Short Review

Interferons as a Potential Therapeutic Drug for COVID-19: A Literature Review of Mechanisms, Current Clinical Trials, and Challenges

Pramod Yadav*, Vishal Chandra, Vikas Raghuvanshi, Amarjeet Yadav, Adhishree Yadav, Samim Ali and Vivek Mani Tripathi

Published: 10 July, 2023 | Volume 4 - Issue 2 | Pages: 048-056

The 2019 COVID-19 pandemic caused by SARS-CoV-2 has resulted in many fatalities worldwide. Despite various types of supportive care, mortality rates for patients with comorbidities remain high. To explore alternative treatment options, interferons (IFNs) have emerged as promising therapeutic drugs for SARS-CoV-2. This review aims to investigate the potential of IFNs as a drug with details on their mechanisms of action, and available data on their use with ongoing clinical trials, results, potential limitations, and challenges.  Recently published research articles, which are systematically searched through online databases, have been selected and found that IFNs have colossal potential in treating SARS-CoV-2 infection by modulating the host’s immune response and inhibiting viral replication and decreasing the severity of disease and hospitalization (p = 0.03, ± 0.05) and (p = 0.04, ± 0.05) respectively. However, due to less available data, more controlled and randomized trials are needed to confirm the efficacy and safety of IFN therapy.  The optimal dosing and duration of IFN therapy also remain to be determined. Although further research is needed the wait for ongoing clinical trial results under investigation is also important for a better understanding of IFN therapy.

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Therapeutic; COVID-19; Immune response; Clinical trials; Antiviral therapy


  1. Bonilauri P, Rugna G. Animal Coronaviruses and SARS-COV-2 in Animals, What Do We Actually Know? Life (Basel). 2021 Feb 5;11(2):123. doi: 10.3390/life11020123. PMID: 33562645; PMCID: PMC7914637.
  2. Petrosillo N, Viceconte G, Ergonul O, Ippolito G, Petersen E. COVID-19, SARS and MERS: are they closely related? Clin Microbiol Infect. 2020 Jun;26(6):729-734. doi: 10.1016/j.cmi.2020.03.026. Epub 2020 Mar 28. PMID: 32234451; PMCID: PMC7176926.
  3. Raghuvanshi V, Yadav P, Ali S. Interferon production by Viral, Bacterial & Yeast system: A comparative overview in 2023. Int Immunopharmacol. 2023 Jul;120:110340. doi: 10.1016/j.intimp.2023.110340. Epub 2023 May 23. PMID: 37230033.
  4. Yadav P, Yadav A.. Interferon Production and Potentiality as a therapeutic drug for SARS-CoV-2. Advances in Pharmacoepidemiology and Drug Safety. 2023; 12(1):1–5. https://doi.org/10.35248/2167-1052.23.12.288
  5. Gili T, Benelli G, Buscarini E, Canetta C, La Piana G, Merli G, Scartabellati A, Viganò G, Sfogliarini R, Melilli G, Assandri R, Cazzato D, Rossi DS, Usai S, Caldarelli G, Tramacere I, Pellegata G, Lauria G. SARS-COV-2 comorbidity network and outcome in hospitalized patients in Crema, Italy. PLoS One. 2021 Mar 25;16(3):e0248498. doi: 10.1371/journal.pone.0248498. PMID: 33765013; PMCID: PMC7993836.
  6. Iftimie S, López-Azcona AF, Vicente-Miralles M, Descarrega-Reina R, Hernández-Aguilera A, Riu F, Simó JM, Garrido P, Joven J, Camps J, Castro A. Risk factors associated with mortality in hospitalized patients with SARS-CoV-2 infection. A prospective, longitudinal, unicenter study in Reus, Spain. PLoS One. 2020 Sep 3;15(9):e0234452. doi: 10.1371/journal.pone.0234452. PMID: 32881860; PMCID: PMC7470256.
