Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice.

The repetitive applications of vaccine boosters have been brought up in face of continuous emergence of SARS-CoV-2 variants with neutralization escape mutations, but their protective efficacy and potential adverse effects remain largely unknown. Here, we compared the humoral and cellular immune responses of an extended course of recombinant receptor binding domain (RBD) vaccine boosters with those from conventional immunization strategy in a Balb/c mice model. Multiple vaccine boosters after the conventional vaccination course significantly decreased RBD-specific antibody titers and serum neutralizing efficacy against the Delta and Omicron variants, and profoundly impaired CD4+ and CD8+T cell activation and increased PD-1 and LAG-3 expressions in these T cells. Mechanistically, we confirmed that extended vaccination with RBD boosters overturned the protective immune memories by promoting adaptive immune tolerance. Our findings demonstrate potential risks with the continuous use of SARS-CoV-2 vaccine boosters, providing immediate implications for the global COVID-19 vaccination enhancement strategies.

A Highly Conserved Peptide Vaccine Candidate Activates Both Humoral and Cellular Immunity Against SARS-CoV-2 Variant Strains.

Facing the imminent need for vaccine candidates with cross-protection against globally circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we present a conserved antigenic peptide RBD9.1 with both T-cell and B-cell epitopes. RBD9.1 can be recognized by coronavirus disease 2019 (COVID-19) convalescent serum, particularly for those with high neutralizing potency. Immunization with RBD9.1 can successfully induce the production of the receptor-binding domain (RBD)-specific antibodies in Balb/c mice. Importantly, the immunized sera exhibit sustained neutralizing efficacy against multiple dominant SARS-CoV-2 variant strains, including B.1.617.2 that carries a point mutation (SL452R) within the sequence of RBD9.1. Specifically, SY451 and SY454 are identified as the key amino acids for the binding of the induced RBD-specific antibodies to RBD9.1. Furthermore, we have confirmed that the RBD9.1 antigenic peptide can induce a S448-456 (NYNYLYRLF)-specific CD8+ T-cell response. Both RBD9.1-specific B cells and the S448-456-specific T cells can still be activated more than 3 months post the last immunization. This study provides a potential vaccine candidate that can generate long-term protective efficacy over SARS-CoV-2 variants, with the unique functional mechanism of activating both humoral and cellular immunity.

Real Workload-Situated Training in COVID-19 Prevention of General Practice Residents in China: A Situated Cognition Study.

Objective: The participation of general practice (GP) residents in COVID-19 prevention and control tasks touched workload participation in public health and disease prevention and control and was also a rare, valuable training experience for the residents and research material for medical education. This experience contributed to the understanding of three key points: First, was the content of the COVID-19 prevention task suited to them, or did it overload them in the present? Second, their competence in the COVID-19 prevention task reflected whether the early medical school training was sufficient or not. Third, what can be drawn from this study to promote public health training in the future? This study aimed to explore these issues by conducting a real epidemic situated training (REST) program. Methods: A situated cognition study was designed that included situational context design, legitimate peripheral participation, and the construction of a community of practice. The Task Cognitive Load Scale (NASA-TLX Scale) and self-developed questionnaires were adopted to conduct a questionnaire survey of resident doctors in a GP training program from West China Hospital of Sichuan University, and 183 questionnaires were collected. SPSS 23.0 statistical software was used for the statistical analysis of data. Results: The NASA scale showed that the intensity of field epidemic prevention and control (training) was tolerable. In particular, there was statistical difference in the cognitive load intensity of training before and after the epidemic occurred at different time points (P < 0.05). This shows that they were early trained and well-prepared before sudden outbreak of the COVID-19. Before the outbreak of the epidemic, the public health knowledge and training received came from undergraduate education (83.16%), early residents program training (69.47%), online self-study (49.16%), and continuing education (20.53%). Conclusion: Former medical school education and training at the regulatory training stage have a good effect and enable residents to master the skills required for epidemic prevention and control and to physically and mentally prepare for the task. After this stage, epidemic prevention and control training in real situations will make important contributions to the self-assessment and performance improvement of public health training.

T Cell Immunity Evaluation and Immunodominant Epitope T Cell Receptor Identification of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein in COVID-19 Convalescent Patients.

