 days or until viral clearance at a single hospital between August 3 and October 7, 2022. An external control was built from real-world data of SARS-CoV-2-infected subjects contemporaneously hospitalized in the same hospital using a propensity score matching (PSM) method. After PSM, 65 participants in the HH-120 group and 103 subjects with comparable baseline characteristics in the external control group were identified. The viral clearance time was significantly shorter in participants receiving the HH-120 nasal spray than that in subjects of the control group (median 8 days vs. 10 days, p < 0.001); the difference was more prominent in those subgroup subjects with higher baseline viral load (median 7.5 days vs. 10.5 days, p < 0.001). The incidence of treatment-emergent adverse events and treatment-related adverse events of HH-120 group were 35.1% (27/77) and 3.9% (3/77), respectively. All the adverse events observed were mild, being of CTCAE grade 1 or 2, and transient. The HH-120 nasal spray showed a favorable safety profile and promising antiviral efficacy in SARS-CoV-2-infected subjects. The results from this study warrant further assessment of the efficacy and safety of the HH-120 nasal spray in large-scale randomized controlled clinical trials.

Fertility in the heart of the COVID-19 storm

We describe how the COVID-19 pandemic affected reproductive choices in New York City, the most acutely impacted area of the United States. We contrast changes in New York City with reproductive outcomes in the rest of the US. We find that births to New York City residents fell 8.4% more between March, 2020 and February 2021 than that would have been expected given trends leading up to the pandemic. Births to US-born residents of New York City fell 5.5% over the same year, triple the observed decline in the rest of the US. Births to foreign-born New York City residents fell 11.4%, twice the decline observed in the rest of the US. Reported induced abortions to New York City residents fell precipitously whereas induced abortions nation-wide rose slightly. The acute downturn and robust recovery in births in New York City maps closely with the spike in mortality and its equally rapid decline three months later. We conclude that the fear and uncertainty in the early months of the pandemic is the best explanation for the sudden, but brief drop in births in New York City.

Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19.

Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 Å and 2.6 Å respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.IMPORTANCEEffective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.

Collateral Impacts of the COVID-19 Pandemic: The New York City Experience.

OBJECTIVE: To adapt an existing surveillance system to monitor the collateral impacts of the COVID-19 pandemic on health outcomes in New York City across 6 domains: access to care, chronic disease, sexual/reproductive health, food/economic insecurity, mental/behavioral health, and environmental health. DESIGN: Epidemiologic assessment. Public health surveillance system. SETTING: New York City. PARTICIPANTS: New York City residents. MAIN OUTCOME MEASURES: We monitored approximately 30 indicators, compiling data from 2006 to 2022. Sources of data include clinic visits, surveillance surveys, vital statistics, emergency department visits, lead and diabetes registries, Medicaid claims, and public benefit enrollment. RESULTS: We observed disruptions across most indicators including more than 50% decrease in emergency department usage early in the pandemic, which rebounded to prepandemic levels by late 2021, changes in reporting levels of probable anxiety and depression, and worsening birth outcomes for mothers who identified as Asian/Pacific Islander or Black. Data are processed in SAS and analyzed using the R Surveillance package to detect possible inflections. Data are updated monthly to an internal Tableau Dashboard and shared with agency leadership. CONCLUSIONS: As the COVID-19 pandemic continues into its third year, public health priorities are returning to addressing non-COVID-19-related diseases and conditions, their collateral impacts, and postpandemic recovery needs. Substantial work is needed to return even to a suboptimal baseline across multiple health topic areas. Our surveillance framework offers a valuable starting place to effectively allocate resources, develop interventions, and issue public communications.

Epidemiological characteristics of the B.1.526 SARS-CoV-2 variant.

