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2_test

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T97","span":{"begin":126,"end":139},"obj":"Body_part"},{"id":"T98","span":{"begin":1508,"end":1513},"obj":"Body_part"},{"id":"T99","span":{"begin":6080,"end":6085},"obj":"Body_part"},{"id":"T100","span":{"begin":8579,"end":8584},"obj":"Body_part"},{"id":"T101","span":{"begin":8963,"end":8968},"obj":"Body_part"},{"id":"T102","span":{"begin":9235,"end":9240},"obj":"Body_part"}],"attributes":[{"id":"A97","pred":"uberon_id","subj":"T97","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A98","pred":"uberon_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/UBERON_0001977"},{"id":"A99","pred":"uberon_id","subj":"T99","obj":"http://purl.obolibrary.org/obo/UBERON_0002542"},{"id":"A100","pred":"uberon_id","subj":"T100","obj":"http://purl.obolibrary.org/obo/UBERON_0001443"},{"id":"A101","pred":"uberon_id","subj":"T101","obj":"http://purl.obolibrary.org/obo/UBERON_0001443"},{"id":"A102","pred":"uberon_id","subj":"T102","obj":"http://purl.obolibrary.org/obo/UBERON_0001443"}],"text":"Neutralizing Antibodies and Convalescent Plasma Therapy for COVID-19\nWhile vaccines are being developed to educate a person’s immune system to make their own nAbs against SARS-CoV-2, there is interest in using adoptive transfer of nAbs as a therapeutic approach (Figure 6D). This strategy has already proven to be effective against SARS-CoV-1 (Cao et al., 2010, Ho et al., 2005, ter Meulen et al., 2004, Park et al., 2020, Sui et al., 2004, Zhu et al., 2007) and MERS-CoV (Forni et al., 2015, Jia et al., 2019, Ying et al., 2015). In the case of SARS-CoV-2, these efforts are primarily centered on identifying nAbs made during natural infections or generating nAbs through animal vaccination approaches.\n\nnAbs Derived from COVID-19 Patients\nPatients who have recovered from SARS-CoV-2 infection are one potential source of nAbs (Chen et al., 2020a, Ju et al., 2020, Walls et al., 2020, Wölfel et al., 2020, Yuan et al., 2020). In an effort to obtain these nAbs, scientists sorted RBD-specific memory B cells and cloned their heavy and light variable regions to express recombinant forms of the corresponding antibodies (Chen et al., 2020a, Ju et al., 2020). Four of the antibodies produced in these studies (31B5, 32D4, P2C-2F6, P2C-1F11) showed high neutralizing potential in vitro, and all inhibited ACE2-RBD binding. Successful antibody-mediated neutralization of SARS-CoV-2 seemed to be dependent on the inhibition of ACE2/RBD binding. However, Chen et al. showed that nearly all antibodies derived from serum of 26 recovered patients bound to S1 and RBD, with only three actually inhibiting ACE2/RBD binding (Chen et al., 2020a). Of note, a SARS-CoV-1-derived neutralizing antibody (47D11) (Wang et al., 2020a) and a single-chain antibody against SARS-CoV-2 (n3130) (Wu et al., 2020c) have also been shown to neutralize SARS-CoV-2 without inhibiting ACE2/RBD binding. Thus, blocking this interaction may not be a prerequisite for an effective SARS-CoV-2 nAb. The generation of a hybridoma producing a monoclonal nAb against SARS-CoV-2 provides the potential for a therapeutic Ab that can be directly administered to patients to block ongoing infection and potentially even as a prophylactic (Figure 6D).