Biology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and the humoral immunoresponse:a systematic review of evidence to support global policy-level actions and research

Background Both population-level epidemiological data and individual-level biological data are needed to control the coronavirus disease 2019(COVID-19)pandemic.Population-level data are widely available and efforts to combat COVID-19 have generated proliferate data on the biology and immunoresponse to the causative pathogen,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).However,there remains a paucity of systemized data on this subject.Objective In this review,we attempt to extract systemized data on the biology and immuno-response to SARS-CoV-2 from the most up-to-date peer-reviewed studies.We will focus on the biology of the virus and immunological variations that are key for determining long-term immunity,transmission potential,and prognosis.Data Sources and Methods Peer-reviewed articles were sourced from the PubMed database and by snowballing search of selected publications.Search terms included:“Novel Coronavirus”OR“COVID-19”OR“SARS-CoV-2”OR“2019-nCoV”AND“Immunity”OR“Immune Response”OR“Antibody Response”OR“Immunologic Response”.Studies published from December 31,2019 to December 31,2020 were included.To ensure validity,papers in pre-print were excluded.Results Of 2889 identified papers,36 were included.Evidence from these studies suggests early seroconversion in patients infected with SARS-CoV-2.Antibody titers appear to markedly increase two weeks after infection,followed by a plateau.A more robust immune response is seen in patients with severe COVID-19 as opposed to mild or asymptomatic presentations.This trend persists with regard to the length of antibody maintenance.However,overall immunity appears to wane within two to three months post-infection.Conclusion Findings of this study indicate that immune responses to SARS-CoV-2 follow the general pattern of viral infection.Immunity generated through natural infection appears to be short,suggesting a need for long-term efforts to control the pandemic.Antibody testing will be essential to gauge the epidemic and inform decision-making on effective strategies for treatment and prevention.Further research is needed to illustrate immunoglobulin-specific roles and neutralizing antibody activity.

Pushing past the tipping points in containment trajectories of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)epidemics:A simple arithmetic rationale for crushing the curve instead of merely flattening it

Countries with ambitious national strategies to crush the curve of their Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)epidemic trajectories include China,Korea,Japan,Taiwan,New Zealand and Australia.However,the United States and many hard-hit European countries,like Ireland,Italy,Spain,France and the United Kingdom,currently appear content to merely flatten the curve of their epidemic trajectories so that transmission persists at rates their critical care services can cope with.Here I present a simple set of arithmetic modelling analyses that are accessible to non-specialists and explain why preferable crush the curve strategies,to eliminate transmission within months,would require only a modest amount of additional containment effort relative to the tipping point targeted by flatten the curve strategies,which allow epidemics to persist at supposedly steady,manageable levels for years,decades or even indefinitely.

Long, thin transmission chains of Severe Acute Respiratory Syndrome Coronavirus 2 may go undetected for several weeks at low to moderate reproduction numbers: Implications for containment and elimination strategy

