Possible effects of sirolimus treatment on the long‑term efficacy of COVID‑19 vaccination in patients with β‑thalassemia: A theoretical perspective

Zurlo,Matteo; Nicoli,Francesco; Borgatti,Monica; Finotti,Alessia; Gambari,Roberto

doi:10.3892/ijmm.2022.5088

Possible effects of sirolimus treatment on the long‑term efficacy of COVID‑19 vaccination in patients with β‑thalassemia: A theoretical perspective

Authors:
- Matteo Zurlo
- Francesco Nicoli
- Monica Borgatti
- Alessia Finotti
- Roberto Gambari
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Affiliations: Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara, Italy, Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, Italy
Published online on: January 19, 2022 https://doi.org/10.3892/ijmm.2022.5088
Article Number: 33

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Abstract

The pandemic caused by the severe acute respiratory syndrome coronavirus (SARS‑CoV‑2), responsible for coronavirus disease 2019 (COVID‑19) has posed a major challenge for global health. In order to successfully combat SARS‑CoV‑2, the development of effective COVID‑19 vaccines is crucial. In this context, recent studies have highlighted a high COVID‑19 mortality rate in patients affected by β‑thalassemia, probably due to their co‑existent immune deficiencies. In addition to a role in the severity of SARS‑CoV‑2 infection and in the mortality rate of COVID‑19‑infected patients with thalassemia, immunosuppression is expected to deeply affect the effectivity of anti‑COVID‑19 vaccines. In the context of the interplay between thalassemia‑associated immunosuppression and the effectiveness of COVID‑19 vaccines, the employment of immunomodulatory molecules is hypothesized. For instance, short‑term treatment with mammalian target of rapamycin inhibitors (such as everolimus and sirolimus) has been found to improve responses to influenza vaccination in adults, with benefits possibly persisting for a year following treatment. Recently, sirolimus has been considered for the therapy of hemoglobinopathies (including β‑thalassemia). Sirolimus induces the expression of fetal hemoglobin (and this may contribute to the amelioration of the clinical parameters of patients with β‑thalassemia) and induces autophagy (thereby reducing the excessive levels of α‑globin). It may also finally contribute to the mobilization of erythroid cells from the bone marrow (thereby reducing anemia). In the present study, the authors present the hypothesis that sirolimus treatment, in addition to its beneficial effects on erythroid‑related parameters, may play a crucial role in sustaining the effects of COVID‑19 vaccination in patients with β‑thalassemia. This hypothesis is based on several publications demonstrating the effects of sirolimus treatment on the immune system.

