Adaptation-proof SARS-CoV-2 vaccine design.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface spike glycoprotein - a major antibody target - is critical for virus entry via engagement of human angiotensin-converting enzyme 2 (ACE2) receptor. Despite successes with existing vaccines and therapies that primarily target the receptor binding domain (RBD) of the spike protein, the susceptibility of RBD to mutations provides escape routes for the SARS-CoV-2 from neutralizing antibodies. On the other hand, structural conservation in the spike protein can be targeted to reduce escape mutations and achieve broad protection. Here, we designed candidate stable immunogens that mimic surface features of selected conserved regions of spike protein through 'epitope grafting,' in which we present the target epitope topology on diverse heterologous scaffolds that can structurally accommodate the spike epitopes. Structural characterization of the epitope-scaffolds showed stark agreement with our computational models and target epitopes. The sera from mice immunized with engineered designs display epitope-scaffolds and spike binding activity. We also demonstrated the utility of the designed epitope-scaffolds in diagnostic applications. Taken all together, our study provides important methodology for targeting the conserved, non-RBD structural motifs of spike protein for SARS-CoV-2 epitope vaccine design and demonstrates the potential utility of 'epitope grafting' in rational vaccine design.

Nano-copper ions assembled cellulose-based composite with antibacterial activity for biodegradable personal protective mask.

The current SARS-CoV-2 pandemic has resulted in the widespread use of personal protective equipment, particularly face masks. However, the use of commercial disposable face masks puts great pressure on the environment. In this study, nano-copper ions assembled cotton fabric used in face masks to impart antibacterial activity has been discussed. To produce the nanocomposite, the cotton fabric was modified by sodium chloroacetate after its mercerization, and assembled with bactericidal nano-copper ions (about 10.61 mg·g-1) through electrostatic adsorption. It demonstrated excellent antibacterial activity against Staphylococcus aureus and Escherichia coli because the gaps between fibers in the cotton fabric allow the nano-copper ions to be fully released. Moreover, the antibacterial efficiency was maintained even after 50 washing cycles. Furthermore, the face mask constructed with this novel nanocomposite upper layer exhibited a high particle filtration efficiency (96.08% ± 0.91%) without compromising the air permeability (28.9 min·L-1). This green, economical, facile, and scalable process of depositing nano-copper ions onto modified cotton fibric has great potential to reduce disease transmission, resource consumption, and environmental impact of waste, while also expanding the range of protective fabrics.

Resource Support for "Mobilization-Participation" in Public Health Emergencies Based on a Complex Network Evolutionary Game.

The organized system of emergency resources with the participation of social subjects features a network, which puts forward new requirements for mobilization policies for public health emergencies. Considering the "mobilization-participation" action of the relationship between the government and social resource subjects and revealing the mechanism of governance measures represent the foundation of developing effective mobilization strategies. To analyze the behavior of subjects in an emergency resource network, this study proposes a framework for the emergency actions of government and social resource subjects, as well as clarifies the functions of relational mechanisms and interorganizational learning in decision making. The game model and its rules of evolution in the network were developed by considering the interventions of rewards and penalties. An emergency resource network was constructed on the basis of a response to the COVID-19 epidemic in a city in China, and a simulation of the "mobilization-participation" game was designed and conducted. We propose a path to promote emergency resource actions by analyzing the initial situations and the interventions' effects. This article suggests that guiding and improving the initial selection of subjects under a certain reward system would be an effective path to facilitate resource support actions during public health emergencies.

Time-Frequency Volatility Spillovers among Major International Financial Markets: Perspective from Global Extreme Events

