Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.

BACKGROUND: Heterologous boosting is suggested to be of use in populations who have received inactivated COVID-19 vaccines. We aimed to assess the safety and immunogenicity of a heterologous vaccination with the mRNA vaccine CS-2034 versus the inactivated BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 omicron (BA.5) variant. METHODS: This trial contains a randomised, double-blind, parallel-controlled study in healthy participants aged 18 years or older (group A) and an open-label cohort in participants 60 years and older (group B), who had received three doses of inactivated whole-virion vaccines at least 6 months before enrolment. Pregnant women and people with major chronic illnesses or a history of allergies were excluded. Eligible participants in group A were stratified by age (18-59 years and ≥60 years) and then randomised by SAS 9.4 in a ratio of 3:1 to receive a dose of the mRNA vaccine (CS-2034, CanSino, Shanghai, China) or inactivated vaccine (BBIBP-CorV, Sinopharm, Beijing, China). Safety and immunogenicity against omicron variants of the fourth dose were evaluated in group A. Participants 60 years and older were involved in group B for safety observations. The primary outcome was geometric mean titres (GMTs) of the neutralising antibodies against omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. The intention-to-treat group was involved in the safety analysis, while all patients in group A who had blood samples taken before and after the booster were involved in the immunogenicity analysis. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575). FINDINGS: Between Oct 13, and Nov 22, 2022, 320 participants were enrolled in group A (240 in the CS-2034 group and 80 in the BBIBP-CorV group) and 113 in group B. Adverse reactions after vaccination were more frequent in CS-2034 recipients (158 [44·8%]) than BBIBP-CorV recipients (17 [21·3%], p<0·0001). However, most adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by eight (2%) of 353 participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14·4-fold (GMT 229·3, 95% CI 202·7-259·4 vs 15·9, 13·1-19·4) higher concentration of neutralising antibodies to SARS-CoV-2 omicron variant BA.5 than did homologous boosting with BBIBP-CorV. The seroconversion rates of SARS-CoV-2-specific neutralising antibody responses were much higher in the mRNA heterologous booster regimen compared with BBIBP-CorV homologous booster regimen (original strain 47 [100%] of 47 vs three [18·8%] of 16; BA.1 45 [95·8%] of 48 vs two [12·5%] 16; and BA.5 233 [98·3%] of 240 vs 15 [18·8%] of 80 by day 28). INTERPRETATION: Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 omicron infections compared with homologous boosting, which could support the emergency use authorisation of CS-2034 in adults. FUNDING: Science and Technology Commission of Shanghai, National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

ESA-FedGNN: Efficient secure aggregation for federated graph neural networks.

Graph Neural Network (GNN) architecture is a state-of-the-art model, which can obtain complete node embedding features and rich data information by aggregating the information of nodes and neighbors. Therefore, GNNs are widely used in electronic shopping, drug discovery (especially for the treatment of COVID-19) and other fields, promoting the explosive development of machine learning. However, user interaction, data sharing and circulation are highly sensitive to privacy, and centralized storage can lead to data isolation. Therefore, Federated Learning with high efficiency and strong security and privacy enhancement technology based on secure aggregation can improve the security dilemma faced by GNN. In this paper, we propose an Efficient Secure Aggregation for Federated Graph Neural Network(ESA-FedGNN), which can efficiently reduce the cost of communication and avoid computational redundancy while ensuring data privacy. Firstly, a novel secret sharing scheme based on numerical analysis is proposed, which employs Fast Fourier Transform to improve the computational power of the neural network in sharing phase, and leverages Newton Interpolation method to deal with the disconnection and loss of the client in reconstruction phase. Secondly, a regular graph embedding based on geometric distribution is proposed, which optimizes the aggregation speed by using data parallelism. Finally, a double mask is adopted to ensure privacy and prevent malicious adversaries from stealing model parameters. We achieve O ( log N log ( log N ) ) improvements compared to O N 2 in state-of-the-art works. This research helps to provide security solutions related to the practical development and application of privacy-preserving graph neural network technology.

Potential of green tea EGCG in neutralizing SARS-CoV-2 Omicron variant with greater tropism toward the upper respiratory tract.

