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LitCovid-PD-FMA-UBERON

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PubTator

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T3","span":{"begin":2960,"end":2972},"obj":"http://purl.obolibrary.org/obo/GO_0000003"},{"id":"T4","span":{"begin":3232,"end":3244},"obj":"http://purl.obolibrary.org/obo/GO_0000003"},{"id":"T5","span":{"begin":3671,"end":3698},"obj":"http://purl.obolibrary.org/obo/GO_0046718"},{"id":"T6","span":{"begin":3677,"end":3692},"obj":"http://purl.obolibrary.org/obo/GO_0044409"},{"id":"T7","span":{"begin":4903,"end":4918},"obj":"http://purl.obolibrary.org/obo/GO_0006955"}],"text":"Discussion\nThere remains an urgent need for a SARS-CoV-2 vaccine as a primary countermeasure to mitigate and eventually contain the spread of COVID-19. The virus’s S glycoprotein makes an attractive vaccine target because it plays a key role in mediating virus entry and is known to be immunogenic (40). Neutralizing antibody responses against S have been identified in SARS-CoV-2−infected individuals (2), and several clinical trials for a SARS-CoV-2 vaccine will test S as an immunogen. While we focused on S, our comparative analyses of other proteins yielded similar conclusions: A randomly selected SARS-CoV-2 sequence could be used as a vaccine candidate, given the similarity of any sequence to the computationally derived optimum vaccine candidate (as defined by the MRCAs or consensus sequence based on all circulating sequences). Vaccines developed using any of these sequences should, theoretically, be effective against all circulating viruses. Vaccine developers could consider designing a vaccine insert with the D614G mutation in S, as this mutation has become dominant worldwide. While mutations that become fixed are often linked to the host immune pressure, this seems unlikely for the SARS-CoV-2 mutation D614G. Because this residue lies at the interface between two subunits, it would not be expected to be part of a critical epitope for vaccine-mediated protection (Fig. 4). As such, pseudoviruses with D614G were as susceptible to neutralization as those with the initial residue D614 (25). A mutation, S612L, that emerged in MERS-CoV after passaging the virus in the presence of two antibodies (in 5/15 clones after 20 passages) (41) warrants the evaluation of the analogous D614G mutation in SARS-CoV-2 for its ability to interfere with the recognition of a distal epitope. A more direct path to viral escape from antibody recognition would be mutations in the RBD, as described for influenza (42, 43). Importantly, we found no mutation in the RBD that was present in more than 1% of SARS-CoV-2 sequences (highest frequency was 0.2% N439K); such rare variants are unlikely to interfere with vaccine efficacy.\nIn the context of rare SARS-CoV-2 mutations, the rapid spread of the D614G mutation is singular and has led authors to hypothesize that viruses with D614G may have enhanced fitness (24). The strongest evidence of a biological effect for this mutation comes from recent reports of an increase in in vitro infectivity or cell entry for pseudoviruses with D614G (25–28). Additional work is needed to evaluate whether the increase in infectivity in vitro translates to increased transmissibility (spread) of SARS-CoV-2 across humans, as there is not necessarily a linear relationship between the two. For example, SARS-CoV mediates cell entry more efficiently than SARS-CoV-2 (with or without the D614G S mutation) (26). Hence, it would be important to understand whether, controlling for epidemiological factors, there are higher reproduction numbers associated with viruses carrying the D614G mutation. While a preliminary comparison of the lineages with either D or G in Washington State did not indicate an obvious advantage for D614G mutants, as they found similar maximal values for the effective reproduction number (https://github.com/blab/ncov-wa-phylodynamics), additional comparisons in different geographic locations should be informative.\nCorrelating in vitro findings with clinical phenotypes can be complicated. During the Ebola outbreak of 2013–2016, some fixed mutations were suspected to confer an advantage to the virus. Specifically, an A82V mutation in the glycoprotein, which, like S for SARS-CoV-2, is critical for the virus entry into host cells, was associated with an increase in infectivity (44–46). Yet, effects varied across cell types (47), and no phenotypic differences were associated with the mutations when viruses were evaluated in vivo in mouse and nonhuman primate models (48), highlighting the difficulty in linking biological mechanisms to outcomes at the population level. So far, no causal association has been identified between the presence of D614G and disease severity (24).\nThese findings, together with our results, illustrate that mutations can spread through the population without necessarily having a selective advantage, especially at the beginning of an epidemic when most individuals are susceptible. Mutations occur more frequently after a host switch, and even slightly deleterious mutations may have an opportunity to spread. Hence, the main signal in our study was one of purifying selection that can ultimately eliminate mildly deleterious mutations. Our analyses showed limited evidence of diversifying selection, with comparable substitution rates in structural proteins versus nonstructural proteins (under a selection paradigm, structural proteins which are essential for viral entry and the target of the host immune response would have higher rates than the nonessential proteins), low estimates of genetic differentiation following the initial outbreak, and phylogenetic patterns adhering to a neutral process of evolution.\nThese data indicate that epidemiologic factors could be sufficient to explain the global spread of mutations such as D614G. A founder effect means that these mutations were likely exported to SARS-CoV-2 naive areas early in the outbreak and therefore given the opportunity to spread widely. As such, on January 28, 2020, a virus carrying the D614G mutation, which was rare among sequences from China, was identified in Germany. Host and environmental factors permitted the establishment of a sustained cluster of infections that propagated this mutation until it became dominant among European sequences and then globally (Fig. 2). We found no evidence that the frequent identification of this mutation was caused by convergent selection events that would have occurred in multiple individuals. Further analyses are needed to characterize the biologic mechanisms behind the spread of the D614G mutation.\nIn summary, our results indicate that, so far, SARS-CoV-2 has evolved through a nondeterministic, noisy process and that random genetic drift has played a dominant role in disseminating unique mutations throughout the world. Yet, it is important to note that founder effects do not exclude that the D614G can confer distinguishing properties in terms of protein stability, infectivity, or transmissibility. SARS-CoV-2 was only recently identified in the human population—a short time frame relative to adaptive processes that can take years to occur. Although we cannot predict whether adaptive selection will be seen in SARS-CoV-2 in the future, the key finding is that SARS-CoV-2 viruses that are currently circulating constitute a homogeneous viral population. Viral diversity has challenged vaccine development efforts for other viruses such as HIV-1, influenza, or Dengue, but these viruses each constitute a more diverse population than SARS-CoV-2 viruses (SI Appendix, Fig. S12). We can therefore be cautiously optimistic that viral diversity should not be an obstacle for the development of a broadly protective SARS-CoV-2 vaccine, and that vaccines in current development should elicit responses that are reactive against currently circulating variants of SARS-CoV-2."}

