Publications by authors named "George F Gao"

544 Publications

Recombinant chimpanzee adenovirus AdC7 expressing dimeric tandem-repeat spike protein RBD protects mice against COVID-19.

Emerg Microbes Infect 2021 Jul 22:1-40. Epub 2021 Jul 22.

Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, The First Affiliated Hospital, Hainan Medical University, Haikou, China.

A safe and effective vaccine is urgently needed to control the unprecedented COVID-19 pandemic. Four adenovirus vectored vaccines expressing spike (S) protein have been approved for use. Here, we generated several recombinant chimpanzee adenovirus (AdC7) vaccines expressing S, receptor-binding domain (RBD) or tandem-repeat dimeric RBD (RBD-tr2). We found vaccination via either intramuscular or intranasal route was highly immunogenic in mice to elicit both humoral and cellular immune responses. AdC7-RBD-tr2 showed higher antibody responses compared to either AdC7-S or AdC7-RBD. Intranasal administration of AdC7-RBD-tr2 additionally induced mucosal immunity with neutralizing activity in bronchoalveolar lavage fluid. Either single-dose or two-dose mucosal administration of AdC7-RBD-tr2 protected mice against SARS-CoV-2 challenge, with undetectable subgenomic RNA in lung and relieved lung injury. AdC7-RBD-tr2-elicted sera preserved the neutralizing activity against the circulating variants, especially the Delta variant. These results support AdC7-RBD-tr2 as a promising COVID-19 vaccine candidate.
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http://dx.doi.org/10.1080/22221751.2021.1959270DOI Listing
July 2021

Protective Zika vaccines engineered to eliminate enhancement of dengue infection via immunodominance switch.

Nat Immunol 2021 Jul 15. Epub 2021 Jul 15.

CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.

Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and its antigenically related Zika virus (ZIKV) because vaccine may prime deleterious antibodies to enhance natural infections. Cross-reactive antibodies targeting the conserved fusion loop epitope (FLE) are known as the main sources of ADE. We design ZIKV immunogens engineered to change the FLE conformation but preserve neutralizing epitopes. Single vaccination conferred sterilizing immunity against ZIKV without ADE of DENV-serotype 1-4 infections and abrogated maternal-neonatal transmission in mice. Unlike the wild-type-based vaccine inducing predominately cross-reactive ADE-prone antibodies, B cell profiling revealed that the engineered vaccines switched immunodominance to dispersed patterns without DENV enhancement. The crystal structure of the engineered immunogen showed the dimeric conformation of the envelope protein with FLE disruption. We provide vaccine candidates that will prevent both ZIKV infection and infection-/vaccination-induced DENV ADE.
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http://dx.doi.org/10.1038/s41590-021-00966-6DOI Listing
July 2021

The molecular basis for SARS-CoV-2 binding to dog ACE2.

Nat Commun 2021 07 7;12(1):4195. Epub 2021 Jul 7.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

SARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.
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http://dx.doi.org/10.1038/s41467-021-24326-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263772PMC
July 2021

Potent inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 by photosensitizers compounds.

Dyes Pigm 2021 Oct 22;194:109570. Epub 2021 Jun 22.

College of Chemistry, Fuzhou University, Fujian, 350108, China.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) posed a major challenge to the public health. Currently, no proven antiviral treatment for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is available. Here we report compounds pentalysine β-carbonylphthalocyanine zinc (ZnPc5K) and chlorin e6 (ce6) potently inhibited the viral infection and replication in vitro with EC values at nanomolar level. These compounds were first identified by screening a panel of photosensitizers for photodynamic viral inactivation. Such viral inactivation strategy is implementable, and has unique advantages, including resistance to virus mutations, affordability compared to the monoclonal antibodies, and lack of long-term toxicity.
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http://dx.doi.org/10.1016/j.dyepig.2021.109570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216852PMC
October 2021

Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species.

