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Adjuvanticity of Processed Aloe vera gel for Influenza Vaccination in Mice

  • Eun-Jung Song (Department of Pharmacy, Korea University College of Pharmacy) ;
  • Erica Espano (Department of Pharmacy, Korea University College of Pharmacy) ;
  • Jeong-Hyun Nam (Department of Pharmacy, Korea University College of Pharmacy) ;
  • Jiyeon Kim (Department of Pharmacy, Korea University College of Pharmacy) ;
  • Kyu-Suk Shim (Univera Co., Ltd.) ;
  • Eunju Shin (Univera Co., Ltd.) ;
  • Young In Park (Department of Pharmacy, Korea University College of Pharmacy) ;
  • Chong-Kil Lee (Department of Pharmaceutics, College of Pharmacy, Chungbuk National University) ;
  • Jeong-Ki Kim (Department of Pharmacy, Korea University College of Pharmacy)
  • Received : 2020.06.01
  • Accepted : 2020.06.29
  • Published : 2020.08.31
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Abstract

The effectiveness of current influenza vaccines is considered suboptimal, and 1 way to improve the vaccines is using adjuvants. However, the current pool of adjuvants used in influenza vaccination is limited due to safety concerns. Aloe vera, or aloe, has been shown to have immunomodulatory functions and to be safe for oral intake. In this study, we explored the potential of orally administered processed Aloe vera gel (PAG) as an adjuvant for influenza vaccines in C57BL/6 mice. We first evaluated its adjuvanticity with a split-type pandemic H1N1 (pH1N1) Ag by subjecting the mice to lethal homologous influenza challenge. Oral PAG administration with the pH1N1 Ag increased survival rates in mice to levels similar to those of alum and MF59, which are currently used as adjuvants in influenza vaccine formulations. Similarly, oral PAG administration improved the survival of mice immunized with a commercial trivalent influenza vaccine against lethal homologous and heterologous virus challenge. PAG also increased hemagglutination inhibition and virus neutralization Ab titers against homologous and heterologous influenza strains following immunization with the split-type pH1N1 Ag or the commercial trivalent vaccine. Therefore, this study demonstrates that PAG may potentially be used as an adjuvant for influenza vaccines.

Keywords

Acknowledgement

This study was supported by the Creation of Aloe Pharmaceuticals (CAP) research grant funded by Univera Co., Ltd., Seoul, Republic of Korea, Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education (2019R1A6A3A01092398) and the Korea University Grants.

