Molecular immunological aspects of diagnostics, prevention and treatment of coronavirus infection
AbstractThe rapid spread of the infection caused by the new coronavirus SARS-CoV-2, which in a short time covered almost the whole world and acquired the pandemic character, has become a serious challenge to the health care system. Unprecedented measures are being taken to organize medical care for infected people, carry out quarantine measures, develop drugs for treatment and prevention of infection. Over the past 2020 year a significant amount of scientific information has been accumulated about the pathogenesis of SARS-CoV-2 infection, the biology of the virus and its interaction with the human immune system. This made it possible to come close to the development of effective substances of countering the spread of a new coronavirus infection - the development of effective vaccines and innovative targeted antiviral drugs. This review is devoted to analysis of the latest advances in the diagnosis, immunoprophylactics and treatment of COVID-19, a disease caused by the novel SARS-CoV-2 coronavirus.
Keywords:coronavirus; SARS-CoV-2; COVID-19; diagnostics; PCR; vaccines; viral vectors; peptide vaccines; inactivated vaccines; immunoprophylactics; antiviral drugs; viral diseases treatment
For citation: Gudima G.O., Khaitov R.M., Kudlay D.A., Khaitov M.R. Molecular immunological aspects of diagnostics, prevention and treatment of coronavirus infection. Immunologiya. 2021; 42 (3): 198-210. DOI: https://doi.org/10.33029/0206-4952-2021-42-3-198-210 (in Russian)
Funding. The study had no sponsor support.
Conflict of interests. Author declares no conflict of interests.
Литература/References
1. Хронология действий ВОЗ по борьбе с COVID-19. URL: https://www.who.int/ru/news/item/29-06-2020-covidtimeline [Listings of WHO’s response to COVID-19. URL: https://www.who.int/ru/news/item/29-06-2020-covidtimeline (in Russian)]
2. Актуальная эпидемическая ситуация в России и мире. Информация Роспотребнадзора. URL: https://www.rospotrebnadzor.ru/region/korono_virus/epid.php [Current epidemic situation in Russia and the world. Rospotrebnadzor. URL: https://www.rospotrebnadzor.ru/region/korono_virus/epid.php (in Russian)]
3. Пащенков М.В., Хаитов М.Р. Иммунный ответ против эпидемических коронавирусов. Иммунология. 2020; 41 (1): 5-18. DOI: https://doi.org/10.33029/0206-4952-2020-41-1-5-18 [Pash-chenkov M.V., Khaitov M.R. Immune response against epidemic coronaviruses. Immunologiya. 2020; 41 (1): 5-18. DOI: https://doi.org/10.33029/0206-4952-2020-41-1-5-18 (in Russian)]
4. Li G., Fan Y., Lai Y., Han T., Li Z., Zhou P., Pan P., Wang W., Hu D., Liu X., Zhang Q., Wu J. Coronavirus infections and immune responses. J. Med. Virol. 2020; 92 (4): 424-32. DOI: https://doi.org/10.1002/jmv.25685
5. Braun J., Loyal L., Frentsch M., Wendisch D., et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020; 587 (7833): 270-4. DOI: https://doi.org/10.1038/s41586-020-2598-9
6. Wiersinga W.J., Rhodes A., Cheng A.C., Peacock S.J., Prescott H.C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020; 324 (8): 782-93. DOI: https://doi.org/10.1001/jama.2020.12839
7. Ahmed S.F., Quadeer A.A., McKay M.R. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses. 2020; 12 (3): 254. DOI: https://doi.org/10.3390/v12030254
8. Grifoni A., Sidney J., Zhang Y, Scheuermann R.H., Peters B., SetteA. A sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2. Cell Host Microbe. 2020; 27 (4): 671-80.e2. DOI: https://doi.org/10.1016/j.chom.2020.03.002
9. Wang M., Li M., Ren R., Li L., Chen E.Q., Li W., Ying B. International expansion of a novel SARS-CoV-2 mutant. J. Virol. 2020; 94 (12): e00567-20. DOI: https://doi.org/10.1128/JVI.00567-20
10. Ahmadpour D., Ahmadpoor P., Rostaing L. Impact of circulating SARS-CoV-2 mutant G614 on the COVID-19 pandemic. Iran. J. Kidney Dis. 2020; 14 (5): 331-4.