  7. Lai Q, Spoletini G, Bianco G, Graceffa D, Agnes S, Rossi M, Lerut J. SARS-CoV2 and immunosuppression: A double-edged sword. Transpl Infect Dis. 2020 Dec;22(6):e13404. doi: 10.1111/tid.13404. Epub 2020 Jul 17. PMID: 32639598; PMCID: PMC7361075.
  8. Minotti C, Tirelli F, Barbieri E, Giaquinto C, Donà D. How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review. J Infect. 2020 Jul;81(1):e61-e66. doi: 10.1016/j.jinf.2020.04.026. Epub 2020 Apr 23. PMID: 32335173; PMCID: PMC7179496.
  9. Yang L, Wang J, Hui P, Yarovinsky TO, Badeti S, Pham K, Liu C. Potential role of IFN-α in COVID-19 patients and its underlying treatment options. Appl Microbiol Biotechnol. 2021 May;105(10):4005-4015. doi: 10.1007/s00253-021-11319-6. Epub 2021 May 5. PMID: 33950278; PMCID: PMC8096625.
  10. Jhuti D, Rawat A, Guo CM, Wilson LA, Mills EJ, Forrest JI. Interferon Treatments for SARS-CoV-2: Challenges and Opportunities. Infect Dis Ther. 2022 Jun;11(3):953-972. doi: 10.1007/s40121-022-00633-9. Epub 2022 Apr 21. PMID: 35445964; PMCID: PMC9022612.
  11. Nakhlband A, Fakhari A, Azizi H. Interferon-beta offers promising avenues to COVID-19 treatment: a systematic review and meta-analysis of clinical trial studies. Naunyn Schmiedebergs Arch Pharmacol. 2021 May;394(5):829-838. doi: 10.1007/s00210-021-02061-x. Epub 2021 Feb 15. PMID: 33587164; PMCID: PMC7883756.
  12. Rubinstein M. Multiple interferon subtypes: the phenomenon and its relevance. J Interferon Res. 1987 Oct;7(5):545-51. doi: 10.1089/jir.1987.7.545. PMID: 2445852.
  13. Khanna NR, Gerriets V. Interferon. Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research. 2022; 447–452. https://doi.org/10.1016/B978-0-12-820649-2.00115-7
  14. Parmar S, Platanias LC. Interferons: mechanisms of action and clinical applications. Curr Opin Oncol. 2003 Nov;15(6):431-9. doi: 10.1097/00001622-200311000-00005. PMID: 14624225.
  15. Taylor MW. Viruses and man: A history of interactions. Viruses and Man: A History of Interactions. 2015; 1–430. https://doi.org/10.1007/978-3-319-07758-1
  16. Dorrington MG, Bradfield CJ, Lack JB, Lin B, Liang JJ, Starr T, Ernst O, Gross JL, Sun J, Miller AH, Steele-Mortimer O, Fraser IDC. Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol. PLoS Pathog. 2021 Mar 8;17(3):e1009395. doi: 10.1371/journal.ppat.1009395. Erratum in: PLoS Pathog. 2021 Aug 4;17(8):e1009821. PMID: 33684179; PMCID: PMC7971856.
  17. Aaronson DS, Horvath CM. A road map for those who don't know JAK-STAT. Science. 2002 May 31;296(5573):1653-5. doi: 10.1126/science.1071545. PMID: 12040185.
  18. Farrar JD, Smith JD, Murphy TL, Murphy KM. Recruitment of Stat4 to the human interferon-alpha/beta receptor requires activated Stat2. J Biol Chem. 2000 Jan 28;275(4):2693-7. doi: 10.1074/jbc.275.4.2693. PMID: 10644731.
  19. Matikainen S, Sareneva T, Ronni T, Lehtonen A, Koskinen PJ, Julkunen I. Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. Blood. 1999 Mar 15;93(6):1980-91. PMID: 10068671.
  20. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749-95. doi: 10.1146/annurev.immunol.15.1.749. PMID: 9143706.