\n\nSARS-CoV-1 nAbs Also Neutralize SARS-CoV-2\nSARS-CoV-1 and SARS-CoV-2 consensus sequences share about 80% identity (Tai et al., 2020). Thus, a wide range of SARS-CoV-1 nAbs have been tested for crossreactivity with SARS-CoV-2, as they could help speed up the development of potential COVID-19 treatments. In a recent study, antibodies were isolated from the memory B cells of an individual who recovered from SARS-CoV-1 infection. While 8 out of 25 isolated antibodies could bind SARS-CoV-2 S protein, one of them (s309; see Table 3 ) also neutralizes SARS-CoV-2 (Pinto et al., 2020). The combination of s309 with a weakly neutralizing antibody that could bind another RBD epitope led to enhanced neutralization potency. In addition, CR3022 (Table 3) was found to bind SARS-CoV-2 RBD (Tian et al., 2020b), but this antibody did not neutralize SARS-CoV-2 (Yuan et al., 2020). Computational simulations identified three amino acids that could be modified on CR3022 to enhance its binding affinity with SARS-CoV-2 RBD (Giron et al., 2020), potentially augmenting its neutralization potential.\nTable 3 Strategies to Isolate SARS-CoV-2 Neutralizing Antibodies\nAb Source Clone Target Type of Antibody Neutralization Inhibition of ACE2/RBD Binding Reference\nDerived from COVID-19 patients 31B532D4 RBD human monoclonal yes yes Chen et al., 2020a\nP2C-2F6P2C-1F11 RBD human monoclonal yes yes Ju et al., 2020\nDerived from SARS-CoV-1 patients CR3022 RBD human monoclonal no no Tian et al., 2020b, Yuan et al., 2020, Giron et al., 2020\nS309 RBD human monoclonal yes no Pinto et al., 2020\nDerived from SARS-CoV-1 or MERS-CoV-1 animal models R325R302R007 S1 rabbit monoclonal yes no Sun et al., 2020\n47D11 S1 recombinant human monoclonal (derived from hybridomas of immunized transgenic H2L2 mice) yes no Wang et al., 2020a\nVHH-72-Fc S Fc-fusion derived from camelids VHH yes yes Wrapp et al., 2020\nS polyclonal mouse antibodies yes N/A Walls et al., 2020, Yuan et al., 2020\nOther ACE2-Fc RBD ACE2-Fc fusion yes N/A Lei et al., 2020a, Li et al., 2020d\nRBD-Fc ACE2 RBD-Fc fusion yes N/A Li et al., 2020d\nN3130 S1 human monoclonal single domain antibody isolated by phage display yes no Wu et al., 2020c\nIVIg N/A polyclonal human IVIg N/A N/A Díez et al., 2020, Shao et al., 2020\nF(ab′)2 RBD horse polyclonal yes N/A Pan et al., 2020\nN/A, not assessed.\n\nnAbs Derived from Animals\nAnimal models represent another tool to generate nAbs against SARS-CoV-2 (Table 3). In one study, the authors developed a protocol to synthetize human nanobodies, smaller antibodies that only contain a variable heavy (VH) chain as first described in camelids (Wu et al., 2020c) (Figure 6D). Another antibody isolated from camelids immunized with SARS-CoV-1 and MERS-CoV S proteins then fused to a human Fc fragment showed neutralization potential against SARS-CoV-2 (VHH-72-Fc) (Wrapp et al., 2020). Genetically modified mice with humanized antibody genes can also be used to generate therapeutic monoclonal antibodies, as successfully experimented against Ebola virus (Levine, 2019). Similar studies are now focused on the use of SARS-CoV-2 or derivatives to generate highly effective nAb in animal models, which can be directly given to infected patients, and efforts are already underway with estimates of clinical trials of pooled antibody cocktails beginning in early summer by Regeneron. Finally, another approach to nAb development is to fuse ACE2 protein and the Fc part of antibodies, as they would bind RBD and potentially be crossreactive among other CoVs (Figure 6D). Indeed, an ACE2-Fc (Lei et al., 2020a) and an RBD-Fc (Li et al., 2020d) have been shown to neutralize both SARS-CoV-1 and SARS-CoV-2 in vitro.\n\nConvalescent Plasma Therapy\nAlthough recombinant nAbs could provide an effective treatment, they will require a significant time investment to develop, test, and bring production to scale before becoming widely available to patients. A faster strategy consists of transferring convalescent plasma (CP) from previously infected individuals that have developed high titer nAbs that target SARS-CoV-2 (Figure 6D). Despite the current lack of appropriately controlled trials, CP therapy has been previously used and shown to be beneficial in several infectious diseases, such as the 1918 influenza pandemic (Luke et al., 2006), H1N1 influenza (Hung et al., 2011), and SARS-CoV-1 (Arabi et al., 2016). Thanks to the development of serological tests (Amanat et al., 2020, Cai et al., 2020, Xiang et al., 2020b, Zhang et al., 2020d), recovered COVID-19 patients can be screened to select plasma with high antibody titers.