The coronavirus disease 2019 (COVID-19) pandemic continues worldwide with many variants arising, some of which are variants of concern (VOCs). A recent VOC, omicron (B.1.1.529), which obtains a large ...number of mutations in the receptor-binding domain (RBD) of the spike protein, has risen to intense scientific and public attention. Here, we studied the binding properties between the human receptor ACE2 (hACE2) and the VOC RBDs and resolved the crystal and cryoelectron microscopy structures of the omicron RBD-hACE2 complex as well as the crystal structure of the delta RBD-hACE2 complex. We found that, unlike alpha, beta, and gamma, omicron RBD binds to hACE2 at a similar affinity to that of the prototype RBD, which might be due to compensation of multiple mutations for both immune escape and transmissibility. The complex structures of omicron RBD-hACE2 and delta RBD-hACE2 reveal the structural basis of how RBD-specific mutations bind to hACE2.
Display omitted
•Omicron, delta, and prototype SARS-CoV-2 RBDs show similar binding strength to hACE2•The complexes of SARS-CoV-2-RBD with hACE2 for omicron and delta variants were resolved•The roles of key residues in the omicron RBD for receptor recognition were identified
Structural analysis of the complexes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RBD with the human ACE2 receptor for omicron and delta reveals variant-specific binding features.
The authors provide an epidemiologic analysis of the first 425 confirmed cases of infection with the novel coronavirus in Wuhan, China. This analysis provides estimates of the epidemic doubling time ...and the basic reproductive number and shows clear evidence of sustained human-to-human transmission.
Since the first cases of COVID-19 were documented in Wuhan, China in 2019, the world has witnessed a devastating global pandemic, with more than 238 million cases, nearly 5 million fatalities and the ...daily number of people infected increasing rapidly. Here we describe the currently available data on the emergence of the SARS-CoV-2 virus, the causative agent of COVID-19, outline the early viral spread in Wuhan and its transmission patterns in China and across the rest of the world, and highlight how genomic surveillance, together with other data such as those on human mobility, has helped to trace the spread and genetic variation of the virus and has also comprised a key element for the control of the pandemic. We pay particular attention to characterizing and describing the international spread of the major variants of concern of SARS-CoV-2 that were first identified in late 2020 and demonstrate that virus evolution has entered a new phase. More broadly, we highlight our currently limited understanding of coronavirus diversity in nature, the rapid spread of the virus and its variants in such an increasingly connected world, the reduced protection of vaccines, and the urgent need for coordinated global surveillance using genomic techniques. In summary, we provide important information for the prevention and control of both the ongoing COVID-19 pandemic and any new diseases that will inevitably emerge in the human population in future generations.
Nationwide nonpharmaceutical interventions (NPIs) have been effective at mitigating the spread of the novel coronavirus disease (COVID-19), but their broad impact on other diseases remains ...under-investigated. Here we report an ecological analysis comparing the incidence of 31 major notifiable infectious diseases in China in 2020 to the average level during 2014-2019, controlling for temporal phases defined by NPI intensity levels. Respiratory diseases and gastrointestinal or enteroviral diseases declined more than sexually transmitted or bloodborne diseases and vector-borne or zoonotic diseases. Early pandemic phases with more stringent NPIs were associated with greater reductions in disease incidence. Non-respiratory diseases, such as hand, foot and mouth disease, rebounded substantially towards the end of the year 2020 as the NPIs were relaxed. Statistical modeling analyses confirm that strong NPIs were associated with a broad mitigation effect on communicable diseases, but resurgence of non-respiratory diseases should be expected when the NPIs, especially restrictions of human movement and gathering, become less stringent.
ZF2001 contains a tandem-repeat dimeric receptor-binding domain of the SARS-CoV-2 spike protein with aluminum hydroxide adjuvant. In a phase 3 trial, 28,904 participants in five countries were ...randomly assigned to receive three doses of ZF2001 or placebo. After 6 months of follow-up, efficacy was 76% against infection, 87% against critical or severe disease, and 86% against death. Most side effects were local, low-grade, and transient.
Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an ...attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.
