The prevalence of SARS-CoV-2 variants of concern(VOCs) is still escalating throughout the world. However, the level of neutralization of the inactivated viral vaccine recipients’ sera and convalescent sera against al...The prevalence of SARS-CoV-2 variants of concern(VOCs) is still escalating throughout the world. However, the level of neutralization of the inactivated viral vaccine recipients’ sera and convalescent sera against all VOCs,including B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta), and B.1.1.529(Omicron) remains to be lack of comparative analysis. Therefore, we constructed pseudoviruses of five VOCs using a lentiviral-based system and analyzed their viral infectivity and neutralization resistance to convalescent and BBIBP-CorV vaccinee serum at different times. Our results show that, compared with the wild-type strain(WT), five VOC pseudoviruses showed higher infection, of which B.1.617.2 and B.1.1.529 variant pseudoviruses exhibited higher infection rates than wild-type or other VOC strains, respectively. Sera from 10 vaccinated individuals at the 1, 3and 5-month post second dose or from 10 convalescent at 14 and 200 days after discharge retained neutralizing activity against all strains but exhibited decreased neutralization activity significantly against the five VOC variant pseudoviruses over time compared to WT. Notably, 100%(30/30) of the vaccinee serum samples showed more than a 2.5-fold reduction in neutralizing activity against B.1.1.529, and 90%(18/20) of the convalescent serum samples showed more than 2.5-fold reduction in neutralization against B.1.1.529. These findings demonstrate the reduced protection against the VOCs in vaccinated and convalescent individuals over time, indicating that it is necessary to have a booster shot and develop new vaccines capable of eliciting broad neutralization antibodies.展开更多
The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral elements.Targeting host dependency factors,e.g.cellular proteins requi...The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral elements.Targeting host dependency factors,e.g.cellular proteins required for viral replication,would help prevent the development of resistance.However,it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors.To this end,we compared three variants of concern and found that the host transcriptional response was conserved,differing only in kinetics and magnitude.Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection.Most of the genes were shared by multiple variants.We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs.All the drugs were highly active against all the tested variants,including new variants that emerged during the study(Delta and Omicron).Mechanistically,we identified reactive oxygen species production as a key step in early viral replication.Antioxidants such as N-acetyl cysteine(NAC)were effective against all the variants in both human lung cells and a humanized mouse model.Our study supports the use of available antioxidant drugs,such as NAC,as a general and effective anti-COVID-19 approach.展开更多
The COVID-19 pandemic has seen multiple waves,in part due to the implementation and relaxation of social distancing measures by the public health authorities around the world,and also caused by the emergence of new va...The COVID-19 pandemic has seen multiple waves,in part due to the implementation and relaxation of social distancing measures by the public health authorities around the world,and also caused by the emergence of new variants of concern(VOCs)of the SARS-Cov-2 virus.As the COVID-19 pandemic is expected to transition into an endemic state,how to manage outbreaks caused by newly emerging VOCs has become one of the primary public health issues.Using mathematical modeling tools,we investigated the dynamics of VOCs,both in a general theoretical framework and based on observations from public health data of past COVID-19 waves,with the objective of understanding key factors that determine the dominance and coexistence of VOCs.Our results show that the transmissibility advantage of a new VOC is a main factor for it to become dominant.Additionally,our modeling study indicates that the initial number of people infected with the new VOC plays an important role in determining the size of the epidemic.Our results also support the evidence that public health measures targeting the newly emerging VOC taken in the early phase of its spread can limit the size of the epidemic caused by the new VOC(Wu et al.,2139Wu,Scarabel,Majeed,Bragazzi,&Orbinski,Wu et al.,2021).展开更多
The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broadspectrum protection against the initial infection and thereby curb the transmission potential.Her...The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broadspectrum protection against the initial infection and thereby curb the transmission potential.Here,we designed a chimeric tripleRBD immunogen,3Ro-NC,harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold.3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern.Notably,intranasal immunization with 3RoNC plus the mucosal adjuvant KFD(3Ro-NC+KFDi.n)elicits coordinated mucosal IgA and higher neutralizing antibody specificity(closer antigenic distance)against the Omicron variant.In Omicron-challenged human ACE2 transgenic mice,3Ro-NC+KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung(85.7-fold)and the nasal turbinate(13.6-fold).Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies.Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection,pathology and transmission potential.展开更多
The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally,from B.1.17(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta) to B.1.1.529(Omicron). The emerging or r...The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally,from B.1.17(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta) to B.1.1.529(Omicron). The emerging or reemerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics,pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 cells. We utilized both animal models of human ACE2(hACE2)transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated.展开更多
SARS-CoV-2 variants are constantly emerging,hampering public health measures in controlling the number of infections.While it is well established that mutations in spike proteins observed for the different variants di...SARS-CoV-2 variants are constantly emerging,hampering public health measures in controlling the number of infections.While it is well established that mutations in spike proteins observed for the different variants directly affect virus entry into host cells,there remains a need for further expansion of systematic and multifaceted comparisons.Here,we comprehensively studied the effect of spike protein mutations on spike expression and proteolytic activation,binding affinity,viral entry efficiency and host cell tropism of eight variants of concern(VOC)and variants of interest(VOI).We found that both the full-length spike and its receptor-binding domain(RBD)of Omicron bind to hACE2 with an affinity similar to that of the wild-type.In addition,Alpha,Beta,Delta and Lambda pseudoviruses gained significantly enhanced cell entry ability compared to the wild-type,while the Omicron pseudoviruses showed a slightly increased cell entry,suggesting the vastly increased rate of transmission observed for Omicron variant is not associated with its affinity to hACE2.We also found that the spikes of Omicron and Mu showed lower S1/S2 cleavage efficiency and inefficiently utilized TMPRSS2 to enter host cells than others,suggesting that they prefer the endocytosis pathway to enter host cells.Furthermore,all variants'pseudoviruses we tested gained the ability to enter the animal ACE2-expressing cells.Especially the infection potential of rats and mice showed significantly increased,strongly suggesting that rodents possibly become a reservoir for viral evolution.The insights gained from this study provide valuable guidance for a targeted approach to epidemic control,and contribute to a better understanding of SARS-CoV-2 evolution.展开更多