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1	Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395:497–506. 2020. View Article : Google Scholar : PubMed/NCBI
2	Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, et al: Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 130:2620–2629. 2020. View Article : Google Scholar : PubMed/NCBI
3	Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S and Nabipour I: COVID-19 cytokine storm: The anger of inflammation. Cytokine. 133:1551512020. View Article : Google Scholar : PubMed/NCBI
4	Nicoli F, Solis-Soto MT, Paudel D, Marconi P, Gavioli R, Appay V and Caputo A: Age-related decline of de novo T cell responsiveness as a cause of COVID-19 severity. Geroscience. 42:1015–1019. 2020. View Article : Google Scholar : PubMed/NCBI
5	Nikolich-Zugich J, Knox KS, Rios CT, Natt B, Bhattacharya D and Fain MJ: SARS-CoV-2 and COVID-19 in older adults: What we may expect regarding pathogenesis, immune responses, and outcomes. Geroscience. 42:505–514. 2020. View Article : Google Scholar : PubMed/NCBI
6	Genebat M, Tarancón-Díez L, de Pablo-Bernal R, Calderón A, Muñoz-Fernández MÁ and Leal M: Coronavirus disease (COVID-19): A Perspective from Immunosenescence. Aging Dis. 12:3–6. 2021. View Article : Google Scholar : PubMed/NCBI
7	Zafari M, Rad MTS, Mohseni F and Nikbakht N: β-Thalassemia Major and Coronavirus-19, mortality and morbidity: A systematic review study. Hemoglobin. 45:1–4. 2021. View Article : Google Scholar : PubMed/NCBI
8	Farmakis D, Giakoumis A, Polymeropoulos E and Aessopos A: Pathogenic aspects of immune deficiency associated with beta-thalassemia. Med Sci Monit. 9:RA19–RA22. 2003.PubMed/NCBI
9	Ghaffari J, Abediankenari S and Nasehi M: Thalassemia and immune system dysfunction-review article. Int J Curr Res. 3:105–108. 2011.
10	Blagosklonny MV: From causes of aging to death from COVID-19. Aging (Albany NY). 12:10004–10021. 2020. View Article : Google Scholar : PubMed/NCBI
11	Kaur SP and Gupta V: COVID-19 vaccine: A comprehensive status report. Virus Res. 288:1981142020. View Article : Google Scholar : PubMed/NCBI
12	Chakraborty C, Sharma AR, Bhattacharya M, Sharma G, Saha RP and Lee SS: Ongoing clinical trials of vaccines to fight against COVID-19 pandemic. Immune Netw. 21:e52021. View Article : Google Scholar : PubMed/NCBI
13	Dorrington MG and Bowdish DM: Immunosenescence and novel vaccination strategies for the elderly. Front Immunol. 4:1712013. View Article : Google Scholar : PubMed/NCBI
14	Tsatsakis A, Vakonaki E, Tzatzarakis M, Flamourakis M, Nikolouzakis TK, Poulas K, Papazoglou G, Hatzidaki E, Papanikolaou NC, Drakoulis N, et al: Immune response (IgG) following full inoculation with BNT162b2 COVID-19 mRNA among healthcare professionals. Int J Mol Med. 48:2002021. View Article : Google Scholar : PubMed/NCBI
15	Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, et al: mTOR inhibition improves immune function in the elderly. Sci Transl Med. 6:268ra1792014. View Article : Google Scholar : PubMed/NCBI
16	Mannick JB, Morris M, Hockey HP, Roma G, Beibel M, Kulmatycki K, Watkins M, Shavlakadze T, Zhou W, Quinn D, et al: TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 10:eaaq15642018. View Article : Google Scholar : PubMed/NCBI
17	Mischiati C, Sereni A, Lampronti I, Bianchi N, Borgatti M, Prus E, Fibach E and Gambari R: Rapamycin-mediated induction of gamma-globin mRNA accumulation in human erythroid cells. Br J Haematol. 126:612–621. 2004. View Article : Google Scholar : PubMed/NCBI
18	Fibach E, Bianchi N, Borgatti M, Zuccato C, Finotti A, Lampronti I, Prus E, Mischiati C and Gambari R: Effects of rapamycin on accumulation of alpha-, beta- and gamma-globin mRNAs in erythroid precursor cells from beta-thalassaemia patients. Eur J Haematol. 77:437–441. 2006. View Article : Google Scholar : PubMed/NCBI