A better understanding of the role of T cells in the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is helpful not only for vaccine development but also for the treatment of COVID-19 patients. In this study, we determined the existence of SARS-CoV-2-specific T cells in the blood of COVID-19 convalescents. Meanwhile, the specific T cell response in the non-RBD region was stronger than in the RBD region. We also found that SARS-CoV-2 S-specific reactive CD4+ T cells exhibited higher frequency than CD8+ T cells in recovered COVID-19 patients, with greater number of corresponding epitopes presented. Importantly, we isolated the SARS-CoV-2-specific CD4+ T cell receptors (TCRs) and inserted the TCRs into allogenic CD4+ T cells. These TCR-T cells can be activated by SARS-CoV-2 spike peptide and produce IFN-γ in vitro. These results might provide valuable information for the development of vaccines and new therapies against COVID-19.

Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants.

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

Spatial Accessibility Assessment of Prehospital EMS with a Focus on the Elderly Population: A Case Study in Ningbo, China.

The spatial accessibility of prehospital EMS is particularly important for the elderly population's physiological functions. Due to the recent expansion of aging populations all over the globe, elderly people's spatial accessibility to prehospital EMS presents a serious challenge. An efficient strategy to address this issue involves using geographic information systems (GIS)-based tools to evaluate the spatial accessibility in conjunction with the spatial distribution of aging people, available road networks, and prehospital EMS facilities. This study employed gravity model and empirical Bayesian Kriging (EBK) interpolation analysis to evaluate the elderly's spatial access to prehospital EMS in Ningbo, China. In our study, we aimed to solve the following specific research questions: In the study area, "what are the characteristics of the prehospital EMS demand of the elderly?" "Do the elderly have equal and convenient spatial access to prehospital EMS?" and "How can we satisfy the prehospital EMS demand of an aging population, improve their spatial access to prehospital EMS, and then ensure their quality of life?" The results showed that 37.44% of patients admitted to prehospital EMS in 2020 were 65 years and older. The rate of utilization of ambulance services by the elderly was 27.39 per 1000 elderly residents. Ambulance use by the elderly was the highest in the winter months and the lowest in the spring months (25.90% vs. 22.38%). As for the disease spectrum, the main disease was found to be trauma and intoxication (23.70%). The mean accessibility score was only 1.43 and nearly 70% of demand points had scored lower than 1. The elderly's spatial accessibility to prehospital EMS had a central-outward gradient decreasing trend from the central region to the southeast and southwest of the study area. Our proposed methodology and its spatial equilibrium results could be taken as a benchmark of prehospital care capacity and help inform authorities' efforts to develop efficient, aging-focused spatial accessibility plans.

Real Workload-Situated Training in COVID-19 Prevention of General Practice Residents in China: A Situated Cognition Study (preprint)

Objective: The participation of general practice (GP) residents in COVID-19 prevention and control tasks touched workload participation in public health and disease prevention and control and was also a rare, valuable training experience for the residents and research material for medical education . This experience contributed to the understanding of three key points: First, was the content of the COVID-19 prevention task suited to them, or did it overload them in the present? Second, their competence in the COVID-19 prevention task reflected whether the early medical school training was sufficient or not .Third, what can be drawn from this study to promote public health training in the future? This study aimed to explore these issues by conducting a real epidemic situated training (REST) program. Methods: A situated cognition study was designed that included situational context design, legitimate peripheral participation, and the construction of a community of practice. The Task Cognitive Load Scale (NASA-TLX Scale) and self-developed questionnaires were adopted to conduct a questionnaire survey of resident doctors in a GP training program from West China Hospital of Sichuan University, and 183 questionnaires were collected. SPSS 23.0 statistical software was used for the statistical analysis of data. Results: The NASA scale showed that the intensity of field epidemic prevention and control (training) was tolerable. In particular, there was no statistical difference in the cognitive load intensity of training before and after the epidemic occurred at different time points (P<0.05). This shows that they were early trained and well prepared before sudden outbreak of the COVID-19.Before the outbreak of the epidemic, the public health knowledge and training received came from undergraduate education (83.16%), early residents program training (69.47%), online self-study (49.16%), and continuing education (20.53%). Conclusion: Former medical school education and training at the regulatory training stage have a good effect and enable residents to master the skills required for epidemic prevention and control and to physically and mentally prepare for the task. After this stage, epidemic prevention and control training in real situations will make important contributions to the self-assessment and performance improvement of public health training,and make participants more competent to face the epidemic task.