In the context of the gradual intensification of the Russia-Ukraine conflict and the continuous spread of the COVID-19 pandemic, this paper concentrates on the impact of global extreme events such as the COVID-19 pandemic and the Russia-Ukraine conflict on the risk spillovers among major international financial markets. First, to measure the impact of the extreme events the on the volatility spillovers among major international financial markets in the time-frequency domain, we combine the TVP-VAR-based connectedness method and BK frequency connectedness approach and focus on the total, directional, and net volatility spillovers. Second, the network visualization method is applied to outline the structural change in the risk contagion, paths, and roles among international financial markets during different periods of global extreme events. The empirical results indicate that the risk spillovers (total, directional, and net spillovers) among international financial markets and the roles played by each market in the process of risk contagion have changed significantly in different periods of global extreme events. Furthermore, volatility spillovers among international financial markets are driven mainly by the high-frequency component (short-term spillovers) during the full sample time. However, the effects of the extreme events also persist in the medium and long terms. Our findings may help understand the dynamics among international financial markets under extreme shocks and provide significant implications for portfolio managers, investors, and government agencies in times of extreme events. [ FROM AUTHOR] Copyright of Discrete Dynamics in Nature & Society is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Magnetic Particle Spectroscopy for Point-of-Care: A Review on Recent Advances.

Since its first report in 2006, magnetic particle spectroscopy (MPS)-based biosensors have flourished over the past decade. Currently, MPS are used for a wide range of applications, such as disease diagnosis, foodborne pathogen detection, etc. In this work, different MPS platforms, such as dual-frequency and mono-frequency driving field designs, were reviewed. MPS combined with multi-functional magnetic nanoparticles (MNPs) have been extensively reported as a versatile platform for the detection of a long list of biomarkers. The surface-functionalized MNPs serve as nanoprobes that specifically bind and label target analytes from liquid samples. Herein, an analysis of the theories and mechanisms that underlie different MPS platforms, which enable the implementation of bioassays based on either volume or surface, was carried out. Furthermore, this review draws attention to some significant MPS platform applications in the biomedical and biological fields. In recent years, different kinds of MPS point-of-care (POC) devices have been reported independently by several groups in the world. Due to the high detection sensitivity, simple assay procedures and low cost per run, the MPS POC devices are expected to become more widespread in the future. In addition, the growth of telemedicine and remote monitoring has created a greater demand for POC devices, as patients are able to receive health assessments and obtain results from the comfort of their own homes. At the end of this review, we comment on the opportunities and challenges for POC devices as well as MPS devices regarding the intensely growing demand for rapid, affordable, high-sensitivity and user-friendly devices.

Recycling spent masks to fabricate flexible hard carbon anode toward advanced sodium energy storage.

The massive discard of spent masks during the COVID-19 pandemic imposes great environmental anxiety to the human society, which calls for a reliable and sustainable outlet to mitigate this issue. In this work, we demonstrate a green design strategy of recycling the spent masks to fabricate hard carbon fabrics toward high-efficient sodium energy storage. After a simple carbonization treatment, flexible hard carbon fabrics composed of interwoven microtubular fibers are obtained. When serving as binder-free anodes of sodium-ion batteries, a large Na-ion storage capacity of 280 mAh g-1 is achieved for the optimized sample. More impressively, the flexible anode exhibits an initial coulombic efficiency of as high as 86% and excellent rate/cycling performance. The real-life practice of the flexible hard carbon is realized in the full-cells. The present study affords an enlightening approach for the recycling fabrication of high value-added hard carbon materials from the spent masks for advanced sodium energy storage.

Robust therapeutic effects on COVID-19 of novel small molecules: Alleviation of SARS-CoV-2 S protein induction of ACE2/TMPRSS2, NOX2/ROS, and MCP-1.

While new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constantly emerge to prolong the pandemic of COVID-19, robust and safe therapeutics are in urgent need. During the previous and ongoing fight against the pandemic in China, Traditional Chinese Medicine (TCM) has proven to be markedly effective in treating COVID-19. Among active ingredients of TCM recipes, small molecules such as quercetin, glabridin, gallic acid, and chrysoeriol have been predicted to target viral receptor angiotensin-converting enzyme 2 (ACE2) via system pharmacology/molecular docking/visualization analyses. Of note, endothelial dysfunction induced by oxidative stress and inflammation represents a critical mediator of acute respiratory distress syndrome (ARDS) and multi-organ injuries in patients with COVID-19. Hence, in the present study, we examined whether quercetin, glabridin, gallic acide and chrysoeriol regulate viral receptors of ACE2 and transmembrane serine protease 2 (TMPRSS2), redox modulator NADPH oxidase isoform 2 (NOX2), and inflammatory protein of monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to mediate therapeutic protection against COVID-19. Indeed, quercetin, glabridin, gallic acide and chrysoeriol completely attenuated SARS-CoV-2 spike protein (S protein)-induced upregulation in ACE2 protein expression in endothelial cells. In addition, these small molecules abolished S protein upregulation of cleaved/active form of TMPRSS2, while native TMPRSS2 was not significantly regulated. Moreover, these small molecules completely abrogated S protein-induced upregulation in NOX2 protein expression, which resulted in alleviated superoxide production, confirming their preventive efficacies against S protein-induced oxidative stress in endothelial cells. In addition, treatment with these small molecules abolished S protein induction of MCP-1 expression. Collectively, our findings for the first time demonstrate that these novel small molecules may be used as novel and robust therapeutic options for the treatment of patients with COVID-19, via effective attenuation of S protein induction of endothelial oxidative stress and inflammation.

