Aspects and issues of marketing authorisation and use of medicinal products for COVID-19 prevention during the pandemic

At the end of 2019, an outbreak of a new coronavirus began in the city of Wuhan (Hubei Province) in the People's Republic of China. The outbreak turned into a pandemic. In the shortest possible time, national and international manufacturers developed preventive COVID-19 vaccines, and the population was vaccinated. During pandemics, accelerated approval of vaccines is an important factor that shortens the time to market with the aim of mass vaccination. The experience of rapidly developing and introducing vaccines into routine practice is not only important for managing the current pandemic, but also valuable in case of extremely likely future ones. The aim of this study was to analyse the main issues associated with assessing the safety and efficacy of vaccines for COVID-19 prevention during their registration and widespread use amid the pandemic and ongoing SARS-CoV-2 evolution. The vaccines for COVID-19 prevention were developed and introduced into healthcare practice very rapidly and under the circumstances of the pandemic, and the use of these vaccines has surfaced a number of concerns requiring further research. The most important issues identified in the performed analysis include, but are not limited to the need for accelerated assessment of the safety and immunogenicity of new vaccines; the lack of immune correlates of protection against SARS-CoV-2; the waning of antibody immunity over time, motivating the need to determine revaccination and post-recovery vaccination timelines; and the emergence of mutant SARS-CoV-2 variants. One of noteworthy aspects is the need to develop recommendations for updating the strain composition of registered COVID-19 vaccines. According to the conclusions, the level of herd immunity, including vaccine-induced protection, plays a certain role in virus evolution during the pandemic. If COVID-19 becomes seasonal, which is a probable scenario, regular revaccination can be essential.

1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–13. https://doi.org/10.1016/S0140-6736(20)30211-7

2. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382(13):1199–207. https://doi.org/10.1056/NEJMoa2001316

3. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5(4):536–44. https://doi.org/10.1038/s41564-020-0695-z

4. Meyerowitz EA, Richterman A, Gandhi RT, Sax PE. Transmission of SARS-CoV-2: a review of viral, host, and environmental factors. Ann Intern Med. 2021;174(1):69–79. https://doi.org/10.7326/M20-5008

5. Meyerowitz EA, Richterman A. SARS-CoV-2 transmission and prevention in the era of the Delta variant. Infect Dis Clin North Am. 2022;36(2):267–93. https://doi.org/10.1016/j.idc.2022.01.007

6. McNeill VF. Airborne transmission of SARS-CoV-2: evidence and implications for engineering controls. Annu Rev Chem Biomol Eng. 2022;13:123–40. https://doi.org/10.1146/annurev-chembioeng-092220-111631

7. Lopez A, Srigley J. Transmission of SARS-CoV-2: still up in the air. Lancet. 2022;399(10324):519. https://doi.org/10.1016/S0140-6736(21)02794-X

8. Greenhalgh T, Jimenez JL, Prather KA, Tufeki Z, Fisman D, Schooley R. Transmission of SARS-CoV-2: still up in the air – Authors' reply. Lancet. 2022;399(10324):519–20. https://doi.org/10.1016/S0140-6736(21)02795-1

9. Meister TL, Dreismeier M, Blanco EV, Brüggemann Y, Heinen N, Kampf G, et al. Low risk of severe acute respiratory syndrome coronavirus 2 transmission by fomites: a clinical observational study in highly infectious coronavirus disease 2019 patients. J Infect Dis. 2022;226(9):1608–15. https://doi.org/10.1093/infdis/jiac170

10. Butot S, Zuber S, Moser M, Baert L. Data on transfer of human coronavirus SARS-CoV-2 from foods and packaging materials to gloves indicate that fomite transmission is of minor importance. Appl Environ Microbiol. 2022;88(7):e0233821. https://doi.org/10.1128/aem.02338-21

11. Baig AM, Khaleeq Ar, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11(7):995–8. https://doi.org/10.1021/acschemneuro.0c00122

12. Bassetti M, Vena A, Giacobbe DR. The novel Chinese coronavirus (2019-nCoV) infections: challenges for fighting the storm. Eur J Clin Invest. 2020;50(3):e13209–13. https://doi.org/10.1111/eci.13209

13. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229):1033–4. https://doi.org/10.1016/S0140-6736(20)30628-0

14. Zanza C, Romenskaya T, Manetti AC, Franceschi F, La Russa R, Bertozzi G, et al. Cytokine storm in COVID-19: immunopathogenesis and therapy. Medicina (Kaunas). 2022;58(2):144. https://doi.org/10.3390/medicina58020144

15. Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636–43. https://doi.org/10.1038/s41591-020-1051-9

16. Ahire E, Kshirsagar SJ. Immune responses induced by different vaccine platforms against coronavirus disease-19. Explor Immunol. 2021;1:243–57. https://doi.org/10.37349/ei.2021.00016

17. He Q, Mao Q, Zhang J, Bian L, Gao F, Wang J, Xu M, Liang Z. COVID-19 vaccines: current understanding on immunogenicity, safety, and further considerations. Front. Immunol. 2021;12:669339. https://doi.org/10.3389/fimmu.2021.669339

18. Walsh EE, Frenck RW Jr, Falsey AR, Kitchin N, Absalon J, Gurtman A, et al. Safety and immunogenicity of two RNA-based Covid-19 Vaccine Candidates. N Engl J Med. 2020;383(25):2439–50. https://doi.org/10.1056/NEJMoa2027906

19. Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P, et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe. 2020;27(3):325–8. https://doi.org/10.1016/j.chom.2020.02.001

20. Sadarangani M, Marchant A, Kollmann TR. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans. Nat Rev Immunol. 2021;21(8):475–84. https://doi.org/10.1038/s41577-021-00578-z

21. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403–16. https://doi.org/10.1056/NEJMoa2035389

22. Dolzhikova IV, Tokarskaya EA, Dzharullaeva AS, Tukhvatulin AI, Shcheblyakov DV, Voronina OL, et al. Virus-vectored Ebola vaccines. Acta Naturae. 2017;9(3):4–11.

23. Logunov DY, Dolzhikova IV, Zubkova OV, Tukhvatullin AI, Shcheblyakov DV, Dzharullaeva AS, 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(10255):887–97. https://doi.org/10.1016/S0140-6736(20)31866-3

24. Dolzhikova IV, Zubkova OV, Tukhvatulin AI, Dzharullaeva AS, Tukhvatulina NM, Shcheblyakov DV, et al. Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: an open phase I/II trial in healthy adults in Russia. Hum Vaccin Immunother. 2017;13(3):613–20. https://doi.org/10.1080/21645515.2016.1238535

25. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, 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(10269): 99–111. https://doi.org/10.1016/S0140-6736(20)32661-1

26. Tatsis N, Ertl HC. Adenoviruses as vaccine vectors. Mol Ther. 2004;10(4):616–29. https://doi.org/10.1016/j.ymthe.2004.07.013

27. Logunov DY, Dolzhikova IV, Shcheblyakov DV, Tukhvatulin AI, Zubkova OV, Dzharullaeva AS, 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 [published correction appears in Lancet. 2021 Feb 20;397(10275):670]. Lancet. 2021;397(10275):671–81. https://doi.org/10.1016/S0140-6736(21)00234-8

28. Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249):479–88. https://doi.org/10.1016/S0140-6736(20)31605-6

29. Ryzhikov AB, Ryzhikov ЕА, Bogryantseva MP, Usova SV, Danilenko ED, Nechaeva EA, et al. A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the “EpiVacCorona” vaccine for the prevention of COVID-19, in volunteers aged 18–60 years (phase I–II). Infektsiya i immunitet = Russian Journal of Infection and Immunity. 2021;11(2):283–96 (In Russ.) https://doi.org/10.15789/2220-7619-ASB-1699

30. Ishmukhametov AA, Siniugina AA, Yagovkina NV, Kuzubov VI, Zakharov KA, Volok VP, et al. Safety and immunogenicity of inactivated whole virion vaccine CoviVac against COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase I/II clinical trial. medRxiv. 2022.02.08.22270658; https://doi.org/10.1101/2022.02.08.22270658

31. Shrestha LB, Foster C, Rawlinson W, Tedla N, Bull RA. Evolution of the SARS-CoV-2 omicron variants BA.1 to BA.5: implications for immune escape and transmission. Rev Med Virol. 2022;32(5):e2381. https://doi.org/10.1002/rmv.2381

32. Frenck RW Jr, Klein NP, Kitchin N, Gurtman A, Absalon J, Lockhart S, et al. Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents. N Engl J Med. 2021;385(3):239–50. https://doi.org/10.1056/NEJMoa2107456

33. Risma KA, Edwards KM, Hummell DS, Little FF, Norton AE, Stallings A, et al. Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines. J Allergy Clin Immunol. 2021;147(6):2075–82. https://doi.org/10.1016/j.jaci.2021.04.002

