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With the success of mRNA vaccines against coronavirus disease 2019 (COVID-19), strategies can now focus on improving vaccine potency, breadth, and stability. We present the design and preclinical evaluation of domain-based mRNA vaccines encoding the wild-type spike-protein receptor-binding (RBD) and/or N-terminal domains (NTD). An NTD-RBD linked candidate vaccine, mRNA-1283, showed improved antigen expression, antibody responses, and stability at refrigerated temperatures (2-8{degrees}C) compared with the clinically available mRNA-1273, which encodes the full-length spike protein. In mice administered mRNA-1283 as a primary series, booster, or variant-specific booster, similar or greater immune responses and protection from viral challenge were observed against wild-type, beta, delta, or omicron (BA. 1) compared with mRNA-1273 immunized mice, especially at lower vaccine dosages. These results support clinical assessment of mRNA-1283 (NCT05137236). One Sentence SummaryA domain-based mRNA vaccine, mRNA-1283, is immunogenic and protective against SARS-CoV-2 and emerging variants in mice.
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The B.1.1.529 Omicron variant jeopardizes vaccines designed with early pandemic spike antigens. Here, we evaluated in mice the protective activity of the Moderna mRNA-1273 vaccine against B.1.1.529 before or after boosting with preclinical mRNA-1273 or mRNA-1273.529, an Omicron-matched vaccine. Whereas two doses of mRNA-1273 vaccine induced high levels of serum neutralizing antibodies against historical WA1/2020 strains, levels were lower against B.1.1.529 and associated with infection and inflammation in the lung. A primary vaccination series with mRNA-1273.529 potently neutralized B.1.1.529 but showed limited inhibition of historical or other SARS-CoV-2 variants. However, boosting with mRNA-1273 or mRNA-1273.529 vaccines increased serum neutralizing titers and protection against B.1.1.529 infection. Nonetheless, the levels of inhibitory antibodies were higher, and viral burden and cytokines in the lung were slightly lower in mice given the Omicron-matched mRNA booster. Thus, in mice, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against B.1.1.529 infection with limited differences in efficacy measured.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic of coronavirus disease 2019 (COVID-19) that has led to more than 3 million deaths worldwide. Safe and effective vaccines are now available, including the mRNA-1273 prototype vaccine, which encodes for the Wuhan SARS-CoV-2 spike (S) protein stabilized in the prefusion conformation by 2 proline substitutions. This vaccine showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. Recently, SARS-CoV-2 variants have emerged, some of which have shown decreased susceptibility to neutralization by vaccine-induced antibody, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. In addition, recent evidence of waning antibody levels after infection or vaccination point to the need for periodic boosting of immunity. Here we present the preliminary evaluation of a clinical study on the use of the prototype mRNA-1273 or modified COVID-19 mRNA vaccines, designed to target emerging SARS-CoV-2 variants as booster vaccines in participants previously vaccinated approximately 6 months earlier with two doses of the prototype vaccine, mRNA-1273. The modified vaccines include a monovalent mRNA-1273.351 encoding for the S protein found in the B.1.351 variant and multivalent mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. As single 50 {micro}g booster vaccinations, both mRNA-1273 and mRNA-1273.351 had acceptable safety profiles and were immunogenic. Antibody neutralization titers against B.1.351 and P.1 variants measured by SARS-CoV-2 pseudovirus neutralization (PsVN) assays before the booster vaccinations, approximately 6 to 8 months after the primary series, were low or below the assay limit of quantification, although geometric mean titers versus the wild-type strain remained above levels likely to be protective. Two weeks after the booster vaccinations, titers against the wild-type original strain, B.1.351, and P.1 variants increased to levels similar to or higher than peak titers after the primary series vaccinations. Although both mRNA-1273 and mRNA-1273.351 boosted neutralization of the wild-type original strain, and B.1.351 and P.1 variants, mRNA-1273.351 appeared to be more effective at increasing neutralization of the B.1.351 virus versus a boost with mRNA-1273. The vaccine trial is ongoing and boosting of clinical trial participants with the multivalent mRNA-1273.211 is currently being evaluated.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic. Safe and effective COVID-19 vaccines are now available, including mRNA-1273, which has shown 94% efficacy in prevention of symptomatic COVID-19 disease. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several variants have shown decreased susceptibility to neutralization by vaccine-induced immunity, most notably B.1.351 (Beta), although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of 2 updated mRNA vaccines designed to target SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the spike protein found in B.1.351 and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against B.1.351, while mRNA-1273.211 was effective at providing broad cross-variant neutralization. A third (booster) dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are being evaluated in pre-clinical challenge and clinical studies.
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The mRNA-1273 vaccine was recently determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit more severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, mRNA-1273- mediated immunity was non-sterilizing and coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provides insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.
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A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins. Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial with a trajectory towards Phase 3 efficacy evaluation.