\nSome studies and case reports on CP therapy for COVID-19 have evaluated the safety and the potential effectiveness of CP therapy in patients with severe disease (Ahn et al., 2020, Duan et al., 2020, Pei et al., 2020, Shen et al., 2020, Zhang et al., 2020b) (Table 4 ). These studies were neither controlled nor randomized, but they suggest that CP therapy is safe and can have a beneficial effect on the clinical course of disease. Further controlled trials are needed to determine the optimal timing and indication for CP therapy. CP therapy has also been proposed for prophylactic use in at-risk individuals, such as those with underlying health conditions or health care workers exposed to COVID-19 patients. The FDA has approved the use of CP to treat critically ill patients (Tanne, 2020). Determining when to administer the CP is also of great importance, as a study in SARS-CoV-1 patients showed that CP was much more efficient when given to patients before day 14 day of illness (Cheng et al., 2005b), as previously shown in influenza (Luke et al., 2006). This study also showed that CP therapy was more efficient in PCR-positive, seronegative patients. The amount of plasma and number of transfusions needed requires further investigation (Table 4).\nTable 4 Clinical Studies of Convalescent Plasma Therapy in COVID-19 Patients\nPatient Characteristics Start of CP Therapy Results Reference\n5 severe patients (30–70 yo) between 10 and 22 days after hospital admission body temperature normalized within 3 days in 4 of 5 patients Shen et al., 2020\nclinical improvement\nviral loads became negative within 12 days of the transfusion\nnAb titers increased\n10 severe patients (34–78 yo) median 16.5 dpo disappearance of clinical symptoms after 3d Duan et al., 2020\nchest CT improved\nelevation of lymphocyte counts in patients with lymphocytopenia.\nincrease in SaO2 in all patients\nresolution of SARS-CoV-2 viremia in 7 patients\nincrease in neutralizing antibody titers in 5 patients\n4 critical patients (31–73 yo) at degradation of symptoms,between 11 and 19 days after hospital admission clinical improvement Zhang et al., 2020b\nreduced viral load\nchest CT improved\n1 moderate patient, 2 critical patients 12 dpo, 27 dpo viral detection negative 4 days after CP Pei et al., 2020\nclinical improvement of 2 patients\n2 severe patients (67 and 71 yo) 7 dpo or 22 dpo clinical improvement Ahn et al., 2020\nreduced viral load\nchest CT improved\nyo, years old; dpo, days post onset of symptoms.\nOverall, CP therapy seems to be associated with improved outcomes and appears to be safe, but RCTs are needed to confirm this. Several clinical trials are currently in progress worldwide (Belhadi et al., 2020)."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T58","span":{"begin":8645,"end":8660},"obj":"Phenotype"},{"id":"T59","span":{"begin":8720,"end":8727},"obj":"Phenotype"}],"attributes":[{"id":"A58","pred":"hp_id","subj":"T58","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A59","pred":"hp_id","subj":"T59","obj":"http://purl.obolibrary.org/obo/HP_0020071"}],"text":"Neutralizing Antibodies and Convalescent Plasma Therapy for COVID-19\nWhile vaccines are being developed to educate a person’s immune system to make their own nAbs against SARS-CoV-2, there is interest in using adoptive transfer of nAbs as a therapeutic approach (Figure 6D). This strategy has already proven to be effective against SARS-CoV-1 (Cao et al., 2010, Ho et al., 2005, ter Meulen et al., 2004, Park et al., 2020, Sui et al., 2004, Zhu et al., 2007) and MERS-CoV (Forni et al., 2015, Jia et al., 2019, Ying et al., 2015). In the case of SARS-CoV-2, these efforts are primarily centered on identifying nAbs made during natural infections or generating nAbs through animal vaccination approaches.