Background: COVID-19 due to SARS-CoV-2 infection has had an enormous adverse impact on global public health. As the COVID-19 pandemic evolves, the WHO declared several variants of concern (VOCs), including Alpha, Beta, Gamma, Delta, and Omicron. Compared with earlier variants, Omicron, now a dominant lineage, exhibits characteristics of enhanced transmissibility, tropism shift toward the upper respiratory tract, and attenuated disease severity. The robust transmission of Omicron despite attenuated disease severity still poses a great challenge for pandemic control. Under this circumstance, its tropism shift may be utilized for discovering effective preventive approaches. Scope and approach: This review aims to estimate the potential of green tea epigallocatechin gallate (EGCG), the most potent antiviral catechin, in neutralizing SARS-CoV-2 Omicron variant, based on current knowledge concerning EGCG distribution in tissues and Omicron tropism. Key findings and conclusions: EGCG has a low bioavailability. Plasma EGCG levels are in the range of submicromolar concentrations following green tea drinking, or reach at most low µM concentrations after pharmacological intervention. Nonetheless, its levels in the upper respiratory tract could reach concentrations as high as tens or even hundreds of µM following green tea consumption or pharmacological intervention. An approach for delivering sufficiently high concentrations of EGCG in the pharynx has been developed. Convincing data have demonstrated that EGCG at tens to hundreds of µM can dramatically neutralize SARS-CoV-2 and effectively eliminate SARS-CoV-2-induced cytopathic effects and plaque formation. Thus, EGCG, which exhibits hyperaccumulation in the upper respiratory tract, deserves closer investigation as an antiviral in the current global battle against COVID-19, given Omicron's greater tropism toward the upper respiratory tract.

Developing Pseudovirus-Based Neutralization Assay against Omicron-Included SARS-CoV-2 Variants.

The global spread of SARS-CoV-2 and its variants poses a serious threat to human health worldwide. Recently, the emergence of Omicron has presented a new challenge to the prevention and control of the COVID-19 pandemic. A convenient and reliable in vitro neutralization assay is an important method for validating the efficiency of antibodies, vaccines, and other potential drugs. Here, we established an effective assay based on a pseudovirus carrying a full-length spike (S) protein of SARS-CoV-2 variants in the HIV-1 backbone, with a luciferase reporter gene inserted into the non-replicate pseudovirus genome. The key parameters for packaging the pseudovirus were optimized, including the ratio of the S protein expression plasmids to the HIV backbone plasmids and the collection time for the Alpha, Beta, Gamma, Kappa, and Omicron pseudovirus particles. The pseudovirus neutralization assay was validated using several approved or developed monoclonal antibodies, underscoring that Omicron can escape some neutralizing antibodies, such as REGN10987 and REGN10933, while S309 and ADG-2 still function with reduced neutralization capability. The neutralizing capacity of convalescent plasma from COVID-19 convalescent patients in Wuhan was tested against these pseudoviruses, revealing the immune evasion of Omicron. Our work established a practical pseudovirus-based neutralization assay for SARS-CoV-2 variants, which can be conducted safely under biosafety level-2 (BSL-2) conditions, and this assay will be a promising tool for studying and characterizing vaccines and therapeutic candidates against Omicron-included SARS-CoV-2 variants.

Developing Pseudovirus-Based Neutralization Assay against Omicron-Included SARS-CoV-2 Variants

The global spread of SARS-CoV-2 and its variants poses a serious threat to human health worldwide. Recently, the emergence of Omicron has presented a new challenge to the prevention and control of the COVID-19 pandemic. A convenient and reliable in vitro neutralization assay is an important method for validating the efficiency of antibodies, vaccines, and other potential drugs. Here, we established an effective assay based on a pseudovirus carrying a full-length spike (S) protein of SARS-CoV-2 variants in the HIV-1 backbone, with a luciferase reporter gene inserted into the non-replicate pseudovirus genome. The key parameters for packaging the pseudovirus were optimized, including the ratio of the S protein expression plasmids to the HIV backbone plasmids and the collection time for the Alpha, Beta, Gamma, Kappa, and Omicron pseudovirus particles. The pseudovirus neutralization assay was validated using several approved or developed monoclonal antibodies, underscoring that Omicron can escape some neutralizing antibodies, such as REGN10987 and REGN10933, while S309 and ADG-2 still function with reduced neutralization capability. The neutralizing capacity of convalescent plasma from COVID-19 convalescent patients in Wuhan was tested against these pseudoviruses, revealing the immune evasion of Omicron. Our work established a practical pseudovirus-based neutralization assay for SARS-CoV-2 variants, which can be conducted safely under biosafety level-2 (BSL-2) conditions, and this assay will be a promising tool for studying and characterizing vaccines and therapeutic candidates against Omicron-included SARS-CoV-2 variants.