19	Zuccato C, Bianchi N, Borgatti M, Lampronti I, Massei F, Favre C and Gambari R: Everolimus is a potent inducer of erythroid differentiation and gamma-globin gene expression in human erythroid cells. Acta Haematol. 117:168–176. 2007. View Article : Google Scholar : PubMed/NCBI
20	Pecoraro A, Troia A, Calzolari R, Scazzone C, Rigano P, Martorana A, Sacco M, Maggio A and Di Marzo R: Efficacy of rapamycin as inducer of HbF in primary erythroid cultures from sickle cell disease and beta-thalassemia patients. Hemoglobin. 39:225–229. 2015. View Article : Google Scholar : PubMed/NCBI
21	Gaudre N, Cougoul P, Bartolucci P, Dörr G, Bura-Riviere A, Kamar N and Del Bello A: Improved fetal hemoglobin with mTOR inhibitor-based immunosuppression in a kidney transplant recipient with sickle cell disease. Am J Transplant. 17:2212–2214. 2017. View Article : Google Scholar : PubMed/NCBI
22	Al-Khatti AA and Alkhunaizi AM: Additive effect of Sirolimus and hydroxycarbamide on fetal haemoglobin level in kidney transplant patients with sickle cell disease. Br J Haematol. 185:959–961. 2019. View Article : Google Scholar : PubMed/NCBI
23	Kahan BD: Sirolimus: A new agent for clinical renal transplantation. Transplant Proc. 29:48–50. 1997. View Article : Google Scholar : PubMed/NCBI
24	Hernández D, Martínez D, Gutiérrez E, López V, Gutiérrez C, García P, Cobelo C, Cabello M, Burgos D, Sola E and González-Molina M: Clinical evidence on the use of anti-mTOR drugs in renal transplantation. Nefrologia. 31:27–34. 2011.PubMed/NCBI
25	Schaffer SA and Ross HJ: Everolimus: Efficacy and safety in cardiac transplantation. Expert Opin Drug Saf. 9:843–854. 2010. View Article : Google Scholar : PubMed/NCBI
26	Tang CY, Shen A, Wei XF, Li QD, Liu R, Deng HJ, Wu YZ and Wu ZJ: Everolimus in de novo liver transplant recipients: A systematic review. Hepatobiliary Pancreat Dis Int. 14:461–469. 2015. View Article : Google Scholar : PubMed/NCBI
27	Ji L, Xie W and Zhang Z: Efficacy and safety of Sirolimus in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Semin Arthritis Rheum. 50:1073–1080. 2020. View Article : Google Scholar : PubMed/NCBI
28	Wang Q, Luo M, Xiang B, Chen S and Ji Y: The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis. Respir Res. 21:552020. View Article : Google Scholar : PubMed/NCBI
29	Sasongko TH, Ismail NF and Zabidi-Hussin Z: Rapamycin and rapalogs for tuberous sclerosis complex. Cochrane Database Syst Rev. 7:CD0112722016.PubMed/NCBI
30	Graillon T, Sanson M, Campello C, Idbaih A, Peyre M, Peyrière H, Basset N, Autran D, Roche C, Kalamarides M, et al: Everolimus and octreotide for patients with recurrent meningioma: Results from the phase II CEVOREM trial. Clin Cancer Res. 26:552–557. 2020. View Article : Google Scholar : PubMed/NCBI
31	Gallo M, Malandrino P, Fanciulli G, Rota F, Faggiano A and Colao A; NIKE Group, : Everolimus as first line therapy for pancreatic neuroendocrine tumours: Current knowledge and future perspectives. J Cancer Res Clin Oncol. 143:1209–1224. 2017. View Article : Google Scholar : PubMed/NCBI
32	Manohar PM, Beesley LJ, Taylor JM, Hesseltine E, Haymart MR, Esfandiari NH, Hanauer DA and Worden FP: Retrospective study of sirolimus and cyclophosphamide in patients with advanced differentiated thyroid cancers. J Thyroid Disord Ther. 4:1882015. View Article : Google Scholar : PubMed/NCBI
33	Hortobagyi GN: Everolimus plus exemestane for the treatment of advanced breast cancer: A review of subanalyses from BOLERO-2. Neoplasia. 17:279–288. 2015. View Article : Google Scholar : PubMed/NCBI
34	Merli M, Ferrario A, Maffioli M, Arcaini L and Passamonti F: Everolimus in diffuse large B-cell lymphomas. Future Oncol. 11:373–383. 2015. View Article : Google Scholar : PubMed/NCBI
35	Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, et al: Phase 3 trial of Everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer. 116:4256–4265. 2010. View Article : Google Scholar : PubMed/NCBI