Hierarchical Model of Multi-level Index to Assess Local Resilience Capability in COVID-19 (preprint)

Background: Globally, there have been 212,544,565 confirmed cases of Corona Virus disease 2019 (COVID-19), including 4,441,428 deaths by 24 August 2021, reported to WHO. Facing the global pandemic of COVID-19, countries and regions have implemented different policies and taken different non-pharmacological interventions (NPIs) according to their own circumstances. However, the quantitative assessment of national policies and local resilience capabilities is a huge challenge. Methods: In order to assess interventions and improve local resilience from a comprehensive perspective, this study aims to establish a multi-dimensional and dynamic prevention and control system. The main body of the system is an index system. To make our evaluation system more scientific and useful, the comparative study with several widely used tools or lessons is conducted to report what they have done. Then analytic hierarchy process (AHP) is used to set up the framework under the concept of a multi-level strategy of public health management. Indicators in the system are determined by literature research and expert interviews. Results: Emergency capability assessment includes building a well-established system, execution of the system, and measurement. The well-established system exhibits several characteristics: 1) considering indicators about whole-of-society involvement, including country-, city-, local community- and individual-level; 2) improving capability at multi-phases, from the preparedness ability to response ability; 3) at both policy level and implementation level. Categories of containment and closure, response in economic system, and response in public health system constitute the main body of the framework. The well-established system does not necessarily apply to all scenarios, and the actual situation should be taken into consideration in the process of implementation/execution. At the stage of measurement, the case of Wuhan/Hubei response is introduced to implement and test our system. Empirical researches will be conducted to verify the index system quantitatively in our future research. Conclusions: Our index system can assess national policies and capabilities quantitatively. When enough data are available, it will become a tool to assess the local resilience capability for countries or regions.

Health-Seeking Behavior of Patients with Cardiovascular Diseases During COVID-19 Epidemic and Post-Epidemic Period in Shanghai, China (preprint)

Background: The COVID-19 pandemic has led to concerns around its subsequent impact on patients with non-COVID-19 diseases, and the health-seeking behavior of such patients must be investigated.Methods: Taking advantage of the remote ECG system covering 278 medical institutions throughout Shanghai, the numbers of hospital visits with ECG examinations during the lockdown (between January 23 and April 7, 2020), post-lockdown (between April 8 and December 31, 2020) and post-epidemic (between January 23 and April 7, 2021) periods were analyzed and compared against those during the same periods of the preceding years (2018 and 2019).Findings: Compared with those of the same period during pre-COVID years, the number of hospital visits decreased during the lockdown (a 38% reduction), followed by a rebound post-lockdown (a 17% increase) and a fall to the baseline level of the post-epidemic period. This decrease-rebound-fallback pattern was largely attributed to the dynamics of visits to community clinics rather than academic hospitals. The number of new COVID-19 cases or deaths announced on a given day correlated negatively with hospital visits during the same day and for the following 42 days, with the correlation at its most prominent at seven days. Hospital visit dynamics differed for various cardiovascular diseases. Whereas hospital visits for sinus bradycardia exhibited a typical decrease-rebound-fallback pattern, hospital visits for ST-segment elevated myocardial infarction did not fall during the lockdown period but did exhibit a subsequent increase during the post-lockdown period. By comparison, the volume for ventricular tachycardia remained constant throughout this entire period.Interpretation: The health-seeking behavior of patients with cardiovascular diseases exhibited a decrease-rebound-fallback pattern following the COVID-19 lockdowns. Hospital visits for diseases with more severe symptoms were less influenced by the lockdowns, showing a resilient demand for healthcare.Funding: Shanghai Hospital Development Center, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Commission, and Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. Declaration of Interest: All authors declare no conflicts of interest.Ethical Approval: This study was approved by the ethics committee at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

Online Study: Understanding the Laws of Self-Regulated Study (preprint)

Background: The sudden COVID-19 outbreak has posed challenges to the normal development of continuing education for general practitioners. Consequently, an online medical training program for family doctors has emerged. Online study helps us better understand the laws of self-regulated learning because we can track the process and outcome of family physicians and compare it to that of face-to-face training programs. The study track the GPCC online program to reveal this principle. Results: By recording learners’ study behaviors and explore the law of learning progress and analyse the impact of latent variables on learning through structural equation models,the study find that the the impact of teacher support and supervision and of internal motivation on learning input and the influence of teacher support and supervision on internal motivation can be researched through online study. Conclusions: Online study helps us better understand the laws of self-regulated learning. It helps to better understand the impact of teacher support, supervision, and internal motivation on learning input , as well as the influence of teacher support and supervision on internal motivation. Examining online study can also help in making effective use of the self-education characteristics of internal motivation and cultivate the ability of independent thinking and learning self-discipline .

