Abstract The immunity of patients who recover from coronavirus disease 2019 (COVID-19) could be long lasting but persist at a lower level. Thus, recovered patients still need to be vaccinated to prevent reinfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or its mutated variants. Here, we report that the inactivated COVID-19 vaccine can stimulate immunity in recovered patients to maintain high levels of anti-receptor-binding domain (RBD) and anti-nucleocapsid protein (NP) antibody titers within 9 months, and high neutralizing activity against the prototype, Delta, and Omicron strains was observed. Nevertheless, the antibody response decreased over time, and the Omicron variant exhibited more pronounced resistance to neutralization than the prototype and Delta strains. Moreover, the intensity of the SARS-CoV-2-specific CD4 + T cell response was also increased in recovered patients who received COVID-19 vaccines. Overall, the repeated antigen exposure provided by inactivated COVID-19 vaccination greatly boosted both the potency and breadth of the humoral and cellular immune responses against SARS-CoV-2, effectively protecting recovered individuals from reinfection by circulating SARS-CoV-2 and its variants. 

/pdf/covid-19-vaccination-boosts-the-potency-and-breadth-of-the-1ywf82gr.pdf

COVID-19 vaccination boosts the potency and breadth of the immune response against SARS-CoV-2 among recovered patients in Wuhan

Treatment strategies with combined agency against severe viral pneumonia in patients with advanced cancer.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.

Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean–Congo hemorrhagic fever virus

Abstract Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS‐CoV‐2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS‐CoV‐2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu‐3) cell lines. TET functioned during the early‐entry stage of SARS‐CoV‐2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5‐human angiotensin‐converting enzyme 2 (hACE2)‐transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS‐CoV‐2‐infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route‐dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off‐target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route‐dependent pulmonary biodistribution of TET associated with its efficacy.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.206

Antiviral effects and tissue exposure of tetrandrine against SARS‐CoV‐2 infection and COVID‐19

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is capable of large‐scale transmission and has caused the coronavirus disease 2019 (COVID‐19) pandemic. Patients with COVID‐19 may experience persistent long‐term health issues, known as long COVID. Both acute SARS‐CoV‐2 infection and long COVID have resulted in persistent negative impacts on global public health. The effective application and development of blood‐derived products are important strategies to combat the serious damage caused by COVID‐19. Since the emergence of COVID‐19, various blood‐derived products that target or do not target SARS‐CoV‐2 have been investigated for therapeutic applications. SARS‐CoV‐2‐targeting blood‐derived products, including COVID‐19 convalescent plasma, COVID‐19 hyperimmune globulin, and recombinant anti‐SARS‐CoV‐2 neutralizing immunoglobulin G, are virus‐targeting and can provide immediate control of viral infection in the short term. Non‐SARS‐CoV‐2‐targeting blood‐derived products, including intravenous immunoglobulin and human serum albumin exhibit anti‐inflammatory, immunomodulatory, antioxidant, and anticoagulatory properties. Rational use of these products can be beneficial to patients with SARS‐CoV‐2 infection or long COVID. With evidence accumulated since the pandemic began, we here summarize the progress of blood‐derived product therapies for COVID‐19, discuss the effective methods and scenarios regarding these therapies, and provide guidance and suggestions for clinical treatment.

Blood‐derived product therapies for SARS‐CoV‐2 infection and long COVID

Coronavirus disease 2019 (COVID‐19) remains a global public health threat. Hence, more effective and specific antivirals are urgently needed. Here, COVID‐19 hyperimmune globulin (COVID‐HIG), a passive immunotherapy, is prepared from the plasma of healthy donors vaccinated with BBIBP‐CorV (Sinopharm COVID‐19 vaccine). COVID‐HIG shows high‐affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike (S) protein, the receptor‐binding domain (RBD), the N‐terminal domain of the S protein, and the nucleocapsid protein; and blocks RBD binding to human angiotensin‐converting enzyme 2 (hACE2). Pseudotyped and authentic virus‐based assays show that COVID‐HIG displays broad‐spectrum neutralization effects on a wide variety of SARS‐CoV‐2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529) in vitro. However, a significant reduction in the neutralization titer is detected against Beta, Delta, and Omicron variants. Additionally, assessments of the prophylactic and treatment efficacy of COVID‐HIG in an Adv5‐hACE2‐transduced IFNAR−/− mouse model of SARS‐CoV‐2 infection show significantly reduced weight loss, lung viral loads, and lung pathological injury. Moreover, COVID‐HIG exhibits neutralization potency similar to that of anti‐SARS‐CoV‐2 hyperimmune globulin from pooled convalescent plasma. Overall, the results demonstrate the potential of COVID‐HIG against SARS‐CoV‐2 infection and provide reference for subsequent clinical trials.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202104333

Potent Anti‐SARS‐CoV‐2 Efficacy of COVID‐19 Hyperimmune Globulin from Vaccine‐Immunized Plasma

The development of anti-SARS-CoV-2 drugs remains important for strategic medicine reserves. 3-chymotrypsin-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp) are key targets for new COVID-19 drugs. Previously, we showed polysaccharides bound 3CLpro to impede SARS-CoV-2 replication. We further hypothesized that natural polysaccharides might block viral replication by binding to both 3CLpro and RdRp. Here, we showed that crude polysaccharide 922 from Syzygium aromaticum almost completely blocked viral replication, while glycoprotein fractions 9222P and 9224P from 922 also showed potent antiviral effects. Although pectic polysaccharide 922211 from 922 interacted with 3CLpro, it showed no antiviral effect. Mechanism studies revealed that 922211, 9221S from 922, and 922 bound 3CLpro; however, only 9222P and 9224P bound RdRp. Further analysis suggested that 9222P and 9224P might suppress RNA elongation. Overall, the antiviral activity of 922 was likely mainly derived from its 9222P and 9224P targeting RdRp, with partial contribution from components interacting with 3CLpro. Additional investigations showed that 922, 9222P, and 9224P were internalized by Vero E6 cells. Intranasal administration of fluorescence and radiolabeled 922 demonstrated efficient pulmonary delivery and sustained retention in vivo. These findings suggest 922 holds promise for further development as an antiviral candidate.

Polysaccharides from Syzygium aromaticum binding to 3CLpro contain glycoproteins interacting with RdRp against SARS-CoV-2

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Potent Anti‐SARS‐CoV‐2 Efficacy of COVID‐19 Hyperimmune Globulin from Vaccine‐Immunized Plasma

Polysaccharides from Syzygium aromaticum binding to 3CLpro contain glycoproteins interacting with RdRp against SARS-CoV-2