Several variants of concern(VOCs)have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first isolated in January 2020.Due to mutations in the spike(S)protein,these VOCs ...Several variants of concern(VOCs)have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first isolated in January 2020.Due to mutations in the spike(S)protein,these VOCs have evolved to enhance viral infectivity and immune evasion.However,whether mutations of the other viral proteins lead to altered viral propagation and drug resistance remains obscure.The replicon is a noninfectious viral surrogate capable of recapitulating certain steps of the viral life cycle.Although several SARS-CoV-2 replicons have been developed,none of them were derived from emerging VOCs and could only recapitulate viral genome replication and subgenomic RNA(sgRNA)transcription.In this study,SARS-CoV-2 replicons derived from the WIV04 strain and two VOCs(the Beta and Delta variants)were prepared by removing the S gene from their genomes,while other structural genes remained untouched.These replicons not only recapitulate viral genome replication and sgRNA transcription but also support the assembly and release of viral-like particles,as manifested by electron microscopic assays.Thus,the S-deletion replicon could recapitulate virtually all the post-entry steps of the viral life cycle and provides a versatile tool for measuring viral intracellular propagation and screening novel antiviral drugs,including inhibitors of virion assembly and release.Through the quantification of replicon RNA released into the supernatant,we demonstrate that viral intracellular propagation and drug response to remdesivir have not yet substantially changed during the evolution of SARS-CoV-2 from the WIV04 strain to the Beta and Delta VOCs.展开更多
The appearance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has caused panic responses around the world because of its high transmission rate and number of mutations.This rev...The appearance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has caused panic responses around the world because of its high transmission rate and number of mutations.This review summarizes the highly mutated regions,the essential infectivity,transmission,vaccine breakthrough and antibody resistance of the Omicron variant of SARSCoV-2.The Omicron is highly transmissible and is spreading faster than any previous variant,but may cause less severe symptoms than previous variants.The Omicron is able to escape the immune system’s defenses and coronavirus disease 2019 vaccines are less effective against the Omicron variant.Early careful preventive steps including vaccination will always be key for the suppression of the Omicron variant.展开更多
Omicron,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant that is now spreading across the world,is the most altered version to emerge so far,with mutations comparable to changes reported in earli...Omicron,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant that is now spreading across the world,is the most altered version to emerge so far,with mutations comparable to changes reported in earlier variants of concern linked with increased transmissibility and partial resistance to vaccineinduced immunity.This article provides an overview of the SARS-CoV-2 variant Omicron(B.1.1.529)by reviewing the literature from major scientific databases.Although clear immunological and clinical data are not yet available,we extrapolated from what is known about mutations present in the Omicron variant of SARS-CoV-2 and offer preliminary indications on transmissibility,severity,and immune escape through existing research and databases.展开更多
The severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)belongs to the genus Beta coronavirus and the family of Coronaviridae.It is a positive-sense,non-segmented single-strand RNA virus.Four common types of hu...The severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)belongs to the genus Beta coronavirus and the family of Coronaviridae.It is a positive-sense,non-segmented single-strand RNA virus.Four common types of human coronaviruses circulate globally,particularly in the fall and winter seasons.They are responsible for 10%-30% of all mild upper respiratory tract infections in adults.These are 229E,NL63 of the Alfacoronaviridae family,OC43,and HKU1 of the Betacoronaviridae family.However,there are three highly pathogenic human coronaviruses:SARS-CoV-2,Middle East respiratory syndrome coronavirus,and the latest pandemic caused by the SARS-CoV-2 infection.All viruses,including SARS-CoV-2,have the inherent tendency to evolve.SARS-CoV-2 is still evolving in humans.Additionally,due to the development of herd immunity,prior infection,use of medication,vaccination,and antibodies,the viruses are facing immune pressure.During the replication process and due to immune pressure,the virus may undergo mutations.Several SARS-CoV-2 variants,including the variants of concern(VOCs),such as B.1.1.7(Alpha),B.1.351(Beta),B.1.617/B.1.617.2(Delta),P.1(Gamma),and B.1.1.529(Omicron)have been reported from various parts of the world.These VOCs contain several important mutations;some of them are on the spike proteins.These mutations may lead to enhanced infectivity,transmissibility,and decreased neutralization efficacy by monoclonal antibodies,convalescent sera,or vaccines.Mutations may also lead to a failure of detection by molecular diagnostic tests,leading to a delayed diagnosis,increased community spread,and delayed treatment.We searched PubMed,EMBASE,Covariant,the Stanford variant Database,and the CINAHL from December 2019 to February 2023 using the following search terms:VOC,SARS-CoV-2,Omicron,mutations in SARS-CoV-2,etc.This review discusses the various mutations and their impact on infectivity,transmissibility,and neutralization efficacy.展开更多
Background:With the ongoing worldwide coronavirus disease 2019(COVID-19)pandemic,an increasing number of viral variants are being identified,which poses a challenge for nucleic acid-based diagnostic tests.Rapid tests,...Background:With the ongoing worldwide coronavirus disease 2019(COVID-19)pandemic,an increasing number of viral variants are being identified,which poses a challenge for nucleic acid-based diagnostic tests.Rapid tests,such as real-time reverse transcription-polymerase chain reaction(rRT-PCR),play an important role in monitoring COVID-19 infection and controlling its spread.However,the changes in the genotypes of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants may result in decreased sensitivity of the rRT-PCR assay and it is necessary to monitor the mutations in primers and probes of SARSCoV-2 detection over time.Methods:We developed two rRT-PCR assays to detect the RNA-dependent RNA polymerase(RdRp)and nucleocapsid(N)genes of SARS-CoV-2.We evaluated these assays together with our previously published assays targeting the ORF1ab and N genes for the detection and confirmation of SARS-CoV-2 and its variants of concern(VOCs).In addition,we also developed two rRT-PCR assays(S484K and S501Y)targeting the spike gene,which when combined with the open reading frames(ORF)1ab assay,respectively,to form duplex rRT-PCR assays,were able to detect SARS-CoV-2 VOCs(lineages B.1.351 and B.1.1.7).Results:Using a SARS-CoV-2 stock with predetermined genomic copies as a standard,the detection limit of both assays targeting RdRp and N was five copies/reaction.Furthermore,no cross-reactions with six others human CoVs(229E,OC43,NL63,HKU1,severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus)were observed using these assays.In addition,the S484K and S501Y assays were combined with the ORF1ab assay,respectively.Conclusions:Four rRT-PCR assays(RdRp,N,S484K,and S501Y)were used to detect SARS-CoV-2 variants,and these assays were shown to be effective in screening for multiple virus strains.展开更多