Severe Acute Respiratory Syndrome Coronavirus 1(SARS-CoV-1)infections almost always caused overt symptoms,so effective case and contact management enabled its effective eradication within months.However,Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)usually causes only mild symptoms,so transmission chains may grow to include several individuals before at least one index case becomes ill enough to self-report for diagnosis and care.Here,simple mathematical models were developed to evaluate the implications of delayed index case detection for retrospective contact tracing and management responses.Specifically,these simulations illustrate how:(1)Contact tracing and management may effectively contain most but not all large SARS-CoV-2 clusters arising at foci with high reproduction numbers because rapidly expanding transmission chains ensure at least one overtly symptomatic index case occurs within two viral generations a week or less apart.(2)However,lower reproduction numbers give rise to thinner transmission chains extending through longer sequences of non-reporting asymptomatic and paucisymptomatic individuals,often spanning three or more viral generations(2 weeks of transmission)before an overtly symptomatic index case occurs.(3)Consequently,it is not always possible to fully trace and contain such long,thin transmission chains,so the community transmission they give rise to is underrepresented in surveillance data.(4)Wherever surveillance systems are weak and/or transmission proceeds within population groups with lower rates of overt clinical symptoms and/or self-reporting,case and contact management effectiveness may be more severely limited,even at the higher reproduction numbers associated with larger outbreaks.(5)Because passive surveillance platforms may be especially slow to detect the thinner transmission chains that occur at low reproduction numbers,establishing satisfactory confidence of elimination may require that no confirmed cases are detected for two full months,throughout which presumptive preventative measures must be maintained to ensure complete collapse of undetected residual transmission.(6)Greater scope exists for overcoming these limitations by enhancing field surveillance for new suspected cases than by improving diagnostic test sensitivity.(7)While population-wide active surveillance may enable complete traceability and containment,this goal may also be achievable through enhanced passive surveillance for paucisymptomatic infections,combining readily accessible decentralized testing with population hypersensitization to self-reporting with mild symptoms.Containment and elimination of SARS-CoV-2 will rely far more upon presumptive,population-wide prevention measures than was necessary for SARS-CoV-1,necessitating greater ambition,political will,investment,public support,persistence and patience.Nevertheless,case and contact management may be invaluable for at least partially containing SARS-CoV-2 transmission,especially larger outbreaks,but only if enabled by sufficiently sensitive surveillance.Furthermore,consistently complete transmission chain containment may be enabled by focally enhanced surveillance around manageably small numbers of outbreaks in the end stages of successful elimination campaigns,so that their endpoints may be accelerated and sustained.

Genomic Evolution and Variation of SARS-CoV-2 in the Early Phase of COVID-19 Pandemic in Guangdong Province,China

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)with unknown origin spread rapidly to 222 countries,areas or territories.To investigate the genomic evolution and variation in the early phase of COVID-19 pandemic in Guangdong,60 specimens of SARS-CoV-2 were used to perform whole genome sequencing,and genomics,amino acid variation and Spike protein structure modeling analyses.Phylogenetic analysis suggested that the early variation in the SARS-CoV-2 genome was still intra-species,with no evolution to other coronaviruses.There were one to seven nucleotide variations(SNVs)in each genome and all SNVs were distributed in various fragments of the genome.The Spike protein bound with human receptor,an amino acid salt bridge and a potential furin cleavage site were found in the SARS-CoV-2 using molecular modeling.Our study clarifed the characteristics of SARS-CoV-2 genomic evolution,variation and Spike protein structure in the early phase of local cases in Guangdong,which provided reference for generating prevention and control strategies and tracing the source of new outbreaks.

新型冠状病毒相关TMPRSS2蛋白结构特征和抗原表位分析

采用生物信息学方法分析预测新型冠状病毒(Severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)跨膜蛋白酶丝氨酸2(transmembrane protease serine 2,TMPRSS2)的理化特性、结构特征和抗原表位,为抗SARS-CoV-2药物研发提供参考。利用ProtParam、ProtScale分析预测TMPRSS2蛋白酶的理化特性;利用COILS Server、SignalP、TMPred、TargetP Server、NetPhos Server、NetNGlyc Server服务器对TMPRSS2蛋白酶结构进行功能结构的分析预测;利用SOPMA、Pfam、SWISS MODEL分析预测TMPRSS2蛋白酶高级结构;利用IEBD分析预测TMPRSS2蛋白酶B细胞、T细胞表位。TMPRSS2蛋白酶氨基酸组成数为492个,其中丝氨酸占比最高;亲水性较高,含10个跨膜螺旋区;具有4个磷酸化位点,3个糖基化修饰点;二级结构中无规则卷曲占据主导地位,三级结构能与已知的5ce.1.1.A(SMTL ID)模型同源建模;存在13个潜在的B细胞表位,12个得分较高的T细胞表位。