Cell 2021 06 24;184(13):3438-3451.e10. Epub 2021 May 24.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.
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http://dx.doi.org/10.1016/j.cell.2021.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142884PMC
June 2021

Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals.

Nat Microbiol 2021 Jul 14;6(7):921-931. Epub 2021 Jun 14.

Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.

Zoonotic arenaviruses can lead to life-threating diseases in humans. These viruses encode a large (L) polymerase that transcribes and replicates the viral genome. At the late stage of replication, the multifunctional Z protein interacts with the L polymerase to shut down RNA synthesis and initiate virion assembly. However, the mechanism by which the Z protein regulates the activity of L polymerase is unclear. Here, we used cryo-electron microscopy to resolve the structures of both Lassa and Machupo virus L polymerases in complex with their cognate Z proteins, and viral RNA, to 3.1-3.9 Å resolutions. These structures reveal that Z protein binding induces conformational changes in two catalytic motifs of the L polymerase, and restrains their conformational dynamics to inhibit RNA synthesis, which is supported by hydrogen-deuterium exchange mass spectrometry analysis. Importantly, we show, by in vitro polymerase reactions, that Z proteins of Lassa and Machupo viruses can cross-inhibit their L polymerases, albeit with decreased inhibition efficiencies. This cross-reactivity results from a highly conserved determinant motif at the contacting interface, but is affected by other variable auxiliary motifs due to the divergent evolution of Old World and New World arenaviruses. These findings could provide promising targets for developing broad-spectrum antiviral drugs.
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http://dx.doi.org/10.1038/s41564-021-00916-wDOI Listing
July 2021

Assessing the extent of community spread caused by mink-derived SARS-CoV-2 variants.

Innovation (N Y) 2021 Aug 7;2(3):100128. Epub 2021 Jun 7.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing 100101, China.

SARS-CoV-2 has recently been found to have spread from humans to minks and then to have transmitted back to humans. However, it is unknown to what extent the human-to-human transmission caused by the variant has reached. Here, we used publicly available SARS-CoV-2 genomic sequences from both humans and minks collected in Denmark and the Netherlands, and combined phylogenetic analysis with Bayesian inference under an epidemiological model, to trace the possibility of person-to-person transmission. The results showed that at least 12.5% of all people being infected with dominated mink-derived SARS-CoV-2 variants in Denmark and the Netherlands were caused by human-to-human transmission, indicating that this "back-to-human" SARS-CoV-2 variant has already caused human-to-human transmission. Our study also indicated the need for monitoring this mink-derived and other animal source "back-to-human" SARS-CoV-2 in future and that prevention and control measures should be tailored to avoid large-scale community transmission caused by the virus jumping between animals and humans.
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http://dx.doi.org/10.1016/j.xinn.2021.100128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182980PMC
August 2021

Distinct durability of IgM/IgG antibody responses in COVID-19 patients with differing severity.

Sci China Life Sci 2021 Jun 2. Epub 2021 Jun 2.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s11427-020-1947-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176871PMC
June 2021

Impact of COVID-19 outbreaks and interventions on influenza in China and the United States.

Nat Commun 2021 05 31;12(1):3249. Epub 2021 May 31.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention/Chinese National Influenza Center, Beijing, China.

Coronavirus disease 2019 (COVID-19) was detected in China during the 2019-2020 seasonal influenza epidemic. Non-pharmaceutical interventions (NPIs) and behavioral changes to mitigate COVID-19 could have affected transmission dynamics of influenza and other respiratory diseases. By comparing 2019-2020 seasonal influenza activity through March 29, 2020 with the 2011-2019 seasons, we found that COVID-19 outbreaks and related NPIs may have reduced influenza in Southern and Northern China and the United States by 79.2% (lower and upper bounds: 48.8%-87.2%), 79.4% (44.9%-87.4%) and 67.2% (11.5%-80.5%). Decreases in influenza virus infection were also associated with the timing of NPIs. Without COVID-19 NPIs, influenza activity in China and the United States would likely have remained high during the 2019-2020 season. Our findings provide evidence that NPIs can partially mitigate seasonal and, potentially, pandemic influenza.
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http://dx.doi.org/10.1038/s41467-021-23440-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167168PMC
May 2021

Risk Factors for Death Among the First 80 543 COVID-19 Cases in China: Relationships Between Age, Underlying Disease, Case Severity, and Region.