To characterize the epidemiological properties of the B.1.526 SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) variant of interest, here we used nine epidemiological and population datasets and model-inference methods to reconstruct SARS-CoV-2 transmission dynamics in New York City, where B.1.526 emerged. We estimated that B.1.526 had a moderate increase (15 to 25%) in transmissibility, could escape immunity in 0 to 10% of previously infected individuals, and substantially increased the infection fatality risk (IFR) among adults 65 or older by >60% during November 2020 to April 2021, compared to estimates for preexisting variants. Overall, findings suggest that new variants like B.1.526 likely spread in the population weeks before detection and that partial immune escape (e.g., resistance to therapeutic antibodies) could offset prior medical advances and increase IFR. Early preparedness for and close monitoring of SARS-CoV-2 variants, their epidemiological characteristics, and disease severity are thus crucial to COVID-19 (coronavirus disease 2019) response.

Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro.

Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO.

Neutralization against SARS-CoV-2 Delta/Omicron variants and B cell response after inactivated vaccination among COVID-19 convalescents.

Emerging SARS-CoV-2 variants have made COVID-19 convalescents susceptible to re-infection and have raised concern about the efficacy of inactivated vaccination in neutralization against emerging variants and antigen-specific B cell response. To this end, a study on a long-term cohort of 208 participants who have recovered from COVID-19 was conducted, and the participants were followed up at 3.3 (Visit 1), 9.2 (Visit 2), and 18.5 (Visit 3) months after SARS-CoV-2 infection. They were classified into three groups (no-vaccination (n = 54), one-dose (n = 62), and two-dose (n = 92) groups) on the basis of the administration of inactivated vaccination. The neutralizing antibody (NAb) titers against the wild-type virus continued to decrease in the no-vaccination group, but they rose significantly in the one-dose and two-dose groups, with the highest NAb titers being observed in the two-dose group at Visit 3. The NAb titers against the Delta variant for the no-vaccination, one-dose, and two-dose groups decreased by 3.3, 1.9, and 2.3 folds relative to the wild-type virus, respectively, and those against the Omicron variant decreased by 7.0, 4.0, and 3.8 folds, respectively. Similarly, the responses of SARS-CoV-2 RBD-specific B cells and memory B cells were boosted by the second vaccine dose. Results showed that the convalescents benefited from the administration of the inactivated vaccine (one or two doses), which enhanced neutralization against highly mutated SARS-CoV-2 variants and memory B cell responses. Two doses of inactivated vaccine among COVID-19 convalescents are therefore recommended for the prevention of the COVID-19 pandemic, and vaccination guidelines and policies need to be updated.

Increasing public concern on insomnia during the COVID-19 outbreak in China: An info-demiology study.

Background: Since December 2019, an unexplained pneumonia has broken out in Wuhan, Hubei Province, China. In order to prevent the rapid spread of this disease, quarantine or lockdown measures were taken by the Chinese government. These measures turned out to be effective in containing the contagious disease. In spite of that, social distancing measures, together with disease itself, would potentially cause certain health risks among the affected population, such as sleep disorder. We herein conducted this web search analysis so as to examine the temporal and spatial changes of public search volume of the mental health topic of "insomnia" during COVID-19 pandemic in China. Methods: The data sources included Baidu Index (BDI) to analyze related search terms and the official website of the National Health Commission of the People's Republic of China to collect the daily number of newly confirmed COVID-19 cases. Following a descriptive analysis of the overall search situation, Spearman's correlation analysis was used to analyze the relationship between the daily insomnia-related search values and the daily newly confirmed cases. The means of search volume for insomnia-related terms during the COVID-19 outbreak period (January 23rd, 2020 to April 8th, 2020) were compared with those during 2016-2019 using Student's t test. Finally, by analyzing the overall daily mean of insomnia in various provinces, we further evaluated whether there existed regional differences in searching for insomnia during the COVID-19 outbreak period. Results: During the COVID-19 outbreak period, the number of insomnia-related searches increased significantly, especially the average daily the BDI for the term "1 min to fall asleep immediately". Spearman's correlation analysis showed that 6 out of the 10 insomnia-related keywords were significantly positively related to the daily newly confirmed cases. Compared with the same period in the past four years, a significantly increased search volume was found in 60.0% (6/10) insomnia-related terms during the COVID-19 outbreak period. We also found that Guangdong province had the highest number of searches for insomnia-related during the pandemic. Conclusions: The surge in the number of confirmed cases during the COVID-19 pandemic has led to an increase in concern and online searches on this topic of insomnia. Further studies are needed to determine whether the search behavior truly reflect the real-time prevalence profile of relevant mental disorders, and further to establish a risk prediction model to determine the prevalence risk of psychopathological disorders, including insomnia, using insomnia-related BDI and other well-established risk factors.

Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan.

OBJECTIVES: This study aimed to describe the full scope of long-term outcomes and the ongoing pathophysiological alterations among COVID-19 survivors. METHODS: We established a longitudinal cohort of 208 COVID-19 convalescents and followed them at 3.3 (interquartile range [IQR]: 1.3, 4.4, visit 1), 9.2 (IQR: 9.0, 9.6, visit 2), and 18.5 (IQR: 18.2, 19.1, visit 3) months after infection, respectively. Serial changes in multiple physical and psychological outcomes were comprehensively characterized. We, in addition, explored the potential risk factors of SARS-CoV-2 antibody response and sequelae symptoms. RESULTS: We observed continuous improvement of sequelae symptoms, lung function, chest computed tomography (CT), 6-minute walk test, and the Borg dyspnea scale, whereas sequelae symptoms (at least one) and abnormal chest CT patterns still existed in 45.2% and about 30% of participants at 18.5 months, respectively. Anxiety and depression disorders were alleviated for the convalescents, although depression status was sustained for a longer duration. CONCLUSIONS: Most COVID-19 convalescents had an overall improved physical and psychological health status, whereas sequelae symptoms, residual lesions on lung function, exercise impairment, and mental health disorders were still observed in a small proportion of participants at 18.5 months after infection. Implementing appropriate preventive and management strategies for the ever-growing COVID-19 population is warranted.

Humoral and cellular immunity of two-dose inactivated COVID-19 vaccination in Chinese children: A prospective cohort study.

Children are the high-risk group for COVID-19, and in need of vaccination. However, humoral and cellular immune responses of COVID-19 vaccine remain unclear in vaccinated children. To establish the rational immunization strategy of inactivated COVID-19 vaccine for children, the immunogenicity of either one dose or two doses of the vaccine in children was evaluated. A prospective cohort study of 322 children receiving inactivated COVID-19 vaccine was established in China. The baseline was conducted after 28 days of the first dose, and the follow-up was conducted after 28 days of the second dose. The median titers of receptor binding domain (RBD)-IgG, and neutralizing antibody (NAb) against prototype strain and Omicron variant after the second dose increased significantly compared to those after the first dose (first dose: 70.0, [interquartile range, 30.0-151.0] vs. second dose: 1261.0 [636.0-2060.0] for RBD-IgG; 2.5 [2.5-18.6] vs. 252.0 [138.6-462.1] for NAb against prototype strain; 2.5 [2.5-2.5] vs. 15.0 [7.8-26.5] for NAb against Omicron variant, all p < 0.05). The flow cytometry results showed that the first dose elicited SARS-CoV-2 specific cellular immunity, while the second dose strengthened SARS-CoV-2 specific IL-2+ or TNF-α+  monofunctional, IFN-γ+ TNF-α+  bifunctional, and IFN-γ- IL-2+ TNF-α+ multifunctional CD4+ T cell responses (p < 0.05). Moreover, SARS-CoV-2 specific memory T cells were generated after the first vaccination, including the central memory T cells and effector memory T cells. The present findings provide scientific evidence for the vaccination strategy of the inactive vaccines among children against COVID-19 pandemic.

Increasing public concern on insomnia during the COVID-19 outbreak in China: An info-demiology study