  21. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005 May;5(5):375-86. doi: 10.1038/nri1604. PMID: 15864272.
  22. Lin FC, Young HA. Interferons: Success in anti-viral immunotherapy. Cytokine Growth Factor Rev. 2014 Aug;25(4):369-76. doi: 10.1016/j.cytogfr.2014.07.015. Epub 2014 Jul 29. PMID: 25156421; PMCID: PMC4182113.
  23. Friedman RM. Clinical uses of interferons. Br J Clin Pharmacol. 2008 Feb;65(2):158-62. doi: 10.1111/j.1365-2125.2007.03055.x. Epub 2007 Dec 7. PMID: 18070219; PMCID: PMC2253698.
  24. George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. Pharmacology and therapeutic potential of interferons. Pharmacol Ther. 2012 Jul;135(1):44-53. doi: 10.1016/j.pharmthera.2012.03.006. Epub 2012 Mar 28. PMID: 22484806.
  25. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003 Jan;4(1):69-77. doi: 10.1038/ni875. Epub 2002 Dec 16. PMID: 12483210.
  26. Ozato K, Uno K, Iwakura Y. Another road to interferon: Yasuichi Nagano's journey. J Interferon Cytokine Res. 2007 May;27(5):349-52. doi: 10.1089/jir.2007.9988. PMID: 17523866.
  27. Rahmani H, Davoudi-Monfared E, Nourian A, Khalili H, Hajizadeh N, Jalalabadi NZ, Fazeli MR, Ghazaeian M, Yekaninejad MS. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int Immunopharmacol. 2020 Nov;88:106903. doi: 10.1016/j.intimp.2020.106903. Epub 2020 Aug 24. PMID: 32862111; PMCID: PMC7445008.
  28. COVID-19 Treatment Guidelines. (n.d.). March 17, 2023. https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/interferons/
  29. Bosi E, Bosi C, Rovere Querini P, Mancini N, Calori G, Ruggeri A, Canzonieri C, Callegaro L, Clementi M, De Cobelli F, Filippi M, Bregni M. Interferon β-1a (IFNβ-1a) in COVID-19 patients (INTERCOP): study protocol for a randomized controlled trial. Trials. 2020 Nov 23;21(1):939. doi: 10.1186/s13063-020-04864-4. PMID: 33225960; PMCID: PMC7681191.
  30. Dinnon KH 3rd, Leist SR, Schäfer A, Edwards CE, Martinez DR, Montgomery SA, West A, Yount BL Jr, Hou YJ, Adams LE, Gully KL, Brown AJ, Huang E, Bryant MD, Choong IC, Glenn JS, Gralinski LE, Sheahan TP, Baric RS. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature. 2020 Oct;586(7830):560-566. doi: 10.1038/s41586-020-2708-8. Epub 2020 Aug 27. Erratum in: Nature. 2021 Feb;590(7844):E22. PMID: 32854108; PMCID: PMC8034761.
  31. Pituch-Noworolska AM. NK cells in SARS-CoV-2 infection. Cent Eur J Immunol. 2022;47(1):95-101. doi: 10.5114/ceji.2022.113078. Epub 2022 Feb 10. PMID: 35600151; PMCID: PMC9115590.
  32. Emani VR, Goswami S, Nandanoor D, Emani SR, Reddy NK, Reddy R. Randomised controlled trials for COVID-19: evaluation of optimal randomisation methodologies-need for data validation of the completed trials and to improve ongoing and future randomised trial designs. Int J Antimicrob Agents. 2021 Jan;57(1):106222. doi: 10.1016/j.ijantimicag.2020.106222. Epub 2020 Nov 12. PMID: 33189891; PMCID: PMC7659806.
  33. Bencze D, Fekete T, Pázmándi K. Correlation between Type I Interferon Associated Factors and COVID-19 Severity. Int J Mol Sci. 2022 Sep 19;23(18):10968. doi: 10.3390/ijms231810968. PMID: 36142877; PMCID: PMC9506204.
