IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

COVID-19 Vaccination Alters NK Cell Dynamics and Transiently Reduces HBsAg Titers Among Patients With Chronic Hepatitis B

  • Hyunjae Shin (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Ha Seok Lee (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology(KAIST)) ;
  • Ji Yun Noh (Division of Infectious Diseases, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine) ;
  • June-Young Koh (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology(KAIST)) ;
  • So-Young Kim (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology(KAIST)) ;
  • Jeayeon Park (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Sung Won Chung (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Moon Haeng Hur (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Min Kyung Park (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Yun Bin Lee (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Yoon Jun Kim (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Jung-Hwan Yoon (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine) ;
  • Jae-Hoon Ko (Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kyong Ran Peck (Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Joon Young Song (Division of Infectious Diseases, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine) ;
  • Eui-Cheol Shin (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology(KAIST)) ;
  • Jeong-Hoon Lee (Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine)
  • Received : 2023.07.16
  • Accepted : 2023.10.10
  • Published : 2023.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Coronavirus disease 2019 (COVID-19) vaccination may non-specifically alter the host immune system. This study aimed to evaluate the effect of COVID-19 vaccination on hepatitis B surface Ag (HBsAg) titer and host immunity in chronic hepatitis B (CHB) patients. Consecutive 2,797 CHB patients who had serial HBsAg measurements during antiviral treatment were included in this study. Changes in the HBsAg levels after COVID-19 vaccination were analyzed. The dynamics of NK cells following COVID-19 vaccination were also examined using serial blood samples collected prospectively from 25 healthy volunteers. Vaccinated CHB patients (n=2,329) had significantly lower HBsAg levels 1-30 days post-vaccination compared to baseline (median, -21.4 IU/ml from baseline), but the levels reverted to baseline by 91-180 days (median, -3.8 IU/ml). The velocity of the HBsAg decline was transiently accelerated within 30 days after vaccination (median velocity: -0.06, -0.39, and -0.04 log10 IU/ml/year in pre-vaccination period, days 1-30, and days 31-90, respectively). In contrast, unvaccinated patients (n=468) had no change in HBsAg levels. Flow cytometric analysis showed that the frequency of NK cells expressing NKG2A, an NK inhibitory receptor, significantly decreased within 7 days after the first dose of COVID-19 vaccine (median, -13.1% from baseline; p<0.001). The decrease in the frequency of NKG2A+ NK cells was observed in the CD56dimCD16+ NK cell population regardless of type of COVID-19 vaccine. COVID-19 vaccination leads to a rapid, transient decline in HBsAg titer and a decrease in the frequency of NKG2A+ NK cells.

Keywords

Acknowledgement

This work was supported by the Institute for Basic Science (IBS), Republic of Korea, under project code IBS-R801-D2. And this work was supported by a Medical Scientist Training Program from the Ministry of Science & ICT of Korea. The authors acknowledge the facilities, and the scientific and technical assistance of the FACS Core Facility and Ms. Jiye Kim at the BioMedical Research Center, Korea Advanced Institute of Science and Technology (KAIST).