Identification of cross-reactive CD8+ T cell receptors with high functional avidity to a SARS-CoV-2 immunodominant epitope and its natural mutant variants.

Despite the growing knowledge of T cell responses in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Here, with a predicted peptide library from SARS-CoV-2 S and N proteins, we found that specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients (15/20) and an epitope from the N protein, N361-369 (KTFPPTEPK), was the most dominant epitope from our selected peptide library. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity that were independent of the CD8 co-receptor. These TCRs exhibited complementary cross-reactivity to several presently reported N361-369 mutant variants, as to the wild-type epitope. Further, the natural functions of these TCRs in the cytotoxic immunity against SARS-CoV-2 were determined with dendritic cells (DCs) and the lung organoid model. We found that the N361-369 epitope could be normally processed and endogenously presented by these different types of antigen presenting cells, to elicit successful activation and effective cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, and illuminated potential ways of viral clearance in COVID-19 patients. These results indicate that utilizing CD8-independent TCRs against SARS-CoV-2-associated antigens may provide functional superiority that is beneficial for the adoptive cell immunotherapies based on natural or genetically engineered T cells. Additionally, this information is highly relevant for the development of the next-generation vaccines with protections against continuously emerged SARS-CoV-2 mutant strains.

The impact of intervention to the incidence of natural focus diseases during the outbreak of COVID-19 in Jiangsu Province, China (preprint)

Doxorubicin (DOX) is a well-known chemotherapeutic drug for most malgnencies including breast cancer and leukemia whilst the usage of DOX is limited owing to its cardiotoxicity. The present study analyzed the effects of crocin on doxorubicin’s cardiotoxic efect in rat myocardium and searched their mechanistic interaction in the pathogenesis of DOX-induced myocardial toxicity. Forty rats were divided into four groups; (a) control (received normal saline as a dose of 1 ml/kg by ip for 15 days), (b) Crocin (received crocin as a dose of 40 mg/kg/24h by ip for 15 days), (c) DOX (received DOX as a dose of 2 mg/kg/48h by ip in six injection, cumulative dose 12 mg/kg), and (d) DOX+Crocin (received DOX as a dose of 2 mg/kg/48h by ip in six injection and crocin as a dose of 40 mg/kg/24h ip for 15 days). According to the present study, DOX administration caused significant increases in lipid indices (triglyseride, low-dencity lipoproteins and very low-dencity lipoproteins) as well as cardiac markers (Creatine kinase-muscle/brain and Cardiac Troponin I). Morever, DOX caused significant increases in oxidative stress parameters (malondialdehyde and total oxidant status) as well as decreases in antioxidant defense systems (glutathione, superoxide dismutase, catalase and total antioxidant status). The present study also demonstrated that co-administration of crocin with DOX significantly ameliorated the lipid profile and biochemical parameters in rats receiving DOX. The results were supported by histopathological and immunohistochemical evaluations. Taken together, our results reveal that crocin might be a cardioprotective agent in DOX treated patients for cancer.

Population Vaccine Effectiveness and its Implication for Control of the Spread of COVID-19 in the US (preprint)

Realized vaccine efficacy in population is highly different from the individual vaccine efficacy measured in clinical trial. The realized vaccine efficacy in population is substantially affected by the vaccine age-stratified prioritization strategy, population age-structure, non-pharmaceutical intervention (NPI). We proposed a population vaccine efficacy which integrated individual vaccine efficacy, vaccine prioritization strategy and NPI to measure and monitor the control of the spread of COVID-19. We found that 11 states in the US had low population vaccine efficacy and 20 states had high population efficacy. We demonstrated that although the proportion of the population who received at least one dose of COVID-19 vaccine across 11 low population vaccine efficacy states, in general, was greater than that in 20 high population vaccine efficacy states, the 11 low population vaccine efficacy states experienced the recent COVID-19 surge, while the number of new cases in the 20 high population vaccine efficacy states exponentially decreased. We demonstrated that the proportions of adults in the population across 50 states were significantly associated with the forecasted ending date of the COVID-19. We show that it was recent low proportion of adults vaccinated in Michigan that caused its COVID-19 surge. Using population vaccination efficacy, we forecasted that the earliest COVID-19 ending states were Hawaii, Arizona, Arkansas, and California (in the end of June, 2021) and the last COVID-19 ending states were Colorado, New York and Michigan (in the Spring, 2022).