A human monoclonal antibody neutralizes SARS-CoV-2 Omicron variants bytargeting the upstream region of spike protein HR2 motif

The continuous emergence of new severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants meansthere is a need to explore additional strategies to develop broad-spectrum vaccines or therapeutics for individuals remaining at risk of coronavirus disease 2019(COVID-19).Neutralizing monoclonal antibody(mAb)that binds to theconserved S2 subunit of the SARS-CoV-2 spike(S)protein alone,or in combination with mAb that binds to the receptor-binding domain(RBD)of S protein,might be effective in eliciting protection from infection by a variety of SARS-CoV2 variants.Using high-throughput single-cell immunoglobulin sequencing of B cells from COVID-19-convalescent donors,we identified a high-affinity S2-specific mAb-39,that could inhibit original SARS-CoV-2 strain,Omicron BA.1,BA.2.86,BA.4,BA.5,and EG.5.1 S protein-mediated membrane fusion,leading to the neutralization of these pseudoviralinfections.Moreover,mAb-39 could also improve the neutralizing activity of anti-RBD antibody against the highlyneutralization-resistant Omicron variants.Molecular docking and point mutation analyses revealed that mAb-39 recognized epitopes within the conserved upstream region of the heptad repeat 2(HR2)motif of the S2 subunit.Collectively,these findings demonstrate that targeting the conserved upstream region of the HR2 motif(e.g.,using mAbs)provides anovel strategy for preventing the infection of SARS-CoV-2 and its variants.

Prolonged existence of SARS-CoV-2 RNAs in the extracellular vesicles of respiratory specimens from patients with negative reverse transcription-polymerase chain reaction

Background and aim:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is primarily in the respiratory tract,particularly in patients with underlying comorbidities.This study aimed to investigate the presence of the virus inside the extracellular vesicles(EVs)in patients with and without chronic liver disease(CLD).Methods:Eighty patients with positive SARS-CoV-2,including twenty-four patients with CLD and fiftysix patients without CLD,and five healthy controls with negative SARS-CoV-2 were enrolled.Nasal swab specimens were tested for the detection of SARS-CoV-2 using reverse transcription-polymerase chain reaction(RT-PCR).Patients with coronavirus disease 2019(COVID-19)were followed up on days 7 and 14.Nasal swab,collected in viral transport media(VTM),and plasma samples were investigated at each time point.EVs were isolated from the nasal swabs(collected in VTM)and plasma using differential ultracentrifugation and estimated at each time point.The transmission or replication by the EVs was assessed in Vero E6 cells.Results:In patients with baseline RT-PCR positive,SARS-CoV-2 RNAs inside the EVs were found in 68/80(85%)patients with higher viral load in the nasal swabs than in the EVs(cycle threshold(Ct)value,23.4±5.7 vs.30.3±5.0,P<0.001).On follow-up at day 7,of the 32 patients negative for COVID-19,15(46.9%)had virus persistence in the EVs(Ct value,30.7±2.7),and on day 14,of the 56 patients with negative SARS-CoV-2,16 patients(28.6%)had positive SARS-CoV-2 RNAs in the EVs(Ct value,31.4±3.0).The mean viral load decreased on days 7 and 14 compared to baseline in the nasal swabs(P<0.001)but not in the EVs.Additionally,SARS-CoV-2 RNAs were undetectable in the plasma,but 12.5% of patients were positive in the plasma EVs.Significantly prolonged and high viral load was found in the EVs on day 14 in COVID-19 patients combined with CLD compared with COVID-19 patients(P?0.0004).We found significant higher levels of EV-associated with endothelial cells and hepatocytes in the COVID-19 t CLD group than COVID-19 group(P?0.032 and P?0.002,respectively),suggesting more endothelial cells and hepatocytes cellular injury in liver disease patients with COVID-19.Interestingly,we also found EVs could transmit SARS-CoV-2 RNAs into Vero E6 cells at 24 h post-infection.Conclusions:The identification of SARS-CoV-2 RNAs in the EVs in patients with negative RT-PCR indicates the persistence of infection and likely recurrence of the infection.It is suggestive of another route of transmission as EVs harbor SARS-CoV-2 RNAs.EV-associated RNAs may determine the ongoing inflammation and clinical course of subjects with undetectable SARS-CoV-2 virus and this may have relevance to better management of patients with CLD.