Clin Infect Dis 2021 May 27. Epub 2021 May 27.

Hubei Center for Disease Control and Prevention, 6 North Zuodaoquan, Hongshan District, Wuhan 430079, China.

Background: Knowledge of COVID-19 epidemiology remains incomplete and crucial questions persist. We aimed to examine risk factors for COVID-19 death.

Methods: A total of 80 543 COVID-19 cases reported in China, nationwide, through April 8, 2020 were included. Risk factors for death were investigated by Cox proportional hazards regression and stratified analyses.

Results: Overall national case fatality ratio (CFR) was 5.64%. Risk factors for death were older age (≥80: adjusted hazard ratio [aHR]=12.58, 95% confidence interval [CI]=6.78-23.33), presence of underlying disease (aHR=1.33, CI=1.19-1.49), worse case severity (severe: aHR=3.86, CI=3.15-4.73; critical: aHR=11.34, CI=9.22-13.95), and near-epicenter region (Hubei: aHR=2.64, CI=2.11-3.30; Wuhan: aHR=6.35, CI=5.04-8.00). CFR increased from 0.35% (30-39 years) to 18.21% (≥70 years) without underlying disease. Regardless of age, CFR increased from 2.50% for no underlying disease to 7.72% for 1, 13.99% for 2, and 21.99% for ≥3. CFR increased with worse case severity from 2.80% (mild), to 12.51% (severe) and 48.60% (critical) regardless of region. Compared to other regions, CFR was much higher in Wuhan regardless of case severity (mild: 3.83% versus 0.14% in Hubei and 0.03% elsewhere; moderate: 4.60% versus 0.21% and 0.06%; severe: 15.92% versus 5.84% and 1.86%; and critical: 58.57% versus 49.80% and 18.39%).

Conclusions: Older patients regardless of underlying disease and patients with underlying disease regardless of age were at elevated risk of death. Higher death rates near the outbreak epicenter and during the surge of cases reflect the deleterious effects of allowing health systems to become overwhelmed.
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http://dx.doi.org/10.1093/cid/ciab493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244662PMC
May 2021

Emerging H5N8 avian influenza viruses.

Science 2021 05;372(6544):784-786

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

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http://dx.doi.org/10.1126/science.abg6302DOI Listing
May 2021

Etiological, epidemiological, and clinical features of acute diarrhea in China.

Nat Commun 2021 04 29;12(1):2464. Epub 2021 Apr 29.

The Institute for Disease Prevention and Control of PLA, Beijing, China.

National-based prospective surveillance of all-age patients with acute diarrhea was conducted in China between 2009‒2018. Here we report the etiological, epidemiological, and clinical features of the 152,792 eligible patients enrolled in this analysis. Rotavirus A and norovirus are the two leading viral pathogens detected in the patients, followed by adenovirus and astrovirus. Diarrheagenic Escherichia coli and nontyphoidal Salmonella are the two leading bacterial pathogens, followed by Shigella and Vibrio parahaemolyticus. Patients aged <5 years had higher overall positive rate of viral pathogens, while bacterial pathogens were more common in patients aged 18‒45 years. A joinpoint analysis revealed the age-specific positivity rate and how this varied for individual pathogens. Our findings fill crucial gaps of how the distributions of enteropathogens change across China in patients with diarrhea. This allows enhanced identification of the predominant diarrheal pathogen candidates for diagnosis in clinical practice and more targeted application of prevention and control measures.
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http://dx.doi.org/10.1038/s41467-021-22551-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085116PMC
April 2021

Serum sample neutralisation of BBIBP-CorV and ZF2001 vaccines to SARS-CoV-2 501Y.V2.