11. Lauer S.A., Grantz K.H., Bi Q., et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann. Intern. Med. 2020; 172 (9): 577-82. DOI: https://doi.org/10.7326/M20-0504
12. Guan W.J., Ni Z.Y., Hu Y., et al.; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020; 382 (18): 1708-20. DOI: https://doi.org/10.1056/NEJMoa2002032
13. Garg S., Kim L., Whitaker M., et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - CoViD-NET, 14 States, March 1-30, 2020. MMWR Morb. Mortal. Wkly Rep. 2020; 69 (15): 458-64. DOI: https://doi.org/10.15585/mmwr.mm6915e3
14. Richardson S., Hirsch J.S., Narasimhan M., et al.; the North-well COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020; 323 (20): 2052-9. DOI: https://doi.org/10.1001/jama.2020.6775
15. Docherty A.B., Harrison E.M., Green C.A., et al.; ISARIC4C investigators. Features of 20 133 UK patients in hospital with CO-VID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020; 369: m1985. DOI: https://doi.org/10.1136/bmj.m1985
16. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) - China, 2020. China CDC Weekly. 2020; 2: 10.
17. Wang W., Xu Y., Gao R., et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020; 323 (18): 1843-4. DOI: https://doi.org/10.1001/jama.2020.3786
18. Sethuraman N., Jeremiah S.S., Ryo A. Interpreting diagnostic tests for SARS-CoV-2. JAMA. 2020; 323 (22): 2249-51. DOI: https://doi.org/10.1001/jama.2020.8259
19. Kucirka L.M., Lauer S.A., Laeyendecker O., Boon D., Lessler J. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann. Intern. Med. 2020; 173 (4): 262-7. DOI: https://doi.org/10.7326/M20-1495
20. Williams E., Bond K., Zhang B., Putland M., Williamson D.A. Saliva as a non-invasive specimen for detection of SARS-CoV-2. J. Clin. Microbiol. 2020; 58 (8): e00776-20. DOI: https://doi.org/10.1128/JCM.00776-20
21. Goncharova E.A., Dedkov V.G., Dolgova A.S., Kassirov I.S., Safonova M.V., Voytsekhovskaya Y., Totolian A.A. One-step quantitative RT-PCR assay with armored RNA controls for detection of SARS-CoV-2. J. Med. Virol. 2021; 93 (3): 1694-701. DOI: https://doi.org/10.1002/jmv.26540
22. URL: https://www.rospotrebnadzor.ru/about/info/news/news_details.php?ELEMENT_ID=16860
23. Guo L., Ren L., Yang S., et al. Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin. Infect. Dis. 2020; 71 (15): 778-85. DOI: https://doi.org/10.1093/cid/ciaa310
24. Zhao J., Yuan Q., Wang H., et al. Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease 2019. Clin. Infect. Dis. 2020; 71 (16): 2027-34. DOI: https://doi.org/10.1093/cid/ciaa344
25. Bond K., Nicholson S., Hoang T., Catton M., Howden B., Williamson D. Post-Market Validation of Three Serological Assays for COVID-19. Office of Health Protection, Commonwealth Government of Australia, 2020.
