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Preprint in English | bioRxiv | ID: ppbiorxiv-472391


Omicron variant continues to spread all over the world. There are lots of scientific questions remaining to be answered for such a devastating variant. There are a dozen of vaccines already in clinical use. The very urgent scientific question would be whether or not these vaccines can protect Omicron variant. Here, we tested the sera from both convalescents and vaccine recipients receiving either inactivated or protein subunits vaccines (CoronaVac from Sinovac, or BBIBP-CoV from Sinopharm, or ZF2001 from Zhifei longcom) for the binding antibody titers (ELISA) and neutralization antibodies titers (pseudovirus neutralization assay). We showed that Omicron do have severe immune escape in convalescents, with 15 of 16 were negative in neutralization. By contrast, in vaccinees who received three jabs of inactivated or protein subunit vaccine, the neutralizing activity was much better preserved. Especially in the ZF2001 group with an extended period of the second and third jab (4-6 months) remains 100% positive in Omicron neutralization, with only 3.1-folds reduction in neutralizing antibody (NAb) titer. In this case, we proposed that, the multi-boost strategy with an extended interval between the second and third jab for immune maturation would be beneficial for NAb against devastating variants such as Omicron.

Preprint in English | medRxiv | ID: ppmedrxiv-21266499


ObjectivesAs the COVID-19 pandemic is still ongoing and SARS-CoV-2 variants are circulating worldwide, an increasing number of breakthrough infections have been detected despite the good efficacy of COVID-19 vaccines. MethodsA prospective, comparative cohort study was conducted in Beijing Ditan Hospital to evaluate the clinical, immunological and genomic characteristics of COVID-19 breakthrough infections. Data on 88 COVID-19 breakthrough cases (vaccinated group) and 41 unvaccinated cases (unvaccinated group) from June 1 to August 20, 2021 were extracted from a cloud database. Among these 129 COVID-19 cases, we successfully sequenced 33 whole genomes, including 16 from the vaccinated group and 17 from the unvaccinated group. ResultsAsymptomatic and mild cases predominated in both groups, but 2 patients developed severe disease in the unvaccinated group. Between the two groups, the median time of viral shedding in the vaccinated group were significantly lower than those in the unvaccinated group (p = 0.003). A comparison of dynamic IgG titres of cases in the two groups indicated that IgG titres in the vaccinated group showed a significantly increasing trend (P =0.028). The CD4+T lymphocyte count was lower in the unvaccinated group, and there was a significant difference between the two groups (p=0.018). In the vaccinated group, the number of moderate cases who received Sinopharm BBIBP (42 cases) was significantly higher than those who received Sinovac Coronavac (p=0.020). Whole-genome sequencing revealed 23 cases of delta variants, including 15 patients from the vaccinated group. However, no significant difference was observed in either the RT-qPCR results or viral shedding time. ConclusionsCOVID-19 vaccine breakthrough infections were mainly asymptomatic and mild, the IgG titres were significantly higher and increased rapidly, and the viral shedding was short. Delta variants may be more likely to cause breakthrough infections, and vaccination may not reduce the viral loads and shedding time.