  34. Shalhoub S. Interferon beta-1b for COVID-19. Lancet. 2020 May 30;395(10238):1670-1671. doi: 10.1016/S0140-6736(20)31101-6. Epub 2020 May 10. PMID: 32401712; PMCID: PMC7211497.
  35. Sosa JP, Ferreira Caceres MM, Ross Comptis J, Quiros J, Príncipe-Meneses FS, Riva-Moscoso A, Belizaire MP, Malanyaon FQ, Agadi K, Jaffery SS, Sahajwani J, Arshia A, Senatus A, Verdecia G, Akano L, Razzack AA, Salam S, Gadamidi VK, Marian S. Effects of Interferon Beta in COVID-19 adult patients: Systematic Review. Infect Chemother. 2021 Jun;53(2):247-260. doi: 10.3947/ic.2021.0028. PMID: 34216119; PMCID: PMC8258298.
  36. Zhou Q, Chen V, Shannon CP, Wei XS, Xiang X, Wang X, Wang ZH, Tebbutt SJ, Kollmann TR, Fish EN. Interferon-α2b Treatment for COVID-19. Front Immunol. 2020 May 15;11:1061. doi: 10.3389/fimmu.2020.01061. Erratum in: Front Immunol. 2020 Oct 27;11:615275. PMID: 32574262; PMCID: PMC7242746.
  37. Aricò E, Castiello L, Bracci L, Urbani F, Lombardo F, Bacigalupo I, Ancidoni A, Vanacore N, Falcione A, Reggiani C, Dutti GM, Maglie MG, Papa O, Bartoletti PL, Ozzella G, Bevilacqua N, Nicastri E, Belardelli F, Sconocchia G. Antiviral and immunomodulatory interferon-beta in high-risk COVID-19 patients: a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Sep 3;22(1):584. doi: 10.1186/s13063-021-05367-6. PMID: 34479601; PMCID: PMC8413691.
  38. Arabi YM, Alothman A, Balkhy HH, Al-Dawood A, AlJohani S, Al Harbi S, Kojan S, Al Jeraisy M, Deeb AM, Assiri AM, Al-Hameed F, AlSaedi A, Mandourah Y, Almekhlafi GA, Sherbeeni NM, Elzein FE, Memon J, Taha Y, Almotairi A, Maghrabi KA, Qushmaq I, Al Bshabshe A, Kharaba A, Shalhoub S, Jose J, Fowler RA, Hayden FG, Hussein MA; And the MIRACLE trial group. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials. 2018 Jan 30;19(1):81. doi: 10.1186/s13063-017-2427-0. PMID: 29382391; PMCID: PMC5791210.
  39. Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020 Jun;178:104791. doi: 10.1016/j.antiviral.2020.104791. Epub 2020 Apr 7. PMID: 32275914; PMCID: PMC7138382.
  40. Arabi YM, Asiri AY, Assiri AM, Abdullah ML, Aljami HA, Balkhy HH, Al Jeraisy M, Mandourah Y, AlJohani S, Al Harbi S, Jokhdar HAA, Deeb AM, Memish ZA, Jose J, Ghazal S, Al Faraj S, Al Mekhlafi GA, Sherbeeni NM, Elzein FE, Hayden FG, Fowler RA, AlMutairi BM, Al-Dawood A, Alharbi NK. Heterogeneity of treatment effect of interferon-β1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels. Sci Rep. 2022 Oct 28;12(1):18186. doi: 10.1038/s41598-022-22742-8. PMID: 36307462; PMCID: PMC9616407.