Background Since December 2019, an unexplained pneumonia has broken out in Wuhan, Hubei Province, China. In order to prevent the rapid spread of this disease, quarantine or lockdown measures were taken by the Chinese government. These measures turned out to be effective in containing the contagious disease. In spite of that, social distancing measures, together with disease itself, would potentially cause certain health risks among the affected population, such as sleep disorder. We herein conducted this web search analysis so as to examine the temporal and spatial changes of public search volume of the mental health topic of “insomnia” during COVID-19 pandemic in China. Methods The data sources included Baidu Index (BDI) to analyze related search terms and the official website of the National Health Commission of the People's Republic of China to collect the daily number of newly confirmed COVID-19 cases. Following a descriptive analysis of the overall search situation, Spearman's correlation analysis was used to analyze the relationship between the daily insomnia-related search values and the daily newly confirmed cases. The means of search volume for insomnia-related terms during the COVID-19 outbreak period (January 23rd, 2020 to April 8th, 2020) were compared with those during 2016–2019 using Student's t test. Finally, by analyzing the overall daily mean of insomnia in various provinces, we further evaluated whether there existed regional differences in searching for insomnia during the COVID-19 outbreak period. Results During the COVID-19 outbreak period, the number of insomnia-related searches increased significantly, especially the average daily the BDI for the term “1 min to fall asleep immediately”. Spearman's correlation analysis showed that 6 out of the 10 insomnia-related keywords were significantly positively related to the daily newly confirmed cases. Compared with the same period in the past four years, a significantly increased search volume was found in 60.0% (6/10) insomnia-related terms during the COVID-19 outbreak period. We also found that Guangdong province had the highest number of searches for insomnia-related during the pandemic. Conclusions The surge in the number of confirmed cases during the COVID-19 pandemic has led to an increase in concern and online searches on this topic of insomnia. Further studies are needed to determine whether the search behavior truly reflect the real-time prevalence profile of relevant mental disorders, and further to establish a risk prediction model to determine the prevalence risk of psychopathological disorders, including insomnia, using insomnia-related BDI and other well-established risk factors. COVID-19;Internet;Baidu index;Insomnia;Web search.

Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells.

Infection by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has posed a severe threat to global public health. The current study revealed that several inhibitors of protein kinases C (PKCs) possess protective activity against SARS-CoV-2 infection. Four pan-PKC inhibitors, Go 6983, bisindolylmaleimide I, enzastaurin, and sotrastaurin, reduced the replication of a SARS-CoV-2 replicon in both BHK-21 and Huh7 cells. A PKCδ-specific inhibitor, rottlerin, was also effective in reducing viral infection. The PKC inhibitors acted at an early step of SARS-CoV-2 infection. Finally, PKC inhibitors blocked the replication of wild-type SARS-CoV-2 in ACE2-expressing A549 cells. Our work highlights the importance of the PKC signaling pathway in infection by SARS-CoV-2 and provides evidence that PKC-specific inhibitors are potential therapeutic agents against SARS-CoV-2. IMPORTANCE There is an urgent need for effective therapeutic drugs to control the pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). We found that several inhibitors of protein kinases C (PKCs) dramatically decrease the replication of SARS-CoV-2 in cultured cells. These PKC inhibitors interfere with an early step of viral infection. Therefore, the rapid and prominent antiviral effect of PKC inhibitors underscores that they are promising antiviral agents and suggests that PKCs are important host factors involved in infection by SARS-CoV-2.

COVID-19 Outbreak - New York City, February 29-June 1, 2020.

New York City (NYC) was an epicenter of the coronavirus disease 2019 (COVID-19) outbreak in the United States during spring 2020 (1). During March-May 2020, approximately 203,000 laboratory-confirmed COVID-19 cases were reported to the NYC Department of Health and Mental Hygiene (DOHMH). To obtain more complete data, DOHMH used supplementary information sources and relied on direct data importation and matching of patient identifiers for data on hospitalization status, the occurrence of death, race/ethnicity, and presence of underlying medical conditions. The highest rates of cases, hospitalizations, and deaths were concentrated in communities of color, high-poverty areas, and among persons aged ≥75 years or with underlying conditions. The crude fatality rate was 9.2% overall and 32.1% among hospitalized patients. Using these data to prevent additional infections among NYC residents during subsequent waves of the pandemic, particularly among those at highest risk for hospitalization and death, is critical. Mitigating COVID-19 transmission among vulnerable groups at high risk for hospitalization and death is an urgent priority. Similar to NYC, other jurisdictions might find the use of supplementary information sources valuable in their efforts to prevent COVID-19 infections.

DExD/H-box helicase 9 intrinsically controls CD8+ T cell-mediated antiviral response through noncanonical mechanisms.

Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.