Preprint in English | medRxiv | ID: ppmedrxiv-21256655


BackgroundThe SARS-CoV-2 B.1.1.7 variant which was first identified in the United Kingdom (U.K.) has increased sharply in numbers worldwide and was reported to be more contagious. On January 17, 2021, a COVID-19 clustered outbreak caused by B.1.1.7 variant occurred in a community in Daxing District, Beijing, China. Three weeks prior, another non-variant (lineage B.1.470) COVID-19 outbreak occurred in Shunyi District, Beijing. This study aimed to investigate the clinical features of B.1.1.7 variant infection. MethodsA prospective cohort study was conducted on COVID-19 cases admitted to Ditan hospital since January 2020. Data of 74 COVID-19 cases from two independent COVID-19 outbreaks in Beijing were extracted as study subjects from a Cloud Database established in Ditan hospital, which included 41 Shunyi cases (Shunyi B.1.470 group) and 33 Daxing cases (Daxing B.1.1.7 group) that have been hospitalized since December 25, 2020 and January 17, 2021, respectively. We conducted a comparison of the clinical characteristics, RT-qPCR results and genomic features between the two groups. FindingsCases from Daxing B.1.1.7 group (15 [45.5%] male; median age, 39 years [range, 30.5, 62.5]) and cases from Shunyi B.1.470 group (25 [61.0%] male; median age, 31 years [range, 27.5, 41.0]) had a statistically significant difference in median age (P =0.014). Seven clinical indicators of Daxing B.1.1.7 group were significantly higher than Shunyi B.1.470 group including patients having fever over 38{degrees}C (14/33 [46.43%] in Daxing B.1.1.7 group vs. 9/41 (21.95%) in Shunyi B.1.470 group [P = 0 .015]), C-reactive protein ([CRP, mg/L], 4.30 [2.45, 12.1] vs. 1.80, [0.85, 4.95], [P = 0.005]), Serum amyloid A ([SAA, mg/L], 21.50 [12.50, 50.70] vs. 12.00 [5.20, 26.95], [P = 0.003]), Creatine Kinase ([CK, U/L]), 110.50 [53.15,152.40] vs. 70.40 [54.35,103.05], [P = 0.040]), D-dimer ([DD, mg/L], 0.31 [0.20, 0.48] vs. 0.24 [0.17,0.31], [P = 0.038]), CD4+ T lymphocyte ([CD4+ T, mg/L], [P = 0.003]), and Ground-glass opacity (GGO) in lung (15/33 [45.45%] vs. 5/41 [12.20%], [P =0.001]). After adjusting for the age factor, B.1.1.7 variant infection was the risk factor for CRP (P = 0.045, Odds ratio [OR] 2.791, CI [1.025, 0.8610]), SAA (0.011, 5.031, [1.459, 17.354]), CK (0.034, 4.34, [0.05, 0.91]), CD4+ T (0.029, 3.31, [1.13, 9.71]), and GGO (0.005, 5.418, [1.656, 17.729]) of patients. The median Ct value of RT-qPCR tests of the N-gene target in the Daxing B.1.1.7 group was significantly lower than the Shunyi B.1.470 group (P=0.036). The phylogenetic analysis showed that only 2 amino acid mutations in spike protein were detected in B.1.470 strains while B.1.1.7 strains had 3 deletions and 7 mutations. InterpretationClinical features including a more serious inflammatory response, pneumonia and a possible higher viral load were detected in the cases infected with B.1.1.7 SARS-CoV-2 variant. It could therefore be inferred that the B.1.1.7 variant may have increased pathogenicity. FundingThe study was funded by the National Key Research and Development Program (grant nos.2020YFC0846200 and 2020YFC0848300) and National Natural Science Foundation of China (grant no. 82072295).

Preprint in English | medRxiv | ID: ppmedrxiv-20248602


BackgroundA safe and effective coronavirus disease 2019 (COVID-19) vaccine is urgently needed to control the ongoing pandemic. Although progress has been made recently with several candidates reporting positive efficacy results, COVID-19 vaccines developed so far cannot meet the global vaccine demand. We developed a protein subunit vaccine against COVID-19, using dimeric form of receptor-binding domain (RBD) as the antigen. We aimed to assess the safety and immunogenicity of this vaccine in humans and determine the appropriate dose and schedule for an efficacy study. MethodsWe did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults aged 18-59 years were enrolled and randomly allocated to three groups to receive three doses of vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 years were enrolled and randomly allocated to six groups to receive vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the former 3 groups given two doses and the latter 3 groups given three doses, 30 days apart. For phase 1 trial, the primary outcome was safety, as measured by the occurrence of adverse events and serious adverse events. The secondary outcome was immunogenicity as measured by the seroconversion rate and magnitude of antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For phase 2 trial, the primary outcome included both safety and immunogenicity. These trials are registered with, NCT04445194 and NCT04466085. FindingsBetween June 22 and September 15, 2020, 50 participants were enrolled to the phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-dose schedule. For both trials, local and systemic adverse reactions were absent or mild in most participants. There were no serious adverse events related to vaccine in either trial. After three doses, neutralizing antibodies were detected in all participants receiving either 25 g or 50 g dose of vaccine in phase 1 study, and in 97% (the 25 g group) and 93% (the 50 g group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 g group and 117.8 for the 50 g group in phase 1, and 102.5 for the 25 g group and 69.1 for the 50 g group in phase 2, exceeding the level of a panel of COVID-19 convalescent samples (GMT, 51). Vaccine induced balanced TH1 and TH2 responses. The 50 g group did not show enhanced immunogenicity compared with the 25 g group. InterpretationThe protein subunit vaccine ZF2001 is well-tolerated and immunogenic. The safety and immunogenicity data from phase 1 and 2 trials for ZF2001 support the use of 25 g vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy. FundingNational Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical.