References

  1. World Health Organization. Influenza (seasonal) [Internet]. Available at https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal) [accessed on 8 May 2019]. 
  2. Ma W, Garcia-Sastre A, Schwemmle M. Expected and unexpected features of the newly discovered bat influenza A-like viruses. PLoS Pathog 2015;11:e1004819. 
  3. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992;56:152-179.  https://doi.org/10.1128/mr.56.1.152-179.1992
  4. World Health Organization. Questions and answers: vaccine effectiveness estimates for seasonal influenza vaccines [Internet]. Available at https://www.who.int/influenza/vaccines/virus/recommendations/201502_qanda_vaccineeffectiveness.pdf [accessed on 8 May 2019]. 
  5. Ohmit SE, Petrie JG, Malosh RE, Cowling BJ, Thompson MG, Shay DK, Monto AS. Influenza vaccine effectiveness in the community and the household. Clin Infect Dis 2013;56:1363-1369.  https://doi.org/10.1093/cid/cit060
  6. Beyer WEP, McElhaney J, Smith DJ, Monto AS, Nguyen-Van-Tam JS, Osterhaus ADME. Cochrane rearranged: support for policies to vaccinate elderly people against influenza. Vaccine 2013;31:6030-6033.  https://doi.org/10.1016/j.vaccine.2013.09.063
  7. Kim JH, Liepkalns J, Reber AJ, Lu X, Music N, Jacob J, Sambhara S. Prior infection with influenza virus but not vaccination leaves a long-term immunological imprint that intensifies the protective efficacy of antigenically drifted vaccine strains. Vaccine 2016;34:495-502.  https://doi.org/10.1016/j.vaccine.2015.11.077
  8. Carrat F, Lavenu A, Cauchemez S, Deleger S. Repeated influenza vaccination of healthy children and adults: borrow now, pay later? Epidemiol Infect 2006;134:63-70.  https://doi.org/10.1017/S0950268805005479
  9. McLean HQ, Thompson MG, Sundaram ME, Meece JK, McClure DL, Friedrich TC, Belongia EA. Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons. Clin Infect Dis 2014;59:1375-1385.  https://doi.org/10.1093/cid/ciu680
  10. Skowronski DM, Chambers C, Sabaiduc S, De Serres G, Winter AL, Dickinson JA, Krajden M, Gubbay JB, Drews SJ, Martineau C, et al. A perfect storm: impact of genomic variation and serial vaccination on low influenza vaccine effectiveness during the 2014-2015 season. Clin Infect Dis 2016;63:21-32.  https://doi.org/10.1093/cid/ciw176
  11. Vesikari T, Kirstein J, Devota Go G, Leav B, Ruzycky ME, Isakov L, de Bruijn M, Oberye J, Heijnen E. Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial. Lancet Respir Med 2018;6:345-356.  https://doi.org/10.1016/S2213-2600(18)30108-5
  12. Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, Verity C. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013;346:f794. 
  13. Stowe J, Andrews N, Kosky C, Dennis G, Eriksson S, Hall A, Leschziner G, Reading P, Shneerson JM, Donegan K, et al. Risk of narcolepsy after AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in adults: a case-coverage study in England. Sleep (Basel) 2016;39:1051-1057.  https://doi.org/10.5665/sleep.5752
  14. Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, Spyr C, Steffen R. Use of the inactivated intranasal influenza vaccine and the risk of Bell's palsy in Switzerland. N Engl J Med 2004;350:896-903.  https://doi.org/10.1056/NEJMoa030595
  15. Lawrence R, Tripathi P, Jeyakumar E. Isolation, purification and evaluation of antibacterial agents from Aloe vera. Braz J Microbiol 2009;40:906-915.  https://doi.org/10.1590/S1517-83822009000400023
  16. Vazquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol 1996;55:69-75.  https://doi.org/10.1016/S0378-8741(96)01476-6
  17. Yonehara A, Tanaka Y, Kulkeaw K, Era T, Nakanishi Y, Sugiyama D. Aloe vera extract suppresses proliferation of neuroblastoma cells in vitro. Anticancer Res 2015;35:4479-4485. 
  18. Balan BJ, Niemcewicz M, Kocik J, Jung L, Skopinska-Rozewska E, Skopinski P. Oral administration of Aloe vera gel, anti-microbial and anti-inflammatory herbal remedy, stimulates cell-mediated immunity and antibody production in a mouse model. Cent Eur J Immunol 2014;39:125-130.  https://doi.org/10.5114/ceji.2014.43711
  19. Kumar S, Tiku AB. Immunomodulatory potential of acemannan (polysaccharide from Aloe vera) against radiation induced mortality in Swiss albino mice. Food Agric Immunol 2016;27:72-86.  https://doi.org/10.1080/09540105.2015.1079594