26. Rodriguez-Morales A.J., Cardona-Ospina J.A., Gutierrez-Ocampo E., et al.; Latin American Network of Coronavirus Disease 2019-COVID-19 Research (LANCOVID-19). Clinical, laboratory and imaging features of COVID-19: a systematic review and metaanalysis. Travel. Med. Infect. Dis. 2020; 34: 101623. DOI: https://doi.org/10.1016/j.tmaid.2020.101623
27. Huang C., Wang Y., Li X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395 (10 223): 497-506. DOI: https://doi.org/10.1016/S0140-6736(20)30183-5
28. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 2020; 18 (4): 844-7. DOI: https://doi.org/10.1111/jth.14768
29. Thachil J., Tang N., Gando S., et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J. Thromb. Haemost. 2020; 18 (5): 1023-6. DOI: https://doi.org/10.1111/jth.14810
30. Levi M., Thachil J., Iba T., Levy J.H. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020; 7 (6): e438-40. DOI: https://doi.org/10.1016/S2352-3026(20)30145-9
31. Guan W.J., Ni Z.Y., Hu Y., et al.; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020; 382 (18): 1708-20. DOI: https://doi.org/10.1056/NEJMoa2002032
32. Chen N., Zhou M., Dong X., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395 (10 223): 50713. DOI: https://doi.org/10.1016/S0140-6736(20)30211-7
33. Wu C., Chen X., Cai Y., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 2020; 180 (7): 934-43. DOI: https://doi.org/10.1001/jamainternmed.2020.0994
34. Shi H., Han X., Jiang N., et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect. Dis. 2020; 20 (4): 425-34. DOI: https://doi.org/10.1016/S1473-3099(20)30086-4
35. Bernheim A., Mei X., Huang M., et al. Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology. 2020; 295 (3): 200463. dOi: https://doi.org/10.1148/radiol.2020200463
36. Draft Landscape and Tracker of COVID-19 Candidate Vaccines. WHO, 2021. URL: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
37. Logunov D.Y, Dolzhikova I.V., Zubkova O.V., Tukhvatulin A.I., et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020; 396 (10 255): 887-97. DOI: https://doi.org/10.1016/S0140-6736(20)31866-3
38. Logunov D.Y, Dolzhikova I.V., Tukhvatullin A.I., Shcheblyakov D.V. Safety and efficacy of the Russian COVID-19 vaccine: more information needed - authors’ reply. Lancet. 2020; 396 (10 256): e54-5. DOI: https://doi.org/10.1016/S0140-6736(20)31970-X
39. Logunov D.Y., Dolzhikova I.V., Shcheblyakov D.V., Tukhvatulin A.I., et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet. 2021; 397 (10 275): 671-81. DOI: https://doi.org/10.1016/S0140-6736(21)00234-8
40. Jones I., Roy P. Sputnik V COVID-19 vaccine candidate appears safe and effective. Comment. Lancet. 2021; 397 (10 275): 642-3. DOI: https://doi.org/10.1016/S0140-6736(21)00191-4
41. Mounting evidence suggests Sputnik COVID vaccine is safe and effective. URL: https://www.nature.com/articles/d41586-021-01813-2
42. Рыжиков А.Б., Рыжиков Е.А., Богрянцева М.П., Гаврилова Е.В. и др. Пептидные иммуногены и вакцинная композиция против коронавирусной инфекции COVID-19 с использованием пептидных иммуногенов. Патент РФ RU2738081, заявка 2020133915 от 14.10.2020, дата регистрации 07.12.2020, опубликовано 07.12.2020, Бюл. №» 34-2020, 28.11.2020-10.12.2020. [Ryzhikov A.B., Ryzhikov E.A., Bogryantseva M.P., Gavrilova E.V., et al. Peptide immunogens and vaccine composition against CO-VID-19 coronavirus infection using peptide immunogens. Patent of the Russian Federation RU2738081, application 2020133915 dated 14.10.2020, registration date 07.12.2020, published 07.12.2020, Bul. No. 34-2020, 28.11.2020-10.12.2020. (in Russian)]