\n\nnAbs Derived from COVID-19 Patients\nPatients who have recovered from SARS-CoV-2 infection are one potential source of nAbs (Chen et al., 2020a, Ju et al., 2020, Walls et al., 2020, Wölfel et al., 2020, Yuan et al., 2020). In an effort to obtain these nAbs, scientists sorted RBD-specific memory B cells and cloned their heavy and light variable regions to express recombinant forms of the corresponding antibodies (Chen et al., 2020a, Ju et al., 2020). Four of the antibodies produced in these studies (31B5, 32D4, P2C-2F6, P2C-1F11) showed high neutralizing potential in vitro, and all inhibited ACE2-RBD binding. Successful antibody-mediated neutralization of SARS-CoV-2 seemed to be dependent on the inhibition of ACE2/RBD binding. However, Chen et al. showed that nearly all antibodies derived from serum of 26 recovered patients bound to S1 and RBD, with only three actually inhibiting ACE2/RBD binding (Chen et al., 2020a). Of note, a SARS-CoV-1-derived neutralizing antibody (47D11) (Wang et al., 2020a) and a single-chain antibody against SARS-CoV-2 (n3130) (Wu et al., 2020c) have also been shown to neutralize SARS-CoV-2 without inhibiting ACE2/RBD binding. Thus, blocking this interaction may not be a prerequisite for an effective SARS-CoV-2 nAb. The generation of a hybridoma producing a monoclonal nAb against SARS-CoV-2 provides the potential for a therapeutic Ab that can be directly administered to patients to block ongoing infection and potentially even as a prophylactic (Figure 6D).\n\nSARS-CoV-1 nAbs Also Neutralize SARS-CoV-2\nSARS-CoV-1 and SARS-CoV-2 consensus sequences share about 80% identity (Tai et al., 2020). Thus, a wide range of SARS-CoV-1 nAbs have been tested for crossreactivity with SARS-CoV-2, as they could help speed up the development of potential COVID-19 treatments. In a recent study, antibodies were isolated from the memory B cells of an individual who recovered from SARS-CoV-1 infection. While 8 out of 25 isolated antibodies could bind SARS-CoV-2 S protein, one of them (s309; see Table 3 ) also neutralizes SARS-CoV-2 (Pinto et al., 2020). The combination of s309 with a weakly neutralizing antibody that could bind another RBD epitope led to enhanced neutralization potency. In addition, CR3022 (Table 3) was found to bind SARS-CoV-2 RBD (Tian et al., 2020b), but this antibody did not neutralize SARS-CoV-2 (Yuan et al., 2020). Computational simulations identified three amino acids that could be modified on CR3022 to enhance its binding affinity with SARS-CoV-2 RBD (Giron et al., 2020), potentially augmenting its neutralization potential.\nTable 3 Strategies to Isolate SARS-CoV-2 Neutralizing Antibodies\nAb Source Clone Target Type of Antibody Neutralization Inhibition of ACE2/RBD Binding Reference\nDerived from COVID-19 patients 31B532D4 RBD human monoclonal yes yes Chen et al., 2020a\nP2C-2F6P2C-1F11 RBD human monoclonal yes yes Ju et al., 2020\nDerived from SARS-CoV-1 patients CR3022 RBD human monoclonal no no Tian et al., 2020b, Yuan et al., 2020, Giron et al., 2020\nS309 RBD human monoclonal yes no Pinto et al., 2020\nDerived from SARS-CoV-1 or MERS-CoV-1 animal models R325R302R007 S1 rabbit monoclonal yes no Sun et al., 2020\n47D11 S1 recombinant human monoclonal (derived from hybridomas of immunized transgenic H2L2 mice) yes no Wang et al., 2020a\nVHH-72-Fc S Fc-fusion derived from camelids VHH yes yes Wrapp et al., 2020\nS polyclonal mouse antibodies yes N/A Walls et al., 2020, Yuan et al., 2020\nOther ACE2-Fc RBD ACE2-Fc fusion yes N/A Lei et al., 2020a, Li et al., 2020d\nRBD-Fc ACE2 RBD-Fc fusion yes N/A Li et al., 2020d\nN3130 S1 human monoclonal single domain antibody isolated by phage display yes no Wu et al., 2020c\nIVIg N/A polyclonal human IVIg N/A N/A Díez et al., 2020, Shao et al., 2020\nF(ab′)2 RBD horse polyclonal yes N/A Pan et al., 2020\nN/A, not assessed.