Since severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)was first identified during late 2019,the sustained spread of this pathogen within the human population has caused worldwide disruption with staggerin...Since severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)was first identified during late 2019,the sustained spread of this pathogen within the human population has caused worldwide disruption with staggering infection rates and death tolls.Due to the accumulation of mutations in SARS‐CoV‐2,the virus has evolved into many variants,five of which have been listed as variants of concern VOCs by the World Health Organization(WHO).Multiple animal models of SARS‐CoV‐2 have been developed to evaluate vaccines and drugs and to assess the pathogenicity,transmissibility and antiviral measures of these VOCs.Here,we review the cutting‐edge research based on mouse,hamster,ferret and non‐human primate models for evaluating SARS‐CoV‐2 with a focus on the Omicron variant,and highlight the importance of updating vaccines in a timely manner in order to mitigate the negative effects of SARS‐CoV‐2 infections in the human population.展开更多
Wastewater surveillance plays an important role in the monitoring of infections of SARS-CoV-2 at the community level.We report here the determination of SARS-CoV-2 and differentiation of its variants of concern in 294...Wastewater surveillance plays an important role in the monitoring of infections of SARS-CoV-2 at the community level.We report here the determination of SARS-CoV-2 and differentiation of its variants of concern in 294 wastewater samples collected from two major Canadian cities from May 2021 to March 2023.The overall method of analysis involved extraction of the virus and viral components using electronegative membranes,in situ stabilization and concentration of the viral RNA onto magnetic beads,and direct analysis of the viral RNA on the magnetic beads.Multiplex reverse transcription quantitative polymerase chain reaction(RT-qPCR)assays,targeting specific and naturally selected mutations in SARS-CoV-2,enabled detection and differentiation of the Alpha,Beta,Gamma,Delta,and Omicron variants.An Omicron triplex RT-qPCR assay targeting three mutations,HV 69−70 deletion,K417N,and L452R,was able to detect and differentiate the Omicron BA.1/BA.3,BA.2/XBB,and BA.4/5.This assay had efficiencies of 90−104%for all three mutation targets and a limit of detection of 28 RNA copies per reaction.Analyses of 294 wastewater samples collected over a two-year span showed the concentrations and trends of Alpha,Beta,Gamma,Delta,and Omicron variants as they emerge in two major Canadian cities participating in the wastewater surveillance program.The trends of specific variants were consistent with clinical reports for the same period.At the beginning of each wave,the corresponding variants were detectable in wastewater.For example,RNA concentrations of the BA.2 variant were as high as 10^(4)copies per 100 mL of wastewater collected in January 2022,when approximately only 50−60 clinical cases of BA.2 infection were reported in Canada.These results show that the strategy and highly sensitive assays for the variants of concern in wastewater are potentially useful for the detection of newly emerging SARS-CoV-2 variants and other viruses for future community biomonitoring.展开更多
Although studies have compared the relative severity of Omicron and Delta variants by assessing the relative risks,there are still gaps in the knowledge of the potential COVID-19 burden these variations may cause.And ...Although studies have compared the relative severity of Omicron and Delta variants by assessing the relative risks,there are still gaps in the knowledge of the potential COVID-19 burden these variations may cause.And the contact patterns in Fujian Province,China,have not been described.We identified 8969 transmission pairs in Fujian,China,by analyzing a contact-tracing database that recorded a SARS-CoV-2 outbreak in September 2021.We estimated the waning vaccine effectiveness against Delta variant infection,contact patterns,and epidemiology distributions,then simulated potential outbreaks of Delta and Omicron variants using a multi-group mathematical model.For instance,in the contact setting without stringent lockdowns,we estimated that in a potential Omicron wave,only 4.7%of infections would occur in Fujian Province among individuals aged>60 years.In comparison,58.75%of the death toll would occur in unvaccinated individuals aged>60 years.Compared with no strict lockdowns,combining school or factory closure alone reduced cumulative deaths of Delta and Omicron by 28.5%and 6.1%,respectively.In conclusion,this study validates the need for continuous mass immunization,especially among elderly aged over 60 years old.And it confirms that the effect of lockdowns alone in reducing infections or deaths is minimal.However,these measurements will still contribute to lowering peak daily incidence and delaying the epidemic,easing the healthcare system's burden.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and ...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.展开更多
Inactivated coronavirus disease 2019(COVID-19)vaccines such as CoronaVac and BBIBP-CorV have been widely used in China.However,more investigation is still needed to understand antibodies'duration and effectiveness...Inactivated coronavirus disease 2019(COVID-19)vaccines such as CoronaVac and BBIBP-CorV have been widely used in China.However,more investigation is still needed to understand antibodies'duration and effectiveness against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants in the real world.In this study,575 participants who had been vaccinated with two or three doses of the inactivated vaccine were recruited.Serum samples were collected and tested for anti-spike IgG and neutralizing antibodies against SARS-CoV-2(original strain,Dela,and Omicron).Unsurprisingly,a third dose of the vaccine significantly enhanced antibody responses against SARS-CoV-2 and its variants.However,despite a booster dose,the neutralizing antibody levels against Omicron,particularly the BA.5.2 subvariant,remained low.There was no sex bias,but an age bias was observed.Notably,the predominant IgG subclass antibodies were IgG1 and IgG2,with a much lower level of IgG4.After the booster shot,the ratio of IgG4 to IgG1 significantly increased.The observation of IgG1 to the IgG4 class switch after repeated inactivated vaccinations underscores the importance of continuous monitoring of subclass antibody responses.Further clinical investigations are required to understand the implications of this class switch for optimizing immunization strategies.展开更多