43. Рыжиков А.Б., Рыжиков Е.А., Богрянцева М.П., Усова С.В. и др. Простое слепое плацебо-контролируемое рандомизированное исследование безопасности, реактогенности и иммуногенно-сти вакцины «ЭпиВакКорона» для профилактики COVID-19 на добровольцах в возрасте 18-60 лет (фаза I-II). Инфекция и иммунитет. 2021; 11 (2): 283-96. DOI: https://doi.org/10.15789/2220-7619-ASB-1699 [Ryzhikov A.B., Ryzhikov Е.А., Bogryantseva M.P., Usova S.V., et al. A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the «EpiVacCo-rona» Vaccine for the prevention of COVID-19, in volunteers aged 18-60 years (phase I-II). Infektsiya i immunitet. 2021; 11 (2): 283-96. DOI: https://doi.org/10.15789/2220-7619-ASB-1699 (in Russian)]
44. URL: https://minzdrav.gov.ru/news/2021/02/20/16138-minz-drav-rossii-zaregistriroval-tretyu-rossiyskuyu-vaktsinu-ot-covid-19
45. URL: https://minzdrav.gov.ru/news/2021/05/06/16566-minz-drav-zaregistriroval-chetvertuyu-rossiyskuyu-vaktsinu-ot-covid-19
46. URL: https://tass.ru/obschestvo/10487285
47. URL: https://iz.ru/1118079/2021-01-29/doklinicheskie-ispy-taniia-vaktciny-ot-covid-19-v-vide-iogurta-zavershat-v-2021-godu
48. URL: http://www.kremlin.ru/events/president/news/65080
49. URL: https://tass.ru/obschestvo/10710029/
50. URL: https://iz.ru/1178883/2021-06-15/v-rf-podali-publikatciiu-ob-effektivnosti-sputnika-v-protiv-indiiskogo-shtamma
51. URL: https://covid19.rosminzdrav.ru/wp-content/uploads/2021/01/1-i-1-155-1.pdf.
52. Коронавирус: статистика. John Hopkins University Corona-virus Resource Center. URL: https://coronavirus.jhu.edu [Coronavirus: statistics. John Hopkins University Coronavirus Resource Center. URL: https://coronavirus.jhu.edu (in Russian)]
53. Polack F.P., Thomas S.J., Kitchin N., Absalon J., et al. Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine. N. Engl. J. Med. 2020; 383 (27): 2603-15. DOI: https://doi.org/10.1056/NEJ-Moa2034577
54. Jackson L.A., Anderson E.J., Rouphael N.G., Roberts P.C., et al. An mRNA vaccine against SARS-CoV-2 - preliminary report. N. Engl. J. Med. 2020; 383 (20): 1920-31. DOI: https://doi.org/10.1056/NEJMoa2022483
55. Anderson E.J., Rouphael N.G., Widge A.T., Jackson L.A., et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 2020; 383 (25): 2427-38. DOI: https://doi.org/10.1056/NEJMoa2028436
56. Voysey M., Clemens S.A.C., Madhi S.A., Weckx L.Y., et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021; 397 (10 269): 99-111. DOI: https://doi.org/10.1016/S0140-6736(20)32661-1
57. URL: https://iz.ru/1137382/2021-03-15/italiia-i-frantciia-vsled-za-frg-priostanovili-ispolzovanie-vaktciny-astrazeneca
58. Study in Adults to Determine the Safety and Immunogenic-ity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, Given in Combination With rAd26-S, Recombinant Adenovirus Type 26 Component of Gam-COVID-Vac Vaccine, for the Prevention of CO-VID-19. ClinicalTrials.gov/NCT04686773.
