Isolation,identification, and genetic evolution analysis of variant strain CH-HK-2021 of G2a porcine epidemic diarrhea virus

Object: To explore genetic evolution relationship of variant porcine epidemic diarrhea virus(PEDV)and antigenic differential sites among variant strain subtypes,so as to lay a foundation for the development of novel vaccines and diagnostic kits. Method: Three PEDV-positive porcine intestinal samples were inoculated on to confluent Vero cells to isolate PEDV. Virus identification was performed by indirect fluorescence assay(IFA), Western blotting,RT-PCR and whole genome sequencing and electron microscopic observation;virus titer was determined by TCID50and the in vitvo proliferation dynamin curve of the virus was drawn. The genome of the isolated strain was divided into 33 segments for RT-PCR amplification, and the SeqMan of Lasergene was used to splice sequences. Then the genetic evolution analysis was performed with MEGA 7.0, and the antigenicity analysis was performed with Jameson-Wolf algorithm in Protean. Result: Typical cytopathic effect appeared in one PEDV-positive porcine intestinal sample in Vero cells when it was blindly passaged to the 6thgeneration and the sample was designated as CH-HK-2021. IFA and Western blotting results showed that the strain CH-HK-2021 could react with PEDV N monoclonal antibody and expected reads were obtained through RT-PCR amplification, which demonstrated this virus was PEDV. Diameter of strain CH-HK-2021 was 80-120 nm and the surface of the virus particles were in spike-like shape, indicating it was coronavirus. The strain could be stably propagated in Vero cells, and it has been passaged to 100thgeneration. After 24 h of infecting the Vero cells, virus titer of strain CH-HK-2021 reached the highest,105.6TCID50/mL. The size whole genome of strain CH-HK-2021 not including poly(A)tail was 28034 bp, with a similarity of 96.0%-98.9% with nucleotide sequence of the PEDV reference strain and a similarity of 93.1%-99.0% with S-base nucleotide sequence of the reference strain. The strain had the highest similarity with nucleotide sequence of variant strain CH/JX/01(KX058031)and the lowest similarity with nucleotide sequence of classical strain AVCT12(LC053455). Strain CH-HK-2021 was a subtype of G2a and it is spreading in China. Strain G2a and variant strain G2b had 42 nucleotide differential sites in S gene and 6 antigenic differential sites;and main differential sites located in subunit S2.

TEMPO: A transformer-based mutation prediction framework for SARS-CoV-2 evolution.

The widespread of SARS-CoV-2 presents a significant threat to human society, as well as public health and economic development. Extensive efforts have been undertaken to battle against the pandemic, whereas effective approaches such as vaccination would be weakened by the continuous mutations, leading to considerable attention being attracted to the mutation prediction. However, most previous studies lack attention to phylogenetics. In this paper, we propose a novel and effective model TEMPO for predicting the mutation of SARS-CoV-2 evolution. Specifically, we design a phylogenetic tree-based sampling method to generate sequence evolution data. Then, a transformer-based model is presented for the site mutation prediction after learning the high-level representation of these sequence data. We conduct experiments to verify the effectiveness of TEMPO, leveraging a large-scale SARS-CoV- 2 dataset. Experimental results show that TEMPO is effective for mutation prediction of SARS- CoV-2 evolution and outperforms several state-of-the-art baseline methods. We further perform mutation prediction experiments of other infectious viruses, to explore the feasibility and robustness of TEMPO, and experimental results verify its superiority. The codes and datasets are freely available at https://github.com/ZJUDataIntelligence/TEMPO.

Safety and immunogenicity of a mosaic vaccine booster against Omicron and other SARS-CoV-2 variants: a randomized phase 2 trial.

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.

Rapid and Sensitive Genotyping of SARS-CoV-2 Key Mutation L452R with an RPA-PfAgo Method.

In the two years of COVID-19 pandemic, the SARS-CoV-2 variants have caused waves of infections one after another, and the pandemic is not ending. The key mutations on the S protein enable the variants with enhanced viral infectivity, immune evasion, and/or antibody neutralization resistance, bringing difficulties to epidemic prevention and control. In support of precise epidemic control and precision medicine of the virus, a fast and simple genotyping method for the key mutations of SARS-CoV-2 variants needs to be developed. By utilizing the specific recognition and cleavage property of the nuclease Argonaute from Pyrococcus furiosus (PfAgo), we developed a recombinase polymerase amplification (RPA) and PfAgo combined method for a rapid and sensitive genotyping of SARS-CoV-2 key mutation L452R. With a delicate design of the strategy, careful screening of the RPA primers and PfAgo gDNA, and optimization of the reaction, the method achieves a high sensitivity of a single copy per reaction, which is validated with the pseudovirus. This is the highest sensitivity that can be achieved theoretically and the highest sensitivity as compared to the available SARS-CoV-2 genotyping assays. Using RPA, the procedure of the method is finished within 1.5 h and only needs a minimum laboratorial support, suggesting that the method can be easily applied locally or on-site. The RPA-PfAgo method established in this study provides a strong support to the precise epidemic control and precision medicine of SARS-CoV-2 variants and can be readily developed for the simultaneous genotyping of multiple SARS-CoV-2 mutations.

