The rapid expansion of the COVID-19 pandemic has made the development of a SARS-CoV-2 vaccine a global health and economic priority. Taking advantage of versatility and rapid development, three ...SARS-CoV-2 mRNA vaccine candidates have entered clinical trials with a two-dose immunization regimen. However, the waning antibody response in convalescent patients after SARS-CoV-2 infection and the emergence of human re-infection have raised widespread concerns about a possible short duration of SARS-CoV-2 vaccine protection. Here, we developed a nucleoside-modified mRNA vaccine in lipid-encapsulated form that encoded the SARS-CoV-2 RBD, termed as mRNA-RBD. A single immunization of mRNA-RBD elicited both robust neutralizing antibody and cellular responses, and conferred a near-complete protection against wild SARS-CoV-2 infection in the lungs of hACE2 transgenic mice. Noticeably, the high levels of neutralizing antibodies in BALB/c mice induced by mRNA-RBD vaccination were maintained for at least 6.5 months and conferred a long-term notable protection for hACE2 transgenic mice against SARS-CoV-2 infection in a sera transfer study. These data demonstrated that a single dose of mRNA-RBD provided long-term protection against SARS-CoV-2 challenge.
Abstract
The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics ...increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.
The most common three-dimensional (3D) printing method is material extrusion, where a pre-made filament is deposited layer-by-layer. In recent years, low-cost polycaprolactone (PCL) material has ...increasingly been used in 3D printing, exhibiting a sufficiently high quality for consideration in cranio-maxillofacial reconstructions. To increase osteoconductivity, prefabricated filaments for bone repair based on PCL can be supplemented with hydroxyapatite (HA). However, few reports on PCL/HA composite filaments for material extrusion applications have been documented. In this study, solvent-free fabrication for PCL/HA composite filaments (HA 0%, 5%, 10%, 15%, 20%, and 25% weight/weight PCL) was addressed, and parameters for scaffold fabrication in a desktop 3D printer were confirmed. Filaments and scaffold fabrication temperatures rose with increased HA content. The pore size and porosity of the six groups' scaffolds were similar to each other, and all had highly interconnected structures. Six groups' scaffolds were evaluated by measuring the compressive strength, elastic modulus, water contact angle, and morphology. A higher amount of HA increased surface roughness and hydrophilicity compared to PCL scaffolds. The increase in HA content improved the compressive strength and elastic modulus. The obtained data provide the basis for the biological evaluation and future clinical applications of PCL/HA material.
Bladder cancer is often prone to recurrence and metastasis. We sought to construct nomogram models to predict the overall survival (OS) and cancer-specific survival (CSS) of bladder cancer patients.
...A reliable random split-sample approach was used to divide patients into two groups: modeling and validation cohorts. Uni-variate and multivariate survival analyses were used to obtain the independent prognostic risk factors based on the modeling cohort. A nomogram was constructed using the R package, "rms". Harrell's concordance index (C-index), calibration curves and receiver operating characteristic (ROC) curves were applied to evaluate the discrimination, sensitivity and specificity of the nomograms using the R packages "hmisc", "rms" and "timeROC". A decision curve analysis (DCA) was used to evaluate the clinical value of the nomograms via R package "stdca.R".
10,478 and 10,379 patients were assigned into nomogram modeling and validation cohorts, respectively (split ratio ≈ 1:1). For OS and CSS, the C-index values for internal validation were 0.738 and 0.780, respectively, and the C-index values for external validation were 0.739 and 0.784, respectively. The area under the ROC curve (AUC) values for 5- and 8-year OS and CSS were all greater than 0.7. The calibration curves show that the predicted probability values of 5- and 8-year OS and CSS are close to the actual OS and CSS. The decision curve analysis revealed that the two nomograms have a positive clinical benefit.
We successfully constructed two nomograms to forecast OS and CSS for bladder cancer patients. This information can help clinicians conduct prognostic evaluations in an individualized manner and tailor personalized treatment plans.
Few models about the personalized prognosis evaluation of buccal mucosa cancer (BMC) patients were reported. We aimed to establish predictive models to forecast the prognosis of BMC patients.