Plasma cell-free DNA promise monitoring and tissue injury assessment of COVID-19.

Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.

Current status of management of medical waste in medical institutions of Chongqing

OBJECTIVE: To understand the status of generation and management of medical waste in medical institutions of Chongqing. METHODS: By means of onsite investigation and questionnaire survey, the generation categories and current status of management of medical waste in 50 medical institutions were investigated from Oct 2021 to Apr 2022 the existing limitations and prominent problems in the whole-process management of medical waste were identified so as to enable the safe disposal of medical waste based on laws and regulations. RESULTS: The average pollutants generation coefficient of medical waste was 0.22-0.72 kg/bed.day among all the grades of hospitals, the average pollutant generation coefficient of medical waste was 0.28-2.30 kg/10 people among grass-root medical institutions. The management of medical waste was more standardized in tertiary hospitals. There were a variety of problems in management of medical waste in clinics and village clinics, such as nonstandard classification of medical waste, unreasonable site selection for temporary storage of medical waste, unsatisfactory transportation means and untimely collection and transportation of medical waste. The problems of chemical, pharmaceutical and pathological medical waste were more prominent. The costs of disposal of medical waste were not strictly implemented in accordance with standards. The packaging, storage, loading, handover and disinfection of COVID-19 medical waste have been carried out in accordance with regulations. CONCLUSION: It is necessary to further standardize the management of medical waste, explore and formulate the collection and transportation modes of medical waste in primary medical institutions, intensify the supervision of classification, collection, storage, transportation and disposal of medical waste, optimize and upgrade the medical waste management information system, and encourage subsidies for the disposal of medical waste in Chongqing medical waste disposal enterprises during the COVID-19 period.

Trends of obesity and overweight among children and adolescents in China.

BACKGROUND: Recent decades have shown a rapid increase in the prevalence of overweight and obesity among Chinese children based on several national surveys. Restrictions due to the coronavirus disease 2019 outbreak have worsened its epidemiology. This review updates the trends in the prevalence of overweight and obesity among Chinese children and adolescents and analyzes the underlying reasons to provide evidence for better policy making. METHODS: Studies published in English and Chinese were retrieved from PubMed, Google Scholar, China National Knowledge Infrastructure and Wanfang. RESULTS: The prevalence of overweight and obesity has been increasing for decades and varies with age, sex and geography but is more pronounced in primary school students. The increase in obesity in boys appeared to be slower, whereas that in girls showed a declining trend. The northern areas of China have persistently maintained the highest levels of obesity with a stable trend in recent years. Meanwhile, the prevalence in eastern regions has dramatically increased. Notably, the overall prevalence of obesity in children has shown a stabilizing trend in recent years. However, the occurrence of obesity-related metabolic diseases increased. The effect of migrants floating into east-coast cities should not be neglected. CONCLUSIONS: The high prevalence of overweight and obesity among Chinese children and adolescents persists but with varying patterns. Obesity-related metabolic diseases occur more frequently despite a stable trend of obesity. Multiple factors are responsible for the changing prevalence. Thus, comprehensive and flexible policies are needed to effectively manage and prevent the burden of obesity and its related complications.

SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy.

Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation (pNF-κB) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.

Neutrophil autophagy and NETosis in COVID-19: perspectives.