Genome-wide Mendelian randomization and single-cell RNA sequencing analyses identify the causal effects of COVID-19 on 41 cytokines.

The elevated levels of inflammatory cytokines have attracted much attention during the treatment of COVID-19 patients. The conclusions of current observational studies are often controversial in terms of the causal effects of COVID-19 on various cytokines because of the confounding factors involving underlying diseases. To resolve this problem, we conducted a Mendelian randomization analysis by integrating the GWAS data of COVID-19 and 41 cytokines. As a result, the levels of 2 cytokines were identified to be promoted by COVID-19 and had unsignificant pleiotropy. In comparison, the levels of 10 cytokines were found to be inhibited and had unsignificant pleiotropy. Among down-regulated cytokines, CCL2, CCL3 and CCL7 were members of CC chemokine family. We then explored the potential molecular mechanism for a significant causal association at a single cell resolution based on single-cell RNA data, and discovered the suppression of CCL3 and the inhibition of CCL3-CCR1 interaction in classical monocytes (CMs) of COVID-19 patients. Our findings may indicate that the capability of COVID-19 in decreasing the chemotaxis of lymphocytes by inhibiting the CCL3-CCR1 interaction in CMs.

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines.

Ionizable cationic lipid-containing lipid nanoparticles (LNPs) are the most clinically advanced non-viral gene delivery platforms, holding great potential for gene therapeutics. This is exemplified by the two COVID-19 vaccines employing mRNA-LNP technology from Pfizer/BioNTech and Moderna. Herein, we develop a chemical library of ionizable cationic lipids through a one-step chemical-biological enzyme-catalyzed esterification method, and the synthesized ionizable lipids were further prepared to be LNPs for mRNA delivery. Through orthogonal design of experiment methodology screening, the top-performing AA3-DLin LNPs show outstanding mRNA delivery efficacy and long-term storage capability. Furthermore, the AA3-DLin LNP COVID-19 vaccines encapsulating SARS-CoV-2 spike mRNAs successfully induced strong immunogenicity in a BALB/c mouse model demonstrated by the antibody titers, virus challenge, and T cell immune response studies. The developed AA3-DLin LNPs are an excellent mRNA delivery platform, and this study provides an overall perspective of the ionizable cationic lipids, from aspects of lipid design, synthesis, screening, optimization, fabrication, characterization, and application.

2D Zn‐Porphyrin‐Based Co(II)‐MOF with 2‐Methylimidazole Sitting Axially on the Paddle–Wheel Units: An Efficient Electrochemiluminescence Bioassay for SARS‐CoV‐2

High electrocatalytic activity with tunable luminescence is crucial for the development of electrochemiluminescence (ECL) luminophores. In this study, a porphyrin‐based heterobimetallic 2D metal organic framework (MOF), [(ZnTCPP)Co2(MeIm)] (1), is successfully self‐assembled from the zinc(II) tetrakis(4‐carboxyphenyl)porphine (ZnTCPP) linker and cobalt(II) ions in the presence of 2‐methylimidazole (MeIm) by a facile one‐pot reaction in methanol at room temperature. On the basis of the experimental results and the theoretical calculations, the MOF 1 contains paddle–wheel [Co2(‐CO2)4] secondary building units (SBUs) axially coordinated by a MeIm ligand, which is very beneficial to the electron transfer between the Co(II) ions and oxygen. Combining the photosensitizers ZnTCPP and the electroactive [Co2(‐CO2)4] SBUs, the 2D MOF 1 possesses an excellent ECL performance, and can be used as a novel ECL probe for rapid nonamplified detection of the RdRp gene of SARS‐CoV‐2 with an extremely low limit of detection (≈30 aM). A novel porphyrin‐based heterobimetallic 2D MOF, [(ZnTCPP)Co2(MeIm)] (1) is constructed to act as an excellent electrochemiluminescence probe for rapid nonamplified detection of SARS‐CoV‐2.

Comprehensive analysis of codon usage patterns of porcine deltacoronavirus and its host adaptability.

