Developing a multiepitope vaccine for the prevention of SARS-CoV-2 and monkeypox virus co-infection: A reverse vaccinology analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and monkeypox virus (MPXV) severely threaten human health; however, currently, no vaccine can prevent a co-infection with both viruses. METHODS: Five antigens were selected to predict dominant T and B cell epitopes screened for immunogenicity, antigenicity, toxicity, and sensitization. After screening, all antigens joined in the construction of a novel multiepitope vaccine. The physicochemical and immunological characteristics, and secondary and tertiary structures of the vaccine were predicted and analyzed using bio- and immunoinformatics. Finally, codon optimization and cloning in-silico were performed. RESULTS: A new multiepitope vaccine, named S7M8, was constructed based on four helper T lymphocyte (HTL) epitopes, six cytotoxic T lymphocyte (CTL) epitopes, five B cell epitopes, as well as Toll-like receptor (TLR) agonists. The antigenicity and immunogenicity scores of the S7M8 vaccine were 0.907374 and 0.6552, respectively. The S7M8 vaccine was comprised of 26.96% α-helices, the optimized Z-value of the tertiary structure was -5.92, and the favored area after majorization in the Ramachandran plot was 84.54%. Molecular docking showed that the S7M8 vaccine could tightly bind to TLR2 (-1100.6 kcal/mol) and TLR4 (-950.3 kcal/mol). In addition, the immune stimulation prediction indicated that the S7M8 vaccine could activate T and B lymphocytes to produce high levels of Th1 cytokines and antibodies. CONCLUSION: S7M8 is a promising biomarker with good antigenicity, immunogenicity, non-toxicity, and non-sensitization. The S7M8 vaccine can trigger significantly high levels of Th1 cytokines and antibodies and may be a potentially powerful tool in preventing SARS-CoV-2 and MPXV.

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial.

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

Early prediction and identification for severe patients during the pandemic of COVID-19: A severe COVID-19 risk model constructed by multivariate logistic regression analysis.

BACKGROUND: As an emergent and fulminant infectious disease, Corona Virus Disease 2019 (COVID-19) has caused a worldwide pandemic. The early identification and timely treatment of severe patients are crucial to reducing the mortality of COVID-19. This study aimed to investigate the clinical characteristics and early predictors for severe COVID-19, and to establish a prediction model for the identification and triage of severe patients. METHODS: All confirmed patients with COVID-19 admitted by the Second Affiliated Hospital of Air Force Medical University were enrolled in this retrospective non-interventional study. The patients were divided into a mild group and a severe group, and the clinical data were compared between the two groups. Univariate and multivariate analysis were used to identify the independent early predictors for severe COVID-19, and the prediction model was constructed by multivariate logistic regression analysis. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the prediction model and each early predictor. RESULTS: A total of 40 patients were enrolled in this study, of whom 19 were mild and 21 were severe. The proportions of patients with venerable age (≥60 years old), comorbidities, and hypertension in severe patients were higher than that of the mild (P < 0.05). The duration of fever and respiratory symptoms, and the interval from illness onset to viral clearance were longer in severe patients (P < 0.05). Most patients received at least one form of oxygen treatments, while severe patients required more mechanical ventilation (P < 0.05). Univariate and multivariate analysis showed that venerable age, hypertension, lymphopenia, hypoalbuminemia and elevated neutrophil lymphocyte ratio (NLR) were the independent high-risk factors for severe COVID-19. ROC curves demonstrated significant predictive value of age, lymphocyte count, albumin and NLR for severe COVID-19. The sensitivity and specificity of the newly constructed prediction model for predicting severe COVID-19 was 90.5% and 84.2%, respectively, and whose positive predictive value, negative predictive value and crude agreement were all over 85%. CONCLUSIONS: The severe COVID-19 risk model might help clinicians quickly identify severe patients at an early stage and timely take optimal therapeutic schedule for them.

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells.

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.