Lancet Microbe 2021 Jul 13;2(7):e285. Epub 2021 Apr 13.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

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http://dx.doi.org/10.1016/S2666-5247(21)00082-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043583PMC
July 2021

Avian influenza A (H7N9) virus: from low pathogenic to highly pathogenic.

Front Med 2021 Apr 16. Epub 2021 Apr 16.

Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, 518114, China.

The avian influenza A (H7N9) virus is a zoonotic virus that is closely associated with live poultry markets. It has caused infections in humans in China since 2013. Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017. H7N9 with low-pathogenicity dominated in the first four waves, whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave, causing wide concern. Specialists and officials from China and other countries responded quickly, controlled the epidemic well thus far, and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts. Here, we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease. It was summarized and discussed from the perspectives of molecular epidemiology, clinical features, virulence and pathogenesis, receptor binding, T-cell responses, monoclonal antibody development, vaccine development, and disease burden. These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses, such as SARS-CoV-2.
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http://dx.doi.org/10.1007/s11684-020-0814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190734PMC
April 2021

Publisher Correction: A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2.

Nat Commun 2021 Apr 15;12(1):2355. Epub 2021 Apr 15.

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

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http://dx.doi.org/10.1038/s41467-021-22820-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047579PMC
April 2021

Identification of NY-ESO-1 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy.

Front Immunol 2021 23;12:644520. Epub 2021 Mar 23.

Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target for T-cell receptor-engineered T cell (TCR-T) therapy, and targeting the human leukocyte antigen (HLA)-A2 restricted NY-ESO-1 epitope has yielded remarkable clinical benefits in the treatment of multiple advanced malignancies. Herein, we report the identification of two NY-ESO-1 epitope-specific murine TCRs obtained from HLA-A0201 transgenic mice. NY-ESO-1 specific TCRs were isolated after vaccinating HLA-A2 transgenic mice with epitope peptides. HZ6 and HZ8 TCRs could specifically bind to NY-ESO-1/HLA-A2 and were capable of cytokine secretion with engineered Jurkat T cells and primary T cells upon recognition with K562 target cells expressing the single-chain trimer (SCT) of NY-ESO-1/HLA-A2. The reactivity profiles of the HZ6 and HZ8 TCRs were found to be distinct from one another when co-cultured with K562 target cells carrying alanine-substituted NY-ESO-1 SCTs. The binding characterization revealed that the recognition pattern of the HZ6 TCR to NY-ESO-1/HLA-A2 was substantially different from the widely used 1G4 TCR. These findings would broaden the understanding of immunogenicity of the NY-ESO-1, and the two identified TCRs may serve as promising candidates for the future development of TCR-T therapy for tumors.
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http://dx.doi.org/10.3389/fimmu.2021.644520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021954PMC
March 2021

Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials.

Lancet Infect Dis 2021 Mar 24. Epub 2021 Mar 24.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Electronic address:

Background: Although several COVID-19 vaccines have been developed so far, they will not be sufficient to meet the global demand. Development of a wider range of vaccines, with different mechanisms of action, could help control the spread of SARS-CoV-2 globally. We developed a protein subunit vaccine against COVID-19 using a dimeric form of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as the antigen. We aimed to assess the safety and immunogenicity of this vaccine, ZF2001, and determine the appropriate dose and schedule for an efficacy study.

