CASTING: A Potent Supramolecular Strategy to Cytosolically Deliver STING Agonist for Cancer Immunotherapy and SARS-CoV-2 Vaccination

Stimulator of interferon genes, namely STING, an adaptor protein located in the endoplasmic reticulum, has been recognized as a shining target for cancer and infection research. However, STING agonists cyclic dinucleotides (CDNs) have shown almost zero efficacy in phase I clinical trials as a monotherapy, likely due to poor cellular permeability and rapid diffusion despite intratumoral injection. These deficiencies further affect other applications of CDNs, such as pandemic SARS-CoV-2 prevention and therapy. Here, we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene, namely CASTING (CAlixarene-STING), to improve CDN druggability, including degradation stability, cellular permeability, and tissue retention. CASTING efficiently enhances the immunostimulatory potency of CDG(SF) [a chemically modified cyclic di-GMP (CDG)] to generate an immunogenic microenvironment for melanoma regression, anti-PD-1 response rate increase, and durable memory formation against tumor recurrence. More importantly, CASTING displays a superior adjuvant activity on SARS-CoV-2 recombinant spike/receptor binding domain vaccines, inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo. Collectively, the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists. [GRAPHICS] .

Implementation and management of drug clinical trials during the period of COVID-19 epidemic

Objective: To explore the implementation and management measures of drug clinical trials during the period of COVID-19 epidemic, protect the safety and rights of subjects, ensure the smooth implementation of clinical trials, and provide reference and suggestions for the management work of clinical trial institutions. Methods: According to the requirements of COVID-19 epidemic prevention and control policies and the national guiding principles for drug clinical trial management, combining the experience of our hospital, we optimized the working process and proposed management measures in four aspects including project and personnel management, subject follow-up management, drug distribution management, and communication between all parties involved in clinical trials. Results and conclusions: During the period of COVID-19 epidemic, our hospital has taken a series of measures which ensured the smooth implementation of more than 200 drug clinical trials and protected the safety and rights of subjects and researchers.

[Correlation analysis of smell and taste loss with COVID-19 outbreak trend based on big data of internet].

Objective: To analyze the correlation between loss of smell/taste and the number of real confirmed cases of coronavirus disease 2019 (COVID-19) worldwide based on Google Trends data, and to explore the guiding role of smell/taste loss for the COVID-19 prevention and control. Methods: "Loss of smell" and "loss of taste" related keywords were searched in the Google Trends platform, the data were obtained from Jan. 1 2019 to Jul. 11 2021. The daily and newly confirmed COVID-19 case number were collected from World Health Organization (WHO) since Dec. 30 2019. All data were statistically analyzed by SPSS 23.0 software. The correlation was finally tested by Spearman correlation analysis. Results: A total of data from 80 weeks were collected. The retrospective analysis was performed on the new trend of COVID-19 confirmed cases in a total of 186 292 441 cases worldwide. Since the epidemic of COVID-19 was recorded on the WHO website, the relative searches related to loss of smell/taste in the Google Trends platform had been increasing globally. The global relative search volumes of "loss of smell" and "loss of taste" on Google Trends was 10.23±2.58 and 16.33±2.47 before the record of epidemic while 80.25±39.81 and 80.45±40.04 after (t value was 8.67, 14.43, respectively, both P<0.001). In the United States and India, the relative searches for "loss of smell" and "loss of taste" after the record of epidemic were also much higher than before (all P<0.001). The correlation coefficients between the trend of weekly new COVID-19 cases and the Google Trends of "loss of smell" in the global, United States, and India was 0.53, 0.76, and 0.82 respectively (all P<0.001), the correlation coefficients with Google Trends of "loss of taste" was 0.54, 0.78, and 0.82 respectively (all P<0.001). The lowest and highest point of loss of smell/taste search curves of Google Trends in different periods appeared 7 to 14 days earlier than that of the weekly newly COVID-19 confirmed cases curves, respectively. Conclusions: There is a significant positive correlation between the number of newly confirmed cases of COVID-19 worldwide and the amount of keywords, such as "loss of smell" and "loss of taste", retrieved in Google Trends. The trend of big data based on Google Trends might predict the outbreak trend of COVID-19 in advance.

[Evaluation of safety of two inactivated COVID-19 vaccines in a large-scale emergency use].

Objective: To evaluate the safety of two inactivated COVID-19 vaccines in a large-scale emergency use. Methods: Based on the "Vaccination Information Collection System", the incidence data of adverse reactions in the population vaccinated with the inactivated COVID-19 vaccines developed by Beijing Institute of Biological Products Co., Ltd and Wuhan Institute of Biological Products Co., Ltd, respectively, in emergency use were collected, and the relevant information were analyzed with descriptive epidemiological and statistical methods. Results: By December 1, 2020, the vaccination information of 519 543 individuals had been collected. The overall incidence rate of adverse reactions was 1.06%, the incidence rate of systemic adverse reactions was 0.69% and the incidence rate of local adverse reactions was 0.37%. The main systemic adverse reactions included fatigue, headache, fever, cough and loss of appetite with the incidence rates of 0.21%, 0.14%, 0.06%, 0.05% and 0.05%, respectively; the main local adverse reactions were injection site pain and injection site swelling with the incidence rates of 0.24% and 0.05%, respectively. Conclusion: The two inactivated COVID-19 vaccines by Beijing Institute of Biological Products Co., Ltd and Wuhan Institute of Biological Products Co., Ltd showed that in the large-scale emergency use, the incidence rate of general reactions was low and no serious adverse reactions were observed after the vaccinations, demonstrating that the vaccines have good safety.

Technical routes for coronavirus vaccine development

Three types of coronavirus, SARS-CoV, MERS-CoV, and SARS-CoV-2, are known to cause severe diseases in humans and cause outbreaks or epidemics. After the outbreak of the epidemic, a number of institutions around the world carried out coronavirus related vaccine research and development, and the vaccines are mainly divided into five types: inactivated virus vaccine, alive-attenuated vaccine, gene recombination subunit vaccine, viral vector vaccine and nucleic acid vaccine. In this review, the progress in coronavirus vaccine development was summarized by analyzing the global research of coronavirus vaccine.