Mutations in SARS-CoV-2 variants of concern(VOCs)have enhanced transmissibility and immune evasion with respect to current vaccines and neutralizing antibodies(NAbs).How naturally occurring spike mutations affect the ...Mutations in SARS-CoV-2 variants of concern(VOCs)have enhanced transmissibility and immune evasion with respect to current vaccines and neutralizing antibodies(NAbs).How naturally occurring spike mutations affect the infectivity and antigenicity of VOCs remains to be investigated.The entry efficiency of individual spike mutations was determined in vitro using pseudotyped viruses.BALB/c mice were immunized with 2-dose DNA vaccines encoding B.1.1.7,B.1.351,B.1.1.529 and their single mutations.Cellular and humoral immune responses were then compared to determine the impact of individual mutations on immunogenicity.In the B.1.1.7 lineage,Del69–70 and Del 144 in NTD,A570D and P681H in SD1 and S982A and D1118H in S2 significantly increased viral entry,whereas T716I resulted in a decrease.In the B.1.351 lineage,L18F and Del 242–244 in the NTD,K417N in the RBD and A701V in S2 also increased viral entry.S982A weakened the generation of binding antibodies.All sera showed reduced cross-neutralization activity against B.1.351,B.1.617.2(Delta)and B.1.1.529(Omicron BA.1).S982A,L18F,and Del 242–244 hindered the induction of cross-NAbs,whereas Del 69–70,Del144,R246I,and K417N showed the opposite effects.B.1.351 elicited adequate broad cross-NAbs against both B.1.351 and B.1.617.2.All immunogens tested,however,showed low neutralization against circulating B.1.1.529.In addition,T-cell responses were unlikely affected by mutations tested in the spike.We conclude that individual spike mutations influence viral infectivity and vaccine immunogenicity.Designing VOC-targeted vaccines is likely necessary to overcome immune evasion from current vaccines and neutralizing antibodies.展开更多
The pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has led to major public health challenges globally.The increasing viral lineages identified indicate that t...The pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has led to major public health challenges globally.The increasing viral lineages identified indicate that the SARS-CoV-2 genome is evolving at a rapid rate.Viral genomic mutations may cause antigenic drift or shift,which are important ways by which SARS-CoV-2 escapes the human immune system and changes its transmissibility and virulence.Herein,we summarize the functional mutations in SARS-CoV-2 genomes to characterize its adaptive evolution to inform the development of vaccination,treatment as well as control and intervention measures.展开更多
The recent coronavirus disease 2019(COVID-19)outbreak has highlighted the inadequacy of our ability to respond to newly emerging viruses.Antiviral medications are the most effective means of combating the pandemic,yet...The recent coronavirus disease 2019(COVID-19)outbreak has highlighted the inadequacy of our ability to respond to newly emerging viruses.Antiviral medications are the most effective means of combating the pandemic,yet their diminishing efficacy and a large population of unvaccinated individuals will create a fertile environment for the virus’s propagation and the emergence of novel variants,posing an ongoing risk of infection for vulnerable populations with compromised immune systems.To treat those infected,effective treatments must be developed.In this review,we discuss a breakthrough in engineered antibody fragments that could provide a protective barrier against the onslaught of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants as well as future other viral infections.展开更多
SARS-CoV-2 has caused global waves of infection since December 2019 and continues to persist today.The emergence of SARS-CoV-2 variants with strong immune evasion capabilities has compromised the effectiveness of exis...SARS-CoV-2 has caused global waves of infection since December 2019 and continues to persist today.The emergence of SARS-CoV-2 variants with strong immune evasion capabilities has compromised the effectiveness of existing vaccines against breakthrough infections.Therefore,it is important to determine the best utilization strategies for different demographic groups given the variety of vaccine options available.In this review,we will discuss the protective efficacy of vaccines during different stages of the epidemic and emphasize the importance of timely updates to target prevalent variants,which can significantly improve immune protection.While it is recognized that vaccine effectiveness may be lower in certain populations such as the elderly,individuals with chronic comorbidities(e.g.,diabetes with poor blood glucose control,those on maintenance dialysis),or those who are immunocompromised compared to the general population,administering multiple doses can result in a strong protective immune response that outweighs potential risks.However,caution should be exercised when considering vaccines that might trigger an intense immune response in populations prone to inflammatory flare or other complications.In conclusion,individuals with special conditions require enhanced and more effective immunization strategies to prevent infection or reinfection,as well as to avoid the potential development of long COVID.展开更多
基金supported by the National Natural Science Foundation of China (82041001, 81761128020)
文摘The prevalence of SARS-CoV-2 variants of concern(VOCs) is still escalating throughout the world. However, the level of neutralization of the inactivated viral vaccine recipients’ sera and convalescent sera against all VOCs,including B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta), and B.1.1.529(Omicron) remains to be lack of comparative analysis. Therefore, we constructed pseudoviruses of five VOCs using a lentiviral-based system and analyzed their viral infectivity and neutralization resistance to convalescent and BBIBP-CorV vaccinee serum at different times. Our results show that, compared with the wild-type strain(WT), five VOC pseudoviruses showed higher infection, of which B.1.617.2 and B.1.1.529 variant pseudoviruses exhibited higher infection rates than wild-type or other VOC strains, respectively. Sera from 10 vaccinated individuals at the 1, 3and 5-month post second dose or from 10 convalescent at 14 and 200 days after discharge retained neutralizing activity against all strains but exhibited decreased neutralization activity significantly against the five VOC variant pseudoviruses over time compared to WT. Notably, 100%(30/30) of the vaccinee serum samples showed more than a 2.5-fold reduction in neutralizing activity against B.1.1.529, and 90%(18/20) of the convalescent serum samples showed more than 2.5-fold reduction in neutralization against B.1.1.529. These findings demonstrate the reduced protection against the VOCs in vaccinated and convalescent individuals over time, indicating that it is necessary to have a booster shot and develop new vaccines capable of eliciting broad neutralization antibodies.
基金supported by the CaRiPaRo Foundation(NewTarCoV2)the Ministry of Education,University and Research(PRIN-2020KSY3KL)+13 种基金supported by the Telethon Foundation Core Grant,European Research Council(ERC)(CellKarma)Regione Campania(PO-FESR 2014-2020,PO-FESR 2014-2020)Italian Ministry of Health(Piano Operativo Salute Traiettoria 3,‘Genomed’).supported by the Giovanni Armenise-Harvard Foundation,the Telethon Foundation(TCP13013)ERC(ERC Starting Grant,‘MetEpiStem’)supported by ERC(ERC Consolidator 615879)the Bill and Melinda Gates Foundation(OPP1035881 and OPP1097238)the Italian Foundation for Cancer Research(AIRC 21850)the Collaborative Center for XDP at Massachusetts General Hospital(239295)supported by the Italian Foundation for Cancer Research(AIRC-MFAG 25745)University of Padua(STARS Consolidator Grant,‘EMERALD’)supported by the Italian Foundation for Cancer Research(AIRC 2135)Italian Ministry of Health(RCR-201923669115,NET-201602361632)supported by the EVA-GLOBAL project that has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement number 871029EVA-GLOBAL provided access to SARS-CoV-2 Alpha and Delta isolates(human nCoV19 isolate/England/MIG457/2020 and hCoV-19/Netherlands/NH-RIVM-27142/2021_P2).