59. A Study to Evaluate The Efficacy, Safety and Immunogenicity of Inactivated SARS-CoV-2 Vaccines (Vero Cell) in Healthy Population Aged 18 Years Old and Above (COVID-19). URL: https://clinical-trials.gov/ct2/show/NCT04510207
60. Wu Z., Hu Y., Xu M., Chen Z., Yang W., Jiang Z., Li M., Jin H., Cui G., Chen P., Wang L., Zhao G., Ding Y., Zhao Y., Yin W. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 2021; Feb 3: S1473-3099(20)30987-7. DOI: https://doi.org/10.1016/S1473-3099(20)30987-7
61. A Study of Ad26.COV2.S for the Prevention of SARS-CoV-2-Mediated COVID-19 in Adult Participants (ENSEMBLE) (NCT04505722). URL: https://clinicaltrials.gov/ct2/show/NCT04505722
62. Ella R., Vadrevu K.M., Jogdand H., Prasad S., Reddy S., Saran-gi V., Ganneru B., Sapkal G., Yadav P., Abraham P., Panda S., Gupta N., Reddy P., Verma S., Kumar Rai S., Singh C., Redkar S.V., Gillurkar C.S., Kushwaha J.S., Mohapatra S., Rao V., Guleria R., Ella K., Bhargava B. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect. Dis. 2021; Jan 21: S1473-3099(20)30942-7. DOI: https://doi.org/10.1016/S1473-3099(20)30942-7
63. An Efficacy and Safety Clinical Trial of an Investigational COVID-19 Vaccine (BBV152) in Adult Volunteers. (NCT04641481). URL: https://clinicaltrials.gov/ct2/show/NCT04641481
64. Alter G., Gorman M., Patel N., Guebre-Xabier M., Zhu A., Atyeo C., Pullen K., Loos C., Goez-Gazi Y., Carrion R., Tian J.H., Yuan D., Bowman K., Zhou B., Maciejewski S., McGrath M., Logue J., Frieman M., Montefiori D., Schendel S., Saphire E.O., Lauffenburger D., Greene A., PortnoffA., Massare M., Ellingsworth L., Glenn G., Smith G., Mann C., Amanat F., Krammer F. Collaboration between the Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M™ vaccination. Res. Sq. 2021; Feb 15: rs.3.rs-200342. DOI: https://doi.org/10.21203/rs.3.rs-200342/v1
65. A Study Looking at the Effectiveness, Immune Response, and Safety of a COVID-19 Vaccine in Adults in the United Kingdom (NCTO4583995). URL: https://www.clinicaltrials.gov/ct2/show/NCT04583995
66. A Study Looking at the Effectiveness and Safety of a COVID-19 Vaccine in South African Adults (NCT04533399). URL: https://www.clinicaltrials.gov/ct2/show/NCT04533399
67. SOBERANA 02-FaseIII. Registro Phblico Cubano de Ensay-os Clinicos (sld.cu). URL: https://rpcec.sld.cu/en/trials/RPCEC00000354-En
68. Steinbuck M.P., Seenappa L.M., Jakubowski A., McNeil L.K., Haqq C.M., DeMuth P.C. A lymph node-targeted Amphiphile vaccine induces potent cellular and humoral immunity to SARS-CoV-2. Sci. Adv. 2021; 7 (6): eabe5819. DOI: https://doi.org/10.1126/sciadv.abe5819
69. Хаитов Р.М. Иммуномодуляторы: мифы и реальность. Иммунология. 2020; 41 (2): 101-6. DOI: https://doi.org/10.33029/0206-4952-2020-41-2-101-106 [Khaitov R.M. Immunomodulators: myths and reality. Immunologiya. 2020; 41 (2): 101-6. DOI: https://doi.org/10.33029/0206-4952-2020-41-2-101-106 (in Russian)]
70. Хаитов Р.М., Пинегин Б.В., Пащенков М.В. Эпителиальные клетки дыхательных путей как равноправные участники врожденного иммунитета и потенциальные мишени для иммуно-тропных средств. Иммунология. 2020; 41 (2): 107-13. DOI: https://doi.org/10.33029/0206-4952-2020-41-2-107-113 [Khaitov R.M., Pinegin B.V., Pashchenkov M.V. Epithelial cells of the respiratory tract as equal participants of innate immunity and potential targets for im-munotropic drugs. Immunologiya. 2020; 41 (2): 107-13. DOI: https://doi.org/10.33029/0206-4952-2020-41-2-107-113 (in Russian)]
71. Sanders J., Monogue M.L., Jodlowski T.Z., Cutrell J.B. Pharmacologic treatments for coronavirus disease 2019 (COVID-19). JAMA. 2020; 323, (18): 1924-36. DOI: https://doi.org/10.1001/jama.2020.6019
