Table Info

Table 2.

Summary of immunological characteristics in severe COVID [38, 46, 65]

Immunologic changes	COVID-19
T cell responses	Lymphopenia in severe cases.
CD8⁺ cells	Severe lymphopenia, a predictor of severe COVID disease.
Th1-Th2 responses	Severe systemic inflammatory response accompanied by cytokine response. Plays a part in the activation of inflammasomes.
Eosinophils	The number of circulating eosinophils has decreased.
Cytokine storm	In severe disease, large numbers of innate and adaptive cytokines are released.
Acute phase reactants	Initial high values are predictors of severe disease.
Specific antibody levels	Virus-specific IgM rises during the acute phase, followed by virus-specific IgG during the recovery phase.

Declarations

Author contributions

AS, VS, AK, MOP wrote the article. BJO and MOP edited and concepted the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

COVID-19 dashboard by the center for systems science and engineering (CSSE) at Johns Hopkins University (JHU) [Internet]. c2022 by Johns Hopkins University & Medicine [cited 2022 Apr 20]. Available from: https://coronavirus.jhu.edu/map.html

Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed. 2020;91:157–60. [DOI] [PubMed] [PMC]

Callaway E, Cyranoski D, Mallapaty S, Stoye E, Tollefson J. The coronavirus pandemic in five powerful charts. Nature. 2020;579:482–3. [DOI] [PubMed]

Sadarangani M, Marchant A, Kollmann TR. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans. Nat Rev Immunol. 2021;21:475–84. [DOI] [PubMed] [PMC]

Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020;586:589–93. [DOI] [PubMed]

Corbett KS, Edwards DK, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. 2020;586:567–71. [DOI] [PubMed] [PMC]

Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, Mahrokhian SH, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science. 2020;369:806–11. [DOI] [PubMed] [PMC]

Smith TRF, Patel A, Ramos S, Elwood D, Zhu X, Yan J, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun. 2020;11:2601. [DOI] [PubMed] [PMC]

Zhu FC, Li YH, Guan XH, Hou LH, Wang WJ, Li JX, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020;395:1845–54. [DOI] [PubMed] [PMC]

10.

van Doremalen N, Lambe T, Spencer A., Belij-Rammerstorfer S, Purushotham JN, Port JR, et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020;586:578–82. [DOI] [PubMed] [PMC]

11.

Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020;369:77–81. [DOI] [PubMed] [PMC]

12.

Wang H, Zhang Y, Huang B, Deng W, Quan Y, Wang W, et al. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell. 2020;182:713–21. [DOI] [PubMed] [PMC]

13.

Chen WH, Strych U, Hotez PJ, Bottazzi ME. The SARS-CoV-2 vaccine pipeline: an overview. Curr Trop Med Rep. 2020;[Epub ahead of print]. [DOI] [PubMed] [PMC]

14.

Jalkanen P, Kolehmainen P, Häkkinen HK, Huttunen M, Tähtinen PA, Lundberg R, et al. COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants. Nat Commun. 2021;12:3991. [DOI] [PubMed] [PMC]

15.

Hanrath AT, Payne BAI, Duncan CJA. Prior SARS-CoV-2 infection is associated with protection against symptomatic reinfection. J Infect. 2021;82:e29–30. [DOI] [PubMed] [PMC]

16.

Hall VJ, Foulkes S, Charlett A, Atti A, Monk EJM, Simmons R, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet. 2021;397:1459–69. [DOI] [PubMed] [PMC]

17.

Chodick G, Tene L, Patalon T, Gazit S, Ben Tov A, Cohen D, et al. Assessment of effectiveness of 1 dose of BNT162b2 vaccine for SARS-CoV-2 infection 13 to 24 days after immunization. JAMA Netw Open. 2021;4:e2115985. [DOI] [PubMed] [PMC]

18.

Gadanec LK, McSweeney KR, Qaradakhi T, Ali B, Zulli A, Apostolopoulos V. Can SARS-CoV-2 virus use multiple receptors to enter host cells? Int J Mol Sci. 2021;22:992. [DOI] [PubMed] [PMC]

19.

Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordjin SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol. 2020;251:228–48. [DOI] [PubMed] [PMC]

20.

Imai Y, Kuba K, Penninger JM. The renin–angiotensin system in acute respiratory distress syndrome. Drug Discov Today Dis Mech. 2006;3:225–9. [DOI] [PubMed] [PMC]

21.

Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112:1104–11. Erratum in: Circ Res. 2013;112:e156. [DOI] [PubMed]

22.

Ibrahim IM, Abdelmalek DH, Elshahat ME, Elfiky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction. J Infect. 2020;80:554–62. [DOI] [PubMed] [PMC]

23.

Triantafilou K, Fradelizi D, Wilson K, Triantafilou M. GRP78, a coreceptor for coxsackievirus A9, interacts with major histocompatibility complex class I molecules which mediate virus internalization. J Virol. 2002;76:633–43. [DOI] [PubMed] [PMC]

24.

Palmeira A, Sousa E, Köseler A, Sabirli R, Gören T, Türkçüer İ, et al. Preliminary virtual screening studies to identify GRP78 inhibitors which may interfere with SARS-CoV-2 infection. Pharmaceuticals (Basel). 2020;13:132. [DOI] [PubMed] [PMC]

25.

Rayner JO, Roberts RA, Kim J, Poklepovic A, Roberts JL, Booth L, et al. AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication. Biochem Pharmacol. 2020;182:114227. [DOI] [PubMed] [PMC]

26.

Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014;88:1293–307. [DOI] [PubMed] [PMC]

27.

Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W. TMPRSS2: a potential target for treatment of influenza virus and coronavirus infections. Biochimie. 2017;142:1–10. [DOI] [PubMed] [PMC]

28.

Dessie G, Mallik T. Role of serine proteases and host cell receptors involved in proteolytic activation, entry of SARS-CoV-2 and its current therapeutic options. Infect Drug Resist. 2021;14:1883–92. [DOI] [PubMed] [PMC]

29.

Bessler W, Holms R, Konopleva M, Ataullakhanov R. Review of Russian ezrin peptide treatment of acute viral respiratory disease and virus induced pneumonia; a potential treatment for covid-19. RG:2.2.10214.57925 [Preprint]. 2020 [cited 2020 Apr 13]. Available from: http://dx.doi.org/10.13140/RG.2.2.10214.57925

30.

Kachuri L, Francis SS, Morrison ML, Wendt GA, Bossé Y, Cavazos TB, et al. The landscape of host genetic factors involved in immune response to common viral infections. Genome Med. 2020;12:93. [DOI] [PubMed] [PMC]

31.

Khanmohammadi S, Rezaei N. Role of Toll-like receptors in the pathogenesis of COVID-19. J Med Virol. 2021;93:2735–9. [DOI] [PubMed] [PMC]

32.

Roth-Cross JK, Bender SJ, Weiss SR. Murine coronavirus mouse hepatitis virus is recognized by MDA5 and induces type I interferon in brain macrophages/microglia. J Virol. 2008;82:9829–38. [DOI] [PubMed] [PMC]

33.

Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVID-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34:327–31. [DOI] [PubMed]

34.

Totura AL, Whitmore A, Agnihothram S, Schäfer A, Katze MG, Heise MT, et al. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio. 2015;6:e00638–15. [DOI] [PubMed] [PMC]

35.

Yazdanpanah F, Hamblin MR, Rezaei N. The immune system and COVID-19: friend or foe? Life Sci. 2020;256:117900. [DOI] [PubMed] [PMC]

36.

van der Made CI, Simons A, Schuur-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. Presence of genetic variants among young men with severe COVID-19. JAMA. 2020;324:663–73. [DOI] [PubMed] [PMC]

37.

van Eijk LE, Binkhorst M, Bourgonje AR, Offringa AK, Mulder DJ, Bos EM, et al. COVID-19: immunopathology, pathophysiological mechanisms, and treatment options. J Pathol. 2021;254:307–31. [DOI] [PubMed] [PMC]

38.

Lowery SA, Sariol A, Perlman S. Innate immune and inflammatory responses to SARS-CoV-2: implications for COVID-19. Cell Host Microbe. 2021;29:1052–62. [DOI] [PubMed] [PMC]

39.

O’Connell P, Aldhamen YA. Systemic innate and adaptive immune responses to SARS-CoV-2 as it relates to other coronaviruses. Hum Vaccin Immunother. 2020;16:2980–91. [DOI] [PubMed] [PMC]

40.

Huang AT, Garcia-Carreras B, Hitchings MDT, Yang B, Katzelnick LC, Rattigan SM, et al. A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity. Nat Commun. 2020;11:4704. [DOI] [PubMed] [PMC]

41.

