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Sea Life Simulation Model Toy, Manual Drawing Animal Model Figures, For (hippocampus)
By Shen Wang 1, † , Ling Li 2, † , Feihu Yan 1, * , Yuwei Gao 1, * , Songtao Yang 1, * and Xianzhu Xia 1
Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China
The worldwide pandemic of coronavirus disease 2019 (COVID-19) has become an unprecedented challenge to global public health. With the intensification of the COVID-19 epidemic, the development of vaccines and therapeutic drugs against the etiological agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also widespread. To prove the effectiveness and safety of these preventive vaccines and therapeutic drugs, available animal models that faithfully recapitulate clinical hallmarks of COVID-19 are urgently needed. Currently, animal models including mice, golden hamsters, ferrets, nonhuman primates, and other susceptible animals have been involved in the study of COVID-19. Moreover, 117 vaccine candidates have entered clinical trials after the primary evaluation in animal models, of which inactivated vaccines, subunit vaccines, virus-vectored vaccines, and messenger ribonucleic acid (mRNA) vaccines are promising vaccine candidates. In this review, we summarize the landscape of animal models for COVID-19 vaccine evaluation and advanced vaccines with an efficacy range from about 50% to more than 95%. In addition, we point out future directions for COVID-19 animal models and vaccine development, aiming at providing valuable information and accelerating the breakthroughs confronting SARS-CoV-2.
Model Tree Classifier For Large Scale Classification
In December 2019, a previously unknown beta coronavirus causing human pneumonia emerged and was soon isolated, named 2019-nCoV [1]. Subsequently, the virus was renamed SARS-CoV-2 and the syndrome was named COVID-19 by the World Health Organization (WHO) [2]. By 17th September 2021, over 226 billion COVID-19 cases have been confirmed, causing 4.65 million deaths worldwide [3]. The progression and dissemination of COVID-19 seriously threatened international health security and caused an immeasurable loss on the global economy. As a result, scientists all over the world are embarking on prophylactic and therapeutic research on SARS-CoV-2.
SARS-CoV-2 is an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) virus encoding 16 non-structural proteins (nsp1-nsp16), several accessory proteins, and four structural proteins, including spike surface glycoprotein (S), matrix protein (M), small envelope protein (E), and nucleocapsid protein (N) [4]. S protein plays a key role in mediating the virus entry via interacting with the receptors of the host cell, and is considered as the main target to induce neutralizing antibodies (NAbs). S protein is composed of S1 and S2 subunits, of which the S1 subunit functions as a receptor-binding subunit while the S2 subunit mediates membrane fusion. Within S1, a region with 194 residues named the receptor binding domain (RBD) is identified as the core sequence for SARS-CoV-2 binding to a host cell. RBD shows a high binding affinity to human angiotensin-converting enzyme 2 (hACE2) and serves the entry and infection of SARS-CoV-2 [5, 6]. Some enzymes, including transmembrane protease serine 2 (TMPRSS2), cathepsin B/L, and RNA-dependent RNA polymerase (RdRp) are key regulators of viral entry, replication, and transcription [5].
This life-threatening COVID-19 is characterized by symptoms of viral pneumonia, including fever, cough, and chest discomfort. In severe cases, dyspnea and bilateral lung infiltration are observed [1, 7]. Generally speaking, elderly patients with comorbidities face a higher risk for SARS-CoV-2 infection and unfavorable prognosis. Current medical knowledge and research on COVID-19 for severe and critical patients’ management and experimental treatments are still evolving, but several protocols on minimizing the risk of infection among the general population, patients, and healthcare workers have been approved and diffused by International Health Authorities [8].
Categories Of Animal Models
Besides the above issues about COVID-19, including clinical characteristics as well as countermeasures, animal models recapitulating the transmission characteristic, pathology, and corresponding immunological response to COVID-19 are foundational and urgent needs. Although great progress has been achieved in the development of prophylactic and therapeutic measures, only a few products have been proven effective. Currently, animal models involved in the study of COVID-19 include mice, golden hamsters, ferrets, nonhuman primates, and pigs. More than 302 vaccine candidates are under development, of which 117 of them have successfully entered clinical trials [9]. Herein, we briefly discuss popular animal models in vaccine evaluation and cutting-edge vaccines of COVID-19, followed by a detailed discussion of their commonalities and personalities as well as their pros and cons. We aim to grasp key information regarding animal models and vaccine research of COVID-19 and provide references for subsequent breakthroughs.
