Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro).

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 µM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 µM, respectively) with low cytotoxicity (CC50 ＞ 50 µM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.

Research on transmission pattern of SARS-CoV-2

Objective: Taking the three outbreaks caused by Delta variant (B.1.617.2) in Guangzhou, Guangdong Province, Nanjing, Jiangsu Province and Zhengzhou, Henan Province as examples, to explore different transmission pattern of SARS-CoV-2 epidemic and to provide basis for scientific prevention and control.

Epidemiological and clinical characteristics of the largest COVID-19 outbreak along the China-Myanmar border in Ruili City, Yunnan Province, China.

Background: Imported COVID-19 patients posed great challenges to border areas' COVID-19 control. However, research was scarce to reveal epidemiological characteristics of COVID-19 in border areas. This study aimed to explore the detailed transmission chains, and reveal epidemiological and clinical characteristics of the largest COVID-19 outbreak caused by Delta variant of concern (VOC) occurred in the China-Myanmar border area. Methods: During the outbreak from July to September, 2021 in Ruili City, Yunnan Province, China, epidemiological investigation data and clinical-related data pertaining to confirmed COVID-19 patients were collected. Patients' contact history data and viral gene sequencing were used for inference of transmission chains. Sociodemographic and epidemiological characteristics, cycle threshold (Ct) value, and antibodies level were compared between patients who were vaccinated against COVID-19 or not. Results: A total of 117 COVID-19 patients were confirmed during the outbreak, among which 86 (73.5%) were breakthrough infections. These patients evenly split between Chinese and Myanmar people (50.4% vs. 49.6%). Most of these patients were mild (45.3%) or moderate (48.7%) infections with no death reported. Multi-source of infection led to 16 transmission chains with a maximum of 45 patients in one chain. Patients vaccinated against COVID-19 before infection had relatively higher antibodies (IgM and IgG) levels and more rapid response to infection than non-vaccinated patients (p < 0.05). Conclusion: Land border areas have greater risks of imported COVID-19 and more complicated epidemics. It should be cautious in formulating entry and exit requirements for border areas. The immune effect of COVID-19 vaccines and related mechanism should be further explored.

Evaluation of humoral immune responses induced by different SARS-CoV-2 spike trimers from wild-type and emerging variants with individual, sequential, and combinational delivered strategies.

The spike trimer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an effective target for inducing neutralizing antibodies by coronavirus disease 2019 (COVID-19) vaccines. However, the diversity of spike protein from emerging SASR-CoV-2 variants has become the major challenge for development of a universal vaccine. To investigate the immunogenicity of spike proteins from various circulating strains including wild type, Delta, and Omicron variants, we produced various natural spike trimers and designed three vaccination strategies, that is, individual, sequential, and bivalent regimens to assess autologous and heterogenous antibody responses in a mouse model. The results indicated that monovalent vaccine strategy with individual spike trimer could only induce binding and neutralizing antibodies against homologous viruses. However, sequential and bivalent immunization with Delta and Omicron spike trimers could induce significantly broader neutralizing antibody responses against heterogenous SARS-CoV-2. Interestingly, the spike trimer from Omicron variant showed superior immunogenicity in inducing antibody response against recently emerging XE variant. Taken together, our data supported the development of novel vaccination strategies or multivalent vaccine against emerging variants.

Cost-effectiveness analysis on COVID-19 surveillance strategy of large-scale sports competition.