Methods: We did two randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials. Phase 1 was done at two university hospitals in Chongqing and Beijing, China, and phase 2 was done at the Hunan Provincial Center for Disease Control and Prevention in Xiangtan, China. Healthy adults aged 18-59 years, without a history of SARS-CoV or SARS-CoV-2 infection, an RT-PCR-positive test result for SARS-CoV-2, a history of contact with confirmed or suspected COVID-19 cases, and severe allergies to any component of the vaccine were eligible for enrolment. In phase 1, participants were randomly assigned (2:2:1) to receive three doses of the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart. In phase 2, participants were randomly assigned (1:1:1:1:1:1) to receive the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart, in either a two-dose schedule or a three-dose schedule. Investigators, participants, and the laboratory team were masked to group allocation. For phase 1, the primary outcome was safety, measured by the occurrence of adverse events and serious adverse events. For phase 2, the primary outcome was safety and immunogenicity (the seroconversion rate and the magnitude, in geometric mean titres [GMTs], of SARS-CoV-2-neutralising antibodies). Analyses were done on an intention-to-treat and per-protocol basis. These trials are registered with ClinicalTrials.gov (NCT04445194 and NCT04466085) and participant follow-up is ongoing.

Findings: Between June 22 and July 3, 2020, 50 participants were enrolled into the phase 1 trial and randomly assigned to receive three doses of placebo (n=10), the 25 μg vaccine (n=20), or the 50 μg vaccine (n=20). The mean age of participants was 32·6 (SD 9·4) years. Between July 12 and July 17, 2020, 900 participants were enrolled into the phase 2 trial and randomly assigned to receive two doses of placebo (n=150), 25 μg vaccine (n=150), or 50 μg vaccine (n=150), or three doses of placebo (n=150), 25 μg vaccine (n=150), or 50 μg vaccine (n=150). The mean age of participants was 43·5 (SD 9·2) years. In both phase 1 and phase 2, adverse events reported within 30 days after vaccination were mild or moderate (grade 1 or 2) in most cases (phase 1: six [60%] of ten participants in the placebo group, 14 [70%] of 20 in the 25 μg group, and 18 [90%] of 20 in the 50 μg group; phase 2: 37 [25%] of 150 in the two-dose placebo group, 43 [29%] of 150 in the two-dose 25 μg group, 50 [33%] of 150 in the two-dose 50 μg group, 47 [31%] of 150 in the three-dose placebo group, 72 [48%] of 150 in the three-dose 25 μg group, and 65 [43%] of 150 in the three-dose 50 μg group). In phase 1, two (10%) grade 3 or worse adverse events were reported in the 50 μg group. In phase 2, grade 3 or worse adverse events were reported by 18 participants (four [3%] in the two-dose 25 μg vaccine group, two [1%] in the two-dose 50 μg vaccine group, two [1%] in the three-dose placebo group, four [3%] in the three-dose 25 μg vaccine group, and six [4%] in the three-dose 50 μg vaccine group), and 11 were considered vaccine related (two [1%] in the two-dose 25 μg vaccine group, one [1%] in the two-dose 50 μg vaccine group, one [1%] in the three-dose placebo group, two [1%] in the three-dose 25 μg vaccine group, and five [3%] in the three-dose 50 μg vaccine group); seven participants reported serious adverse events (one [1%] in the two-dose 25 μg vaccine group, one [1%] in the two-dose 50 μg vaccine group, two [1%] in the three-dose placebo group, one [1%] in the three-dose 25 μg vaccine group, and two [1%] in the three-dose 50 μg vaccine group), but none was considered vaccine related. In phase 2, on the two-dose schedule, seroconversion rates of neutralising antibodies 14 days after the second dose were 76% (114 of 150 participants) in the 25 μg group and 72% (108 of 150) in the 50 μg group; on the three-dose schedule, seroconversion rates of neutralising antibodies 14 days after the third dose were 97% (143 of 148 participants) in the 25 μg group and 93% (138 of 148) in the 50 μg group. In the two-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the second dose were 17·7 (95% CI 13·6-23·1) in the 25 μg group and 14·1 (10·8-18·3) in the 50 μg group. In the three-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the third dose were 102·5 (95% CI 81·8-128·5) in the 25 μg group and 69·1 (53·0-90·0) in the 50 μg group.