A Rapid and Efficient Screening System for Neutralizing Antibodies and Its Application for SARS-CoV-2.

After the pandemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 have been developed for the prophylactic and therapeutic purposes. However, few methodologies are described in detail on how to rapidly and efficiently generate effective NAbs to SARS-CoV-2. Here, we integrated and optimized a strategically screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific NAbs within 6 days, followed by additional 9 days for antibody production and function analysis. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited advanced neutralizing potency and high affinity, with the top two NAbs showing half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides an effective methodology with high applicable value for discovering potential preventative and therapeutic NAbs for the emerging infectious diseases.

Control Measures During the COVID-19 Outbreak Reduced the Transmission of Hand, Foot, and Mouth Disease (preprint)

Background: Control measures during the coronavirus disease 2019 (COVID-19) outbreak may have limited the spread of infectious diseases. This study aimed to analyse the impact of COVID-19 on the spread of hand, foot, and mouth disease (HFMD) in China. Methods: A mathematical model was established to fit the reported data of HFMD in six selected cities in mainland China from 2015 to 2020. The absolute difference (AD) and relative difference (RD) between the reported incidence in 2020, and simulated maximum, minimum, or median incidence of HFMD in 2015-2019 were calculated. Findings: The incidence and Reff of HFMD have decreased in six selected cities since the outbreak of COVID-19, and in the second half of 2020, the incidence and R eff of HFMD have rebounded. The results show that the total attack rate (TAR) in 2020 was lower than the maximum, minimum, and median TAR fitted in previous years in six selected cities (except Changsha city). For the maximum, median, minimum fitted TAR, the range of RD (%) is 42·20-99·20%, 36·35-98·41% 48·35-96·23% (except Changsha city) respectively. Interpretation: Based on the incidence data of six cities from 2015 to 2019, the SEIAR model demonstrated a significant effect on the incidence of HFMD. During the period of COVID-19, the incidence and R eff of HFMD decreased, the prevention and control measures taken during the period of COVID-19, such as school suspension, home quarantine, closing all kinds of leisure places, wearing masks, advocating frequent hand washing, etc., have not only effectively suppressed the spread of COVID-19 epidemic, but also have significantly contributed to the containment of HFMD transmission.Funding Statement: This study was partly supported by the Bill & Melinda Gates Foundation (INV-005834).Declaration of Interests: The authors declare no conflicts of interests.

The Impact of Intervention to Routine Surveillance of Natural Focal Diseases During the Outbreak of COVID-19 in Jiangsu Province, China (preprint)

Background: With the strength intervention of China, the outbreak of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) had a great control effect. The measures may influence the development and progression of others infectious diseases.Method: The data of daily coronavirus virus disease 2019 (COVID-19) confirmed cases from January 3, 2020 to April 30, 2020 and natural focal disease cases from January, 2005 to April, 2020 were collected from Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial CDC). We describe and compare the data of natural focal diseases from January to April, 2020 with the same months from 2015 to 2019 in the four aspects: trend of incidence, regional, age and sex distribution. Nonparametric tests were used to analyzed to the difference between the duration from onset of illness to date of diagnosis of natural focal diseases and the same period of the previous year. Results: The incidence of malaria in February (0.9 per 10,000,000 people), March (0.3 per 10,000,000 people) and April (0.1 per 10,000,000 people) 2020 less than the lower limit for range of February (1.6-4.5 per 10,000,000 people), March (0.8-3.3 per 10,000,000 people) and April (1.0-2.9 per 10,000,000 people) from 2015 to 2019 respectively. The incidence of brucellosis in February was 0.9 (per 10,000,000 people), less than the lower limit for the range from 2015 to 2019 (1.6-4.5 per 10,000,000 people). The incidence of hemorrhagic fever (HF) in March was 1.0 (per 10,000,000 people), less than the lower limit for the range from 2015 to 2019 (1.4-2.6 per 10,000,000 people). However, the incidence of Severe Fever with Thrombocytopenia Syndrome (SEFT) in March was 0.3 (per 10,000,000 people), higher than the upper limit for the range from 2015 to 2019 (0.0-0.1 per 10,000,000 people). Furthermore, we respectively observed the incidence with various degree of reduction in male, 20-60 years old and both rural and urban areas. Conclusions: In Jiangsu province, the incidence of natural focal diseases decreased during the outbreak of COVID-19 in 2020, especially malaria, HF and SEFT. The impact of interventions were felt most by male individuals within the age group of 20-50 years. The interventions for COVID-19 may control the epidemics of natural focal diseases.