Preprint in English | medRxiv | ID: ppmedrxiv-20175455


BackgroundBoth COVID-19 and influenza A contribute to increased mortality among the elderly and those with existing comorbidities. Changes in the underlying immune mechanisms determine patient prognosis. This study aimed to analyze the role of lymphocyte subsets in the immunopathogenesisof COVID-19 and severe influenza A, and examined the clinical significance of their alterations in the prognosis and recovery duration. MethodsBy retrospectively reviewing of patients in four groups (healthy controls, severe influenza A, non-severe COVID-19 and severe COVID-19) who were admitted to Ditan hospital between 2018 to 2020, we performed flow cytometric analysis and compared the absolute counts of leukocytes, lymphocytes, and lymphocyte subsets of the patients at different time points (weeks 1- 4). ResultsWe reviewed the patients data of 110 healthy blood donors, 80 Non-severe-COVID-19, 19 Severe-COVID-19 and 43 severe influenza A. We found total lymphocytes (0.93 x109/L, 0.84 x109/L vs 1.78 x109/L, P < 0.0001) and lymphocyte subsets (T cells, CD4+ and CD8+ T cell subsets) of both severe patients to be significantly lower than those of healthy donors at early infection stages. Further, significant dynamic variations were observed at different time points (weeks 1-4). ConclusionsOur study indicates lymphopenia to be associated with disease severity and suggests the plausible role of lymphocyte subsets in disease progression, which in turn affects prognosis and recovery duration in patients with severe COVID-19 and influenza A.

Preprint in English | medRxiv | ID: ppmedrxiv-20021584


BackgroundSevere ill patients with 2019 novel coronavirus (2019-nCoV) infection progressed rapidly to acute respiratory failure. We aimed to select the most useful prognostic factor for severe illness incidence. MethodsThe study prospectively included 61 patients with 2019-nCoV infection treated at Beijing Ditan Hospital from January 13, 2020 to January 31, 2020. Prognostic factor of severe illness was selected by the LASSO COX regression analyses, to predict the severe illness probability of 2019-CoV pneumonia. The predictive accuracy was evaluated by concordance index, calibration curve, decision curve and clinical impact curve. ResultsThe neutrophil-to-lymphocyte ratio (NLR) was identified as the independent risk factor for severe illness in patients with 2019-nCoV infection. The NLR had a c-index of 0.807 (95% confidence interval, 0.676-0.38), the calibration curves fitted well, and the decision curve and clinical impact curve showed that the NLR had superior standardized net benefit. In addition, the incidence of severe illness was 9.1% in age [≥] 50 and NLR < 3.13 patients, and half of patients with age [≥] 50 and NLR [≥] 3.13 would develop severe illness. Based on the risk stratification of NLR with age, the study developed a 2019-nCoV pneumonia management process. ConclusionsThe NLR was the early identification of risk factors for 2019-nCoV severe illness. Patients with age [≥] 50 and NLR [≥] 3.13 facilitated severe illness, and they should rapidly access to intensive care unit if necessary.