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Objective:To investigate the labial surface angle and Collum angle of anterior teeth using cone-beam computed tomography (CBCT), and to provide guidance for proper setting of torque for avoiding alveolar fenestration and dehiscence.Methods:CBCT data of 200 patients (66 males, age ranging from 18 to 40 years, with average 26.7 years) were screened and imported into Invivo 5.4, the middle labio-lingual sections of anterior teeth were obtained, and the Collum angle and labial surface angle were measured respectively. One-way ANOVA was used to analyze the discrepancies of the two measurements among teeth. Pearson correlation analysis was performed to detect the association between the two measurements.Results:The Collum angles (labial surface angles) in upper central incisor, lateral incisor, canine and lower central incisor, lateral incisor and canine were 0.17±5.11° (15.50±2.91°), -5.67±5.74° (15.52±3.50°), -5.56±4.67° (20.07±3.66°), -3.97±4.49° (14.40±3.20°), -6.50±4.03° (14.76±3.25°), -3.70±4.91° (18.27±3.07°) respectively; the positive Collum angles indicated the lingually bent root relative to crown, while the negative indicated the labially bent root. The labial surface angles in upper and lower canine were significantly larger than that of intra-arch central and lateral incisors ( P<0.001). On the contrary, no significant differences were detected between central and lateral incisors in the maxilla and mandible ( P>0.05, P>0.05). Moreover, except for the maxillary central incisor, the Collum angle and labial surface angle were positively correlated. Conclusions:The values of Collum angle among anterior teeth are significantly different, and the obvious lingual-bent root are more likely accompanied with the greater labial surface curve, which might cause variable torqueing and be necessary to elevate before treatment.
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Objective To investigate the effect of dexmedetomidine on postoperative cognitive function in elderly patients undergoing general anesthesia.Methods A total of 100 elderly patients undergoing elective surgery were enrolled.The patients were randomly divided into observation group and control group,with 50 patients in each group.The observation group was given dexmedetomidine + 0.9％ sodium chloride injection before induction anesthesia.The control group was given 0.9％ sodium chloride injection.The remaining anesthesia induction and maintenance time were same in the two groups.The cognitive function and postoperative cognitive dysfunction(POCD) were evaluated by MMSE scale.The blood pressure and heart rate before and after operation and at the end of the operation,the levels of serum tumor necrosis factor α(TNF-α) before operation,at the end of the operation and postoperative 3,7 days were measured.Results At postoperative 1 day and 3 days,the MMSE scores of the observation group were (24.6 ± 0.7) points and (27.2 ± 1.1) points,respectively,which were significantly higher than those of the control group [(22.4 ± 0.6) points,(27.2 ± 1.1) points,t =3.64,3.97,all P ＜ 0.05].And 6 cases in the observation group occurred cognitive dysfunction,which was significantly lower than 20 cases of the control group (x2 =5.38,P ＜0.05).At the end of the operation and postoperative 3 days,the serum levels of TNF-α in the observation group were (28.52 ± 3.73) ng/L,(28.82 ± 4.13) ng/L,respectively,which were significantly lower than those in the control group[(37.14 ± 3.62) ng/L,(38.27 ± 3.47) ng/L,t =5.21,4.89,all P ＜ 0.05].At the beginning of the operation,the systolic blood pressure,diastolic blood pressure,heart rate of the observation group were (124.53 ±3.84) mmHg,(79.32 ± 4.38) mmHg,(70.45 ± 5.32) times/min,respectively,which were significantly lower than those of the control group [(145.36 ± 4.72) mmHg,(93.17 ± 3.82) mmHg,(86.79 ± 4.26) times/min],the differences were statistically significant(t =5.83,4.97,4.58,all P ＜ 0.05).Conclusion In the elderly patients undergoing general anesthesia,the use of pumped dexmedetomidine has little effect on the postoperative cognitive function.The mechanism may be related to stabilizing the blood flow dynamics,decrease the high expression of TNF-α,which is worthy of clinical application.
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Objective To analyze pathological and ultrasound imaging features of breast cancer in young women. Methods The pathological and ultrasound imaging data of 42 young female breast cancer patients(≤35 years old,the young group)between January 2016 and October 2017 from the Fourth Affiliated Hospital of China Medical University were retrospectively analyzed. Meanwhile, 62 elder female breast cancer patients (> 60 years old, the elder group) simultaneously diagnosed by pathology (age≥60 years) were randomly selected as the control group. Results The vessel carcinoma embolus rate and lymph node metastasis positive rate in the young group were higher than those in the elder group [31.0 % (13/42) vs. 29.0 %(18/62),59.5 %(25/42)vs.38.7 %(24/62)],and there was no difference between the two groups(χ2=16.187, χ2= 5.749, both P< 0.05). Compared with the elder group, the expression of estrogen receptor (ER) in the young group was lower (χ2= 11.598, P = 0.001). The positive rates of Ki-67 and human epidermal growth factor receptor-2 (HER-2) in the young group were higher (χ2= 5.396, P = 0.024; χ2= 5.166, P =0.026). Inhomogeneous internal echo of breast cancer, microcalcifications, flow classification (grade Ⅱ-Ⅲ) and resistance index (RI) ratio in the young group were higher than those in the elder group [83.3 % (35/42) vs. 59.7 % (37/62), P = 6.576; 57.1 % (24/42) vs. 22.6 % (14/62), P = 12.899; 78.6 % (33/42) vs. 58.1 % (36/62), P = 4.716; 83.3 % (35/42) vs. 59.7 % (37/62), P= 6.578], and the differences were statistically significant (all P < 0.05). Conclusion The young female breast cancer patients have a higher rate of malignancy,invasion and metastasis rate compared with the elder breast cancer patients.