The porcine deltacoronavirus (PDCoV) is a newly discovered pig enteric coronavirus that can infect cells from various species. In Haiti, PDCoV infections in children with acute undifferentiated febrile fever were recently reported. Considering the great potential of inter-species transmission of PDCoV, we performed a comprehensive analysis of codon usage patterns and host adaptation profiles of 54 representative PDCoV strains with the spike (S) gene. Phylogenetic analysis of the PDCoV S gene indicates that the PDCoV strains can be divided into five genogroups. We found a certain codon usage bias existed in the S gene, in which the synonymous codons are often ended with U or A. Heat map analysis revealed that all the PDCoV strains shared a similar codon usage trend. The PDCoV S gene with a dN/dS ratio lower than 1 reveals a negative selection on the PDCoV S gene. Neutrality analysis showed that natural selection is the dominant force in shaping the codon usage bias of the PDCoV S gene. Unexpectedly, host adaptation analysis reveals a higher adaptation level of PDCoV to Homo sapiens and Gallus gallus than to Sus scrofa. Compared to the USA lineage, the PDCoV strains in the Early China lineage and Thailand lineage were less adapted to their hosts, which indicates that the evolutionary process plays an important role in the adaptation ability of PDCoV. These findings of this study add to our understanding of PDCoV's evolution, adaptability, and inter-species transmission.

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants.

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein ­ the so-called spike protein ­ all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.

Is replacing red meat with other protein sources associated with lower risks of coronary heart disease and all-cause mortality? A meta-analysis of prospective studies.

CONTEXT: A high amount of red meat consumption has been associated with higher risks of coronary heart disease (CHD) and all-cause mortality in a single food-exposure model. However, this model may overlook the potentially differential influence of red meat on these outcomes depending on the foods replaced by red meat. OBJECTIVE: A PRISMA-compliant meta-analysis of prospective observational studies was performed to quantify the risks of CHD and all-cause mortality associated with the replacement of total, unprocessed, or processed red meat with fish/seafood, poultry, dairy, eggs, nuts, and legumes. DATA SOURCES: The PubMed and Web of Science databases were searched to identify relevant articles published in any language from database inception to October 30, 2021. DATA EXTRACTION: The prospective observational studies were considered relevant if they reported relative risks (RRs) and 95%CIs for the associations of interest. DATA ANALYSIS: Thirteen articles were included. A random-effects model was used to estimate the summary RRs and 95%CIs for the associations of interest. Replacing total red meat with poultry (RR, 0.88, 95%CI, 0.82-0.96; I2 = 0%), dairy (RR, 0.90, 95%CI, 0.88-0.92; I2 = 0%), eggs (RR, 0.86, 95%CI, 0.79-0.94; I2 = 7.1%), nuts (RR, 0.84, 95%CI, 0.74-0.95; I2 = 66.8%), or legumes (RR, 0.84, 95%CI, 0.74-0.95; I2 = 7.3%) was associated with a lower risk of CHD, whereas substituting fish/seafood (RR, 0.91, 95%CI, 0.79-1.04; I2 = 69.5%) for total red meat was not associated with the risk of CHD. The replacement of total red meat with fish/seafood (RR, 0.92, 95%CI, 0.89-0.96; I2 = 86.9%), poultry (RR, 0.92, 95%CI, 0.90-0.95; I2 = 61.6%), eggs (RR, 0.91, 95%CI, 0.87-0.95; I2 = 33.8%), or nuts (RR, 0.92, 95%CI, 0.87-0.97; I2 = 81.9%) was associated with a lower risk of all-cause mortality, whereas the substitution of dairy (RR, 0.97, 95%CI, 0.93-1.01; I2 = 33.9%) or legumes (RR, 0.97, 95%CI, 0.93-1.01; I2 = 53.5%) for total red meat was not associated with the risk of all-cause mortality. Lower risks of CHD and all-cause mortality were more consistently observed for processed red meat replacements than for unprocessed red meat replacements. The results did not materially change when the analyses of total, processed, and unprocessed red meat were restricted to the studies that used a uniform substitution amount per unit of 1 serving/d. CONCLUSION: Keeping red meat, particularly processed red meat, consumption to a minimum along with increasing healthier alternative protein sources to replace red meat in the diet may contribute to the prevention of CHD and premature death. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021259446.

Nonstructural Protein 1 of Variant PEDV Plays a Key Role in Escaping Replication Restriction by Complement C3.