34. Montano D. Frequency and associations of adverse reactions of COVID-19 vaccines reported to pharmacovigilance systems in the European Union and the United States. Front Public Health. 2021;9:756633. https://doi.org/10.3389/fpubh.2021.756633

35. Blumenthal KG, Phadke NA, Bates DW. Safety surveillance of COVID-19 mRNA vaccines through the Vaccine Safety Datalink. JAMA. 2021,12;326(14):1375–7. https://doi.org/10.1001/jama.2021.14808

36. Cai C, Peng Y, Shen E, Huang Q, Chen Y, Liu P, Guo C, et al. A comprehensive analysis of the efficacy and safety of COVID-19 vaccines. Mol Ther. 2021;29(9):2794–2805. https://doi.org/10.1016/j.ymthe.2021.08.001

37. Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, et.al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J Med Virol. 2021;93(2):1013–22. https://doi.org/10.1002/jmv.26368

38. Corti D, Purcell LA, Snell G, Veesler D. Tackling COVID-19 with neutralizing monoclonal antibodies. Cell. 2021;184:3086–108. https://doi.org/10.1016/j.cell.2021.05.005

39. Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Falci DR, Sarkis E, et al. Early treatment for Covid-19 with SARSCoV-2 neutralizing antibody Sotrovimab. N Engl J Med. 2021;385(21):1941–50. https://doi.org/10.1056/NEJMoa2107934

40. Khoury DS, Wheatley AK, Ramuta MD, Reynaldi A, Cromer D, Subbarao K, et. al. Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models. Nat Rev Immunol. 2020;20(12):727–38. https://doi.org/10.1038/s41577-020-00471-1

41. Dai L, Gao GF. Viral targets for vaccines against COVID-19. Nat Rev Immunol. 2021;21(2):73–82. https://doi.org/10.1038/s41577-020-00480-0

42. Baklaushev VP, Averyanov AV, Sotnikiva AG, Perkina AS, Ivanov AV, Yusubalieva GM, et al. Safety and efficacy of convalescent plasma for COVID-19: the preliminary results of a clinical study. Klinicheskaya praktika = Journal of Clinical Practice. 2020;11(2):38–50 (In Russ.). https://doi.org/10.17816/clinpract35168

43. Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020;396(10249):467–78. https://doi.org/10.1016/S0140-6736(20)31604-4

44. Andrews N, Stowe J, Kirsebom F, Toffa S, Rickeard T, Gallagher E, et al. Covid-19 vaccine effectiveness against the Omicron (B.1.1.529) variant. N Engl J Med. 2022;386(16):1532–46. https://doi.org/10.1056/NEJMoa2119451

45. Buchan SA, Chung H, Brown KA, Austin PC, Fell DB, Gubbay JB, et al. Estimated effectiveness of COVID-19 vaccines against Omicron or Delta symptomatic infection and severe outcomes. JAMA Netw Open. 2022;5(9):e2232760. https://doi.org/10.1001/jamanetworkopen.2022.32760

46. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, et al. Protection of BNT162b2 vaccine booster against Covid-19 in Israel. N Engl J Med. 2021;385(15):1393–400. https://doi.org/10.1056/NEJMoa2114255

47. Stowe J, Andrews N, Kirsebom F, Ramsay M, Bernal JL. Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation, a test negative case-control study. Nat Commun. 2022;13(1):5736. https://doi.org/10.1038/s41467-022-33378-7

48. Topol EJ, Iwasaki A. Operation Nasal Vaccine-Lightning speed to counter COVID-19. Sci Immunol. 2022;7(74):eadd9947. https://doi.org/10.1126/sciimmunol.add9947

49. Higdon MM, Baidya A, Walter KK, Patel MK, Issa H, Espié E, et al. Duration of effectiveness of vaccination against COVID-19 caused by the omicron variant. Lancet Infect Dis. 2022;22(8):1114–6. https://doi.org/10.1016/S1473-3099(22)00409-1

50. Focosi D, Maggi F. Recombination in coronaviruses, with a focus on SARS-CoV-2. Viruses. 2022;14(6):1239. https://doi.org/10.3390/v14061239

51. Nichols GL, Gillingham EL, Macintyre HL, Vardoulakis S, Hajat S, Sarran CE, et al. Coronavirus seasonality, respiratory infections and weather. BMC Infect Dis. 2021;21(1):1101. https://doi.org/10.1186/s12879-021-06785-2

52. Wiemken TL, Khan F, Nguyen JL, Jodar L, McLaughlin JM. Is COVID-19 seasonal? A time series modeling approach. medRxiv. 2022.06.17.22276570. https://doi.org/10.1101/2022.06.17.22276570