Euroasian Journal of Hepato-Gastroenterology

Register      Login

VOLUME 11 , ISSUE 2 ( July-December, 2021 ) > List of Articles

Original Article

HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis

Yoel A Fleites, Jorge Aguiar, Zurina Cinza, Monica Bequet, Elieser Marrero, Maritania Vizcaíno, Idelsis Esquivel, Marisol Diaz, Adriana Sin-Mayor, Maura Garcia, Sara M Martinez, Abrahan Beato, Ana G Galarraga, Yssel Mendoza-Mari, Iris Valdés, Gerardo García, Gilda Lemos, Isabel Gonzalez, Camila Canaán-Haden, Nelvis Figueroa, Rachel Oquendo, Sheikh MF Akbar, Mamun A Mahtab, Mohammad H Uddin, Gerardo E Guillén, Verena L Muzio, Eduardo Penton, JC Aguilar

Keywords : Immunity, Innate, Postexposure, Prophylaxis, SARS-CoV-2, Therapy

Citation Information : Fleites YA, Aguiar J, Cinza Z, Bequet M, Marrero E, Vizcaíno M, Esquivel I, Diaz M, Sin-Mayor A, Garcia M, Martinez SM, Beato A, Galarraga AG, Mendoza-Mari Y, Valdés I, García G, Lemos G, Gonzalez I, Canaán-Haden C, Figueroa N, Oquendo R, Akbar SM, Mahtab MA, Uddin MH, Guillén GE, Muzio VL, Penton E, Aguilar J. HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis. Euroasian J Hepatogastroenterol 2021; 11 (2):59-70.

DOI: 10.5005/jp-journals-10018-1344

License: CC BY-NC 4.0

Published Online: 22-10-2021

Copyright Statement:  Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.


Abstract

Introduction: More than 180 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 4 million coronavirus disease-2019 (COVID-19) patients have died in 1.5 years of the pandemic. A novel therapeutic vaccine (NASVAC) has shown to be safe and to have immunomodulating and antiviral properties against chronic hepatitis B (CHB). Materials and methods: A phase I/II, open-label controlled and randomized clinical trial of NASVAC as a postexposure prophylaxis treatment was designed with the primary aim of assessing the local and systemic immunomodulatory effect of NASVAC in a cohort of suspected and SARS-CoV-2 risk-contact patients. A total of 46 patients, of both sexes, 60 years or older, presenting with symptoms of COVID-19 were enrolled in the study. Patients received NASVAC (100 µg per Ag per dose) via intranasal at days 1, 7, and 14 and sublingual, daily for 14 days. Results and discussion: The present study detected an increased expression of toll-like receptors (TLR)-related genes in nasopharyngeal tonsils, a relevant property considering these are surrogate markers of SARS protection in the mice model of lethal infection. The HLA-class II increased their expression in peripheral blood mononuclear cell\'s (PBMC\'s) monocytes and lymphocytes, which is an attractive property taking into account the functional impairment of innate immune cells from the periphery of COVID-19-infected subjects. NASVAC was safe and well tolerated by the patients with acute respiratory infections and evidenced a preliminary reduction in the number of days with symptoms that needs to be confirmed in larger studies. Conclusions: Our data justify the use of NASVAC as preemptive therapy or pre-/postexposure prophylaxis of SARS-CoV-2 and acute respiratory infections in general. The use of NASVAC or their active principles has potential as immunomodulatory prophylactic therapies in other antiviral settings like dengue as well as in malignancies like hepatocellular carcinoma where these markers have shown relation to disease progression.