\n\nnAbs Derived from Animals\nAnimal models represent another tool to generate nAbs against SARS-CoV-2 (Table 3). In one study, the authors developed a protocol to synthetize human nanobodies, smaller antibodies that only contain a variable heavy (VH) chain as first described in camelids (Wu et al., 2020c) (Figure 6D). Another antibody isolated from camelids immunized with SARS-CoV-1 and MERS-CoV S proteins then fused to a human Fc fragment showed neutralization potential against SARS-CoV-2 (VHH-72-Fc) (Wrapp et al., 2020). Genetically modified mice with humanized antibody genes can also be used to generate therapeutic monoclonal antibodies, as successfully experimented against Ebola virus (Levine, 2019). Similar studies are now focused on the use of SARS-CoV-2 or derivatives to generate highly effective nAb in animal models, which can be directly given to infected patients, and efforts are already underway with estimates of clinical trials of pooled antibody cocktails beginning in early summer by Regeneron. Finally, another approach to nAb development is to fuse ACE2 protein and the Fc part of antibodies, as they would bind RBD and potentially be crossreactive among other CoVs (Figure 6D). Indeed, an ACE2-Fc (Lei et al., 2020a) and an RBD-Fc (Li et al., 2020d) have been shown to neutralize both SARS-CoV-1 and SARS-CoV-2 in vitro.\n\nConvalescent Plasma Therapy\nAlthough recombinant nAbs could provide an effective treatment, they will require a significant time investment to develop, test, and bring production to scale before becoming widely available to patients. A faster strategy consists of transferring convalescent plasma (CP) from previously infected individuals that have developed high titer nAbs that target SARS-CoV-2 (Figure 6D). Despite the current lack of appropriately controlled trials, CP therapy has been previously used and shown to be beneficial in several infectious diseases, such as the 1918 influenza pandemic (Luke et al., 2006), H1N1 influenza (Hung et al., 2011), and SARS-CoV-1 (Arabi et al., 2016). Thanks to the development of serological tests (Amanat et al., 2020, Cai et al., 2020, Xiang et al., 2020b, Zhang et al., 2020d), recovered COVID-19 patients can be screened to select plasma with high antibody titers.\nSome studies and case reports on CP therapy for COVID-19 have evaluated the safety and the potential effectiveness of CP therapy in patients with severe disease (Ahn et al., 2020, Duan et al., 2020, Pei et al., 2020, Shen et al., 2020, Zhang et al., 2020b) (Table 4 ). These studies were neither controlled nor randomized, but they suggest that CP therapy is safe and can have a beneficial effect on the clinical course of disease. Further controlled trials are needed to determine the optimal timing and indication for CP therapy. CP therapy has also been proposed for prophylactic use in at-risk individuals, such as those with underlying health conditions or health care workers exposed to COVID-19 patients. The FDA has approved the use of CP to treat critically ill patients (Tanne, 2020). Determining when to administer the CP is also of great importance, as a study in SARS-CoV-1 patients showed that CP was much more efficient when given to patients before day 14 day of illness (Cheng et al., 2005b), as previously shown in influenza (Luke et al., 2006). This study also showed that CP therapy was more efficient in PCR-positive, seronegative patients. The amount of plasma and number of transfusions needed requires further investigation (Table 4).