72. Wang M., Cao R., Zhang L., et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30 (3): 269-71. DOI: https://doi.org/10.1038/s41422-020-0282-0
73. Magagnoli J., Narendran S., Pereira F., et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med. (N.Y.). 2020; 1 (1): 114-27.e3. DOI: https://doi.org/10.1016/j.medj.2020.06.001
74. Mahevas M., Tran V.T., Roumier M., et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020; 369: m1844. DOI: https://doi.org/10.1136/bmj.m1844
75. Tang W., Cao Z., Han M., et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020; 369: m1849. DOI: https://doi.org/10.1136/bmj.m1849
76. Rosenberg E.S., Dufort E.M., Udo T., et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020; 323 (24): 2493-502. DOI: https://doi.org/10.1001/jama.2020.8630
77. Geleris J., Sun Y., Platt J., et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N. Engl. J. Med. 2020; 382 (25): 2411-8. DOI: https://doi.org/10.1056/NEJ-Moa2012410
78. Scavone C., Brusco S., Bertini M., et al. Current pharmacological treatments for COVID-19: what’s next? Br. J. Pharmacol. 2020; 177 (21): 4813-24. DOI: https://doi.org/10.1111/bph.15072
79. Cao B., Wang Y., Wen D., et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N. Engl. J. Med. 2020; 382 (19): 1787-99. DOI: https://doi.org/10.1056/NEJMoa2001282
80. Beigel J.H., Tomashek K.M., Dodd L.E., et al. Remdesivir for the treatment of COVID-19: preliminary report. N. Engl. J. Med. 2020; 383 (19): 1813-26. DOI: https://doi.org/10.1056/NEJMoa2007764
81. Goldman J.D., Lye D.C.B., Hui D.S., et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N. Engl. J. Med. 2020; 83 (19): 1827-37. DOI: https://doi.org/10.1056/NEJMoa2015301
82. White K.M., Rosales R., Yildiz S., Kehrer T., Miorin L., Moreno E., Jangra S., Uccellini M.B., Rathnasinghe R., Coughlan L., Mar-tinez-Romero C., Batra J., Rojc A., Bouhaddou M., Fabius J.M., Ober-nier K., Dejosez M., Guillen M.J., Losada A., Aviles P., Schotsaert M., Zwaka T., Vignuzzi M., Shokat K.M., Krogan N.J., Garcia-Sastre A. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 2021; Jan 25: eabf4058. DOI: https://doi.org/10.1126/science.abf4058
83. Concept Study to Evaluate the Safety Profile of Plitidepsin in Patients With COVID-19 (APLICOV-PC). ClinicalTrials.gov Identifier: NCT04382066. URL: https://www.clinicaltrials.gov/ct2/show/NCT04382066
84. Shen C., Wang Z., Zhao F., et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020; 323 (16): 1582-9. DOI: https://doi.org/10.1001/jama.2020.4783
85. Li L., Zhang W., Hu Y., et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020; 324 (5): 460-70. DOI: https://doi.org/10.1001/jama.2020.10044
86. Wang C., Li W., Drabek D., et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 2020; 11 (1): 2251. DOI: https://doi.org/10.1038/s41467-020-16256-y
87. Brouwer P.J.M., Caniels T.G., van der Straten K., et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science. 2020; 369 (6504): 643-50. DOI: https://doi.org/10.1126/science.abc5902
88. URL: https://mosgorzdrav.ru/ru-RU/news/default/card/5489.html
89. Alzghari S.K., Acuna V.S. Supportive treatment with tocili-zumab for COVID-19: a systematic review. J. Clin. Virol. 2020; 127: 104380. DOI: https://doi.org/10.1016/jjcv.2020.104380