Why lockdown?Why national unity?Why global solidarity?Simplified arithmetic tools for decision-makers,health professionals,journalists and the general public to explore containment options for the 2019 novel coronavirus

As every country in the world struggles with the ongoing COVID-19 pandemic,it is essential that as many people as possible understand the epidemic containment,elimination and exclusion strategies required to tackle it.Simplified arithmetic models of COVID-19 transmission,control and elimination are presented in user-friendly Shiny and Excel formats that allow non-specialists to explore,query,critique and understand the containment decisions facing their country and the world at large.Although the predictive model is broadly applicable,the simulations presented are based on parameter values representative of the United Republic of Tanzania,which is still early enough in its epidemic cycle and response to avert a national catastrophe.The predictions of these models illustrate(1)why ambitious lock-down interventions to crush the curve represent the only realistic way for individual countries to contain their national-level epidemics before they turn into outright catastrophes,(2)why these need to be implemented so early,so stringently and for such extended periods,(3)why high prevalence of other pathogens causing similar symptoms to mild COVID-19 precludes the use of contact tracing as a substitute for lock down interventions to contain and eliminate epidemics,(4)why partial containment strategies intended to merely flatten the curve,by maintaining epidemics at manageably low levels,are grossly unrealistic,and(5)why local elimination may only be sustained after lock down ends if imported cases are comprehensively excluded,so international co-operation to conditionally re-open trade and travel between countries certified as free of COVID-19 represents the best strategy for motivating progress towards pandemic eradication at global level.The three sequential goals that every country needs to emphatically embrace are contain,eliminate and exclude.As recently emphasized by the World Health Organization,success will require widespread genuine national unity and unprecedented global solidarity.

Development and validation of an individualized nomogram for early prediction of the duration of SARS-CoV-2 shedding in COVID-19 patients with non-severe disease

With the number of cases of coronavirus disease-2019(COVID-19)increasing rapidly,the World Health Organization(WHO)has recommended that patients with mild or moderate symptoms could be released from quarantine without nucleic acid retesting,and self-isolate in the community.This may pose a potential virus transmission risk.We aimed to develop a nomogram to predict the duration of viral shedding for individual COVID-19 patients.This retrospective multicentric study enrolled 135 patients as a training cohort and 102 patients as a validation cohort.Significant factors associated with the duration of viral shedding were identified by multivariate Cox modeling in the training cohort and combined to develop a nomogram to predict the probability of viral shedding at 9,13,17,and 21 d after admission.The nomogram was validated in the validation cohort and evaluated by concordance index(C-index),area under the curve(AUC),and calibration curve.A higher absolute lymphocyte count(P=0.001)and lymphocyte-to-monocyte ratio(P=0.013)were correlated with a shorter duration of viral shedding,while a longer activated partial thromboplastin time(P=0.007)prolonged the viral shedding duration.The C-indices of the nomogram were 0.732(95%confidence interval(CI):0.685-0.777)in the training cohort and 0.703(95%CI:0.642-0.764)in the validation cohort.The AUC showed a good discriminative ability(training cohort:0.879,0.762,0.738,and 0.715 for 9,13,17,and 21 d;validation cohort:0.855,0.758,0.728,and 0.706 for 9,13,17,and 21 d),and calibration curves were consistent between outcomes and predictions in both cohorts.A predictive nomogram for viral shedding duration based on three easily accessible factors was developed to help estimate appropriate self-isolation time for patients with mild or moderate symptoms,and to control virus transmission.