Post N, Eddy D, Huntley C, van Schalkwyk MCI, Shrotri M, Leeman D, et al. Antibody response to SARS-CoV-2 infection in humans: a systematic review. PLoS One. 2020;15:e0244126. [DOI] [PubMed] [PMC]

42.

Polat C, Ergunay K. Insights into the virologic and immunologic features of SARS-COV-2. World J Clin Cases. 2021;9:5007–18. [DOI] [PubMed] [PMC]

43.

Chen M, Wu Y, Jia W, Yin M, Hu Z, Wang R, et al. The predictive value of serum amyloid A and C-reactive protein levels for the severity of coronavirus disease 2019. Am J Transl Res. 2020;12:4569–75. [PubMed] [PMC]

44.

Yap JKY, Moriyama M, Iwasaki A. Inflammasomes and pyroptosis as therapeutic targets for COVID-19. J Immunol. 2020;205:307–12. [DOI] [PubMed] [PMC]

45.

Solimani F, Meier K, Ghoreschi K. Janus kinase signaling as risk factor and therapeutic target for severe SARS-CoV-2 infection. Eur J Immunol. 2021;51:1071–5. [DOI] [PubMed] [PMC]

46.

Boechat JL, Chora I, Morais A, Delgado L. The immune response to SARS-CoV-2 and COVID-19 immunopathology–current perspectives. Pulmonology. 2021;27:423–37. [DOI] [PubMed] [PMC]

47.

Kothari A, Singh V, Nath UK, Kumar S, Rai V, Kaushal K, et al. Immune dysfunction and multiple treatment modalities for the SARS-CoV-2 pandemic: races of uncontrolled running sweat? Biology (Basel). 2020;9:243. [DOI] [PubMed] [PMC]

48.

Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. 2020;509:280–7. [DOI] [PubMed] [PMC]

49.

Lokugamage KG, Hage A, de Vries M, Valero-Jimenez AM, Schindewolf C, Dittmann M, et al. Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV. J Virol. 2020;94:e01410–20. [DOI] [PubMed] [PMC]

50.

Park A, Iwasaki A. Type I and Type III interferons–induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe. 2020;27:870–8. [DOI] [PubMed] [PMC]

51.

Kim YM, Shin EC. Type I and III interferon responses in SARS-CoV-2 infection. Exp Mol Med. 2021;53:750–60. [DOI] [PubMed] [PMC]

52.

Galani IE, Rovina N, Lampropoulou V, Triantafyllia V, Manioudaki M, Pavlos E, et al. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat Immunol. 2021;22:32–40. [DOI] [PubMed]

53.

Sahu U, Biswas D, Singh AK, Khare P. Mechanism involved in the pathogenesis and immune response against SARS-CoV-2 infection. Virusdisease. 2021;32:211–9. [DOI] [PubMed] [PMC]

54.

Kaklamanos A, Belogiannis K, Skendros P, Gorgoulis VG, Vlachoyiannopoulos PG, Tzioufas AG. COVID-19 Immunobiology: lessons learned, new questions arise. Front Immunol. 2021;12:719023. [DOI] [PubMed] [PMC]

55.

Meftahi GH, Jangravi Z, Sahraei H, Bahari Z. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”. Inflamm Res. 2020;69:825–39. [DOI] [PubMed] [PMC]

56.

Orsini G, Legitimo A, Failli A, Massei F, Biver P, Consolini R. Enumeration of human peripheral blood dendritic cells throughout the life. Int Immunol. 2012;24:347–56. [DOI] [PubMed]

57.

Lee PI, Hu YL, Chen PY, Huang YC, Hsueh PR. Are children less susceptible to COVID-19? J Microbiol Immunol Infect. 2020;53:371–2. [DOI] [PubMed] [PMC]

58.

Augusto G, Mohsen MO, Zinkhan S, Liu X, Vogel M, Bachmann MF. In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion. Allergy. 2022;77:111–7. [DOI] [PubMed] [PMC]

59.

Mengist HM, Kombe Kombe AJ, Mekonnen D, Abebaw A, Getachew M, Jin T. Mutations of SARS-CoV-2 spike protein: implications on immune evasion and vaccine-induced immunity. Semin Immunol. 2021;55:101533. [DOI] [PubMed] [PMC]

60.

Lazarevic I, Pravica V, Miljanovic D, Cupic M. Immune evasion of SARS-CoV-2 emerging variants: what have we learnt so far? Viruses. 2021;13:1192. [DOI] [PubMed] [PMC]

61.