90. Старшинова А.А., Кушнарева Е.А., Малкова А.М., Дов-галюк И.Ф., Кудлай Д.А. Новая коронавирусная инфекция: особенности клинического течения, возможности диагностики, лечения и профилактики инфекции у взрослых и детей. Вопросы современной педиатрии. 2020; 19 (2): 123-31. DOI: https://doi.org/10.15690/vsp.v19i2.2105. [Starshinova A.A., Kushnareva E.A., Malkova A.M., Dovgalyuk I.F., Kudlay D.A. New coronavirus infection: features of the clinical course, the possibility of diagnosis, treatment and prevention of infection in adults and children. Voprosy sovremennoy pediatrii. 2020; 19 (2): 123-31. DOI: https://doi.org/10.15690/vsp.v19i2.2105 (in Russian)]
91. Alhazzani W., Moller M.H., Arabi Y.M., et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Intensive Care Med. 2020; 46 (5): 854-87. DOI: https://doi.org/10.1007/s00134-020-06022-5
92. Wilson K.C., Chotirmall S.H., Bai C., Rello J.; International Task Force on COVID-19. COVID-19: Interim Guidance on Management Pending Empirical Evidence. American Thoracic Society, 2020. URL: https://www.thoracic.org/covid/covid-19-guidance.pdf (date of access July 7, 2020)
93. Horby P., Lim W.S., Emberson J., Mafham M., Bell J., et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv. 2020 June 22. DOI: https://doi.org/10.1101/2020.06.22.20137273:24
94. Evaluation of the Safety of CD24-Exosomes in Patients With COVID-19 Infection. URL: https://clinicaltrials.gov/ct2/show/study/NCT04747574
95. Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Временные методические рекомендации. Версия 11 (07.05.2021). Министерство здравоохранения Российской Федерации. URL: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/055/735/original/BMP_COVID-19.pdf [Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). The provisional guidelines. Version 11 (07.05.2021). Ministry of Health of Russian Federation. URL: https://static-0.minz-drav.gov.ru/system/attachments/attaches/000/055/735/original/BMP_ COVID-19.pdf (in Russian)]
96. Хаитов М.Р., Шиловский И.П., Кофиади И. А., Сергеев И.В., Козлов И.Б., Смирнов В.В., Кожихова К.В., Колоскова О.О., Андреев С.М., Жернов Ю.В., Никонова А. А. Средство для ингибирования репликации вируса SARS-CoV-2, опосредованного РНК-интерференцией. Патент № 2733361 от 15.09.2020. Заявка №2020123316от 14.07.2020. [Khaitov M.R., Shilovsky I.P., KofiadiI.A., Sergeev I.V., Kozlov I.B., Smirnov V.V., Kozhikhova K.V., Kolosko-va O.O., Andreev S M., Zhernov Yu.V., Nikonova A.A. An agent for inhibiting the replication of the SARS-CoV-2 virus mediated by RNA interference. Patent No. 2733361, 15.09. 2020. Application No. 2020123316, 14.06.2020. (in Russian)]
97. Хаитов М.Р., Шиловский И.П., Кожихова К.В., Кофиади И.А., Смирнов В.В., Колоскова О.О., Сергеев И.В., Трофимов Д.Ю., Трухин В.П., Скворцова В.И. Комбинированное лекарственное средство, обладающее противовирусным эффектом в отношении нового коронавируса SARS-CoV-2. Патент № 2746362 от 12.04.2021. Заявка № 2021106335 от 11.03.2021. [Khaitov M.R., Shilovsky I.P., Kozhikhova K.V., Kofiadi I.A., Smirnov V.V., Koloskova O.O., Sergeev I.V., Trofimov D.Yu., Tru-khin V.P., Skvortsova V.I. Combined drug with antiviral effect against the novel SARS-CoV-2 coronavirus. Patent No. 2746362, 12.04.2021. Application No. 2021106335, 11.03.2021. (in Russian)]
98. Khaitov M., Nikonova A., Shilovskiy I., Kozhikhova K., Kofiadi I., Vishnyakova L., Nikolsky A., Gattinger P., Kovchina V., Barvinskaya E., Yumashev K., Smirnov V., Maerle A., Kozlov I., Shatilov A., Timofeeva A., Andreev S., Koloskova O., Kuznetsova N., Vasina D., Nikiforova M., Rybalkin S., Sergeev I., Trofimov D., Martynov A., Berzin I., Gushchin V., Kovalchuk A., Borisevich S., Valenta R., Khaitov R., Skvortsova V. Silencing of SARS-CoV-2 with modified siRNA-peptide dendrimer formulation. Allergy. 2021; Apr 10. DOI: https://doi.org/10.1111/all.14850