Seasonal coronaviruses and SARS-CoV-2:effects of preexisting immunity during the COVID-19 pandemic

Although the coronavirus disease 2019(COVID-19)epidemic is still ongoing,vaccination rates are rising slowly and related treatments and drugs are being developed.At the same time,there is increasing evidence of preexisting immunity against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)in humans,mainly consisting of preexisting antibodies and immune cells(including T cells and B cells).The presence of these antibodies is mainly due to the seasonal prevalence of four common coronavirus types,especially OC43 and HKU1.The accumulated relevant evidence has suggested that the target of antibodies is mainly the S2 subunit of S protein,followed by evolutionary conservative regions such as the nucleocapsid(N)protein.Additionally,preexisting memory T and B cells are also present in the population.Preexisting antibodies can help the body protect against SARS-CoV-2 infection,reduce the severity of COVID-19,and rapidly increase the immune response post-infection.These multiple effects can directly affect disease progression and even the likelihood of death in certain individuals.Besides the positive effects,preexisting immunity may also have negative consequences,such as antibody-dependent enhancement(ADE)and original antigenic sin(OAS),the prevalence of which needs to be further established.In the future,more research should be focused on evaluating the role of preexisting immunity in COVID-19 outcomes,adopting appropriate policies and strategies for fighting the pandemic,and vaccine development that considers preexisting immunity.

Symptomatic COVID-19 in University Students: A School-Wide Web-Based Questionnaire Survey during the Omicron Variant Outbreak

Aim: To detect risk and preventive factors associated with the Omicron variant infection in university students, a combination of a web-based survey and multivariate logistic regression analysis was introduced as the front-line initiatives by the school health practitioners. Design: Questionnaire survey. Methods: The school-wide web-based questionnaire survey was conducted among our university students as a part of the annual health check-up in April, 2023. The positive outcome was confined to the first symptomatic COVID-19 onset during the Omicron variant outbreak. Results: In this self-administered survey, risk or protective associations were merely estimated statistically in university students (n = 5406). In measured factors, karaoke and club/group activities could maintain the statistical significance in adjusted odds ratios (ORs) as relative risk factors, and science course, measles/ rubella (MR) vaccination, and COVID-19 vaccination remained as relative protective factors in adjusted OR analyses. Club/group activities with member gathering and karaoke sing-along sessions in university students may frequently have WHO’s three Cs. These risk factors are still important topics for the infection control of COVID-19 in university students. Together with some recent reports from other researchers, the significant protective role of MR vaccine in our survey warrants further clinical investigation. If the breakthrough infection continuously constitutes the majority of infection, real data in test-negative case-control or web-based questionnaire design continue to be important for statistical analysis to determine the minimal requirement of our strategies which may be equivalent to or replace COVID-19 vaccines.

Ratiometric fluorescence immunoassay of SARS-CoV-2 nucleocapsid protein via Si-FITC nanoprobe-based inner filter effect

The global pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus has necessitated rapid,easy-to-use,and accurate diagnostic methods to monitor the virus infection.Herein,a ratiometric fluorescence enzyme-linked immunosorbent assay(ELISA)was developed using Si-fluorescein isothiocyanate nanoparticles(FITC NPs)for detecting SARSCoV-2 nucleocapsid(N)protein.Si-FITC NPs were prepared by a one-pot hydrothermal method using 3-aminopropyl triethoxysilane(APTES)-FITC as the Si source.This method did not need post-modification and avoided the reduction in quantum yield and stability.The p-nitrophenyl(pNP)produced by the alkaline phosphatase(ALP)-mediated hydrolysis of pnitrophenyl phosphate(pNPP)could quench Si fluorescence in Si-FITC NPs via the inner filter effect.In ELISA,an immunocomplex was formed by the recognition of capture antibody/N protein/reporter antibody.ALP-linked secondary antibody bound to the reporter antibody and induced pNPP hydrolysis to specifically quench Si fluorescence in Si-FITC NPs.The change in fluorescence intensity ratio could be used for detecting N protein,with a wide linearity range(0.01-10.0 and 50-300 ng/mL)and low detection limit(0.002 ng/mL).The concentration of spiked SARS-CoV-2 N protein could be determined accurately in human serum.Moreover,this proposed method can accurately distinguish coronavirus disease 2019(COVID-19)and non-COVID-19 patient samples.Therefore,this simple,sensitive,and accurate method can be applied for the early diagnosis of SARS-CoV-2 virus infection.