文摘The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral elements.Targeting host dependency factors,e.g.cellular proteins required for viral replication,would help prevent the development of resistance.However,it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors.To this end,we compared three variants of concern and found that the host transcriptional response was conserved,differing only in kinetics and magnitude.Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection.Most of the genes were shared by multiple variants.We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs.All the drugs were highly active against all the tested variants,including new variants that emerged during the study(Delta and Omicron).Mechanistically,we identified reactive oxygen species production as a key step in early viral replication.Antioxidants such as N-acetyl cysteine(NAC)were effective against all the variants in both human lung cells and a humanized mouse model.Our study supports the use of available antioxidant drugs,such as NAC,as a general and effective anti-COVID-19 approach.
基金funded in part by NSERC Alliance COVID-19 grant(ALLRP 555037-20)NSERC Discovery grant(RGPIN-2020-04134 Li)the CIHR funded Mathematical Modelling of COVID-19 Task Force,and the NSERC-PHAC EIDM Network“Mathematics for Public Health(MfPH)”.
文摘The COVID-19 pandemic has seen multiple waves,in part due to the implementation and relaxation of social distancing measures by the public health authorities around the world,and also caused by the emergence of new variants of concern(VOCs)of the SARS-Cov-2 virus.As the COVID-19 pandemic is expected to transition into an endemic state,how to manage outbreaks caused by newly emerging VOCs has become one of the primary public health issues.Using mathematical modeling tools,we investigated the dynamics of VOCs,both in a general theoretical framework and based on observations from public health data of past COVID-19 waves,with the objective of understanding key factors that determine the dominance and coexistence of VOCs.Our results show that the transmissibility advantage of a new VOC is a main factor for it to become dominant.Additionally,our modeling study indicates that the initial number of people infected with the new VOC plays an important role in determining the size of the epidemic.Our results also support the evidence that public health measures targeting the newly emerging VOC taken in the early phase of its spread can limit the size of the epidemic caused by the new VOC(Wu et al.,2139Wu,Scarabel,Majeed,Bragazzi,&Orbinski,Wu et al.,2021).
基金This work was supported in whole or in part by the National Key R&D Program of China(grant number:2021YFC2302602 to JY)the strategic priority research program(grant number XDB29010101)+1 种基金key project(2020YJFK-Z-0149)of the Chinese Academy of Sciences(to Z-LS)This study was also supported by the National Natural Science Foundation of China(31970878 to JY,92169104 and 31970881 to Y-QC),Shenzhen Science and Technology Program (Grant number: RCJC20210706092009004 and JCYJ20190807154603596 to Y-QC).
文摘The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broadspectrum protection against the initial infection and thereby curb the transmission potential.Here,we designed a chimeric tripleRBD immunogen,3Ro-NC,harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold.3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern.Notably,intranasal immunization with 3RoNC plus the mucosal adjuvant KFD(3Ro-NC+KFDi.n)elicits coordinated mucosal IgA and higher neutralizing antibody specificity(closer antigenic distance)against the Omicron variant.In Omicron-challenged human ACE2 transgenic mice,3Ro-NC+KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung(85.7-fold)and the nasal turbinate(13.6-fold).Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies.Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection,pathology and transmission potential.
基金supported by the Major Science and Technique Programs in Yunnan Province(grant No.202102AA310055)the Bureau of Frontier Sciences and Education,CAS(grant no.QYZDJ-SSW-SMC005 to Y.G.Y.)+2 种基金the Key project of the CAS“Light of West China”Program(to D.Y.)Yunnan Province(202001AS070023 to D.Y.)Yunnan Fundamental Research Projects(grant No.202201AW070020 to J.Z.)
文摘The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally,from B.1.17(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta) to B.1.1.529(Omicron). The emerging or reemerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics,pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 cells. We utilized both animal models of human ACE2(hACE2)transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No.XDB29050100)the National Key Research and Development Program of China (Grant No.2022YFC0869900,2022YFC2303501,2020YFC0861100)the Program of the Chinese Academy of Sciences (Grant No.2020YJFK-Z-0150).
文摘SARS-CoV-2 variants are constantly emerging,hampering public health measures in controlling the number of infections.While it is well established that mutations in spike proteins observed for the different variants directly affect virus entry into host cells,there remains a need for further expansion of systematic and multifaceted comparisons.Here,we comprehensively studied the effect of spike protein mutations on spike expression and proteolytic activation,binding affinity,viral entry efficiency and host cell tropism of eight variants of concern(VOC)and variants of interest(VOI).We found that both the full-length spike and its receptor-binding domain(RBD)of Omicron bind to hACE2 with an affinity similar to that of the wild-type.In addition,Alpha,Beta,Delta and Lambda pseudoviruses gained significantly enhanced cell entry ability compared to the wild-type,while the Omicron pseudoviruses showed a slightly increased cell entry,suggesting the vastly increased rate of transmission observed for Omicron variant is not associated with its affinity to hACE2.We also found that the spikes of Omicron and Mu showed lower S1/S2 cleavage efficiency and inefficiently utilized TMPRSS2 to enter host cells than others,suggesting that they prefer the endocytosis pathway to enter host cells.Furthermore,all variants'pseudoviruses we tested gained the ability to enter the animal ACE2-expressing cells.Especially the infection potential of rats and mice showed significantly increased,strongly suggesting that rodents possibly become a reservoir for viral evolution.The insights gained from this study provide valuable guidance for a targeted approach to epidemic control,and contribute to a better understanding of SARS-CoV-2 evolution.