Interpretation: The protein subunit vaccine ZF2001 appears to be well tolerated and immunogenic. The safety and immunogenicity data from the phase 1 and 2 trials support the use of the 25 μg dose in a three-dose schedule in an ongoing phase 3 trial for large-scale evaluation of ZF2001's safety and efficacy.

Funding: National 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.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1473-3099(21)00127-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990482PMC
March 2021

ADAM17 is an essential attachment factor for classical swine fever virus.

PLoS Pathog 2021 03 8;17(3):e1009393. Epub 2021 Mar 8.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Classical swine fever virus (CSFV) is an important pathogen in the swine industry. Virion attachment is mediated by envelope proteins Erns and E2, and E2 is indispensable. Using a pull-down assay with soluble E2 as the bait, we demonstrated that ADAM17, a disintegrin and metalloproteinase 17, is essential for CSFV entry. Loss of ADAM17 in a permissive cell line eliminated E2 binding and viral entry, but compensation with pig ADAM17 cDNA completely rescued these phenotypes. Similarly, ADAM17 silencing in primary porcine fibroblasts significantly impaired virus infection. In addition, human and mouse ADAM17, which is highly homologous to pig ADAM17, also mediated CSFV entry. The metalloproteinase domain of ADAM17 bound directly to E2 protein in a zinc-dependent manner. A surface exposed region within this domain was mapped and shown to be critical for CSFV entry. These findings clearly demonstrate that ADAM17 serves as an essential attachment factor for CSFV.
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http://dx.doi.org/10.1371/journal.ppat.1009393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971878PMC
March 2021

Spatiotemporal visualization for the global COVID-19 surveillance by balloon chart.

Infect Dis Poverty 2021 Mar 1;10(1):21. Epub 2021 Mar 1.

Center for Global Public Health, Chinese Center for Disease Control and Prevention, Changping District, Beijing, 102206, China.

Background: Considering the widespread of coronavirus disease 2019 (COVID-19) pandemic in the world, it is important to understand the spatiotemporal development of the pandemic. In this study, we aimed to visualize time-associated alterations of COVID-19 in the context of continents and countries.

Methods: Using COVID-19 case and death data from February to December 2020 offered by Johns Hopkins University, we generated time-associated balloon charts with multiple epidemiological indicators including crude case fatality rate (CFR), morbidity, mortality and the total number of cases, to compare the progression of the pandemic within a specific period across regions and countries, integrating seven related dimensions together. The area chart is used to supplement the display of the balloon chart in daily new COVID-19 case changes in UN geographic regions over time. Javascript and Vega-Lite were chosen for programming and mapping COVID-19 data in browsers for visualization.

Results: From February 1st to December 20th 2020, the COVID-19 pandemic spread across UN subregions in the chronological order. It was first reported in East Asia, and then became noticeable in Europe (South, West and North), North America, East Europe and West Asia, Central and South America, Southern Africa, Caribbean, South Asia, North Africa, Southeast Asia and Oceania, causing several waves of epidemics in different regions. Since October, the balloons of Europe, North America and West Asia have been rising rapidly, reaching a dramatically high morbidity level ranging from 200 to 500/10 000 by December, suggesting an emerging winter wave of COVID-19 which was much bigger than the previous ones. By late December 2020, some European and American countries displayed a leading mortality as high as or over 100/100 000, represented by Belgium, Czechia, Spain, France, Italy, UK, Hungary, Bulgaria, Peru, USA, Argentina, Brazil, Chile and Mexico. The mortality of Iran was the highest in Asia (over 60/100 000), and that of South Africa topped in Africa (40/100 000). In the last 15 days, the CFRs of most countries were at low levels of less than 5%, while Mexico had exceptional high CFR close to 10%.