\nTable 4 Clinical Studies of Convalescent Plasma Therapy in COVID-19 Patients\nPatient Characteristics Start of CP Therapy Results Reference\n5 severe patients (30–70 yo) between 10 and 22 days after hospital admission body temperature normalized within 3 days in 4 of 5 patients Shen et al., 2020\nclinical improvement\nviral loads became negative within 12 days of the transfusion\nnAb titers increased\n10 severe patients (34–78 yo) median 16.5 dpo disappearance of clinical symptoms after 3d Duan et al., 2020\nchest CT improved\nelevation of lymphocyte counts in patients with lymphocytopenia.\nincrease in SaO2 in all patients\nresolution of SARS-CoV-2 viremia in 7 patients\nincrease in neutralizing antibody titers in 5 patients\n4 critical patients (31–73 yo) at degradation of symptoms,between 11 and 19 days after hospital admission clinical improvement Zhang et al., 2020b\nreduced viral load\nchest CT improved\n1 moderate patient, 2 critical patients 12 dpo, 27 dpo viral detection negative 4 days after CP Pei et al., 2020\nclinical improvement of 2 patients\n2 severe patients (67 and 71 yo) 7 dpo or 22 dpo clinical improvement Ahn et al., 2020\nreduced viral load\nchest CT improved\nyo, years old; dpo, days post onset of symptoms.\nOverall, CP therapy seems to be associated with improved outcomes and appears to be safe, but RCTs are needed to confirm this. Several clinical trials are currently in progress worldwide (Belhadi et al., 2020)."}

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T1","span":{"begin":8831,"end":8842},"obj":"http://purl.obolibrary.org/obo/GO_0009056"},{"id":"T210","span":{"begin":993,"end":999},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T211","span":{"begin":1331,"end":1363},"obj":"http://purl.obolibrary.org/obo/GO_0097282"},{"id":"T212","span":{"begin":2567,"end":2573},"obj":"http://purl.obolibrary.org/obo/GO_0007613"}],"text":"Neutralizing Antibodies and Convalescent Plasma Therapy for COVID-19\nWhile vaccines are being developed to educate a person’s immune system to make their own nAbs against SARS-CoV-2, there is interest in using adoptive transfer of nAbs as a therapeutic approach (Figure 6D). This strategy has already proven to be effective against SARS-CoV-1 (Cao et al., 2010, Ho et al., 2005, ter Meulen et al., 2004, Park et al., 2020, Sui et al., 2004, Zhu et al., 2007) and MERS-CoV (Forni et al., 2015, Jia et al., 2019, Ying et al., 2015). In the case of SARS-CoV-2, these efforts are primarily centered on identifying nAbs made during natural infections or generating nAbs through animal vaccination approaches.\n\nnAbs Derived from COVID-19 Patients\nPatients who have recovered from SARS-CoV-2 infection are one potential source of nAbs (Chen et al., 2020a, Ju et al., 2020, Walls et al., 2020, Wölfel et al., 2020, Yuan et al., 2020). In an effort to obtain these nAbs, scientists sorted RBD-specific memory B cells and cloned their heavy and light variable regions to express recombinant forms of the corresponding antibodies (Chen et al., 2020a, Ju et al., 2020). Four of the antibodies produced in these studies (31B5, 32D4, P2C-2F6, P2C-1F11) showed high neutralizing potential in vitro, and all inhibited ACE2-RBD binding. Successful antibody-mediated neutralization of SARS-CoV-2 seemed to be dependent on the inhibition of ACE2/RBD binding. However, Chen et al. showed that nearly all antibodies derived from serum of 26 recovered patients bound to S1 and RBD, with only three actually inhibiting ACE2/RBD binding (Chen et al., 2020a). Of note, a SARS-CoV-1-derived neutralizing antibody (47D11) (Wang et al., 2020a) and a single-chain antibody against SARS-CoV-2 (n3130) (Wu et al., 2020c) have also been shown to neutralize SARS-CoV-2 without inhibiting ACE2/RBD binding. Thus, blocking this interaction may not be a prerequisite for an effective SARS-CoV-2 nAb. The generation of a hybridoma producing a monoclonal nAb against SARS-CoV-2 provides the potential for a therapeutic Ab that can be directly administered to patients to block ongoing infection and potentially even as a prophylactic (Figure 6D).