Immunomodulatory effects of selenium-enriched peptides from soybean in cyclophosphamide-induced immunosuppressed mice.

In this study, selenium-enriched soybean peptides (<3 kDa, named Se-SPep) was isolated and purified from the selenium-enriched soybean protein (Se-SPro) hydrolysate by ultrafiltration. The in-vivo immunomodulatory effects of Se-SPep were investigated in cyclophosphamide-induced immunosuppressed mice. Se-SPep treatment could alleviate the atrophy of immune organs and weight loss observed in immunosuppressive mice. Besides, Se-SPep administration could dramatically improve total protein, albumin, white blood cell, immunoglobulin (Ig) M, IgG, and IgA levels in blood. Moreover, Se-SPep strongly stimulated interleukin-2 (IL-2), interferon-gamma (IFN-γ), nitric oxide (NO), and cyclic guanosine monophosphate productions by up-regulating mRNA expressions of IL-2, IFN-γ, and inducible NO synthase in spleen tissue. Furthermore, Se-SPep exhibits more effective immunomodulatory activity compared to Se-SPro and SPep. In conclusion, Se-SPep could effectively enhance the immune capacity of immunosuppressive mice. These findings confirm Se-SPep is an effective immunomodulator with potential application in functional foods or dietary supplements.

COVID-19 outbreak - New York City, February 29-June 1, 2020

This article used supplementary information sources and relied on direct data importation and matching of patient identifiers for data on hospitalisation status, the occurrence of death, race/ethnicity, and presence of underlying medical conditions. The highest rates of cases, hospitalisations, and deaths were concentrated in communities of color, high poverty areas, and among persons aged 75 years or with underlying conditions. The crude fatality rate was 9.2% overall and 32.1% among hospitalised patients. Using these data to prevent additional infections among NYC residents during subsequent waves of the pandemic, particularly among those at highest risk for hospitalisation and death, is critical. Mitigating COVID-19 transmission among vulnerable groups at high risk for hospitalisation and death is an urgent priority. Similar to NYC, other jurisdictions might find the use of supplementary information sources valuable in their efforts to prevent COVID-19 infections. This report describes cases of laboratory-confirmed COVID-19 among NYC residents diagnosed during 29 February 29 to 1 June, 2020, that were reported to DOHMH. DOHMH began COVID-19 surveillance in January 2020 when testing capacity for SARS-CoV-2 (the virus that causes COVID-19) using real time reverse transcription polymerase chain reaction (RT-PCR) was limited by strict testing criteria because of limited test availability only through CDC. The NYC and New York State public health laboratories began testing hospitalised patients at the end of February and early March. DOHMH encouraged patients with mild symptoms to remain at home rather than seek health care because of shortages of personal protective equipment and laboratory tests at hospitals and clinics. Commercial laboratories began testing for SARS-CoV-2 in mid to late March. During 29 February 29 to 15 March, patients with laboratory confirmed COVID-19 were interviewed by DOHMH, and close contacts were identified for monitoring. The rapid rise in laboratory-confirmed cases (cases) quickly made interviewing all patients, as well as contact tracing, unsustainable. Subsequent case investigations first included medical chart review for patients who were hospitalised or who had died, but then progressed to chart review only for patients who had died, and then finally only for deaths in patients aged <65 years. Mitigating COVID-19 transmission among vulnerable groups at high risk for hospitalisation and death is an urgent priority.