Conclusions: We creatively used visualization integrating 7-dimensional epidemiologic and spatiotemporal indicators to assess the progression of COVID-19 pandemic in terms of transmissibility and severity. Such methodology allows public health workers and policy makers to understand the epidemics comparatively and flexibly.
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http://dx.doi.org/10.1186/s40249-021-00800-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919986PMC
March 2021

mRNA vaccines: A matter of delivery.

EClinicalMedicine 2021 Feb 3;32:100746. Epub 2021 Feb 3.

CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.

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http://dx.doi.org/10.1016/j.eclinm.2021.100746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889829PMC
February 2021

Susceptibility and Attenuated Transmissibility of SARS-CoV-2 in Domestic Cats.

J Infect Dis 2021 04;223(8):1313-1321

Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Domestic cats, an important companion animal, can be infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This has aroused concern regarding the ability of domestic cats to spread the virus that causes coronavirus disease 2019. We systematically demonstrated the pathogenesis and transmissibility of SARS-CoV-2 in cats. Serial passaging of the virus between cats dramatically attenuated the viral transmissibility, likely owing to variations of the amino acids in the receptor-binding domain sites of angiotensin-converting enzyme 2 between humans and cats. These findings provide insight into the transmissibility of SARS-CoV-2 in cats and information for protecting the health of humans and cats.
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http://dx.doi.org/10.1093/infdis/jiab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928776PMC
April 2021

Antibody seroprevalence in the epicenter Wuhan, Hubei, and six selected provinces after containment of the first epidemic wave of COVID-19 in China.

Lancet Reg Health West Pac 2021 Mar 5;8:100094. Epub 2021 Feb 5.

National Institute for Viral Disease Control and Prevention (China CDC), Beijing, China.

Background: China implemented containment measures to stop SARS-CoV-2 transmission in response to the COVID-19 epidemic. After the first epidemic wave, we conducted population-based serological surveys to determine extent of infection, risk factors for infection, and neutralization antibody levels to assess the real infections in the random sampled population.

Methods: We used a multistage, stratified cluster random sampling strategy to conduct serological surveys in three areas - Wuhan, Hubei Province outside Wuhan, and six provinces selected on COVID-19 incidence and containment strategy. Participants were consenting individuals >1 year old who resided in the survey area >14 days during the epidemic. Provinces screened sera for SARS-CoV-2-specific IgM, IgG, and total antibody by two lateral flow immunoassays and one magnetic chemiluminescence enzyme immunoassay; positive samples were verified by micro-neutralization assay.

Findings: We enrolled 34,857 participants (overall response rate, 92%); 427 were positive by micro-neutralization assay. Wuhan had the highest weighted seroprevalence (4•43%, 95% confidence interval [95%CI]=3•48%-5•62%), followed by Hubei-ex-Wuhan (0•44%, 95%CI=0•26%-0•76%), and the other provinces (<0•1%). Living in Wuhan (adjusted odds ratio aOR=13•70, 95%CI= 7•91-23•75), contact with COVID-19 patients (aOR=7•35, 95%CI=5•05-10•69), and age over 40 (aOR=1•36, 95%CI=1•07-1•72) were significantly associated with SARS-CoV-2 infection. Among seropositives, 101 (24%) reported symptoms and had higher geometric mean neutralizing antibody titers than among the 326 (76%) without symptoms (30±2•4 vs 15±2•1, <0•001).

Interpretation: The low overall extent of infection and steep gradient of seropositivity from Wuhan to the outer provinces provide evidence supporting the success of containment of the first wave of COVID-19 in China. SARS-CoV-2 infection was largely asymptomatic, emphasizing the importance of active case finding and physical distancing. Virtually the entire population of China remains susceptible to SARS-CoV-2; vaccination will be needed for long-term protection.

Funding: This study was supported by the Ministry of Science and Technology (2020YFC0846900) and the National Natural Science Foundation of China (82041026, 82041027, 82041028, 82041029, 82041030, 82041032, 82041033).
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http://dx.doi.org/10.1016/j.lanwpc.2021.100094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864613PMC
March 2021

A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2.