Zoonotic coronaviruses represent an ongoing threat to public health. The classical porcine epidemic diarrhea virus (PEDV) first appeared in the early 1970s. Since 2010, outbreaks of highly virulent PEDV variants have caused great economic losses to the swine industry worldwide. However, the strategies by which PEDV variants escape host immune responses are not fully understood. Complement component 3 (C3) is considered a central component of the three complement activation pathways and plays a crucial role in preventing viral infection. In this study, we found that C3 significantly inhibited PEDV replication in vitro, and both variant and classical PEDV strains induced high levels of interleukin-1ß (IL-1ß) in Huh7 cells. However, the PEDV variant strain reduces C3 transcript and protein levels induced by IL-1ß compared with the PEDV classical strain. Examination of key molecules of the C3 transcriptional signaling pathway revealed that variant PEDV reduced C3 by inhibiting CCAAT/enhancer-binding protein ß (C/EBP-ß) phosphorylation. Mechanistically, PEDV nonstructural protein 1 (NSP1) inhibited C/EBP-ß phosphorylation via amino acid residue 50. Finally, we constructed recombinant PEDVs to verify the critical role of amino acid 50 of NSP1 in the regulation of C3 expression. In summary, we identified a novel antiviral role of C3 in inhibiting PEDV replication and the viral immune evasion strategies of PEDV variants. Our study reveals new information on PEDV-host interactions and furthers our understanding of the pathogenic mechanism of this virus. IMPORTANCE The complement system acts as a vital link between the innate and the adaptive immunity and has the ability to recognize and neutralize various pathogens. Activation of the complement system acts as a double-edged sword, as appropriate levels of activation protect against pathogenic infections, but excessive responses can provoke a dramatic inflammatory response and cause tissue damage, leading to pathological processes, which often appear in COVID-19 patients. However, how PEDV, as the most severe coronavirus causing diarrhea in piglets, regulates the complement system has not been previously reported. In this study, for the first time, we identified a novel mechanism of a PEDV variant in the suppression of C3 expression, showing that different coronaviruses and even different subtype strains differ in regulation of C3 expression. In addition, this study provides a deeper understanding of the mechanism of the PEDV variant in immune escape and enhanced virulence.

Lipid-Polymer Hybrid "Particle-in-Particle" Nanostructure Gene Delivery Platform Explored for Lyophilizable DNA and mRNA COVID-19 Vaccines.

SARS-CoV-2 has led to a worldwide pandemic, catastrophically impacting public health and the global economy. Herein, a new class of lipid-modified polymer poly (ß-amino esters) (L-PBAEs) is developed via enzyme-catalyzed esterification and further formulation of the L-PBAEs with poly(d,l-lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-PEG) leads to self-assembly into a "particle-in-particle" (PNP) nanostructure for gene delivery. Out of 24 PNP candidates, the top-performing PNP/C12-PBAE nanoparticles efficiently deliver both DNA and mRNA in vitro and in vivo, presenting enhanced transfection efficacy, sustained gene release behavior, and excellent stability for at least 12 months of storage at -20 °C after lyophilization without loss of transfection efficacy. Encapsulated with spike encoded plasmid DNA and mRNA, the lipid-modified polymeric PNP COVID-19 vaccines successfully elicit spike-specific antibodies and Th1-biased T cell immune responses in immunized mice even after 12 months of lyophilized storage at -20 °C. This newly developed lipid-polymer hybrid PNP nanoparticle system demonstrates a new strategy for both plasmid DNA and mRNA delivery with the capability of long-term lyophilized storage.

The minimal COVID-19 vaccination coverage and efficacy to compensate for a potential increase of transmission contacts, and increased transmission probability of the emerging strains.

BACKGROUND: Mass immunization is a potentially effective approach to finally control the local outbreak and global spread of the COVID-19 pandemic. However, it can also lead to undesirable outcomes if mass vaccination results in increased transmission of effective contacts and relaxation of other public health interventions due to the perceived immunity from the vaccine. METHODS: We designed a mathematical model of COVID-19 transmission dynamics that takes into consideration the epidemiological status, public health intervention status (quarantined/isolated), immunity status of the population, and strain variations. Comparing the control reproduction numbers and the final epidemic sizes (attack rate) in the cases with and without vaccination, we quantified some key factors determining when vaccination in the population is beneficial for preventing and controlling future outbreaks. RESULTS: Our analyses predicted that there is a critical (minimal) vaccine efficacy rate (or a critical quarantine rate) below which the control reproduction number with vaccination is higher than that without vaccination, and the final attack rate in the population is also higher with the vaccination. We also predicted the worst case scenario occurs when a high vaccine coverage rate is achieved for a vaccine with a lower efficacy rate and when the vaccines increase the transmission efficient contacts. CONCLUSIONS: The analyses show that an immunization program with a vaccine efficacy rate below the predicted critical values will not be as effective as simply investing in the contact tracing/quarantine/isolation implementation. We reached similar conclusions by considering the final epidemic size (or attack rates). This research then highlights the importance of monitoring the impact on transmissibility and vaccine efficacy of emerging strains.

Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients in a randomized phase 2 trial.

NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluate the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in BBIBP-CorV recipients in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who have administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, are randomized 1:1 to receive either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The incidence of adverse reactions is low, and the overall safety profile is quite similar between two booster regimens. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster are significantly higher than those by BBIBP-CorV booster against not only SARS-CoV-2 prototype strain but also multiple variants of concerns (VOCs). Especially, the neutralizing antibody GMT against Omicron variant induced by heterologous NVSI-06-08 booster reaches 367.67, which is substantially greater than that boosted by BBIBP-CorV (GMT: 45.03). In summary, NVSI-06-08 is safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which is immunogenically superior to the homologous boost with another dose of BBIBP-CorV.

Effects of COVID-19 vaccination status, vaccine type, and vaccination interval on IVF pregnancy outcomes in infertile couples.

PURPOSE: This study aimed to explore whether the coronavirus disease (COVID-19) vaccination of both partners in infertile couples, different types of COVID-19 vaccines, and the interval between complete vaccination and oocyte retrieval or embryo transfer (ET) affect the quality of embryos and pregnancy rates in in vitro fertilization (IVF). METHODS: This was a prospective cohort study, comprising 735 infertile couples conducted between December 6, 2021, and March 31, 2022, in a single university hospital-based IVF center. The patients were divided into different groups according to the vaccination status of both partners in infertile couples, type of vaccine, and interval between complete vaccination and IVF treatment. The embryo quality and pregnancy rates were compared among different groups. RESULTS: The results showed that embryo quality and pregnancy rates had no significant differences among different groups. The multivariate regression model showed that the vaccination status of both infertile couples, types of vaccines, and intervals had no significant effects on the clinical pregnancy rate. CONCLUSIONS: The vaccination status of both partners in infertile couples, different types of vaccines, and time intervals have no effect on embryo quality and pregnancy rates in IVF. This is the first study to compare the vaccination status of both partners in infertile couples and the impact of different vaccine types on pregnancy rates and embryo quality in detail. Our findings provide evidence of vaccine safety for infertile couples wishing to undergo IVF treatment. This evidence is crucial for decision-making by clinicians and policymakers involved in IVF cycles.

Immunogenicity and safety of NVSI-06-07 as a heterologous booster after priming with BBIBP-CorV: a phase 2 trial.

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1-3 months, 4-6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01-63.85 folds on day 28 after vaccination, whereas only 4.20-16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron.

CT Imaging Research Progress in COVID-19.

The highly contagious novel Coronavirus Disease 2019 (COVID-19) broke out at the end of 2019 and has lasted for nearly one year, and the pandemic is still rampant around the world. The diagnosis of COVID-19 is on the basis of the combination of epidemiological history, clinical symptoms, and laboratory and imaging examinations. Among them, imaging examination is of importance in the diagnosis of patients with suspected clinical cases, the investigation of asymptomatic infections and family clustering, the judgment of patient recovery, rediagnosis after disease recurrence, and prognosis prediction. This article reviews the research progress of CT imaging examination in the COVID-19 pandemic.

An engineered bispecific human monoclonal antibody against SARS-CoV-2.

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.

Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2.

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

Using mobile phone big data to discover the spatial patterns of rural migrant workers’ return to work in China’s three urban agglomerations in the post-COVID-19 era

Knowing how workers return to work is a key policymaking issue for economic recovery in the post-COVID-19 era. This paper uses country-wide time-series mobile phone big data (comparing monthly and annual figures), obtained between February 2019 and October 2019 and between February 2020 and October 2020, to discover the spatial patterns of rural migrant workers? (RMWs?) return to work in China?s three urban agglomerations (UAs): the Beijing?Tianjin?Hebei Region, the Yangtze River Delta and the Pearl River Delta. Spatial patterns of RMWs? return to work and how these patterns vary with location, city level and human attribute were investigated using the fine-scale social sensing related to post-pandemic human mobility. The results confirmed the multidimensional spatiotemporal differentiations, interaction effects between variable pairs and effects of the actual situation on the changing patterns of RMWs? return to work. The spatial patterns of RMWs? return to work in China?s major three UAs can be regarded as a comprehensive and complex interaction result accompanying the nationwide population redistribution, which was affected by various hidden factors. Our findings provide crucial implications and suggestions for data-informed policy decisions for a harmonious society in the post-COVID-19 era.