Acute Hepatitis of Unknown Origin in Children: Early Observations from the 2022 Outbreak

Recent reports of acute hepatitis of unknown origin in previously healthy children have been increasing worldwide.The main characteristics of the affected children were jaundice and gastrointestinal symptoms.Their serum aminotransaminase levels were above 500 IU/L,with negative tests for hepatitis viruses A–E.By 31 May 2022,the outbreak had affected over 800 children under the age of 16 years in more than 40 countries,resulting in acute liver failure in approximately 10%,including at least 21 deaths and 38 patients requiring liver transplantation.There was still no confirmed cause or causes,although there were several different working hypotheses,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),adenovirus serotype 41,or SARS-CoV-2 superantigen-mediated immune cell activation.Here,we review early observations of the 2022 outbreak which may inform diagnosis,treatment,and prevention in the context of an overlapping COVID-19 pandemic.

Impact of liver enzymes on SARS-CoV-2 infection and the severity of clinical course of COVID-19

Background and aim Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the virus responsible for the current pandemic,can have multi-organ impact.Recent studies show that liver injury could be a manifestation of the disease,and that liver disease could also be related to a worse prognosis.Our aim was to compare the characteristics of patients with severe coronavirus disease 2019(COVID-19)due to SARS-CoV-2 who required intubation versus stable hospitalized patients to identify the early biochemical predictive factors of a severe course of COVID-19 and subsequent requirement for intubation,specifically in Mexican.Methods This was an observational case-control study nested in a cohort study.Complete medical records of patients admitted for confirmed COVID-19 at a tertiary level center in Mexico City were reviewed.Clinical and biochemical data were collected,and the characteristics of patients who required invasive mechanical ventilation(IMV)(cases)were compared with stable hospitalized patients without ventilation(controls).Results We evaluated 166 patients with COVID-19 due to SARS-CoV-2 infection;114(68.7%)were men,the mean age was 50.6±13.3 years,and 27(16.3%)required IMV.The comparative analysis between cases and controls showed(respectively)significantly lower blood oxygen saturation(SpO_(2))(73.5±12.0%vs.83.0±6.8%,P<0.0001)and elevated alanine aminotransferase(ALT)(128(14–1123)IU/L vs.33(8–453)IU/L,P=0.003),aspartate aminotransferase(AST)(214(17–1247)vs.44(12–498)IU/L,P=0.001),lactic dehydrogenase(LDH)(764.6±401.9 IU/L vs.461.0±185.6 IU/L,P=0.001),and D-dimer(3463(524–34,227)ng/mL vs.829(152–41,923)ng/mL,P=0.003)concentrations.Patients in the cases group were older(58.6±12.7 years vs.49.1±12.8 years,P=0.001).Multivariate analysis showed that important factors at admission predicting the requirement for IMV during hospitalization for COVID-19 were AST≥250 IU/L(odds ratio(OR)=64.8,95%confidence interval(CI)7.5–560.3,P<0.0001)and D-dimer≥3500 ng/mL(OR=4.1,95%CI 1.2–13.7,P=0.02).Conclusions Our study confirms the importance of monitoring liver enzymes in hospitalized patients with COVID-19;seriously ill patients have significantly elevated AST and D-dimer concentrations,which have prognostic implications in the SARS-CoV-2 disease course.

