Human monoclonal antibody F61 nasal spray effectively protected high-risk populations from SARS-CoV-2 variants during the COVID-19 pandemic from late 2022 to early 2023 in China.

Following the national dynamic zero-COVID strategy adjustment, the utilization of broad-spectrum nasal neutralizing antibodies may offer an alternative approach to controlling the outbreak of Omicron variants between late 2022 and early 2023 in China. This study involved an investigator-initiated trial (IIT) to assess the pharmacokinetic, safety and efficacy of the F61 nasal spray. A total of 2,008 participants were randomly assigned to receive F61 nasal spray (24 mg/0.8 mL/dose) or normal saline (0.8 mL/dose) and 1336 completed the follow-up in the IIT. Minimal absorption of F61 antibody into the bloodstream was detected in individuals receiving F61 nasal spray for seven consecutive days. No treatment-emergent adverse reactions of grade 3 severity or higher were reported. In the one-dose cohort, the 7-day cumulative SARS-CoV-2 infection rate was 79.0% in the F61 group and 82.6% in the placebo group, whereas, in the multiple-dose (once daily for 7 consecutive days) cohort, the rates were 6.55% in the F61 group and 23.83% in the placebo group. The laboratory-confirmed efficacy of F61 was 3.78% (-3.74%-10.75%) in the one-dose cohort and 72.19% (57.33%-81.87%) in the multiple-dose cohort. In the real-world study, 60,225 volunteers in four different regions were administered the F61 nasal spray based on the subject's wishes, over 90% efficacy rate was observed against different Omicron variants. The F61 nasal spray, with its favourable safety profile, could be a promising prophylactic monoclonal antibody against SARS-CoV-2 VOCs.

Nasal delivery of broadly neutralizing antibodies protects mice from lethal challenge with SARS-CoV-2 delta and omicron variants.

Multiple new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have constantly emerged, as the delta and omicron variants, which have developed resistance to currently gained neutralizing antibodies. This highlights a critical need to discover new therapeutic agents to overcome the variants mutations. Despite the availability of vaccines against coronavirus disease 2019 (COVID-19), the use of broadly neutralizing antibodies has been considered as an alternative way for the prevention or treatment of SARS-CoV-2 variants infection. Here, we show that the nasal delivery of two previously characterized broadly neutralizing antibodies (F61 and H121) protected K18-hACE2 mice against lethal challenge with SARS-CoV-2 variants. The broadly protective efficacy of the F61 or F61/F121 cocktail antibodies was evaluated by lethal challenge with the wild strain (WIV04) and multiple variants, including beta (B.1.351), delta (B.1.617.2), and omicron (B.1.1.529) at 200 or 1000 TCID50, and the minimum antibody administration doses (5-1.25 â€‹mg/kg body weight) were also evaluated with delta and omicron challenge. Fully prophylactic protections were found in all challenged groups with both F61 and F61/H121 combination at the administration dose of 20 â€‹mg/kg body weight, and corresponding mice lung viral RNA showed negative, with almost all alveolar septa and cavities remaining normal. Furthermore, low-dose antibody treatment induced significant prophylactic protection against lethal challenge with delta and omicron variants, whereas the F61/H121 combination showed excellent results against omicron infection. Our findings indicated the potential use of broadly neutralizing monoclonal antibodies as prophylactic and therapeutic agent for protection of current emerged SARS-CoV-2 variants infection.

Structural basis of a two-antibody cocktail exhibiting highly potent and broadly neutralizing activities against SARS-CoV-2 variants including diverse Omicron sublineages.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), especially the latest Omicron, have exhibited severe antibody evasion. Broadly neutralizing antibodies with high potency against Omicron are urgently needed for understanding the working mechanisms and developing therapeutic agents. In this study, we characterized the previously reported F61, which was isolated from convalescent patients infected with prototype SARS-CoV-2, as a broadly neutralizing antibody against all VOCs including Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4 sublineages by utilizing antigen binding and cell infection assays. We also identified and characterized another broadly neutralizing antibody D2 with epitope distinct from that of F61. More importantly, we showed that a combination of F61 with D2 exhibited synergy in neutralization and protecting mice from SARS-CoV-2 Delta and Omicron BA.1 variants. Cryo-Electron Microscopy (Cryo-EM) structures of the spike-F61 and spike-D2 binary complexes revealed the distinct epitopes of F61 and D2 at atomic level and the structural basis for neutralization. Cryo-EM structure of the Omicron-spike-F61-D2 ternary complex provides further structural insights into the synergy between F61 and D2. These results collectively indicated F61 and F61-D2 cocktail as promising therapeutic antibodies for combating SARS-CoV-2 variants including diverse Omicron sublineages.

Chemiluminescence Immunoassay Based Serological Immunoassays for Detection of SARS-CoV-2 Neutralizing Antibodies in COVID-19 Convalescent Patients and Vaccinated Population.