Nat Commun 2021 02 3;12(1):776. Epub 2021 Feb 3.

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

The rapid expansion of the COVID-19 pandemic has made the development of a SARS-CoV-2 vaccine a global health and economic priority. Taking advantage of versatility and rapid development, three SARS-CoV-2 mRNA vaccine candidates have entered clinical trials with a two-dose immunization regimen. However, the waning antibody response in convalescent patients after SARS-CoV-2 infection and the emergence of human re-infection have raised widespread concerns about a possible short duration of SARS-CoV-2 vaccine protection. Here, we developed a nucleoside-modified mRNA vaccine in lipid-encapsulated form that encoded the SARS-CoV-2 RBD, termed as mRNA-RBD. A single immunization of mRNA-RBD elicited both robust neutralizing antibody and cellular responses, and conferred a near-complete protection against wild SARS-CoV-2 infection in the lungs of hACE2 transgenic mice. Noticeably, the high levels of neutralizing antibodies in BALB/c mice induced by mRNA-RBD vaccination were maintained for at least 6.5 months and conferred a long-term notable protection for hACE2 transgenic mice against SARS-CoV-2 infection in a sera transfer study. These data demonstrated that a single dose of mRNA-RBD provided long-term protection against SARS-CoV-2 challenge.
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http://dx.doi.org/10.1038/s41467-021-21037-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858593PMC
February 2021

One Hundred Days of Coronavirus Disease 2019 Prevention and Control in China.

Clin Infect Dis 2021 01;72(2):332-339

Chinese Center for Disease Control and Prevention, Beijing, China.

The epidemic of novel coronavirus disease was first reported in China in late December 2019 and was brought under control after some 2 months in China. However, it has become a global pandemic, and the number of cases and deaths continues to increase outside of China. We describe the emergence of the pandemic, detail the first 100 days of China's response as a phase 1 containment strategy followed by phase 2 containment, and briefly highlight areas of focus for the future. Specific, simple, and pragmatic strategies used in China for risk assessment, prioritization, and deployment of resources are described. Details of implementation, at different risk levels, of the traditional public health interventions are shared. Involvement of society in mounting a whole country response and challenges experienced with logistics and supply chains are described. Finally, the methods China is employing to cautiously restart social life and economic activity are outlined.
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http://dx.doi.org/10.1093/cid/ciaa725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314211PMC
January 2021

Two immunogenic recombinant protein vaccine candidates showed disparate protective efficacy against Zika virus infection in rhesus macaques.

Vaccine 2021 02 13;39(6):915-925. Epub 2021 Jan 13.

Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. Electronic address:

Zika virus (ZIKV) infection has caused major public health problems recently. To develop subunit vaccines for ZIKV, we have previously constructed recombinant ZIKV envelope protein domain III (EDIII), and the entire ectodomain (E80, which comprises EDI, EDII and EDIII), as vaccine candidates and showed both of them being immunogenic and protective in murine models. In this follow-up study, we compared these vaccine candidates in non-human primates. Both of them elicited neutralizing antibody responses, but only E80 immunization inhibited ZIKV infection in both peripheral blood and monkey tissues, whereas EDIII increased blood ZIKV RNA through possibly antibody-dependent enhancement. Further investigations revealed that the virion-binding antibody response in E80 immunized monkeys persisted longer and stronger than in EDIII immunized monkeys. These results demonstrate that E80 is superior to EDIII as a vaccine candidate, and that the magnitude, quality and durability of virion-binding neutralizing antibodies are correlates of protection.
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http://dx.doi.org/10.1016/j.vaccine.2020.12.077DOI Listing
February 2021

Structural biology in the fight against COVID-19.

Nat Struct Mol Biol 2021 01;28(1):2-7

Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.

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http://dx.doi.org/10.1038/s41594-020-00544-8DOI Listing
January 2021
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