BACKGROUND: Nucleic acid test (NAT) could effectively control the spread of COVID-19 caused by large-scale sports competitions. However, quantitative analysis on the appropriate frequency of NAT is scarce, and the cost-effectiveness and necessity of high-frequency NAT remain to be fully explored and validated. This study aims to optimize the COVID-19 surveillance strategies through cost-effectiveness analysis for the Tokyo 2020 Olympic Games and the upcoming Beijing 2022 Olympic Winter Games. METHODS: A total of 18 scenarios were designed regarding the NAT frequency, symptom monitoring, and strengthening close-contact control. An agent-based stochastic dynamic model was used to compare the cost-effectiveness of different NAT scenarios and optimize the surveillance strategies. The dynamics of the proposed model included the arrival and departure of agents, transmission of the disease according to Poisson processes, and quarantine of agents based on regular NATs and symptom onset. Accumulative infections, cost, and incremental cost-effectiveness ratio (ICER) were simulated in the frame of the model. ICER was used to compare the cost-effectiveness of different scenarios. Univariate sensitivity analysis was performed to test the robustness of the results. RESULTS: In Scenario 16, where the competition-related personnel (CRP) received NAT daily and national sports delegation (NSD) with quarantined infections accepted an additional NAT daily, accumulative infection was 320.90 (90 initial infections), the total cost was (United States Dollar) USD 8 920 000, and the cost of detecting out each infection was USD 27 800. Scenario 16 would reduce the total cost by USD 22 570 000 (avoid 569.61 infections), USD 1 420 000 (avoid 47.2 infections) compared with Scenario 10 (weekly NAT, strengthened close contact control) and Scenario 7 (daily NAT, no strengthened close contact control), respectively. Sensitivity analysis showed that the result was most sensitive to the change in basic reproductive number. CONCLUSIONS: High-frequency NATs such as bidaily, daily, and twice a day were cost-effective. NAT daily for CRP with strengthening close-contact control could be prioritized in defense against COVID-19 at large-scale sports competitions. This study could assist policymakers by assessing the cost-effectiveness of NAT scenarios and provide the host country with an optimal COVID-19 surveillance strategy.

Impact of Regions with COVID-19 Cases on COVID-Zero Regions by Population Mobility - Worldwide, 2021.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: Reducing population mobility and increasing the vaccination rate for severe acute respiratory syndrome coronavirus 2 can decrease the transmission of coronavirus disease 2019 (COVID-19). WHAT IS ADDED BY THIS REPORT?: In order to reduce the incidence of COVID-19 to the levels of influenza after restoring normal mobility, the efficacy against infection needs to be increased to 40% and the efficacy against symptomatic disease needs to be increased to 90%. The efficacy against infection has a more important impact compared to efficacy against symptomatic disease or death on the transmission of COVID-19 at the population level. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?: The population should continue maintaining non-pharmaceutical interventions and minimize international movement to prevent transmission of COVID-19. Furthermore, developing new vaccines or promoting booster vaccinations should be considered to increase efficacy.

The Epidemic of Sexually Transmitted Diseases Under the Influence of COVID-19 in China.

Background: Prevention and control of HIV/AIDS and other sexually transmitted diseases (STDs) are major public health priorities in China, but are influenced by the COVID-19 epidemic. In this study, we aimed to quantitatively explore the impact of the COVID-19 epidemic and its control measures on five major STD epidemics in China. Methods: A monthly number of newly reported cases of HIV/AIDS, hepatitis B and C, gonorrhea, and syphilis from January 2010 to December 2020 were extracted to establish autoregressive integrated moving average (ARIMA) models. Each month's absolute percentage error (APE) between the actual value and model-predicted value of each STD in 2020 was calculated to evaluate the influence of the COVID-19 epidemic on the STDs. Pearson correlation analysis was conducted to explore the confirmed COVID-19 case numbers and the COVID-19 control measures' correlations with the case numbers and the APEs of five STDs in 2020. Results: The actual number of five STDs in China was more than 50% lower than the predicted number in the early days of the COVID-19 epidemic, especially in February. Among them, the actual number of cases of hepatitis C, gonorrhea, and syphilis in February 2020 was more than 100% lower than the predicted number (APE was -102.3, -109.0, and -100.4%, respectively). After the sharply declines of STDs' reported cases in early 2020, the case numbers recovered quickly after March. The epidemic of STDs was negatively associated with the COVID-19 epidemic and its control measures, especially for restrictions on gathering size, close public transport, and stay-at-home requirements (p < 0.05). Conclusion: COVID-19 had a significant but temporary influence on the STD epidemic in China. The effective control of COVID-19 is vital for STD prevention. STD services need to be improved to prevent STDs from becoming a secluded corner in the shadow of COVID-19.

Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro.

Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir's limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 µM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.

Association between human coronaviruses' epidemic and environmental factors on a global scale.