The COVID-19 pandemic has caused substantial losses worldwide in people's lives, health, and property. Currently, COVID-19 is still prominent worldwide without any specific drug treatment. The SARS-CoV-2 pathogen is the cause of various systemic diseases, mainly acute pneumonia. Within the pathological process, neutrophils are recruited to infected sites, especially in the lungs, for the first stage of removing invading SARS-CoV-2 through a range of mechanisms. Macroautophagy/autophagy, a conserved autodegradation process in neutrophils, plays a crucial role in the neutrophil phagocytosis of pathogens. NETosis refers to neutrophil cell death, while auto-inflammatory factors and antigens release NETs. This review summarizes the latest research progress and provides an in-depth explanation of the underlying mechanisms of autophagy and NETosis in COVID-19. Furthermore, after exploring the relationship between autophagy and NETosis, we discuss potential targets and treatment options. This review keeps up with the latest research on COVID-19 from neutrophil autophagy and NETosis with a new perspective, which can guide the urgent development of antiviral drugs and provide guidance for the clinical treatment of COVID-19.Abbreviations: AKT1: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; AP: autophagosome; ARDS: acute respiratory distress syndrome; ATG: autophagy related; BECN1: beclin 1; cfDNA: cell-free DNA; COVID-19: coronavirus disease 2019; CQ: chloroquine; DMVs: double-membrane vesicles; ELANE/NE: elastase, neutrophil expressed; F3: coagulation factor III, tissue factor; HCQ: hydroxychloroquine; MAP1LC3/LC3: microtubule associated protein 1 light chain of 3; MPO: myeloperoxidase; MTORC1: mechanistic target of rapamycin kinase complex 1; NETs: neutrophil traps; NSP: nonstructural protein; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SKP2: S-phase kinase associated protein 2; TCC: terminal complement complex; ULK1: unc-51 like.

Hospital dual-channel adoption decisions with telemedicine referral and misdiagnosis.

With the rapid development of telemedicine and the impact of the COVID-19 pandemic, more and more patients are now resorting to using telemedicine channels for healthcare services. However, for hospitals, there exists a lack of managerial guidance in place to help them adopt telemedicine in a practical and standardized way. This study considers a hospital operating with both telemedicine (virtual) and face-to-face (physical) medical channels, and which allocates its capacity by also taking into account the possibility of both referrals and misdiagnosis. Methodologically, we construct a game model based on a queuing framework. We first analyze equilibrium strategies for patient arrivals. Then we propose the necessary conditions for a hospital to develop a telemedicine channel and to operate both channels simultaneously. Finally, we find the optimal decisions for the service level of telemedicine, which can also be regarded as the optimal proportion of diseases treated by telemedicine, and the optimal hospital capacity allocation ratio between the two channels. We also find that hospitals in a full coverage market (e.g., for certain small-scale hospitals and community hospitals or cancer hospitals) are more difficult to adopt telemedicine than hospitals in a partial coverage market (e.g., for comprehensive large-scale hospitals with many potential patients). Small-scale hospitals are more suited to operating telemedicine as a gatekeeper to help triage patients, while large hospitals are more prone to regard telemedicine as a medical channel for providing professional medical services to patients. We also analyze the effects of the telemedicine cure rate and the cost ratio of telemedicine to the physical hospital on the overall healthcare system performance, including the physical hospital arrival rate, patients' waiting time, total profit, and social welfare. Then we compare the performance, ex ante versus ex post, the implementation of telemedicine. It is shown that when the market is partially covered, the total social welfare is always higher than it was before the implementation. However, as far as the profit goes, if the telemedicine cure rate is low and the cost ratio is high, the total hospital profit may be lower than it was prior to using telemedicine. However, the profit and social welfare of hospitals in the full coverage market are always lower than it was before the implementation. In addition, the waiting time in the hospital is always higher than that before the implementation, which means that the implementation of telemedicine will make patients who must receive treatment in the physical hospital face even worse congestion than before. More insights and results are gleaned from a series of numerical studies.

Research on the Characteristics of Safety Culture and Obstacle Factors among Residents under the Influence of COVID-19 in China.