\n\nSARS-CoV-1 nAbs Also Neutralize SARS-CoV-2\nSARS-CoV-1 and SARS-CoV-2 consensus sequences share about 80% identity (Tai et al., 2020). Thus, a wide range of SARS-CoV-1 nAbs have been tested for crossreactivity with SARS-CoV-2, as they could help speed up the development of potential COVID-19 treatments. In a recent study, antibodies were isolated from the memory B cells of an individual who recovered from SARS-CoV-1 infection. While 8 out of 25 isolated antibodies could bind SARS-CoV-2 S protein, one of them (s309; see Table 3 ) also neutralizes SARS-CoV-2 (Pinto et al., 2020). The combination of s309 with a weakly neutralizing antibody that could bind another RBD epitope led to enhanced neutralization potency. In addition, CR3022 (Table 3) was found to bind SARS-CoV-2 RBD (Tian et al., 2020b), but this antibody did not neutralize SARS-CoV-2 (Yuan et al., 2020). Computational simulations identified three amino acids that could be modified on CR3022 to enhance its binding affinity with SARS-CoV-2 RBD (Giron et al., 2020), potentially augmenting its neutralization potential.\nTable 3 Strategies to Isolate SARS-CoV-2 Neutralizing Antibodies\nAb Source Clone Target Type of Antibody Neutralization Inhibition of ACE2/RBD Binding Reference\nDerived from COVID-19 patients 31B532D4 RBD human monoclonal yes yes Chen et al., 2020a\nP2C-2F6P2C-1F11 RBD human monoclonal yes yes Ju et al., 2020\nDerived from SARS-CoV-1 patients CR3022 RBD human monoclonal no no Tian et al., 2020b, Yuan et al., 2020, Giron et al., 2020\nS309 RBD human monoclonal yes no Pinto et al., 2020\nDerived from SARS-CoV-1 or MERS-CoV-1 animal models R325R302R007 S1 rabbit monoclonal yes no Sun et al., 2020\n47D11 S1 recombinant human monoclonal (derived from hybridomas of immunized transgenic H2L2 mice) yes no Wang et al., 2020a\nVHH-72-Fc S Fc-fusion derived from camelids VHH yes yes Wrapp et al., 2020\nS polyclonal mouse antibodies yes N/A Walls et al., 2020, Yuan et al., 2020\nOther ACE2-Fc RBD ACE2-Fc fusion yes N/A Lei et al., 2020a, Li et al., 2020d\nRBD-Fc ACE2 RBD-Fc fusion yes N/A Li et al., 2020d\nN3130 S1 human monoclonal single domain antibody isolated by phage display yes no Wu et al., 2020c\nIVIg N/A polyclonal human IVIg N/A N/A Díez et al., 2020, Shao et al., 2020\nF(ab′)2 RBD horse polyclonal yes N/A Pan et al., 2020\nN/A, not assessed.\n\nnAbs Derived from Animals\nAnimal models represent another tool to generate nAbs against SARS-CoV-2 (Table 3). In one study, the authors developed a protocol to synthetize human nanobodies, smaller antibodies that only contain a variable heavy (VH) chain as first described in camelids (Wu et al., 2020c) (Figure 6D). Another antibody isolated from camelids immunized with SARS-CoV-1 and MERS-CoV S proteins then fused to a human Fc fragment showed neutralization potential against SARS-CoV-2 (VHH-72-Fc) (Wrapp et al., 2020). Genetically modified mice with humanized antibody genes can also be used to generate therapeutic monoclonal antibodies, as successfully experimented against Ebola virus (Levine, 2019). Similar studies are now focused on the use of SARS-CoV-2 or derivatives to generate highly effective nAb in animal models, which can be directly given to infected patients, and efforts are already underway with estimates of clinical trials of pooled antibody cocktails beginning in early summer by Regeneron. Finally, another approach to nAb development is to fuse ACE2 protein and the Fc part of antibodies, as they would bind RBD and potentially be crossreactive among other CoVs (Figure 6D). Indeed, an ACE2-Fc (Lei et al., 2020a) and an RBD-Fc (Li et al., 2020d) have been shown to neutralize both SARS-CoV-1 and SARS-CoV-2 in vitro.