The development of rapid serological detection methods re urgently needed for determination of neutralizing antibodies in sera. In this study, four rapid methods (ACE2-RBD inhibition assay, S1-IgG detection, RBD-IgG detection, and N-IgG detection) were established and evaluated based on chemiluminescence technology. For the first time, a broadly neutralizing antibody with high affinity was used as a standard for the quantitative detection of SARS-CoV-2 specific neutralizing antibodies in human sera. Sera from COVID-19 convalescent patients (N = 119), vaccinated donors (N = 86), and healthy donors (N = 299) confirmed by microneutralization test (MNT) were used to evaluate the above methods. The result showed that the ACE2-RBD inhibition assay calculated with either ACE2-RBD binding inhibition percentage rate or ACE2-RBD inhibiting antibody concentration were strongly correlated with MNT (r ≥ 0.78, p < 0.0001) and also highly consistent with MNT (Kappa Value ≥ 0.94, p < 0.01). There was also a strong correlation between the two evaluation indices (r ≥ 0.99, p < 0.0001). Meanwhile, S1-IgG and RBD-IgG quantitative detection were also significantly correlated with MNT (r ≥ 0.73, p < 0.0001), and both methods were highly correlated with each other (r ≥ 0.95, p < 0.0001). However, the concentration of N-IgG antibodies showed a lower correlation with the MNT results (r < 0.49, p < 0.0001). The diagnostic assays presented here could be used for the evaluation of SARS-CoV-2 vaccine immunization effect and serological diagnosis of COVID-19 patients, and could also have guiding significance for establishing other rapid serological methods to surrogate neutralization tests for SARS-CoV-2.

Antibody Cocktail Exhibits Broad Neutralization Activity Against SARS-CoV-2 and SARS-CoV-2 Variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated multiple variants resistant to therapeutic antibodies. In this study, 12 high-affinity antibodies were generated from convalescent donors in early outbreaks using immune antibody phage display libraries. Of them, two RBD-binding antibodies (F61 and H121) showed high-affinity neutralization against SARS-CoV-2, whereas three S2-target antibodies failed to neutralize SARS-CoV-2. Following structure analysis, F61 identified a linear epitope located in residues G446-S494, which overlapped with angiotensin-converting enzyme 2 (ACE2) binding sites, while H121 recognized a conformational epitope located on the side face of RBD, outside from ACE2 binding domain. Hence the cocktail of the two antibodies achieved better performance of neutralization to SARS-CoV-2. Importantly, these two antibodies also showed efficient neutralizing activities to the variants including B.1.1.7 and B.1.351, and reacted with mutations of N501Y, E484K, and L452R, indicated that it may also neutralize the recent India endemic strain B.1.617. The unchanged binding activity of F61 and H121 to RBD with multiple mutations revealed a broad neutralizing activity against variants, which mitigated the risk of viral escape. Our findings revealed the therapeutic basis of cocktail antibodies against constantly emerging SARS-CoV-2 variants and provided promising candidate antibodies to clinical treatment of COVID-19 patients infected with broad SARS-CoV-2 variants.

Abnormal upregulation of cardiovascular disease biomarker PLA2G7 induced by proinflammatory macrophages in COVID-19 patients.

High rate of cardiovascular disease (CVD) has been reported among patients with coronavirus disease 2019 (COVID-19). Importantly, CVD, as one of the comorbidities, could also increase the risks of the severity of COVID-19. Here we identified phospholipase A2 group VII (PLA2G7), a well-studied CVD biomarker, as a hub gene in COVID-19 though an integrated hypothesis-free genomic analysis on nasal swabs (n = 486) from patients with COVID-19. PLA2G7 was further found to be predominantly expressed by proinflammatory macrophages in lungs emerging with progression of COVID-19. In the validation stage, RNA level of PLA2G7 was identified in nasal swabs from both COVID-19 and pneumonia patients, other than health individuals. The positive rate of PLA2G7 were correlated with not only viral loads but also severity of pneumonia in non-COVID-19 patients. Serum protein levels of PLA2G7 were found to be elevated and beyond the normal limit in COVID-19 patients, especially among those re-positive patients. We identified and validated PLA2G7, a biomarker for CVD, was abnormally enhanced in COVID-19 at both nucleotide and protein aspects. These findings provided indications into the prevalence of cardiovascular involvements seen in patients with COVID-19. PLA2G7 could be a potential prognostic and therapeutic target in COVID-19.

Hemorrhagic Fever with Renal Syndrome - Liaoning Province, China, 1999-2018.

What is already known on this topic? Hemorrhagic fever with renal syndrome (HFRS) is endemic in Liaoning Province. Both Seoul and Hantaan virus are circulating in rodents, and epidemic outbreaks and sporadic cases have been recorded every year since the disease was recognized. What is added by this report? The epidemic trend of HFRS over the past 20 years (1999-2018) in Liaoning was analyzed, which showed both regional complexity and consistence with the epidemic in China. Genetic and antigenic stability of the circulating hantavirus were demonstrated, which suggested the effectiveness of the approved inactivated vaccine currently used in China. What are the implications for public health practice? Precise risk-based strategic practices that are integrated and regional are required for further improvement of the prevention and control of HFRS.