Before clinical trials, COVID-19 vaccines need pre-clinical evaluations to ensure their safety and efficacy. COVID-19 animal models are fundamental and essential needs in this phase. Here, we retrospected the basic background and the development paths of COVID-19 animal models. More importantly, we paid close attention to the unique features that animal models required for COVID-19 vaccine evaluation. Animal models as well as susceptible animals (potential animal models) of COVID-19 were summarized in Figure 1. Characteristics of these animal models were summarized in Table 1.
Mouse models are the most frequently used animal models in the preclinical study of vaccines. Mouse models are economical, abundant, well-characterized, easy to handle and manipulate, which are all characteristics that support the extensive development of mouse models. However, SARS-CoV-2 exhibited limited affinity to murine ACE2 [10], indicating that mouse models are less susceptible to SARS-CoV-2, which hindered the full application of mouse models. Subsequently, this issue was handled from three directions: hACE2 transgenic mice, hACE2 transduced mice as well as mice-adapted SARS-CoV-2.
Cross Species Behavior Analysis With Attention Based Domain Adversarial Deep Neural Networks
In the hACE2 transgenic C3B6 mouse [11], a high viral load in lungs and pre-exposure protection were accomplished. Based on CRISPR/Cas9 knock-in technology, the mACE2 gene of the C57BL/6 mouse model was completely replaced with hACE2 (termed hACE2 mice) [12]. Viral loads, interstitial pneumonia, and elevated cytokines occurred in SARS-CoV-2 infected hACE2 mice. In hACE2 mice, the viral RNA load in the lungs was much higher and the distribution of hACE2 in various tissues was more in line with human conditions in comparison to other hACE2 genetically engineered mice generated by pronuclear microinjection [11, 13]. In particular, the pathological changes observed in aged hACE2 mice were more obvious. Interestingly, intragastric infection of SARS-CoV-2 has been established in hACE2 mice, suggesting that the intestinal tract may be another transmission route of SARS-CoV-2. For mucosal-associated COVID-19 vaccines, especially oral vaccines, hACE2 mice are a reasonable choice. Besides, transgenic hACE2 mice models exhibited typical pathological changes in lungs for SARS-CoV-2-induced acute respiratory illness [14]. This is of significance for the evaluation of vaccines against SARS-CoV-2-induced severe acute respiratory distress syndrome (ARDS).
The hACE2-transduced models were established by transducing hACE2 mainly through replication-defective adenoviruses in BALB/c and C57BL/6 mice [15, 16]. Corresponding clinical signs (weight loss, severe pulmonary pathology) and virus replication in the lungs were observed in hACE2-transduced models after SARS-CoV-2 infection. However, anti-vector immunity limits the full application of this animal model to a certain extent.
Mouse-adapted SARS-CoV-2 was obtained by serial passages, of which MASCp6 was achieved after six passages of SARS-CoV-2 in aged (9 months old) BALB/c mice. MASCp6 efficiently infected both the aged and young (6 weeks old) BALB/c mice. It replicated efficiently in the lung and trachea, resulting in moderate pneumonia as well as inflammatory responses [17]. A key substitution of N501Y in RBD was predicted to contribute to the enhanced infectivity of MACSp6 in mice. Besides, a mouse-adapted SARS-CoV-2 HRB26M efficiently infected the upper and lower respiratory tract of young BALB/c mice and C57BL/6J mice [18]. Subsequently, a lethal mouse-adapted SARS-CoV-2 MA10, which caused acute lung injury (ALI) in young and aged BALB/c mice, was isolated after ten passages in young BALB/c mice. It exhibited the epidemiological characteristics of COVID-19 disease as well as aspects of host genetics, age, cellular tropisms, elevated Th1 cytokines, and loss of surfactant expression and pulmonary function linked to the pathological features of ALI [19]. Interestingly, SARS-CoV-2 MA10 showed no mortality in ten-week-old C57BL/6J mice. The process of adaptation introduced multiple point mutations into the virus genome that are responsible for increasing virulence; yet whether this artificially-introduced genetic divergence compromises the relevance of the adapted viruses in the first place
Pdf] Tradition, Not Science, Is The Basis Of Animal Model Selection In Translational And Applied Research.