Display omitted
•A dimeric form of MERS-CoV RBD is highly immunogenic and protective in mice•RBD-dimer structure guides further design of a homogeneous dimer by tandem repeat•The strategy is generalizable to design beta-CoV vaccines against COVID-19 and SARS•CoV RBD-dimer immunogens can be produced at high yields in pilot scale production
Gao et al. present the structure-guided design of a coronavirus immunogen comprised of two protein subunits each containing the virus spike receptor binding domain fused together via a disulfide link or tandem repeat. The immunogen elicits strong immunogenicity in mice and protects them against viral challenge. The vaccine design strategy can be universally applied to SARS, MERS, COVID-19, and other CoV vaccines to counter emerging threats.
Summary Background Human infections with different avian influenza viruses—eg, H5N1, H9N2, and H7N9—have raised concerns about pandemic potential worldwide. We report the first human infection with a ...novel reassortant avian influenza A H10N8 virus. Methods We obtained and analysed clinical, epidemiological, and virological data from a patient from Nanchang City, China. Tracheal aspirate specimens were tested for influenza virus and other possible pathogens by RT-PCR, viral culture, and sequence analyses. A maximum likelihood phylogenetic tree was constructed. Findings A woman aged 73 years presented with fever and was admitted to hospital on Nov 30, 2013. She developed multiple organ failure and died 9 days after illness onset. A novel reassortant avian influenza A H10N8 virus was isolated from the tracheal aspirate specimen obtained from the patient 7 days after onset of illness. Sequence analyses revealed that all the genes of the virus were of avian origin, with six internal genes from avian influenza A H9N2 viruses. The aminoacid motif GlnSerGly at residues 226–228 of the haemagglutinin protein indicated avian-like receptor binding preference. A mixture of glutamic acid and lysine at residue 627 in PB2 protein—which is associated with mammalian adaptation—was detected in the original tracheal aspirate samples. The virus was sensitive to neuraminidase inhibitors. Sputum and blood cultures and deep sequencing analysis indicated no co-infection with bacteria or fungi. Epidemiological investigation established that the patient had visited a live poultry market 4 days before illness onset. Interpretation The novel reassortant H10N8 virus obtained is distinct from previously reported H10N8 viruses. The virus caused human infection and could have been associated with the death of a patient. Funding Emergency Research Project on human infection with avian influenza H7N9 virus, the National Basic Research Program of China, and the National Mega-projects for Infectious Diseases.
We have surveyed avian influenza virus (AIV) genomes from live poultry markets within China since 2014. Here we present a total of 16,091 samples that were collected from May 2016 to February 2019 in ...23 provinces and municipalities in China. We identify 2048 AIV-positive samples and perform next generation sequencing. AIV-positive rates (12.73%) from samples had decreased substantially since 2016, compared to that during 2014-2016 (26.90%). Additionally, H9N2 has replaced H5N6 and H7N9 as the dominant AIV subtype in both chickens and ducks. Notably, novel reassortants and variants continually emerged and disseminated in avian populations, including H7N3, H9N9, H9N6 and H5N6 variants. Importantly, almost all of the H9 AIVs and many H7N9 and H6N2 strains prefer human-type receptors, posing an increased risk for human infections. In summary, our nation-wide surveillance highlights substantial changes in the circulation of AIVs since 2016, which greatly impacts the prevention and control of AIVs in China and worldwide.
The emergence of a novel avian-origin influenza A virus strain (H7N9) causing severe human disease in China has raised serious concerns. In this report, key clinical and virologic features of this ...outbreak are presented.
Sporadic human infections with avian influenza A viruses, which usually occur after recent exposure to poultry, have caused a wide spectrum of illness, ranging from conjunctivitis and upper respiratory tract disease to pneumonia and multiorgan failure. Low pathogenic avian influenza A (H7N2, H7N3, H9N2, or H10N7)
1
–
4
virus infections have caused lower respiratory tract illness that is mild (conjunctivitis or uncomplicated influenza-like illness) to moderate in severity. Most human infections with highly pathogenic avian influenza (HPAI) A (H7) viruses have resulted in conjunctivitis (H7N3) or uncomplicated influenza illness, but one case of fatal acute respiratory distress syndrome (ARDS) was reported . . .
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.
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.
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.
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.
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.
For the Chinese translation of the abstract see Supplementary Materials section.
PDF