This study established a comprehensive evaluation indicator model for the safety culture among residents during COVID-19 and an obstacle degree model for the identification of the major factors affecting the residents' safety culture. The results show that the overall level of the safety culture among residents was 0.6059. Safety education, channels for learning knowledge regarding safety, and implementation of safety management systems are currently the major obstacles affecting safety culture among residents, but there is still space for improvement in the future. Furthermore, the level of safety culture was strongly related to the distance from the infected, because this changes the risk of viral infection. There are also differences in obstacle factors in different regions. Therefore, it is necessary to implement measures targeting the improvement of safety culture in accordance with the risk of viral infection. Strategies for strengthening the safety culture are also given in this study for consideration in strategic decision making with the aim of promoting the improvement of safety culture among residents, which may help to reduce the risk of infection with COVID-19 for residents.

Heath management app use in Parkinson's disease and quality of life during the COVID-19 pandemic.

BACKGROUND: Social distancing during the COVID-19 pandemic affected follow-up visits and medication availability for patients with Parkinson's disease (PD). As a promising strategy to deal with these challenges, the implementation of health management smartphone apps was accelerated. However, whether more intense use of such apps could improve the quality of life (QoL) for PD patients during the COVID-19 pandemic was unknown. METHODS: Using a PD management app, this observational study assessed changes in QoL, as determined by PD Questionnaire 8 (PDQ-8), among PD patients before (Jan 20, 2019 to Oct 6, 2019) and after the beginning of the COVID-19 lockdown (Jan 20, 2020 to Oct 6, 2020). According to adherence to use of the app, participants were divided into low adherence, moderate adherence, and high adherence groups. A total of 4979 PD patients registered in the app, and 226 PD patients were enrolled, including 57 patients with low adherence, 112 with moderate adherence and 57 with high adherence. A generalized linear model was used to evaluate the change of PDQ-8 scores across these three different adherence groups. RESULTS: After the COVID-19 lockdown (1-year follow-up), the PDQ-8 scores are reduced by 0.8 (95% CI, 0.3-1.4) in all participants (P = 0.004). After adjustment for age, gender, education, disease duration and levodopa equivalent dose, PDQ-8 scores significantly less reduced in the high adherence group (0.3; 95% CI, 0.6-1.2) compared to the low adherence (1.9; 95% CI, 0.7-3.1) (P = 0.040) and moderate adherence groups (0.6; 95% CI, 0.2-1.3) (P = 0.012). CONCLUSIONS: A health management smartphone-based app might be a way to both measure and improve QoL among PD patients, provided that sufficient adherence is achieved.

The COVID-19 pandemic had an enormous impact on the lives of people living with Parkinson's disease (PD), given social distancing measures, and reduced access to healthcare. As a way to mitigate this, the use of health management apps was accelerated. However, there is a lack of studies on whether the use of such apps could over time affect the quality of life of people living with PD. Here, we analyzed changes in the quality of life of people living with PD using a health management app, before and after social distancing. We found that patients with high adherence to use of the app experienced a lower reduction of their quality of life. Using a health management smartphone app represents a novel approach that might help patients with PD improve their quality of life.

Characterization and pathogenicity of the porcine epidemic diarrhea virus isolated in China.

Piglet diarrhea caused by the porcine epidemic diarrhea virus (PEDV) is a common problem on pig farms in China associated with high morbidity and mortality rates. In this study, three PEDV isolates were successfully detected after the fourth blind passage in Vero cells. The samples were obtained from infected piglet farms in Jilin (Changchun), and Shandong (Qingdao) Provinces of China and were designated as CH/CC-1/2018, CH/CC-2/2018, and CH/QD/2018. According to the analysis of the complete S protein gene sequence, the CH/CC-1/2018 and CH/CC-2/2018 were allocated to the G2b branch, while CH/QD/2018 was located in the G1a interval and was closer to the vaccine strain CV777. Successful detection and identification of the isolated strains were carried out using electron microscopy and indirect immunofluorescence. Meanwhile, animal challenge experiments and viral RNA copies determination were used to compare the pathogenicity. The results showed that CH/CC-1/2018 in Changchun was more pathogenic than CH/QD/2018 in Qingdao. In conclusion, the discovery of these new strains is conducive to the development of vaccines to prevent the pandemic of PEDV, especially that the CH/CC-1/2018, and CH/CC-2/2018 were not related to the classical vaccine strain CV777.