Besides the above issues about COVID-19, including clinical characteristics as well as countermeasures, animal models recapitulating the transmission characteristic, pathology, and corresponding immunological response to COVID-19 are foundational and urgent needs. Although great progress has been achieved in the development of prophylactic and therapeutic measures, only a few products have been proven effective. Currently, animal models involved in the study of COVID-19 include mice, golden hamsters, ferrets, nonhuman primates, and pigs. More than 302 vaccine candidates are under development, of which 117 of them have successfully entered clinical trials [9]. Herein, we briefly discuss popular animal models in vaccine evaluation and cutting-edge vaccines of COVID-19, followed by a detailed discussion of their commonalities and personalities as well as their pros and cons. We aim to grasp key information regarding animal models and vaccine research of COVID-19 and provide references for subsequent breakthroughs.
Before clinical trials, COVID-19 vaccines need pre-clinical evaluations to ensure their safety and efficacy. COVID-19 animal models are fundamental and essential needs in this phase. Here, we retrospected the basic background and the development paths of COVID-19 animal models. More importantly, we paid close attention to the unique features that animal models required for COVID-19 vaccine evaluation. Animal models as well as susceptible animals (potential animal models) of COVID-19 were summarized in Figure 1. Characteristics of these animal models were summarized in Table 1.
Mouse models are the most frequently used animal models in the preclinical study of vaccines. Mouse models are economical, abundant, well-characterized, easy to handle and manipulate, which are all characteristics that support the extensive development of mouse models. However, SARS-CoV-2 exhibited limited affinity to murine ACE2 [10], indicating that mouse models are less susceptible to SARS-CoV-2, which hindered the full application of mouse models. Subsequently, this issue was handled from three directions: hACE2 transgenic mice, hACE2 transduced mice as well as mice-adapted SARS-CoV-2.
Cross Species Behavior Analysis With Attention Based Domain Adversarial Deep Neural Networks
In the hACE2 transgenic C3B6 mouse [11], a high viral load in lungs and pre-exposure protection were accomplished. Based on CRISPR/Cas9 knock-in technology, the mACE2 gene of the C57BL/6 mouse model was completely replaced with hACE2 (termed hACE2 mice) [12]. Viral loads, interstitial pneumonia, and elevated cytokines occurred in SARS-CoV-2 infected hACE2 mice. In hACE2 mice, the viral RNA load in the lungs was much higher and the distribution of hACE2 in various tissues was more in line with human conditions in comparison to other hACE2 genetically engineered mice generated by pronuclear microinjection [11, 13]. In particular, the pathological changes observed in aged hACE2 mice were more obvious. Interestingly, intragastric infection of SARS-CoV-2 has been established in hACE2 mice, suggesting that the intestinal tract may be another transmission route of SARS-CoV-2. For mucosal-associated COVID-19 vaccines, especially oral vaccines, hACE2 mice are a reasonable choice. Besides, transgenic hACE2 mice models exhibited typical pathological changes in lungs for SARS-CoV-2-induced acute respiratory illness [14]. This is of significance for the evaluation of vaccines against SARS-CoV-2-induced severe acute respiratory distress syndrome (ARDS).
The hACE2-transduced models were established by transducing hACE2 mainly through replication-defective adenoviruses in BALB/c and C57BL/6 mice [15, 16]. Corresponding clinical signs (weight loss, severe pulmonary pathology) and virus replication in the lungs were observed in hACE2-transduced models after SARS-CoV-2 infection. However, anti-vector immunity limits the full application of this animal model to a certain extent.
Mouse-adapted SARS-CoV-2 was obtained by serial passages, of which MASCp6 was achieved after six passages of SARS-CoV-2 in aged (9 months old) BALB/c mice. MASCp6 efficiently infected both the aged and young (6 weeks old) BALB/c mice. It replicated efficiently in the lung and trachea, resulting in moderate pneumonia as well as inflammatory responses [17]. A key substitution of N501Y in RBD was predicted to contribute to the enhanced infectivity of MACSp6 in mice. Besides, a mouse-adapted SARS-CoV-2 HRB26M efficiently infected the upper and lower respiratory tract of young BALB/c mice and C57BL/6J mice [18]. Subsequently, a lethal mouse-adapted SARS-CoV-2 MA10, which caused acute lung injury (ALI) in young and aged BALB/c mice, was isolated after ten passages in young BALB/c mice. It exhibited the epidemiological characteristics of COVID-19 disease as well as aspects of host genetics, age, cellular tropisms, elevated Th1 cytokines, and loss of surfactant expression and pulmonary function linked to the pathological features of ALI [19]. Interestingly, SARS-CoV-2 MA10 showed no mortality in ten-week-old C57BL/6J mice. The process of adaptation introduced multiple point mutations into the virus genome that are responsible for increasing virulence; yet whether this artificially-introduced genetic divergence compromises the relevance of the adapted viruses in the first place
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