\n\nConvalescent Plasma Therapy\nAlthough recombinant nAbs could provide an effective treatment, they will require a significant time investment to develop, test, and bring production to scale before becoming widely available to patients. A faster strategy consists of transferring convalescent plasma (CP) from previously infected individuals that have developed high titer nAbs that target SARS-CoV-2 (Figure 6D). Despite the current lack of appropriately controlled trials, CP therapy has been previously used and shown to be beneficial in several infectious diseases, such as the 1918 influenza pandemic (Luke et al., 2006), H1N1 influenza (Hung et al., 2011), and SARS-CoV-1 (Arabi et al., 2016). Thanks to the development of serological tests (Amanat et al., 2020, Cai et al., 2020, Xiang et al., 2020b, Zhang et al., 2020d), recovered COVID-19 patients can be screened to select plasma with high antibody titers.\nSome studies and case reports on CP therapy for COVID-19 have evaluated the safety and the potential effectiveness of CP therapy in patients with severe disease (Ahn et al., 2020, Duan et al., 2020, Pei et al., 2020, Shen et al., 2020, Zhang et al., 2020b) (Table 4 ). These studies were neither controlled nor randomized, but they suggest that CP therapy is safe and can have a beneficial effect on the clinical course of disease. Further controlled trials are needed to determine the optimal timing and indication for CP therapy. CP therapy has also been proposed for prophylactic use in at-risk individuals, such as those with underlying health conditions or health care workers exposed to COVID-19 patients. The FDA has approved the use of CP to treat critically ill patients (Tanne, 2020). Determining when to administer the CP is also of great importance, as a study in SARS-CoV-1 patients showed that CP was much more efficient when given to patients before day 14 day of illness (Cheng et al., 2005b), as previously shown in influenza (Luke et al., 2006). This study also showed that CP therapy was more efficient in PCR-positive, seronegative patients. The amount of plasma and number of transfusions needed requires further investigation (Table 4).\nTable 4 Clinical Studies of Convalescent Plasma Therapy in COVID-19 Patients\nPatient Characteristics Start of CP Therapy Results Reference\n5 severe patients (30–70 yo) between 10 and 22 days after hospital admission body temperature normalized within 3 days in 4 of 5 patients Shen et al., 2020\nclinical improvement\nviral loads became negative within 12 days of the transfusion\nnAb titers increased\n10 severe patients (34–78 yo) median 16.5 dpo disappearance of clinical symptoms after 3d Duan et al., 2020\nchest CT improved\nelevation of lymphocyte counts in patients with lymphocytopenia.\nincrease in SaO2 in all patients\nresolution of SARS-CoV-2 viremia in 7 patients\nincrease in neutralizing antibody titers in 5 patients\n4 critical patients (31–73 yo) at degradation of symptoms,between 11 and 19 days after hospital admission clinical improvement Zhang et al., 2020b\nreduced viral load\nchest CT improved\n1 moderate patient, 2 critical patients 12 dpo, 27 dpo viral detection negative 4 days after CP Pei et al., 2020\nclinical improvement of 2 patients\n2 severe patients (67 and 71 yo) 7 dpo or 22 dpo clinical improvement Ahn et al., 2020\nreduced viral load\nchest CT improved\nyo, years old; dpo, days post onset of symptoms.\nOverall, CP therapy seems to be associated with improved outcomes and appears to be safe, but RCTs are needed to confirm this. Several clinical trials are currently in progress worldwide (Belhadi et al., 2020)."}

LitCovid-PubTator

LitCovid-sentences

PMC:7200337 / 93975-103487 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7200337 / 93975-103487 JSON TXT