Novi sevi SARS-CoV-2 (virusa, odgovornega za COVID-19): Ali bi lahko bil pristop 'nevtralizirajočih protiteles' odgovor na hitro mutacijo?

Several new strains of the virus have emerged since the pandemic began. New variants were reported as early as February 2020. The current variant that has brought the UK to standstill this Christmas is said to be 70% more infectious. In view of emerging strains, will several vaccines being developed worldwide still be effective enough against the new variants as well? ‘Neutralising Antibody’ approach targeting the virus seems to offer a hopeful option in this current climate of uncertainty. The status is that eight neutralizing antibodies against SARS-CoV-2 are currently undergoing clinical trials, including trials of ‘antibody cocktails’ aimed at overcoming possibility of the virus developing resistance to a single neutralizing antibody by accumulating spontaneous mutations.

O SARS-CoV-2 virus odgovoren za Covid-19 pandemic belong to the betacoronavirus genus in the coronaviridae family of virusi. To virus has a positive-sense RNA genome, meaning the single strand RNA act as messenger RNA while directly translating into viral proteins in the host. The genome of SARS-CoV-2 encodes four structural proteins {spike (S), envelope (E), membrane (M), and nucleocapsid (N)} and 16 non-structural proteins. While the structural proteins play role in receptor recognition on the host cell, membrane fusion, and subsequent viral entry; the non-structural proteins (NSPs) play crucial role in replicative functions such as RNA polymerization by the RNA-dependent RNA polymerase (RdRp, NSP12). 

Significantly, RNA virus polymerases do not have proofreading nuclease activity, meaning there is no mechanism available to check for the errors during transcription or replication. Therefore, virusi of this family display extremely high rates of variation or mutation. This drives their genome variability and evolution thereby providing them extreme level of adaptability and helping the virus escape the immunity of the host and developing resistance against the vaccines ^(1,2,3). Obviously, it has always been nature of RNA virusi, including coronaviruses to undergo mutations in their genome at extremely high rates all the time due to the reasons mentioned above. These replication errors that help the virus overcome negative selection pressure, lead to adaptation of the virus. In the long run, more the error rate, more the adaptation. Yet, Covid-19 is the first documented coronavirus pandemic in history. It is the fifth documented pandemic since the 1918’s Spanish flu; all of the earlier four documented pandemics were caused by flu virusi ⁽⁴⁾.  

Apparently, human coronaviruses have been building up mutations and adapting in the last 50 years. There have been several epidemics since 1966, when the first epidemic episode was recorded. The first lethal human koronavirusi epidemic was in 2002 in Guangdong Province, China that was caused by the varianta SARS-CoV, ki ji je leta 2012 sledila epidemija v Savdski Arabiji z različico MERS-CoV. Trenutna epizoda, ki jo je povzročila različica SARS-CoV-2, se je začela decembra 2019 v Wuhanu na Kitajskem in se je nato razširila po vsem svetu in postala prva pandemija koronavirusa, ki je povzročila Covid-19 bolezen. Zdaj obstaja več podrazličic, razširjenih po različnih celinah. SARS-CoV-2 je pokazal tudi prenos med vrstami med ljudmi in živalmi ter nazaj na ljudi⁽⁵⁾.

The vaccine development against human koronavirus did start after 2002 epidemic. Several vaccines against SARS-CoV and MERS-CoV were developed and underwent preclinical trials but few entered human trials. None of them received FDA approval though ⁽⁶⁾. Ta prizadevanja so prišla prav pri razvoju cepiva proti SARS-CoV-2 z uporabo obstoječih predkliničnih podatkov, vključno s tistimi v zvezi z zasnovo cepiva, izvedenimi med razvojem kandidatov za cepiva proti SARS-CoV in MERS-CoV ⁽⁷⁾. V tem trenutku obstaja več cepiv proti SARS-CoV-2 v zelo napredni fazi; le nekaj jih je že odobrenih kot EUA (dovoljenje za uporabo v sili). Približno pol milijona ljudi z visokim tveganjem v Združenem kraljestvu je že prejelo Pfizer mRNA cepivo. And, here comes the report of newly emerged, highly infectious strain (or, sub-strain) of SARS-CoV-2 in the UK this Christmas time. Temporarily named VUI-202012/01 or B117, this variant has 17 mutations including one in spike protein. More infectious doesn’t necessarily mean that the virus has become more dangerous for humans. Naturally, one wonders if these vaccines will still be effective enough against the new variants as well. It is argued that a single mutation in the spike should not make vaccines (‘spike region’ targeting) vaccine ineffective but as the mutations accumulate over time, vaccines may need fine tuning to accommodate antigenic drift ^(8,9)

Pristop protiteles: ponovni poudarek na nevtralizirajočih protitelesih je lahko nujen 

V tem ozadju je "protitelesni pristop" (vključuje "nevtralizirajoča protitelesa proti SARS-CoV-2 virus‘ and ‘therapeutic antibodies against Covid-19-associated hyperinflammation’) gains significance. Neutralizing antibodies against SARS-CoV-2 virus and its variants may serve as a ‘ready to use’ passive immunity tool.  