PDF Share
  1. Bugra A, Das T, Arslan MN, et al. Postmortem pathological changes in extrapulmonary organs in SARS-CoV-2 rt-PCR–positive cases: a single-center experience. Irish J Med Sci (1971) 2021:1–11. DOI: 10.1007/s11845-021-02638-8.
  2. Damiani S, Fiorentino M, De Palma A, et al. Pathological post-mortem findings in lungs infected with SARS-CoV-2. J Pathol 2021;253(1): 31–40. DOI: 10.1002/path.5549.
  3. Walensky RP, Del Rio C. From mitigation to containment of the COVID-19 pandemic: putting the SARS-CoV-2 genie back in the bottle. JAMA 2020;323(19):1889–1890. DOI: 10.1001/jama.2020.6572.
  4. Sultana J, Crisafulli S, Gabbay F, et al. Challenges for drug repurposing in the COVID-19 pandemic era. Front Pharmacol 2020;11:588654. DOI: 10.3389/fphar.2020.588654.
  5. Chaudhry R, Dranitsaris G, Mubashir T, et al. A country level analysis measuring the impact of government actions, country preparedness and socioeconomic factors on COVID-19 mortality and related health outcomes. EClinicalMedicine. 2020:100464. DOI: 10.1016/j.eclinm.2020.100464.
  6. Ahmad T, Chaudhuri R, Joshi MC, et al. COVID-19: The emerging immunopathological determinants for recovery or death. Front Microbiol 2020;11:588409. DOI: 10.3389/fmicb.2020.588409.
  7. Islam MA, Mazumder MA, Akhter N, et al. Extraordinary survival benefits of severe and critical patients with COVID-19 by immune modulators: the outcome of a clinical trial in Bangladesh. Euroasian J Hepatogastroenterol 2020;10(2):68–75. DOI: 10.5005/jp-journals-10018-1327.
  8. Cortegiani A, Ippolito M, Greco M, et al. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology 2021;27(1):52–66. DOI: 10.1016/j.pulmoe.2020.07.003.
  9. Kikkert M. Innate immune evasion by human respiratory RNA viruses. J Innate Immun 2020;12(1):4–20. DOI: 10.1159/000503030.
  10. Thorne LG, Bouhaddou M, Reuschl AK, et al. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B. 1.1. 7 UK variant. bioRxiv 2021. DOI: 10.1101/2021.06.06.446826.
  11. Fernández G, Sanchez AL, Jerez E, et al. Five-year follow-up of chronic hepatitis B patients immunized by nasal route with the therapeutic vaccine HeberNasvac. Euroasian J Hepatogastroenterol 2018;8(2):133. DOI: 10.5005/jp-journals-10018-1279.
  12. Al-Mahtab M, Akbar SM, Aguilar JC, et al. Therapeutic potential of a combined hepatitis B surface antigen and core antigen vaccine in patients with chronic hepatitis B. Hepatol Int 2013;7(4):981–989. DOI: 10.1007/s12072-013-9486-4.
  13. Al Mahtab M, Akbar SMF, Aguilar JC, et al. Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS One 2018;13(8):e0201236. DOI: 10.1371/journal.pone.0201236.
  14. Yoshida O, Akbar SM, Kohara M, et al. Induction of anti-HBs and reduction of HBs antigen by nasal administration of a therapeutic vaccine containing HBs and HBc antigen (NASVAC) in patients with chronic hepatitis B. Boston, MA, USA: American Association for Study of the Liver; 2019.
  15. Hiasa Y, Yoshida O, Guillen G, et al. The HB vaccine containing HBs and HBc antigen (NASVAC) can effectively induce anti-HBs antibody in non-responders to the prophylactic vaccine. Boston, MA, USA: American Association for Study of the Liver; 2019.
  16. Yoshida O, Imai Y, Akbar SMF, et al. HBsAg reduction by nasal administration of A therapeutic vaccine containing HBsAg and HBcAg (NASVAC) in a patients with chronic HBV infection: the results of 18 months follow-up. The Liver Meeting, AASLD, November 13–16, 2020.