An Engineered Receptor-Binding Domain Improves the Immunogenicity of Multivalent SARS-CoV-2 Vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino-acid fragment of the 1,273-amino-acid S-protein protomer. The RBD is the primary SARS-CoV-2 neutralizing epitope and a critical target of any SARS-CoV-2 vaccine. Here, we show that this RBD conjugated to each of two carrier proteins elicited more potent neutralizing responses in immunized rodents than did a similarly conjugated proline-stabilized S-protein ectodomain. Nonetheless, the native RBD is expressed inefficiently, limiting its usefulness as a vaccine antigen. However, we show that an RBD engineered with four novel glycosylation sites (gRBD) is expressed markedly more efficiently and generates a more potent neutralizing responses as a DNA vaccine antigen than the wild-type RBD or the full-length S protein, especially when fused to multivalent carriers, such as a Helicobacter pylori ferritin 24-mer. Further, gRBD is more immunogenic than the wild-type RBD when administered as a subunit protein vaccine. Our data suggest that multivalent gRBD antigens can reduce costs and doses, and improve the immunogenicity, of all major classes of SARS-CoV-2 vaccines.IMPORTANCE All available vaccines for coronavirus disease 2019 (COVID-19) express or deliver the full-length SARS-CoV-2 spike (S) protein. We show that this antigen is not optimal, consistent with observations that the vast majority of the neutralizing response to the virus is focused on the S-protein receptor-binding domain (RBD). However, this RBD is not expressed well as an independent domain, especially when expressed as a fusion protein with a multivalent scaffold. We therefore engineered a more highly expressed form of the SARS-CoV-2 RBD by introducing four glycosylation sites into a face of the RBD normally occluded in the full S protein. We show that this engineered protein, gRBD, is more immunogenic than the wild-type RBD or the full-length S protein in both genetic and protein-delivered vaccines.

Estimating the infection-fatality risk of SARS-CoV-2 in New York City during the spring 2020 pandemic wave: a model-based analysis.

BACKGROUND: As the COVID-19 pandemic continues to unfold, the infection-fatality risk (ie, risk of death among all infected individuals including those with asymptomatic and mild infections) is crucial for gauging the burden of death due to COVID-19 in the coming months or years. Here, we estimate the infection-fatality risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in New York City, NY, USA, the first epidemic centre in the USA, where the infection-fatality risk remains unclear. METHODS: In this model-based analysis, we developed a meta-population network model-inference system to estimate the underlying SARS-CoV-2 infection rate in New York City during the 2020 spring pandemic wave using available case, mortality, and mobility data. Based on these estimates, we further estimated the infection-fatality risk for all ages overall and for five age groups (<25, 25-44, 45-64, 65-74, and ≥75 years) separately, during the period March 1 to June 6, 2020 (ie, before the city began a phased reopening). FINDINGS: During the period March 1 to June 6, 2020, 205 639 people had a laboratory-confirmed infection with SARS-CoV-2 and 21 447 confirmed and probable COVID-19-related deaths occurred among residents of New York City. We estimated an overall infection-fatality risk of 1·39% (95% credible interval 1·04-1·77) in New York City. Our estimated infection-fatality risk for the two oldest age groups (65-74 and ≥75 years) was much higher than the younger age groups, with a cumulative estimated infection-fatality risk of 0·116% (0·0729-0·148) for those aged 25-44 years and 0·939% (0·729-1·19) for those aged 45-64 years versus 4·87% (3·37-6·89) for those aged 65-74 years and 14·2% (10·2-18·1) for those aged 75 years and older. In particular, weekly infection-fatality risk was estimated to be as high as 6·72% (5·52-8·01) for those aged 65-74 years and 19·1% (14·7-21·9) for those aged 75 years and older. INTERPRETATION: Our results are based on more complete ascertainment of COVID-19-related deaths in New York City than other places and thus probably reflect the true higher burden of death due to COVID-19 than that previously reported elsewhere. Given the high infection-fatality risk of SARS-CoV-2, governments must account for and closely monitor the infection rate and population health outcomes and enact prompt public health responses accordingly as the COVID-19 pandemic unfolds. FUNDING: National Institute of Allergy and Infectious Diseases, National Science Foundation Rapid Response Research Program, and New York City Department of Health and Mental Hygiene.

SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity.

SARS-CoV-2 variants with spike (S)-protein D614G mutations now predominate globally. We therefore compare the properties of the mutated S protein (SG614) with the original (SD614). We report here pseudoviruses carrying SG614 enter ACE2-expressing cells more efficiently than those with SD614. This increased entry correlates with less S1-domain shedding and higher S-protein incorporation into the virion. Similar results are obtained with virus-like particles produced with SARS-CoV-2 M, N, E, and S proteins. However, D614G does not alter S-protein binding to ACE2 or neutralization sensitivity of pseudoviruses. Thus, D614G may increase infectivity by assembling more functional S protein into the virion.