O nevtralizirajoča protitelesa ciljno usmerjeni na virusi directly in the host and can provide quick protection especially against any newly emerged variants. This route has not shown much progress yet but has the potential to address the problem of antigenic drift and possible vaccine mismatch presented by the fast-mutating and evolving SARS-CoV-2 virus. As on 28 July 2020, eight neutralizing antibodies against SARS-CoV-2 virus (namely LY-CoV555, JS016, REGN-COV2, TY027, BRII-196, BRII-198, CT-P59, and SCTA01) were undergoing clinical evaluation. Of these neutralising antibodies, LY-CoV555 is monoklonsko protitelo (mAb). VIR-7831, LY-CoV016, BGB-DXP593, REGN-COV2 in CT-P59 so druga monoklonska protitelesa, ki se preizkušajo kot nevtralizirajoča protitelesa. Koktajli protiteles lahko premagajo morebitno odpornost proti enemu nevtralizirajočemu protitelesu, zato so tudi koktajli, kot so REGN-COV2, AZD7442 in COVI-SHIELD, v kliničnih preskušanjih. Vendar pa lahko sevi postopoma razvijejo odpornost tudi na koktajle. Poleg tega lahko obstaja tveganje za povečanje, odvisno od protiteles (ADE), zaradi protitelesa that only bind to the virus and are incapable of neutralising them, thereby worsening disease progression ^(10,11). Za reševanje teh vprašanj je potrebno kontinuirano inovativno raziskovalno delo. 

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Povezani članek: COVID-19: V Združenem kraljestvu se začnejo poskusi 'nevtralizirajočih protiteles'

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Reference: 

1. Elena S and Sanjuán R., 2005. Adaptive Value of High Mutation Rates of RNA Virusi: Separating Causes from Consequences. ASM Journal of Virology. DOI: https://doi.org/10.1128/JVI.79.18.11555-11558.2005   

2. Bębenek A. in Ziuzia-Graczyk I., 2018. Zvestoba replikacije DNK – stvar lektoriranja. Trenutna genetika. 2018; 64(5): 985–996. DOI: https://doi.org/10.1007/s00294-018-0820-1  

3. Pachetti M., Marini B., et al., 2020. Nastajajoče vroče točke mutacije SARS-CoV-2 vključujejo novo različico RNA-odvisne RNA polimeraze. Časopis za translacijsko medicino, letnik 18, številka članka: 179 (2020). Objavljeno: 22. 2020. XNUMX. DOI: https://doi.org/10.1186/s12967-020-02344-6 

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5. Munnink B., Sikkema R., et al., 2020. Prenos SARS-CoV-2 na farmah kun med človekom in kuno ter nazaj na človeka. Znanost 10. november 2020: eabe5901. DOI: https://doi.org/10.1126/science.abe5901  

6. Li Y., Chi W., et al., 2020. Razvoj cepiva proti koronavirusu: od SARS in MERS do COVID-19. Journal of Biomedical Science letnik 27, številka članka: 104 (2020). Objavljeno: 20. decembra 2020. DOI: https://doi.org/10.1186/s12929-020-00695-2  

7. Krammer F., 2020. Cepiva SARS-CoV-2 v razvoju. Narava letnik 586, strani 516–527 (2020). Objavljeno: 23. septembra 2020. DOI: https://doi.org/10.1038/s41586-020-2798-3  

8. Koyama T., Weeraratne D., et al., 2020. Pojav variant drifta, ki lahko vplivajo na razvoj cepiva proti COVID-19 in zdravljenje s protitelesi. Patogeni 2020, 9(5), 324; DOI: https://doi.org/10.3390/pathogens9050324  

9. BMJ 2020. Novice. Covid-19: V Združenem kraljestvu so odkrili novo različico koronavirusa. Objavljeno 16. decembra 2020. DOI: https://doi.org/10.1136/bmj.m4857  

10. Renn A., Fu Y., et al., 2020. Plodovit cevovod nevtralizirajočih protiteles prinaša upanje za premagovanje SARS-Cov-2. Trendi v farmakoloških znanostih. Letnik 41, številka 11, november 2020, strani 815-829. DOI: https://doi.org/10.1016/j.tips.2020.07.004  

11. Tuccori M., Ferraro S., et al., 2020. Anti-SARS-CoV-2 nevtralizirajoča monoklonska protitelesa: klinični načrt. mAbs, letnik 12, 2020 – številka 1. Objavljeno na spletu: 15. december 2020. DOI: https://doi.org/10.1080/19420862.2020.1854149 

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