  41. Alavi Darazam I, Shokouhi S, Pourhoseingholi MA, Naghibi Irvani SS, Mokhtari M, Shabani M, Amirdosara M, Torabinavid P, Golmohammadi M, Hashemi S, Azimi A, Jafarazadeh Maivan MH, Rezaei O, Zali A, Hajiesmaeili M, Shabanpour Dehbsneh H, Hoseyni Kusha A, Taleb Shoushtari M, Khalili N, Soleymaninia A, Gachkar L, Khoshkar A. Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial. Sci Rep. 2021 Apr 13;11(1):8059. doi: 10.1038/s41598-021-86859-y. PMID: 33850184; PMCID: PMC8044200.
  42. Nguyen HA, Cooke GS, Day JN, Flower B, Phuong LT, Hung TM, Dung NT, Khoa DB, Hung LM, Kestelyn E, Thwaites GE, Chau NVV; SEARCH Investigators; Turner HC. The direct-medical costs associated with interferon-based treatment for Hepatitis C in Vietnam. Wellcome Open Res. 2020 Sep 11;4:129. doi: 10.12688/wellcomeopenres.15408.2. PMID: 32734002; PMCID: PMC7372532.
  43. Bittner B, Richter W, Schmidt J. Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities. BioDrugs. 2018 Oct;32(5):425-440. doi: 10.1007/s40259-018-0295-0. PMID: 30043229; PMCID: PMC6182494.
  44. Hauschild A, Gogas H, Tarhini A, Middleton MR, Testori A, Dréno B, Kirkwood JM. Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer. 2008 Mar 1;112(5):982-94. doi: 10.1002/cncr.23251. PMID: 18236459.
  45. Interferon Beta-1a Subcutaneous Injection: MedlinePlus Drug Information. (n.d.). March 24, 2023. https://medlineplus.gov/druginfo/meds/a604005.html
  46. Kim YM, Shin EC. Type I and III interferon responses in SARS-CoV-2 infection. Exp Mol Med. 2021 May;53(5):750-760. doi: 10.1038/s12276-021-00592-0. Epub 2021 May 6. PMID: 33953323; PMCID: PMC8099704.
  47. Zheng F, Zhou Y, Zhou Z, Ye F, Huang B, Huang Y, Ma J, Zuo Q, Tan X, Xie J, Niu P, Wang W, Xu Y, Peng F, Zhou N, Cai C, Tang W, Xiao X, Li Y, Zhou Z, Jiang Y, Xie Y, Tan W, Gong G. SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial. Int J Infect Dis. 2020 Oct;99:84-91. doi: 10.1016/j.ijid.2020.07.053. Epub 2020 Aug 3. PMID: 32758689; PMCID: PMC7397938.
  48. WHO Solidarity Trial Consortium; Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernández García C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Røttingen JA, Swaminathan S. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2. PMID: 33264556; PMCID: PMC7727327.
  49. Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, Gabbay FJ, Davies DE, Holgate ST, Ho LP, Clark T, Djukanovic R, Wilkinson TMA; Inhaled Interferon Beta COVID-19 Study Group. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021 Feb;9(2):196-206. doi: 10.1016/S2213-2600(20)30511-7. Epub 2020 Nov 12. PMID: 33189161; PMCID: PMC7836724.
  50. Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, Kazemzadeh H, Yekaninejad MS. A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e01061-20. doi: 10.1128/AAC.01061-20. PMID: 32661006; PMCID: PMC7449227.
  51. Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, Borgia SM, Boggild AK, Powis J, McCready J, Tan DHS, Chan T, Coburn B, Kumar D, Humar A, Chan A, O'Neil B, Noureldin S, Booth J, Hong R, Smookler D, Aleyadeh W, Patel A, Barber B, Casey J, Hiebert R, Mistry H, Choong I, Hislop C, Santer DM, Lorne Tyrrell D, Glenn JS, Gehring AJ, Janssen HLA, Hansen BE. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial. Lancet Respir Med. 2021 May;9(5):498-510. doi: 10.1016/S2213-2600(20)30566-X. Epub 2021 Feb 5. PMID: 33556319; PMCID: PMC7906707.


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