  17. Akbar SMF, Mahtab MA, Aguilar JC, et al. Repurposing NASVAC, a Hepatitis B therapeutic vaccine, for pre- and post-exposure prophylaxis of SARS-CoV-2 infection. J Antivir Antiretrovir 2021;13 (20):1000004. (S20:004). Available from: https://doi.org/10.21203/rs.3.rs-438628/v1.
  18. Mudgal R, Nehul S, Tomar S. Prospects for mucosal vaccine: shutting the door on SARS-CoV-2. Hum Vaccin Immunother 2020;16(12): 2921–2931. DOI: 10.1080/21645515.2020.1805992.
  19. Burki T. Behind Cuba's successful pandemic response. Lancet Infect Dis 2021;21(4):465–466. DOI: 10.1016/S1473-3099(21)00159-6.
  20. Xu J, Yang Y, Sun J, et al. Expression of Toll-like receptors and their association with cytokine responses in peripheral blood mononuclear cells of children with acute rotavirus diarrhoea. Clin Exp Immunol 2006;144(3):376–381. DOI: 10.1111/j.1365-2249.2006.03079.x.
  21. Patent Application: CU 2020-0028: Priority date: 20.04.2020. International presentation date: 20.04.2021.Viral nucleoproteins and formulations thereof.
  22. Cooper A, Tal G, Lider O, et al. Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2. J Immunol 2005;175(5):3165–3176. DOI: 10.4049/jimmunol.175.5.3165.
  23. Lee BO, Tucker A, Frelin L, et al. Interaction of the hepatitis B core antigen and the innate immune system. J Immunol 2009;182(11):6670–6681. DOI: 10.4049/jimmunol.0803683.
  24. Kumaki Y, Salazar AM, Wandersee MK, et al. Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol®(Poly IC: LC), in a lethal SARS-CoV-infected BALB/c mouse model. Antiviral Res 2017;139:1–12. DOI: 10.1016/j.antiviral.2016.12.007.
  25. Zhao J, Wohlford-Lenane C, Zhao J, et al. Intranasal treatment with poly (I•C) protects aged mice from lethal respiratory virus infections. J Virol 2012;86(21):11416–11424. DOI: 10.1128/JVI.01410-12.
  26. Prasad K, Khatoon F, Rashid S, et al. Targeting hub genes and pathways of innate immune response in COVID-19: a network biology perspective. Int J Biol Macromol 2020;163:1–8. DOI: 10.1016/j.ijbiomac.2020.06.228.
  27. Aich P, Wilson HL, Kaushik RS, et al. Comparative analysis of innate immune responses following infection of newborn calves with bovine rotavirus and bovine coronavirus. J Gen Virol 2007;88(10):2749–2761. DOI: 10.1099/vir.0.82861-0.
  28. Nelemans T, Kikkert M. Viral innate immune evasion and the pathogenesis of emerging RNA virus infections. Viruses 2019;11(10):961. DOI: 10.3390/v11100961.
  29. Bagchi A, Herrup EA, Warren HS, et al. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol 2007;178(2):1164–1171. DOI: 10.4049/jimmunol.178.2.1164.
  30. Zhu Q, Egelston C, Gagnon S, et al. Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J Clin Invest 2010;120(2): 607–616. DOI: 10.1172/JCI39293.
  31. Zhu Q, Egelston C, Vivekanandhan A, et al. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc Natl Acad Sci 2008;105(42):16260–16265. DOI: 10.1073/pnas.0805325105.
  32. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med 2020;173(8):623–631. DOI: 10.7326/M20-4207.
  33. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med 2020;383(6):517–525. DOI: 10.1056/NEJMoa2016638.
  34. Curtis N, Sparrow A, Ghebreyesus TA, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet 2020;395(10236):1545–1546. DOI: 10.1016/S0140-6736(20)31025-4.
  35. Grange JM. Complications of bacille Calmette-Guérin (BCG) vaccination and immunotherapy and their management. Commun Dis Public Health 1998;1(2):84–88. PMID: 9644119.