基金supported by grants from the National Key Research and Development Project of China (2020YFC0845900)the China Postdoctoral Science Foundation (2020T130021ZX,2021M693198)
文摘Several variants of concern(VOCs)have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first isolated in January 2020.Due to mutations in the spike(S)protein,these VOCs have evolved to enhance viral infectivity and immune evasion.However,whether mutations of the other viral proteins lead to altered viral propagation and drug resistance remains obscure.The replicon is a noninfectious viral surrogate capable of recapitulating certain steps of the viral life cycle.Although several SARS-CoV-2 replicons have been developed,none of them were derived from emerging VOCs and could only recapitulate viral genome replication and subgenomic RNA(sgRNA)transcription.In this study,SARS-CoV-2 replicons derived from the WIV04 strain and two VOCs(the Beta and Delta variants)were prepared by removing the S gene from their genomes,while other structural genes remained untouched.These replicons not only recapitulate viral genome replication and sgRNA transcription but also support the assembly and release of viral-like particles,as manifested by electron microscopic assays.Thus,the S-deletion replicon could recapitulate virtually all the post-entry steps of the viral life cycle and provides a versatile tool for measuring viral intracellular propagation and screening novel antiviral drugs,including inhibitors of virion assembly and release.Through the quantification of replicon RNA released into the supernatant,we demonstrate that viral intracellular propagation and drug response to remdesivir have not yet substantially changed during the evolution of SARS-CoV-2 from the WIV04 strain to the Beta and Delta VOCs.
文摘The appearance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has caused panic responses around the world because of its high transmission rate and number of mutations.This review summarizes the highly mutated regions,the essential infectivity,transmission,vaccine breakthrough and antibody resistance of the Omicron variant of SARSCoV-2.The Omicron is highly transmissible and is spreading faster than any previous variant,but may cause less severe symptoms than previous variants.The Omicron is able to escape the immune system’s defenses and coronavirus disease 2019 vaccines are less effective against the Omicron variant.Early careful preventive steps including vaccination will always be key for the suppression of the Omicron variant.
文摘Omicron,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant that is now spreading across the world,is the most altered version to emerge so far,with mutations comparable to changes reported in earlier variants of concern linked with increased transmissibility and partial resistance to vaccineinduced immunity.This article provides an overview of the SARS-CoV-2 variant Omicron(B.1.1.529)by reviewing the literature from major scientific databases.Although clear immunological and clinical data are not yet available,we extrapolated from what is known about mutations present in the Omicron variant of SARS-CoV-2 and offer preliminary indications on transmissibility,severity,and immune escape through existing research and databases.
文摘The severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)belongs to the genus Beta coronavirus and the family of Coronaviridae.It is a positive-sense,non-segmented single-strand RNA virus.Four common types of human coronaviruses circulate globally,particularly in the fall and winter seasons.They are responsible for 10%-30% of all mild upper respiratory tract infections in adults.These are 229E,NL63 of the Alfacoronaviridae family,OC43,and HKU1 of the Betacoronaviridae family.However,there are three highly pathogenic human coronaviruses:SARS-CoV-2,Middle East respiratory syndrome coronavirus,and the latest pandemic caused by the SARS-CoV-2 infection.All viruses,including SARS-CoV-2,have the inherent tendency to evolve.SARS-CoV-2 is still evolving in humans.Additionally,due to the development of herd immunity,prior infection,use of medication,vaccination,and antibodies,the viruses are facing immune pressure.During the replication process and due to immune pressure,the virus may undergo mutations.Several SARS-CoV-2 variants,including the variants of concern(VOCs),such as B.1.1.7(Alpha),B.1.351(Beta),B.1.617/B.1.617.2(Delta),P.1(Gamma),and B.1.1.529(Omicron)have been reported from various parts of the world.These VOCs contain several important mutations;some of them are on the spike proteins.These mutations may lead to enhanced infectivity,transmissibility,and decreased neutralization efficacy by monoclonal antibodies,convalescent sera,or vaccines.Mutations may also lead to a failure of detection by molecular diagnostic tests,leading to a delayed diagnosis,increased community spread,and delayed treatment.We searched PubMed,EMBASE,Covariant,the Stanford variant Database,and the CINAHL from December 2019 to February 2023 using the following search terms:VOC,SARS-CoV-2,Omicron,mutations in SARS-CoV-2,etc.This review discusses the various mutations and their impact on infectivity,transmissibility,and neutralization efficacy.
基金This work was supported by grants from the National Key Research and Development Program of China(Nos.2016YFD0500301,2021YFC0863300,and 2020YFC0840900).
文摘Background:With the ongoing worldwide coronavirus disease 2019(COVID-19)pandemic,an increasing number of viral variants are being identified,which poses a challenge for nucleic acid-based diagnostic tests.Rapid tests,such as real-time reverse transcription-polymerase chain reaction(rRT-PCR),play an important role in monitoring COVID-19 infection and controlling its spread.However,the changes in the genotypes of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants may result in decreased sensitivity of the rRT-PCR assay and it is necessary to monitor the mutations in primers and probes of SARSCoV-2 detection over time.Methods:We developed two rRT-PCR assays to detect the RNA-dependent RNA polymerase(RdRp)and nucleocapsid(N)genes of SARS-CoV-2.We evaluated these assays together with our previously published assays targeting the ORF1ab and N genes for the detection and confirmation of SARS-CoV-2 and its variants of concern(VOCs).In addition,we also developed two rRT-PCR assays(S484K and S501Y)targeting the spike gene,which when combined with the open reading frames(ORF)1ab assay,respectively,to form duplex rRT-PCR assays,were able to detect SARS-CoV-2 VOCs(lineages B.1.351 and B.1.1.7).Results:Using a SARS-CoV-2 stock with predetermined genomic copies as a standard,the detection limit of both assays targeting RdRp and N was five copies/reaction.Furthermore,no cross-reactions with six others human CoVs(229E,OC43,NL63,HKU1,severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus)were observed using these assays.In addition,the S484K and S501Y assays were combined with the ORF1ab assay,respectively.Conclusions:Four rRT-PCR assays(RdRp,N,S484K,and S501Y)were used to detect SARS-CoV-2 variants,and these assays were shown to be effective in screening for multiple virus strains.
基金supported by grants from the National Key R&D Program of China(No.2021YFC0863400)the Alliance of International Science Organizations(No.ANSO-CR-SP-2020-02)+2 种基金the Natural Science Foundation of Shanghai(No.20ZR1463900)the National Natural Science Foundation of China(No.32070933)as well as G4 funding from Institut Pasteur,Fondation Merieux and Chinese Academy of Sciences to G.W.,and the International Affairs Department of the Institut Pasteur of Paris.