Environmental factors could influence the epidemic of virus in human; however, the association remains intricate, and the evidence is still not clear in human coronaviruses (HCoVs). We aimed to explore and compare the associations between HCoVs' epidemic and environmental factors globally. Four common HCoVs' data were collected by a systematic literature review, and data of MERS, SARS, and COVID-19 were collected from the World Health Organization's reports. Monthly positive rates of common HCoVs and incidence rates of MERS, SARS, and COVID-19 were calculated. Geographical coordinates were used to link virus data and environmental data. Generalized additive models (GAMs) were used to quantitatively estimate the association of environmental factors with HCoVs' epidemic. We found that there are wide associations between HCoVs and environmental factors on a global scale, and some of the associations were nonlinear. In addition, COVID-19 has the most similarities in associations' direction with common HCoVs, especially for HCoV-HKU1 in four environmental factors including the significantly negative associations with average temperature, precipitation, vegetation coverage (p<0.05), and the U-shaped association with temperature range. This study strengthened the relevant research evidences and provided significant insights into the epidemic rules of HCoVs in general. The similarities between COVID-19 and common HCoVs indicated that it is critically important to strengthen surveillance on common HCoVs and pay more attention to environmental factors' role in surveillance and early warning of HCoVs' epidemic.

Novel Monoclonal Antibodies and Recombined Antibodies Against Variant SARS-CoV-2.

The mutants resulted from the ongoing SARS-CoV-2 epidemic have showed resistance to antibody neutralization and vaccine-induced immune response. The present study isolated and identified two novel SARS-CoV-2 neutralizing antibodies (nAbs) from convalescent COVID-19 patients. These two nAbs (XG81 and XG83) were then systemically compared with nine nAbs that were reconstructed by using published data, and revealed that, even though these two nAbs shared targeting epitopes on spike protein, they were different from any of the nine nAbs. Compared with XG81, XG83 exhibited a higher RBD binding affinity and neutralization potency against wild-typed pseudovirus, variant pseudoviruses with mutated spike proteins, such as D614G, E484Q, and A475V, as well as the authentic SARS-CoV-2 virus. To explore potential broadly neutralizing antibodies, heavy and light chains from all 18 nAbs (16 published nAbs, XG81 and XG83) were cross-recombined, and some of the functional antibodies were screened and studied for RBD binding affinity, and neutralizing activity against pseudovirus and the authentic SARS-CoV-2 virus. The results demonstrated that several recombined antibodies had a more potent neutralization activity against variant pseudoviruses compared with the originally paired Abs. Taken together, the novel neutralizing antibodies identified in this study are a likely valuable addition to candidate antibody drugs for the development of clinical therapeutic agents against SARS-CoV-2 to minimize mutational escape.

Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies.

Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.

Comparison of Clinical Characteristics Among COVID-19 and Non-COVID-19 Pediatric Pneumonias: A Multicenter Cross-Sectional Study.

Background: The pandemic of Coronavirus Disease 2019 (COVID-19) brings new challenges for pediatricians, especially in the differentiation with non-COVID-19 pneumonia in the peak season of pneumonia. We aimed to compare the clinical characteristics of pediatric patients with COVID-19 and other respiratory pathogens infected pneumonias. Methods: We conducted a multi-center, cross-sectional study of pediatric inpatients in China. Based on pathogenic test results, pediatric patients were divided into three groups, including COVID-19 pneumonia group, Non-COVID-19 viral (NCV) pneumonia group and Non-viral (NV) pneumonia group. Their clinical characteristics were compared by Kruskal-Wallis H test or chi-square test. Results: A total of 636 pediatric pneumonia inpatients, among which 87 in COVID-19 group, 194 in NCV group, and 355 in NV group, were included in analysis. Compared with NCV and NV patients, COVID-19 patients were older (median age 6.33, IQR 2.00-12.00 years), and relatively fewer COVID-19 patients presented fever (63.2%), cough (60.9%), shortness of breath (1.1%), and abnormal pulmonary auscultation (18.4%). The results were verified by the comparison of COVID-19, respiratory syncytial virus (RSV) and influenza A (IFA) pneumonia patients. Approximately 42.5%, 44.8%, and 12.6% of the COVID-19 patients presented simply ground-glass opacity (GGO), simply consolidation, and the both changes on computed tomography (CT) scans, respectively; the proportions were similar as those in NCV and NV group (p>0.05). Only 47.1% of COVID-19 patients had both lungs pneumonia, which was significantly lower than that proportion of nearly 80% in the other two groups. COVID-19 patients presented lower proportions of increased white blood cell count (16.5%) and abnormal procalcitonin (PCT) (10.7%), and a higher proportion of decreased lymphocyte count (44.0%) compared with the other two groups. Conclusion: Majority clinical characteristics of pediatric COVID-19 pneumonia patients were milder than non-COVID-19 patients. However, lymphocytopenia remained a prominent feature of COVID-19 pediatric pneumonia.