Viral and Antibody Kinetics of COVID-19 Patients with Different Disease Severities in Acute and Convalescent Phases:A 6-Month Follow-Up Study

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread rapidly around the world,posing a major threat to human health and the economy.Currently,long-term data on viral shedding and the serum antibody responses in COVID-19 patients are still limited.Herein,we report the clinical features,viral RNA loads,and serum antibody levels in a cohort of 112 COVID-19 patients admitted to the Honghu People’s Hospital,Hubei Province,China.Overall,5.36%(6/112)of patients showed persistent viral RNA shedding(>45 days).The peak viral load was higher in the severe disease group than in the mild group(median cycle threshold value,36.4 versus 31.5;P=0.002).For most patients the disappearance of IgM antibodies occurred approximately 4–6 weeks after symptoms onset,while IgG persisted for over 194 days after the onset of symptoms,although patients showed a 46%reduction in antibodies titres against SARS-CoV-2 nucleocapsid protein compared with the acute phase.We also studied18 asymptomatic individuals with RT-qPCR confirmed SARS-CoV-2 infection together with 17 symptomatic patients,and the asymptomatic individuals were the close contacts of these symptomatic cases.Delayed IgG seroconversion and lower IgM seropositive rates were observed in asymptomatic individuals.These data indicate that higher viral loads and stronger antibody responses are related to more severe disease status in patients with SARS-CoV-2 infection,and the antibodies persisted in the recovered patient for more than 6 months so that the vaccine may provide protection against SARS-CoV-2 infection.

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

Multiple new variants of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)have constantly emerged,as the delta and omicron variants,which have developed resistance to currently gained neutralizing antibodies.This highlights a critical need to discover new therapeutic agents to overcome the variants mutations.Despite the availability of vaccines against coronavirus disease 2019(COVID-19),the use of broadly neutralizing antibodies has been considered as an alternative way for the prevention or treatment of SARS-Co V-2 variants infection.Here,we show that the nasal delivery of two previously characterized broadly neutralizing antibodies(F61 and H121)protected K18-h ACE2 mice against lethal challenge with SARS-Co V-2 variants.The broadly protective efficacy of the F61 or F61/F121 cocktail antibodies was evaluated by lethal challenge with the wild strain(WIV04)and multiple variants,including beta(B.1.351),delta(B.1.617.2),and omicron(B.1.1.529)at 200or 1000 TCID_(50),and the minimum antibody administration doses(5-1.25 mg/kg body weight)were also evaluated with delta and omicron challenge.Fully prophylactic protections were found in all challenged groups with both F61 and F61/H121 combination at the administration dose of 20 mg/kg body weight,and corresponding mice lung viral RNA showed negative,with almost all alveolar septa and cavities remaining normal.Furthermore,low-dose antibody treatment induced significant prophylactic protection against lethal challenge with delta and omicron variants,whereas the F61/H121 combination showed excellent results against omicron infection.Our findings indicated the potential use of broadly neutralizing monoclonal antibodies as prophylactic and therapeutic agent for protection of current emerged SARS-Co V-2 variants infection.

Summary of the Detection Kits for SARS-CoV-2 Approved by the National Medical Products Administration of China and Their Application for Diagnosis of COVID-19

The on-going global pandemic of coronavirus disease 2019(COVID-19)caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has been underway for about 11 months.Through November 20,2020,51 detection kits for SARS-CoV-2 nucleic acids(24 kits),antibodies(25 kits),or antigens(2 kits)have been approved by the National Medical Products Administration of China(NMPA).Convenient and reliable SARS-CoV-2 detection assays are urgently needed worldwide for strategic control of the pandemic.In this review,the detection kits approved in China are summarised and the three types of tests,namely nucleic acid,serological and antigen detection,which are available for the detection of COVID-19 are discussed in detail.The development of novel detection kits will lay the foundation for the control and prevention of the COVID-19 pandemic globally.