References

  1. Thomas DL. Global elimination of chronic hepatitis. N Engl J Med 2019;380:2041-2050.
  2. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol 2016;16:509-523.
  3. Tout I, Loureiro D, Mansouri A, Soumelis V, Boyer N, Asselah T. Hepatitis B surface antigen seroclearance: immune mechanisms, clinical impact, importance for drug development. J Hepatol 2020;73:409-422.
  4. Yip TC, Wong GL, Chan HL, Tse YK, Lam KL, Lui GC, Wong VW. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol 2019;70:361-370.
  5. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, Hernan MA, Lipsitch M, Reis B, Balicer RD. BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting. N Engl J Med 2021;384:1412-1423.
  6. Altmann DM, Boyton RJ. COVID-19 vaccination: the road ahead. Science 2022;375:1127-1132.
  7. Moss P. The T cell immune response against SARS-CoV-2. Nat Immunol 2022;23:186-193.
  8. Osawa Y, Ohtake T, Suto D, Akita T, Yamada H, Kohgo Y, Murata K. Cases of rapid hepatitis B surface antigen reduction after COVID-19 vaccination. Intern Med 2023;62:51-57.
  9. Boettler T, Csernalabics B, Salie H, Luxenburger H, Wischer L, Salimi Alizei E, Zoldan K, Krimmel L, Bronsert P, Schwabenland M, et al. SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis. J Hepatol 2022;77:653-659.
  10. Hasegawa N, Matsuoka R, Ishikawa N, Endo M, Terasaki M, Seo E, Tsuchiya K. Autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination: case report and literature review. Clin J Gastroenterol 2022;15:791-795.
  11. Efe C, Kulkarni AV, Terziroli Beretta-Piccoli B, Magro B, Stattermayer A, Cengiz M, Clayton-Chubb D, Lammert C, Bernsmeier C, Gul O, et al. Liver injury after SARS-CoV-2 vaccination: features of immune-mediated hepatitis, role of corticosteroid therapy and outcome. Hepatology 2022;76:1576-1586.
  12. Lensen R, Netea MG, Rosendaal FR. Hepatitis C virus reactivation following COVID-19 vaccination - a case report. Int Med Case Rep J 2021;14:573-576.
  13. Hu CY, Tsou Y, Chung M, Lin N, Chen C, Lee P, Liu C. Hepatitis B virus infection flare induced acute-on-chronic liver failure after COVID-19 vaccination: a case report. Hepat Mon 2021;21:e126460.
  14. Chung GE, Kim JY, Shin H, Hong JH, Hur MH, Cho H, Park MK, Choi NR, Kim J, Lee YB, et al. Correlation between results of semi-quantitative and quantitative tests for hepatitis B virus surface antigen among patients achieving viral suppression with antiviral treatment. Diagnostics (Basel) 2022;12:1757.
  15. Kim H, Jee YM, Song BC, Shin JW, Yang SH, Mun HS, Kim HJ, Oh EJ, Yoon JH, Kim YJ, et al. Molecular epidemiology of hepatitis B virus (HBV) genotypes and serotypes in patients with chronic HBV infection in Korea. Intervirology 2007;50:52-57.
  16. Korea Centers for Disease Control and Prevention. Coronavirus (COVID-19), Republic of Korea [Internet]. Available at https://ncov.kdca.go.kr/en/ [accessed on 15 January 2023].
  17. Central Disease Control Headquarters (KR). COVID-19 antibody positivity survey results and plans (press release) [Internet]. Available at https://www.kdca.go.kr/ [accessed on 15 January 2023].
  18. Seto WK, Lam YF, Fung J, Wong DK, Huang FY, Hung IF, Lai CL, Yuen MF. Changes of HBsAg and HBV DNA levels in Chinese chronic hepatitis B patients after 5 years of entecavir treatment. J Gastroenterol Hepatol 2014;29:1028-1034.
  19. Chen CH, Hu TH, Wang JH, Lai HC, Hung CH, Lu SN, Peng CY. Comparison of HBsAg changes between HBeAg-negative patients who discontinued or maintained entecavir therapy. Hepatol Int 2020;14:317-325.
  20. Fisicaro P, Valdatta C, Boni C, Massari M, Mori C, Zerbini A, Orlandini A, Sacchelli L, Missale G, Ferrari C. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 2009;58:974-982.
  21. Tong S, Liu G, Li M, Li X, Liu Q, Peng H, Li S, Ren H, Yin W. Natural killer cell activation contributes to hepatitis B viral control in a mouse model. Sci Rep 2017;7:314.
  22. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001;19:197-223.
  23. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9:503-510.
  24. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood 2001;97:3146-3151.
  25. Li F, Wei H, Wei H, Gao Y, Xu L, Yin W, Sun R, Tian Z. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology 2013;144:392-401.
  26. Creelan BC, Antonia SJ. The NKG2A immune checkpoint - a new direction in cancer immunotherapy. Nat Rev Clin Oncol 2019;16:277-278.
  27. Rehermann B. Natural killer cells in viral hepatitis. Cell Mol Gastroenterol Hepatol 2015;1:578-588.
  28. Zhang C, Wang XM, Li SR, Twelkmeyer T, Wang WH, Zhang SY, Wang SF, Chen JZ, Jin X, Wu YZ, et al. NKG2A is a NK cell exhaustion checkpoint for HCV persistence. Nat Commun 2019;10:1507.
  29. Azzolini E, Pozzi C, Germagnoli L, Oresta B, Carriglio N, Calleri M, Selmi C, De Santis M, Finazzi S, Carlo-Stella C, et al. mRNA COVID-19 vaccine booster fosters B- and T-cell responses in immunocompromised patients. Life Sci Alliance 2022;5:e202201381.
  30. Diniz MO, Schurich A, Chinnakannan SK, Duriez M, Stegmann KA, Davies J, Kucykowicz S, Suveizdyte K, Amin OE, Alcock F, et al. NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner. Sci Transl Med 2022;14:eabi4670.
  31. La Sala L, Gandini S, Bruno A, Allevi R, Gallazzi M, Senesi P, Palano MT, Meregalli P, Longhi E, Sommese C, et al. SARS-CoV-2 immunization orchestrates the amplification of IFNγ-producing T cell and NK cell persistence. Front Immunol 2022;13:798813.
  32. Ma Q, Dong X, Liu S, Zhong T, Sun D, Zong L, Zhao C, Lu Q, Zhang M, Gao Y, et al. Hepatitis B e antigen induces NKG2A+ natural killer cell dysfunction via regulatory T cell-derived interleukin 10 in chronic hepatitis B virus infection. Front Cell Dev Biol 2020;8:421.
  33. van Hall T, Andre P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, Vivier E. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer 2019;7:263.
  34. Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Blery M, Bonnafous C, Gauthier L, Morel A, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 2018;175:1731-1743.e13.
  35. De Maria A, Bozzano F, Cantoni C, Moretta L. Revisiting human natural killer cell subset function revealed cytolytic CD56dimCD16+ NK cells as rapid producers of abundant IFN-γon activation. Proc Natl Acad Sci U S A 2011;108:728-732.
  36. Guidotti LG, Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 2001;19:65-91.
  37. Zin Tun GS, Gleeson D, Al-Joudeh A, Dube A. Immune-mediated hepatitis with the Moderna vaccine, no longer a coincidence but confirmed. J Hepatol 2022;76:747-749.
  38. Bril F. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: one or even several swallows do not make a summer. J Hepatol 2021;75:1256-1257.
  39. Rowley MW, Patel A, Zhou W, Wong M, Seetharam AB. Immune reconstitution syndrome with initiation of treatment of HBV/HIV co-infection: activity flare associated with E antigen seroconversion. Ann Hepatol 2019;18:220-224.
  40. Park KH, Ryu JH, Bae H, Yun S, Jang JH, Han K, Cho BS, Kim HJ, Lee H, Oh EJ. Delayed NK cell reconstitution and reduced NK activity increased the risks of CMV disease in allogeneic-hematopoietic stem cell transplantation. Int J Mol Sci 2020;21:3663.