The ...complete clinicopathological information of BMC patients from the surveillance, epidemiology and end results program was collected and reviewed retrospectively. Two nomograms were established and validated to predict long-term overall survival (OS) and cancer-specific survival (CSS) of BMC patients based on multivariate Cox regression survival analysis.
1155 patients were included. 693 and 462 patients were distributed into modeling and validation groups with 6:4 split-ratio via a random split-sample method. Based on the survival analysis, independent prognostic risk factors (variables that can be used to estimate disease recovery and relapse chance) influencing OS and CSS were obtained to establish nomograms. Then, we divided the modeling group into high- and low-risk cohorts. The low-risk cohort had improved OS and CSS compared to the high-risk cohort, which was statistically significant after the Log-rank test (p < 0.05). Furthermore, we used the concordance index (C-index), calibration curve to validate the nomograms, showing high accuracy. The decision curve analyses (DCA) revealed that the nomograms had evident clinical value.
We constructed two credible nomogram models, which would give the surgeons reference to provide an individualized assessment of BMC patients.
Our aim was to establish a “nomogram” model to forecast the overall survival (OS) and cancer‐specific survival (CSS) of oral squamous cell carcinoma (OSCC) patients. The clinicopathological data for ...the 10,533 OSCC patients were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used a credible random split‐sample method to divide 10,533 patients into two cohorts: 7046 patients in the modeling cohort and 3487 patients in the external validation cohort (split‐ratio = 2:1). The median follow‐up period was 32 months (1–119 months). We developed nomograms to predict 5‐ and 8‐year OS and CSS of OSCC patients with a Cox proportional hazards model. The precision of the nomograms was assessed by the concordance index (C‐index) and calibration curves through internal and external validation. The C‐indexes of internal validation regarding 5‐ and 8‐year OS and CSS were 0.762 and 0.783, respectively. In addition, the external validation's C‐indexes were 0.772 and 0.800. Based on a large‐sample analysis targeting the SEER database, we established two nomograms to predict long‐term OS and CSS for OSCC patients successfully, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.
We successfully established two nomograms predicting overall survival(OS) and cancer‐specific survival(CSS) of OSCC patients collected from SEER database. The validation results of the nomograms through the concordance index (C‐index) and calibration curves showed that the model were credible, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.
Increasing severe morbidity and mortality by simultaneous or sequential infections with SARS-CoV-2 and influenza A viruses (IAV), especially in the elderly and obese patients, highlight the urgency ...of developing a combination vaccine against COVID-19 and influenza.
Self-assembling SARS-CoV-2 RBD-trimer and Influenza H1N1 HA1-trimer antigens were constructed, upon the stable fusion core in post-fusion conformation. Immunogenicity of SARS-CoV-2 RBD-trimer vaccine and H1N1 HA1-trimer antigens candidates were evaluated in mice. Protection efficacy of a combination vaccine candidate against SARS-CoV-2 and IAV challenge was identified using the K18-hACE2 mouse model.
Both the resultant RBD-trimer for SARS-CoV-2 and HA1-trimer for H1N1 influenza fully exposed receptor-binding motifs (RBM) or receptor-binding site (RBS). Two-dose RBD-trimer induced significantly higher binding and neutralizing antibody titers, and also a strong Th1/Th2 balanced cellular immune response in mice. Similarly, the HA1-trimer vaccine was confirmed to exhibit potent immunogenicity in mice. A combination vaccine candidate, composed of RBD-trimer and HA1-trimer, afforded high protection efficacy in mouse models against stringent lethal SARS-CoV-2 and homogenous H1N1 influenza co-infection, characterized by 100% survival rate.
Our results represent a proof of concept for a combined vaccine candidate based on trimerized receptor binding domain against co-epidemics of COVID-19 and influenza.
This project was funded by the Strategic Priority Research Program of CAS (XDB29040201), the National Natural Science Foundation of China (81830050, 81901680, and 32070569) and China Postdoctoral Science Foundation (2021M703450).
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