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

Severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)has precipitated multiple variants resistant to therapeutic antibodies.In this study,12 high-affinity antibodies were generated from convalescent donors in early outbreaks using immune antibody phage display libraries.Of them,two RBD-binding antibodies(F61 and H121)showed high-affinity neutralization against SARS-Co V-2,whereas three S2-target antibodies failed to neutralize SARS-Co V-2.Following structure analysis,F61 identified a linear epitope located in residues G446–S494,which overlapped with angiotensinconverting enzyme 2(ACE2)binding sites,while H121 recognized a conformational epitope located on the side face of RBD,outside from ACE2 binding domain.Hence the cocktail of the two antibodies achieved better performance of neutralization to SARS-Co V-2.Importantly,these two antibodies also showed efficient neutralizing activities to the variants including B.1.1.7 and B.1.351,and reacted with mutations of N501 Y,E484 K,and L452 R,indicated that it may also neutralize the recent India endemic strain B.1.617.The unchanged binding activity of F61 and H121 to RBD with multiple mutations revealed a broad neutralizing activity against variants,which mitigated the risk of viral escape.Our findings revealed the therapeutic basis of cocktail antibodies against constantly emerging SARS-Co V-2 variants and provided promising candidate antibodies to clinical treatment of COVID-19 patients infected with broad SARS-Co V-2 variants.

Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates

The ongoing coronavirus disease 2019(COVID-19)pandemic caused more than 96 million infections and over 2 million deaths worldwide so far.However,there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the disease causative agent.Vaccine is the most effective approach to eradicate a pathogen.The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations.Here we evaluated the safety,immunogenicity,and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates.Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates,and subsequently provided partial(in low dose)or full(in high dose)protection of challenge in the tested animals.In addition,passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice.These results warranted positive outcomes in future clinical trials in humans.

Altered gut microbiota composition in children and their caregivers infected with the SARS‑CoV‑2 Omicron variant

Background Gut microbiota alterations have been implicated in the pathogenesis of coronavirus disease 2019(COVID-19).This study aimed to explore gut microbiota changes in a prospective cohort of COVID-19 children and their asymptomatic caregivers infected with the severe acute respiratory syndrome coronavirus type 2(SARS-CoV-2)Omicron variant.Methods A total of 186 participants,including 59 COVID-19 children,50 asymptomatic adult caregivers,52 healthy children(HC),and 25 healthy adults(HA),were recruited between 15 April and 31 May 2022.The gut microbiota composition was determined by 16S rRNA gene sequencing in fecal samples collected from the participants.Gut microbiota functional profling was performed by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States(PICRUSt)software.Results The gut microbiota analysis of beta diversity revealed that the fecal microbial community of COVID-19 children remained far distantly related to HC.The relative abundances of the phyla Actinobacteria and Firmicutes were decreased,whereas Bacteroidetes,Proteobacteria,and Verrucomicrobiota were increased in COVID-19 children.Feces from COVID-19 children exhibited notably lower abundances of the genera Blautia,Bifdobacterium,Fusicatenibacter,Streptococcus,and Romboutsia and higher abundances of the genera Prevotella,Lachnoclostridium,Escherichia-Shigella,and Bacteroides than those from HC.The enterotype distributions of COVID-19 children were characterized by a high prevalence of enterotype Bacteroides.Similar changes in gut microbiota compositions were observed in asymptomatic caregivers.Furthermore,the microbial metabolic activities of KEGG(Kyoto Encyclopedia of Genes and Genomes)and COG(cluster of orthologous groups of proteins)pathways were perturbed in feces from subjects infected with the SARS-CoV-2 Omicron variant.Conclusion Our data reveal altered gut microbiota compositions in both COVID-19 children and their asymptomatic caregivers infected with the SARS-CoV-2 Omicron variant,which further implicates the critical role of gut microbiota in COVID-19 pathogenesis.