  36. Sánchez Ramón S, Manzanares M, Candelas G. MUCOSAL anti-infections vaccines: beyond conventional vaccines. Reumatol Clin 2020;16(1):49–55. DOI: 10.1016/j.reuma.2018.10.012.
  37. Sánchez-Ramón S, Conejero L, Netea MG, et al. Trained immunity-based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations. Front Immunol 2018;9:2936. DOI: 10.3389/fimmu.2018.02936.
  38. Sánchez-Ramón S, Pérez de Diego R, Dieli-Crimi R, et al. Extending the clinical horizons of mucosal bacterial vaccines: current evidence and future prospects. Curr Drug Targets 2014;15(12):1132–1143. DOI: 10.2174/1389450115666141020160705.
  39. Alecsandru D, Valor L, Sánchez-Ramón S, et al. Sublingual therapeutic immunization with a polyvalent bacterial preparation in patients with recurrent respiratory infections: immunomodulatory effect on antigen-specific memory CD4+ T cells and impact on clinical outcome. Clin Exp Immunol 2011;164(1):100–107. DOI: 10.1111/j.1365-2249.2011.04320.x.
  40. Altimmune: waiting for their next move against COVID-19. News article. 16.06.2020. Available from: https://ir.altimmune.com/investors/news-articles.
  41. Altimmune Receives Award from U.S. Department of Defense to Fund Phase 1/2 Clinical Trial of T-COVID™ in Outpatients with Early COVID-19. Press release. 29.06.2020. Available from: www.altimmune.com.
  42. Metcalf TU, Cubas RA, Ghneim K, et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 2015;14(3):421–432. DOI: 10.1111/acel.12320.
  43. Arunachalam PS, Wimmers F, Mok CK, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 2020;369(6508):1210–1220. DOI: 10.1126/science.abc6261.
  44. Lobaina Y, Hardtke S, Wedemeyer H, et al. In vitro stimulation with HBV therapeutic vaccine candidate Nasvac activates B and T cells from chronic hepatitis B patients and healthy donors. Mol Immunol 2015;63(2):320–327. DOI: 10.1016/j.molimm.2014.08.003.
  45. Akbar SM, Yoshida O, Chen S, et al. Immune modulator and antiviral potential of DCs pulsed with both hepatitis B surface antigen and core antigen for treating chronic HBV infection. Antivir Ther 2010;15(6):887–895. DOI: 10.3851/IMP1637.
  46. Monk PD, Marsden RJ, Tear VJ, et al. 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;9(2):196–206. DOI: 10.1016/S2213-2600(20)30511-7.
  47. Akbar SMF, Al Mahtab M, Aguilar JC, et al. Role of pegylated interferon in patients with chronic liver diseases in the context of SARS-CoV-2 Infection. Euroasian J Hepatogastroenetrol 2021;11(1):27–31. DOI: 10.5005/jp-journals-10018-1341.
  48. Varchetta S, Mele D, Oliviero B, et al. Unique immunological profile in patients with COVID-19. Cell Mol Immunol 2021;18(3):604–612. DOI: 10.1038/s41423-020-00557-9.
  49. Sariol CA, Martínez MI, Rivera F, et al. Decreased dengue replication and an increased anti-viral humoral response with the use of combined Toll-like receptor 3 and 7/8 agonists in macaques. PLoS One 2011;6(4):e19323. DOI: 10.1371/journal.pone.0019323.
  50. Yuan MM, Xu YY, Chen L, et al. TLR3 expression correlates with apoptosis, proliferation and angiogenesis in hepatocellular carcinoma and predicts prognosis. BMC Cancer 2015;15(1):1–6. DOI: 10.1186/s12885-015-1262-5.
  51. Bonnin M, Fares N, Testoni B, et al. Toll-like receptor 3 downregulation is an escape mechanism from apoptosis during hepatocarcinogenesis. J Hepatol 2019;71(4):763–772. DOI: 10.1016/j.jhep.2019.05.031.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.