LitCovid-sentences

2_test

{"project":"2_test","denotations":[{"id":"32868447-19538115-132542403","span":{"begin":299,"end":301},"obj":"19538115"},{"id":"32868447-29514901-132542404","span":{"begin":1653,"end":1655},"obj":"29514901"},{"id":"32868447-25414313-132542405","span":{"begin":1918,"end":1920},"obj":"25414313"},{"id":"32868447-31452511-132542406","span":{"begin":1922,"end":1924},"obj":"31452511"},{"id":"32868447-32697968-132542407","span":{"begin":2315,"end":2317},"obj":"32697968"},{"id":"32868447-28238624-132542408","span":{"begin":3748,"end":3750},"obj":"28238624"},{"id":"32868447-28084671-132542408","span":{"begin":3748,"end":3750},"obj":"28084671"},{"id":"32868447-27847361-132542408","span":{"begin":3748,"end":3750},"obj":"27847361"},{"id":"32868447-30333174-132542409","span":{"begin":3795,"end":3797},"obj":"30333174"},{"id":"32868447-29742435-132542410","span":{"begin":3939,"end":3941},"obj":"29742435"},{"id":"32868447-32697968-132542411","span":{"begin":4144,"end":4146},"obj":"32697968"}],"text":"Discussion\nThere remains an urgent need for a SARS-CoV-2 vaccine as a primary countermeasure to mitigate and eventually contain the spread of COVID-19. The virus’s S glycoprotein makes an attractive vaccine target because it plays a key role in mediating virus entry and is known to be immunogenic (40). Neutralizing antibody responses against S have been identified in SARS-CoV-2−infected individuals (2), and several clinical trials for a SARS-CoV-2 vaccine will test S as an immunogen. While we focused on S, our comparative analyses of other proteins yielded similar conclusions: A randomly selected SARS-CoV-2 sequence could be used as a vaccine candidate, given the similarity of any sequence to the computationally derived optimum vaccine candidate (as defined by the MRCAs or consensus sequence based on all circulating sequences). Vaccines developed using any of these sequences should, theoretically, be effective against all circulating viruses. Vaccine developers could consider designing a vaccine insert with the D614G mutation in S, as this mutation has become dominant worldwide. While mutations that become fixed are often linked to the host immune pressure, this seems unlikely for the SARS-CoV-2 mutation D614G. Because this residue lies at the interface between two subunits, it would not be expected to be part of a critical epitope for vaccine-mediated protection (Fig. 4). As such, pseudoviruses with D614G were as susceptible to neutralization as those with the initial residue D614 (25). A mutation, S612L, that emerged in MERS-CoV after passaging the virus in the presence of two antibodies (in 5/15 clones after 20 passages) (41) warrants the evaluation of the analogous D614G mutation in SARS-CoV-2 for its ability to interfere with the recognition of a distal epitope. A more direct path to viral escape from antibody recognition would be mutations in the RBD, as described for influenza (42, 43). Importantly, we found no mutation in the RBD that was present in more than 1% of SARS-CoV-2 sequences (highest frequency was 0.2% N439K); such rare variants are unlikely to interfere with vaccine efficacy.\nIn the context of rare SARS-CoV-2 mutations, the rapid spread of the D614G mutation is singular and has led authors to hypothesize that viruses with D614G may have enhanced fitness (24). The strongest evidence of a biological effect for this mutation comes from recent reports of an increase in in vitro infectivity or cell entry for pseudoviruses with D614G (25–28). Additional work is needed to evaluate whether the increase in infectivity in vitro translates to increased transmissibility (spread) of SARS-CoV-2 across humans, as there is not necessarily a linear relationship between the two. For example, SARS-CoV mediates cell entry more efficiently than SARS-CoV-2 (with or without the D614G S mutation) (26). Hence, it would be important to understand whether, controlling for epidemiological factors, there are higher reproduction numbers associated with viruses carrying the D614G mutation. While a preliminary comparison of the lineages with either D or G in Washington State did not indicate an obvious advantage for D614G mutants, as they found similar maximal values for the effective reproduction number (https://github.com/blab/ncov-wa-phylodynamics), additional comparisons in different geographic locations should be informative.