36	Kaech SM and Cui W: Transcriptional control of effector and memory CD8⁺ T cell differentiation. Nat Rev Immunol. 12:749–761. 2012. View Article : Google Scholar : PubMed/NCBI
37	Nicoli F, Paul S and Appay V: Harnessing the induction of CD8⁺T-cell responses through metabolic regulation by pathogen-recognition-receptor triggering in antigen presenting cells. Front Immunol. 9:23722018. View Article : Google Scholar : PubMed/NCBI
38	Amiel E, Everts B, Freitas TC, King IL, Curtis JD, Pearce EL and Pearce EJ: Inhibition of mechanistic target of Rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J Immunol. 189:2151–2158. 2012. View Article : Google Scholar : PubMed/NCBI
39	Araki K, Youngblood B and Ahmed R: The role of mTOR in memory CD8 T-cell differentiation. Immunol Rev. 235:234–243. 2010. View Article : Google Scholar : PubMed/NCBI
40	Nicoli F, Papagno L, Frere JJ, Cabral-Piccin MP, Clave E, Gostick E, Toubert A, Price DA, Caputo A and Appay V: Naïve CD8⁺ T-cells engage a versatile metabolic program upon activation in humans and differ energetically from memory CD8⁺ T-Cells. Front Immunol. 9:27362018. View Article : Google Scholar : PubMed/NCBI
41	Zhang S, Pruitt M, Tran D, Du Bois W, Zhang K, Patel R, Hoover S, Simpson RM, Simmons J, Gary J, et al: B cell-specific deficiencies in mTOR limit humoral immune responses. J Immunol. 191:1692–1703. 2013. View Article : Google Scholar : PubMed/NCBI
42	Nicoli F: Angry, Hungry T-Cells: How Are T-Cell responses induced in low nutrient conditions? Immunometabolism. 2:e2000042020.
43	Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, Rawlings SA, Sutherland A, Premkumar L, Jadi RS, et al: Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 181:1489–1501, e15. 2020. View Article : Google Scholar : PubMed/NCBI
44	Schulien I, Kemming J, Oberhardt V, Wild K, Seidel LM, Sagar Killmer S, Daul F, Salvat Lago M, Decker A, et al: Characterization of pre-existing and induced SARS-CoV-2-specific CD8⁺ T cells. Nat Med. 27:78–85. 2021. View Article : Google Scholar : PubMed/NCBI
45	Gallerani E, Proietto D, Dallan B, Campagnaro M, Pacifico S, Albanese V, Marzola E, Marconi P, Caputo A, Appay V, et al: Impaired Priming of SARS-CoV-2-specific naive CD8⁺ T cells in older subjects. Front Immunol. 12:6930542021. View Article : Google Scholar : PubMed/NCBI
46	Frasca D and Blomberg BB: Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology. 17:7–19. 2016. View Article : Google Scholar : PubMed/NCBI
47	Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, et al: The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol. 14:1266–1276. 2013. View Article : Google Scholar : PubMed/NCBI
48	Cohen J: Infectious disease. Immune suppressant unexpectedly boosts flu vaccine. Science. 342:4132013. View Article : Google Scholar : PubMed/NCBI
49	Blasi F, Gramegna A, Sotgiu G, Saderi L, Voza A, Aliberti S and Amati F: SARS-CoV-2 vaccines: A critical perspective through efficacy data and barriers to herd immunity. Respir Med. 180:1063552021. View Article : Google Scholar : PubMed/NCBI
50	Cunningham AL, McIntyre P, Subbarao K, Booy R and Levin MJ: Vaccines for older adults. BMJ. 372:n1882021. View Article : Google Scholar : PubMed/NCBI
51	Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N and Tsatsakis A: Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review). Int J Mol Med. 46:467–488. 2020. View Article : Google Scholar : PubMed/NCBI
52	Gassen NC, Papies J, Bajaj T, Emanuel J, Dethloff F, Chua RL, Trimpert J, Heinemann N, Niemeyer C, Weege F, et al: SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals. Nat Commun. 12:38182021. View Article : Google Scholar : PubMed/NCBI
53	Patocka J, Kuca K, Oleksak P, Nepovimova E, Valis M, Novotny M and Klimova B: Rapamycin: Drug repurposing in SARS-CoV-2 infection. Pharmaceuticals (Basel). 14:2172021. View Article : Google Scholar : PubMed/NCBI