McCallum M, Bassi J, De Marco A, Chen A, Walls AC, Di Iulio J, et al. SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern. Science. 2021;373:648–54. [DOI] [PubMed]

62.

Lei X, Dong X, Ma R, Wang W, Xiao X, Tian Z, et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun. 2020;11:3810. [DOI] [PubMed] [PMC]

63.

Lotfi R, Kalmarzi RN, Roghani SA. A review on the immune responses against novel emerging coronavirus (SARS-CoV-2). Immunol Res. 2021;69:213–24. [DOI] [PubMed] [PMC]

64.

Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy. 2020;75:1564–81. [DOI] [PubMed] [PMC]

65.

Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363–74. [DOI] [PubMed] [PMC]

66.

Lanata De Las Casas CF, Gotuzzo Herencia E. Strategies and current status of the race to develop a SARS-CoV-2 vaccine. Rev Peru Med Exp Salud Publica. 2020;37:401–2. Spanish. [DOI] [PubMed]

67.

Plotkin S. History of vaccination. Proc Natl Acad Sci U S A. 2014;111:12283–7. [DOI] [PubMed] [PMC]

68.

Sanchez-Felipe L, Vercruysse T, Sharma S, Ma J, Lemmens V, Van Looveren D, et al. A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate. Nature. 2021;590:320–25. [DOI] [PubMed]

69.

Vogel AB, Lambert L, Kinnear E, Busse D, Erbar S, Reuter KC, et al. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. Mol Ther. 2018;26:446–55. [DOI] [PubMed] [PMC]

70.

Wu S, Zhong G, Zhang J, Shuai L, Zhang Z, Wen Z, et al. A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nat Commun. 2020;11:4081. [DOI] [PubMed] [PMC]

71.

Kyriakidis NC, López-Cortés A, González EV, Grimaldos AB, Prado EO. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. NPJ Vaccines. 2021;6:28. [DOI] [PubMed] [PMC]

72.

Basith S, Manavalan B, Lee G, Kim SG, Choi S. Toll-like receptor modulators: a patent review (2006–2010). Expert Opin Ther Pat. 2011;21:927–44. [DOI] [PubMed]

73.

Garçon N, Vaughn DW, Didierlaurent AM. Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion. Expert Rev Vaccines. 2012;11:349–66. [DOI] [PubMed]

74.

Ward BJ, Gobeil P, Séguin A, Atkins J, Boulay I, Charbonneau PY, et al. Phase 1 trial of a candidate recombinant virus-like particle vaccine for covid-19 disease produced in plants. medRxiv. [Preprint]. 2020 [cited 2020 Apr 11]. Available from: https://www.medrxiv.org/content/10.1101/2020.11.04.20226282v1

75.

Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020;586:516–27. [DOI] [PubMed]

76.

Hobernik D, Bros M. DNA vaccines-how far from clinical use? Int I Mol Sci. 2018;19:3605. [DOI] [PubMed] [PMC]

77.

Sharma O, Sultan AA, Ding H, Triggle CR. A review of the progress and challenges of developing a vaccine for COVID-19. Front Immunol. 2020;11:585354. [DOI] [PubMed] [PMC]

78.

Strizova Z, Smetanova J, Bartunkova J, Milota T. Principles and challenges in anti-COVID-19 vaccine development. Int Arch Allergy Immunol. 2021;182:339–49. [DOI] [PubMed] [PMC]

79.

Zhou P, Li Z, Xie L, An D, Fan Y, Wang X, et al. Research progress and challenges to coronavirus vaccine development. J Med Virol. 2021;93:741–54. [DOI] [PubMed]

80.

Malik YS, Kumar N, Sircar S, Kaushik R, Bhat S, Dhama K, et al. Coronavirus disease pandemic (COVID-19): challenges and a global perspective. Pathogens. 2020;9:519. [DOI] [PubMed] [PMC]

81.

Begum J, Mir NA, Dev K, Buyamayum B, Wani MY, Raza M. Challenges and prospects of COVID-19 vaccine development based on the progress made in SARS and MERS vaccine development. Transbound Emerg Dis. 2021;68:1111–24. [DOI] [PubMed] [PMC]

82.

Randolph HE, Barreiro LB. Herd immunity: understanding COVID-19. Immunity. 2020;52:737–41. [DOI] [PubMed] [PMC]