Broadly neutralizing antibodies against Omicron-included SARS-CoV-2 variants induced by vaccination.

The SARS-CoV-2 Omicron variant shows substantial resistance to neutralization by infection- and vaccination-induced antibodies, highlighting the demands for research on the continuing discovery of broadly neutralizing antibodies (bnAbs). Here, we developed a panel of bnAbs against Omicron and other variants of concern (VOCs) elicited by vaccination of adenovirus-vectored COVID-19 vaccine (Ad5-nCoV). We also investigated the human longitudinal antibody responses following vaccination and demonstrated how the bnAbs evolved over time. A monoclonal antibody (mAb), named ZWD12, exhibited potent and broad neutralization against SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa, Delta, and Omicron by blocking the spike protein binding to the angiotensin-converting enzyme 2 (ACE2) and provided complete protection in the challenged prophylactic and therapeutic K18-hACE2 transgenic mouse model. We defined the ZWD12 epitope by determining its structure in complex with the spike (S) protein via cryo-electron microscopy. This study affords the potential to develop broadly therapeutic mAb drugs and suggests that the RBD epitope bound by ZWD12 is a rational target for the design of a broad spectrum of vaccines.

Management Strategies for Patients Presenting With Symptomatic Lymphadenopathy and Breast Edema After Recent COVID-19 Vaccination.

Ipsilateral axillary lymphadenopathy is a well-documented finding associated with COVID-19 vaccination. Varying guidelines have been published for the management of asymptomatic patients who have a history of recent vaccination and present with incidental lymphadenopathy at screening mammography. Some experts recommend follow-up imaging, and others suggest that clinical management, rather than repeat imaging or biopsy, is appropriate. Symptomatic patients with lymphadenopathy and/or additional abnormal imaging findings should be treated differently depending on risk factors and clinical scenarios. Although ipsilateral lymphadenopathy is well documented, ipsilateral breast edema after COVID-19 vaccination has been rarely reported. The combination of ipsilateral lymphadenopathy and diffuse breast edema after COVID-19 vaccination presents a clinical management challenge because edema can obscure underlying abnormalities at imaging. For symptomatic patients with lymphadenopathy and associated breast parenchymal abnormality, prompt action is appropriate, including diagnostic evaluation and consideration of tissue sampling. This approach may prevent delays in diagnosis and treatment of patients with malignancy masked by symptoms from the vaccination.

COVID-19 epidemic outside China: 34 founders and exponential growth.

COVID-19 raised tension both within China and internationally. Here, we used mathematical modeling to predict the trend of patient diagnosis outside China in future, with the aim of easing anxiety regarding the emergent situation. According to all diagnosis number from WHO website and combining with the transmission mode of infectious diseases, the mathematical model was fitted to predict future trend of outbreak. Daily diagnosis numbers from countries outside China were downloaded from WHO situation reports. The data used for this analysis were collected from January 21, 2020 and currently end at February 28, 2020. A simple regression model was developed based on these numbers, as follows: [Formula: see text], where [Formula: see text] is the total diagnosed patient till the i-th day and t=1 at February 1, 2020. Based on this model, we estimate that there were approximately 34 undetected founder patients at the beginning of the spread of COVID-19 outside China. The global trend was approximately exponential, with an increase rate of 10-fold every 19 days. Through establishment of this model, we call for worldwide strong public health actions, with reference to the experiences learned from China and Singapore.

A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2.

Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo-eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.