\nCorrelating in vitro findings with clinical phenotypes can be complicated. During the Ebola outbreak of 2013–2016, some fixed mutations were suspected to confer an advantage to the virus. Specifically, an A82V mutation in the glycoprotein, which, like S for SARS-CoV-2, is critical for the virus entry into host cells, was associated with an increase in infectivity (44–46). Yet, effects varied across cell types (47), and no phenotypic differences were associated with the mutations when viruses were evaluated in vivo in mouse and nonhuman primate models (48), highlighting the difficulty in linking biological mechanisms to outcomes at the population level. So far, no causal association has been identified between the presence of D614G and disease severity (24).\nThese findings, together with our results, illustrate that mutations can spread through the population without necessarily having a selective advantage, especially at the beginning of an epidemic when most individuals are susceptible. Mutations occur more frequently after a host switch, and even slightly deleterious mutations may have an opportunity to spread. Hence, the main signal in our study was one of purifying selection that can ultimately eliminate mildly deleterious mutations. Our analyses showed limited evidence of diversifying selection, with comparable substitution rates in structural proteins versus nonstructural proteins (under a selection paradigm, structural proteins which are essential for viral entry and the target of the host immune response would have higher rates than the nonessential proteins), low estimates of genetic differentiation following the initial outbreak, and phylogenetic patterns adhering to a neutral process of evolution.\nThese data indicate that epidemiologic factors could be sufficient to explain the global spread of mutations such as D614G. A founder effect means that these mutations were likely exported to SARS-CoV-2 naive areas early in the outbreak and therefore given the opportunity to spread widely. As such, on January 28, 2020, a virus carrying the D614G mutation, which was rare among sequences from China, was identified in Germany. Host and environmental factors permitted the establishment of a sustained cluster of infections that propagated this mutation until it became dominant among European sequences and then globally (Fig. 2). We found no evidence that the frequent identification of this mutation was caused by convergent selection events that would have occurred in multiple individuals. Further analyses are needed to characterize the biologic mechanisms behind the spread of the D614G mutation.\nIn summary, our results indicate that, so far, SARS-CoV-2 has evolved through a nondeterministic, noisy process and that random genetic drift has played a dominant role in disseminating unique mutations throughout the world. Yet, it is important to note that founder effects do not exclude that the D614G can confer distinguishing properties in terms of protein stability, infectivity, or transmissibility. SARS-CoV-2 was only recently identified in the human population—a short time frame relative to adaptive processes that can take years to occur. Although we cannot predict whether adaptive selection will be seen in SARS-CoV-2 in the future, the key finding is that SARS-CoV-2 viruses that are currently circulating constitute a homogeneous viral population. Viral diversity has challenged vaccine development efforts for other viruses such as HIV-1, influenza, or Dengue, but these viruses each constitute a more diverse population than SARS-CoV-2 viruses (SI Appendix, Fig. S12). We can therefore be cautiously optimistic that viral diversity should not be an obstacle for the development of a broadly protective SARS-CoV-2 vaccine, and that vaccines in current development should elicit responses that are reactive against currently circulating variants of SARS-CoV-2."}

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