文摘Since severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)was first identified during late 2019,the sustained spread of this pathogen within the human population has caused worldwide disruption with staggering infection rates and death tolls.Due to the accumulation of mutations in SARS‐CoV‐2,the virus has evolved into many variants,five of which have been listed as variants of concern VOCs by the World Health Organization(WHO).Multiple animal models of SARS‐CoV‐2 have been developed to evaluate vaccines and drugs and to assess the pathogenicity,transmissibility and antiviral measures of these VOCs.Here,we review the cutting‐edge research based on mouse,hamster,ferret and non‐human primate models for evaluating SARS‐CoV‐2 with a focus on the Omicron variant,and highlight the importance of updating vaccines in a timely manner in order to mitigate the negative effects of SARS‐CoV‐2 infections in the human population.
文摘Wastewater surveillance plays an important role in the monitoring of infections of SARS-CoV-2 at the community level.We report here the determination of SARS-CoV-2 and differentiation of its variants of concern in 294 wastewater samples collected from two major Canadian cities from May 2021 to March 2023.The overall method of analysis involved extraction of the virus and viral components using electronegative membranes,in situ stabilization and concentration of the viral RNA onto magnetic beads,and direct analysis of the viral RNA on the magnetic beads.Multiplex reverse transcription quantitative polymerase chain reaction(RT-qPCR)assays,targeting specific and naturally selected mutations in SARS-CoV-2,enabled detection and differentiation of the Alpha,Beta,Gamma,Delta,and Omicron variants.An Omicron triplex RT-qPCR assay targeting three mutations,HV 69−70 deletion,K417N,and L452R,was able to detect and differentiate the Omicron BA.1/BA.3,BA.2/XBB,and BA.4/5.This assay had efficiencies of 90−104%for all three mutation targets and a limit of detection of 28 RNA copies per reaction.Analyses of 294 wastewater samples collected over a two-year span showed the concentrations and trends of Alpha,Beta,Gamma,Delta,and Omicron variants as they emerge in two major Canadian cities participating in the wastewater surveillance program.The trends of specific variants were consistent with clinical reports for the same period.At the beginning of each wave,the corresponding variants were detectable in wastewater.For example,RNA concentrations of the BA.2 variant were as high as 10^(4)copies per 100 mL of wastewater collected in January 2022,when approximately only 50−60 clinical cases of BA.2 infection were reported in Canada.These results show that the strategy and highly sensitive assays for the variants of concern in wastewater are potentially useful for the detection of newly emerging SARS-CoV-2 variants and other viruses for future community biomonitoring.
基金supported by the Bill&Melinda Gates Foundation(INV-005834),Natural Science Foundation of Fujian Province(NO.2021J01353,NO.2020J01094)National Science and Technology Major Project of the Ministry of Science and Technology of China(NO.2018ZX10734402-007)+1 种基金Research on accurate prediction and timely response system for out-breaks of new infectious diseases(SRPG2200702)Fundamental Research Funds for the Central Universities(No.20720230001).
文摘Although studies have compared the relative severity of Omicron and Delta variants by assessing the relative risks,there are still gaps in the knowledge of the potential COVID-19 burden these variations may cause.And the contact patterns in Fujian Province,China,have not been described.We identified 8969 transmission pairs in Fujian,China,by analyzing a contact-tracing database that recorded a SARS-CoV-2 outbreak in September 2021.We estimated the waning vaccine effectiveness against Delta variant infection,contact patterns,and epidemiology distributions,then simulated potential outbreaks of Delta and Omicron variants using a multi-group mathematical model.For instance,in the contact setting without stringent lockdowns,we estimated that in a potential Omicron wave,only 4.7%of infections would occur in Fujian Province among individuals aged>60 years.In comparison,58.75%of the death toll would occur in unvaccinated individuals aged>60 years.Compared with no strict lockdowns,combining school or factory closure alone reduced cumulative deaths of Delta and Omicron by 28.5%and 6.1%,respectively.In conclusion,this study validates the need for continuous mass immunization,especially among elderly aged over 60 years old.And it confirms that the effect of lockdowns alone in reducing infections or deaths is minimal.However,these measurements will still contribute to lowering peak daily incidence and delaying the epidemic,easing the healthcare system's burden.
基金supported by the National Key R&D Program of China(Grant No.2021YFC0863300)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB0490000)+6 种基金the CAMS Innovation Fund for Medical Sciences(Grant No.2021-I2M-1-024)the STI2030-Major Projects(Grant No.2021ZD0200900)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(Grant No.82221004)the National Natural Science Foundation of China(Grant Nos.32121001,32200460,and 32200460)the K.C.Wong Education Foundation(Grant No.GJTD-2019-08)the Shanghai Municipal Science and Technology Major Project,China(Grant No.2017SHZDZX01)the China National Postdoctoral Program for Innovative Talents(Grant No.BX2021291).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused the persistent coronavirus disease 2019(COVID-19)pandemic,which has resulted in millions of deaths worldwide and brought an enormous public health and global economic burden.The recurring global wave of infections has been exacerbated by growing variants of SARS-CoV-2.In this study,the virological characteristics of the original SARS-CoV-2 strain and its variants of concern(VOCs;including Alpha,Beta,and Delta)in vitro,as well as differential transcriptomic landscapes in multiple organs(lung,right ventricle,blood,cerebral cortex,and cerebellum)from the infected rhesus macaques,were elucidated.The original strain of SARS-CoV-2 caused a stronger innate immune response in host cells,and its VOCs markedly increased the levels of subgenomic RNAs,such as N,Orf9b,Orf6,and Orf7ab,which are known as the innate immune antagonists and the inhibitors of antiviral factors.Intriguingly,the original SARS-CoV-2 strain and Alpha variant induced larger alteration of RNA abundance in tissues of rhesus monkeys than Beta and Delta variants did.Moreover,a hyperinflammatory state and active immune response were shown in the right ventricles of rhesus monkeys by the up-regulation of inflammation-and immune-related RNAs.Furthermore,peripheral blood may mediate signaling transmission among tissues to coordinate the molecular changes in the infected individuals.Collectively,these data provide insights into the pathogenesis of COVID-19 at the early stage of infection by the original SARS-CoV-2 strain and its VOCs.