Knowledge Adaptive Multi-Way Matching Network for Biomedical Named Entity Recognition via Machine Reading Comprehension.

Rapid and effective utilization of biomedical literature is paramount to combat diseases like COVID19. Biomedical named entity recognition (BioNER) is a fundamental task in text mining that can help physicians accelerate knowledge discovery to curb the spread of the COVID-19 epidemic. Recent approaches have shown that casting entity extraction as the machine reading comprehension task can significantly improve model performance. However, two major drawbacks impede higher success in identifying entities (1) ignoring the use of domain knowledge to capture the context beyond sentences and (2) lacking the ability to deeper understand the intent of questions. In this paper, to remedy this, we introduce and explore external domain knowledge which cannot be implicitly learned in text sequence. Previous works have focused more on text sequence and explored little of the domain knowledge. To better incorporate domain knowledge, a multi-way matching reader mechanism is devised to model representations of interaction between sequence, question and knowledge retrieved from Unified Medical Language System (UMLS). Benefiting from these, our model can better understand the intent of questions in complex contexts. Experimental results indicate that incorporating domain knowledge can help to obtain competitive results across 10 BioNER datasets, achieving absolute improvement of up to 2.02% in the f1 score.

pH-Sensitive and Biodegradable Mn3(PO4)2·3H2O Nanoparticles as an Adjuvant of Protein-Based Bivalent COVID-19 Vaccine to Induce Potent and Broad-Spectrum Immunity.

Developing a novel and potent adjuvant with great biocompatibility for immune response augmentation is of great significance to enhance vaccine efficacy. In this work, we prepared a long-term stable, pH-sensitive, and biodegradable Mn3(PO4)2·3H2O nanoparticle (nano-MnP) by simply mixing MnCl2/NaH2PO4/Na2HPO4 solution for the first time and employed it as an immune stimulant in the bivalent COVID-19 protein vaccine comprised of wild-type S1 (S1-WT) and Omicron S1 (S1-Omicron) proteins as antigens to elicit a broad-spectrum immunity. The biological experiments indicated that the nano-MnP could effectively activate antigen-presenting cells through the cGAS-STING pathway. Compared with the conventional Alum-adjuvanted group, the nano-MnP-adjuvanted bivalent vaccine elicited approximately 7- and 8-fold increases in IgG antibody titers and antigen-specific IFN-γ secreting T cells, respectively. Importantly, antisera of the nano-MnP-adjuvanted group could effectively cross-neutralize the SARS-CoV-2 and its five variants of concern (VOCs) including Alpha, Beta, Gamma, Delta, and Omicron, demonstrating that this bivalent vaccine based on S1-WT and S1-Omicron proteins is an effective vaccine design strategy to induce broad-spectrum immune responses. Collectively, this nano-MnP material may provide a novel and efficient adjuvant platform for various prophylactic and therapeutic vaccines and provide insights for the development of the next-generation manganese adjuvant.

Novel sialoglycan linkage for constructing adjuvant-protein conjugate as potent vaccine for COVID-19.

Self-adjuvanting protein vaccines have been proved to be highly immunogenic with efficient codelivery of adjuvant and antigen. Current protein vaccines with built-in adjuvants are all modified at the peptide backbone of antigen protein, which could not achieve minor epitope interference and adjuvant multivalency at the same time. Herein, we developed a new conjugate strategy to construct effective adjuvant-protein vaccine with adjuvant cluster effect and minimal epitope interference. The toll-like receptor 7 agonist (TLR7a) is covalently conjugated on the terminal sialoglycans of SARS-CoV-2-S1 protein, leading to intracellular release of the small-molecule stimulators with greatly reduced risks of systemic toxicity. The resulting TLR7a-S1 conjugate elicited strong activation of immune cells in vitro, and potent antibody and cellular responses with a significantly enhanced Th1-bias in vivo. TLR7a-S1-induced antibody also effectively cross-neutralized all variants of concern. This sialoglycoconjugation approach to construct protein conjugate vaccines will have more applications to combat SARS-CoV-2 and other diseases.