Forecasting the Effectiveness of Interventions to Control the Second Wave of COVID-19 Outbreaks: A Modelling Study in 12 Countries of 6 Regions (preprint)

Background: In most countries, it is hard to effectively control coronavirus disease 2019 (COVID-19). This study conducted the most comprehensive evaluation of the effects of pharmacological (like vaccination, pharmacotherapy ) and non-pharmacological (like isolation, social distancing and mask-wearing) interventions taken singly or in combination for the first time globally.Methods: We estimate that across these 12 countries that are different but presentative, interventions prevented or delayed roughly millions of confirmed cases. This study constructs mathematical model, which interventions includes vaccination, pharmacotherapy, isolation, social distancing and mask-wearing , and analyses the effect of these interventions used alone and in combination.Findings: The basic reproduction number (R0) of each country mostly range from 3 to 5. In terms of the effect of single intervention, for countries such as China, South Korea, Thailand, US, South Africa and Algeria, it is preferred to recommend these countries to adopt isolation to prevent and control the second wave of COVID-19 outbreak, while for countries such as Russia, UK, Saudi Arabia, India and Brazil, wearing masks is the best choice. Especially pharmacotherapy can play a good role in Iran. When combinations with different interventions were taken, the situation was different. For US, Brazil and Algeria, the combination of “Vaccination & Isolation & Wearing mask” is recommended in these countries to prevent and control the development of COVID-19, and the combination of “Isolation & Social distancing & Wearing mask” is recommended in UK and China. For the rest, we suggest that Russia, Iran, Saudi Arabia, India, Thailand and South Africa take the intervention measures of “Vaccination & Medical treatment & Isolation & Wearing mask”, “Vaccination & Medical treatment”, “Vaccination & Social distancing & Wearing mask”, “Medical treatment & Social distancing & Wearing mask”, “Vaccination & Medical Treatment & Isolation”, “Vaccination & Medical Treatment & Wearing mask”, respectively to deal with the second wave of outbreaks that may come by the end of this year.Interpretation: Our model is operable and selective for the prevention and control of epidemic situations in various countries. These findings may help policy makers in the 180+ countries where COVID-19 has been reported around the world to identify the most effective and socioeconomically acceptable measures to prevent and control the second wave of COVID-19 epidemic, and inform if when these policies should be deployed, intensified or replaced.Funding: This study was partly supported by the Bill & Melinda Gates Foundation (INV-005834), the Science and Technology Program of Fujian Province (No: 2020Y0002), the Xiamen New Coronavirus Prevention and Control Emergency Tackling Special Topic Program (No: 3502Z2020YJ03), and the Open Research Fund of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (SKLVD2019KF005).Declaration of Interests: The authors declare no competing interests.

Effectiveness of Pharmacological Interventions to Control COVID-19: An Age-Specific Modelling Study (preprint)

Background: Novel coronavirus disease 2019 (COVID-19) causes an immense disease burden. Only drugs or vaccines can eliminate the virus. Methods: We adopted our age-specific transmission model by susceptible-exposed-infectious -critically ill-asymptomatic-removed (SEICAR) model. Effects of different drug types were simulated by changing transmission rate (β), critical case fatality rate (fc), and disease duration of each age group. Evaluation indexes were based on outbreak duration(OD), cumulative number of cases(CNC), total attack rate(TAR), peak date(PD), number of peak cases(NPC), and case fatality rate(f). Findings: When without intervention, changing in β and disease duration, as the age increased, OD decreased, TAR increased, PD advanced, CCN and NPC initially increased and then decreased, while f decreased first and then increased. When disease duration and β remained unchanged, changing fc did not affect the epidemic. All age groups had 40% shorter disease duration but unchanged fc, while β was reduced by 60%, which reduced TAR of group 1 (≤14 years) from 2·35% to 0·09%; f of group 4 (≥65 years) was reduced from 1·04% to 0·05%. Interpretation: Drugs had different age-dependent effects. If a drug can control the disease duration or β of all age groups, younger people would have the fastest transmission control and seniors will have the best improvement in disease severity. Funding: The Bill & Melinda Gates Foundation (INV-005834); the Science and Technology Program of Fujian Province (No: 2020Y0002), and the Xiamen New Coronavirus Prevention and Control Emergency Tackling Special Topic Program (No: 3502Z2020YJ03).Declaration of Interests: The authors declare no competing interests.