基金the Key Project of the Natural Science Foundation of Tianjin,China(No.20JCZDJC00090).The funders played no role in the study design,data collection and analysis,decision to publish,or manuscript preparation.
文摘Inactivated coronavirus disease 2019(COVID-19)vaccines such as CoronaVac and BBIBP-CorV have been widely used in China.However,more investigation is still needed to understand antibodies'duration and effectiveness against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants in the real world.In this study,575 participants who had been vaccinated with two or three doses of the inactivated vaccine were recruited.Serum samples were collected and tested for anti-spike IgG and neutralizing antibodies against SARS-CoV-2(original strain,Dela,and Omicron).Unsurprisingly,a third dose of the vaccine significantly enhanced antibody responses against SARS-CoV-2 and its variants.However,despite a booster dose,the neutralizing antibody levels against Omicron,particularly the BA.5.2 subvariant,remained low.There was no sex bias,but an age bias was observed.Notably,the predominant IgG subclass antibodies were IgG1 and IgG2,with a much lower level of IgG4.After the booster shot,the ratio of IgG4 to IgG1 significantly increased.The observation of IgG1 to the IgG4 class switch after repeated inactivated vaccinations underscores the importance of continuous monitoring of subclass antibody responses.Further clinical investigations are required to understand the implications of this class switch for optimizing immunization strategies.
基金This study was supported by the Hong Kong Research Grants Council Collaborative Research Fund(C7156-20GF to ZC and C1134-20GF)the Research Grants Council General Research Fund(GRF17117422)+5 种基金the Hong Kong Health and Medical Research Fund(COVID1903010-Project 4,COVID190123 and 19181012)the Shenzhen Science and Technology Program(JSGG20200225151410198 and JCYJ20210324131610027)HKU Development Fund and LKS Faculty of Medicine Matching Fund to AIDS Institutethe Hong Kong Innovation and Technology Fundthe Hong Kong Health@InnoHK,Innovation and Technology Commissiona generous donation from the Friends of Hope Education Fund.ZC’s team was also partly supported by the Theme-Based Research Scheme(T11-706/18-N and T11-709/21-N).
文摘Mutations in SARS-CoV-2 variants of concern(VOCs)have enhanced transmissibility and immune evasion with respect to current vaccines and neutralizing antibodies(NAbs).How naturally occurring spike mutations affect the infectivity and antigenicity of VOCs remains to be investigated.The entry efficiency of individual spike mutations was determined in vitro using pseudotyped viruses.BALB/c mice were immunized with 2-dose DNA vaccines encoding B.1.1.7,B.1.351,B.1.1.529 and their single mutations.Cellular and humoral immune responses were then compared to determine the impact of individual mutations on immunogenicity.In the B.1.1.7 lineage,Del69–70 and Del 144 in NTD,A570D and P681H in SD1 and S982A and D1118H in S2 significantly increased viral entry,whereas T716I resulted in a decrease.In the B.1.351 lineage,L18F and Del 242–244 in the NTD,K417N in the RBD and A701V in S2 also increased viral entry.S982A weakened the generation of binding antibodies.All sera showed reduced cross-neutralization activity against B.1.351,B.1.617.2(Delta)and B.1.1.529(Omicron BA.1).S982A,L18F,and Del 242–244 hindered the induction of cross-NAbs,whereas Del 69–70,Del144,R246I,and K417N showed the opposite effects.B.1.351 elicited adequate broad cross-NAbs against both B.1.351 and B.1.617.2.All immunogens tested,however,showed low neutralization against circulating B.1.1.529.In addition,T-cell responses were unlikely affected by mutations tested in the spike.We conclude that individual spike mutations influence viral infectivity and vaccine immunogenicity.Designing VOC-targeted vaccines is likely necessary to overcome immune evasion from current vaccines and neutralizing antibodies.
基金supported by the Medical and Health Science and Technology Innovation Project of Chinese Academy of Medical Sciences(No.2021-I2M-1-040)。
文摘The pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has led to major public health challenges globally.The increasing viral lineages identified indicate that the SARS-CoV-2 genome is evolving at a rapid rate.Viral genomic mutations may cause antigenic drift or shift,which are important ways by which SARS-CoV-2 escapes the human immune system and changes its transmissibility and virulence.Herein,we summarize the functional mutations in SARS-CoV-2 genomes to characterize its adaptive evolution to inform the development of vaccination,treatment as well as control and intervention measures.
文摘The recent coronavirus disease 2019(COVID-19)outbreak has highlighted the inadequacy of our ability to respond to newly emerging viruses.Antiviral medications are the most effective means of combating the pandemic,yet their diminishing efficacy and a large population of unvaccinated individuals will create a fertile environment for the virus’s propagation and the emergence of novel variants,posing an ongoing risk of infection for vulnerable populations with compromised immune systems.To treat those infected,effective treatments must be developed.In this review,we discuss a breakthrough in engineered antibody fragments that could provide a protective barrier against the onslaught of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants as well as future other viral infections.
基金supported by the National Natural Science Foundation of China(82241056,82170015,82100009,82030002)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-048)+1 种基金New Cornerstone Science Foundation,National Key R&D Program of China(2023YFC2306300)National Key R&D Program of China(2023YFC2306300).
文摘SARS-CoV-2 has caused global waves of infection since December 2019 and continues to persist today.The emergence of SARS-CoV-2 variants with strong immune evasion capabilities has compromised the effectiveness of existing vaccines against breakthrough infections.Therefore,it is important to determine the best utilization strategies for different demographic groups given the variety of vaccine options available.In this review,we will discuss the protective efficacy of vaccines during different stages of the epidemic and emphasize the importance of timely updates to target prevalent variants,which can significantly improve immune protection.While it is recognized that vaccine effectiveness may be lower in certain populations such as the elderly,individuals with chronic comorbidities(e.g.,diabetes with poor blood glucose control,those on maintenance dialysis),or those who are immunocompromised compared to the general population,administering multiple doses can result in a strong protective immune response that outweighs potential risks.However,caution should be exercised when considering vaccines that might trigger an intense immune response in populations prone to inflammatory flare or other complications.In conclusion,individuals with special conditions require enhanced and more effective immunization strategies to prevent infection or reinfection,as well as to avoid the potential development of long COVID.