  20. Alam S, Ali I, Giri KY, Gokkulakrishnan S, Natu SS, Faisal M, Agarwal A, Sharma H. Efficacy of Aloe vera gel as an adjuvant treatment of oral submucous fibrosis. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:717-724.  https://doi.org/10.1016/j.oooo.2013.08.003
  21. Chinnah AD, Baig MA, Tizard IR, Kemp MC. Antigen dependent adjuvant activity of a polydispersed beta-(1,4)-linked acetylated mannan (acemannan). Vaccine 1992;10:551-557.  https://doi.org/10.1016/0264-410X(92)90356-O
  22. Im SA, Oh ST, Song S, Kim MR, Kim DS, Woo SS, Jo TH, Park YI, Lee CK. Identification of optimal molecular size of modified Aloe polysaccharides with maximum immunomodulatory activity. Int Immunopharmacol 2005;5:271-279.  https://doi.org/10.1016/j.intimp.2004.09.031
  23. Palmer DF. Advanced laboratory techniques for influenza diagnosis. Atlanta, GA: U.S. Dept. of Health and Human Services, Public Health Service, Center for Disease Control, Bureau of Laboratories; 1980. 
  24. World Health Organization. WHO manual on animal influenza diagnosis and surveillance [Internet]. Available at https://www.who.int/csr/resources/publications/influenza/whocdscsrncs20025rev.pdf [accessed on 19 May 2009]. 
  25. Kida H, Brown LE, Webster RG. Biological activity of monoclonal antibodies to operationally defined antigenic regions on the hemagglutinin molecule of A/Seal/Massachusetts/1/80 (H7N7) influenza virus. Virology 1982;122:38-47.  https://doi.org/10.1016/0042-6822(82)90375-0
  26. Black S. Safety and effectiveness of MF-59 adjuvanted influenza vaccines in children and adults. Vaccine 2015;33 Suppl 2:B3-B5.  https://doi.org/10.1016/j.vaccine.2014.11.062
  27. Khurana S, Verma N, Yewdell JW, Hilbert AK, Castellino F, Lattanzi M, Del Giudice G, Rappuoli R, Golding H. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci Transl Med 2011;3:85ra48. 
  28. Sehgal I, Winters WD, Scott M, Kousoulas K. An in vitro and in vivo toxicologic evaluation of a stabilized Aloe vera gel supplement drink in mice. Food Chem Toxicol 2013;55:363-370.  https://doi.org/10.1016/j.fct.2013.01.012
  29. Sehgal I, Winters WD, Scott M, David A, Gillis G, Stoufflet T, Nair A, Kousoulas K. Toxicologic assessment of a commercial decolorized whole leaf Aloe vera juice, lily of the desert filtered whole leaf juice with aloesorb. J Toxicol 2013;2013:802453. 
  30. Vahedi G, Taghavi M, Maleki AK, Habibian R. The effect of Aloe vera extract on humoral and cellular immune response in rabbit. Afr J Biotechnol 2011;10:5225-5228. 
  31. Christensen JP, Doherty PC, Branum KC, Riberdy JM. Profound protection against respiratory challenge with a lethal H7N7 influenza A virus by increasing the magnitude of CD8(+) T-cell memory. J Virol 2000;74:11690-11696.  https://doi.org/10.1128/JVI.74.24.11690-11696.2000
  32. Schotsaert M, Ysenbaert T, Smet A, Schepens B, Vanderschaeghe D, Stegalkina S, Vogel TU, Callewaert N, Fiers W, Saelens X. Long-lasting cross-protection against influenza A by neuraminidase and M2e-based immunization strategies. Sci Rep 2016;6:24402. 
  33. Sridhar S. Heterosubtypic T-cell immunity to influenza in humans: challenges for universal T-cell influenza vaccines. Front Immunol 2016;7:195.
  34. Teijaro JR, Verhoeven D, Page CA, Turner D, Farber DL. Memory CD4 T cells direct protective responses to influenza virus in the lungs through helper-independent mechanisms. J Virol 2010;84:9217-9226. https://doi.org/10.1128/JVI.01069-10
  35. Lee JK, Lee MK, Yun YP, Kim Y, Kim JS, Kim YS, Kim K, Han SS, Lee CK. Acemannan purified from Aloe vera induces phenotypic and functional maturation of immature dendritic cells. Int Immunopharmacol 2001;1:1275-1284. https://doi.org/10.1016/S1567-5769(01)00052-2
  36. Womble D, Helderman JH. The impact of acemannan on the generation and function of cytotoxic T-lymphocytes. Immunopharmacol Immunotoxicol 1992;14:63-77. https://doi.org/10.3109/08923979209009213
  37. Thunyakitpisal P, Ruangpornvisuti V, Kengkwasing P, Chokboribal J, Sangvanich P. Acemannan increases NF-κB/DNA binding and IL-6/-8 expression by selectively binding Toll-like receptor-5 in human gingival fibroblasts. Carbohydr Polym 2017;161:149-157. https://doi.org/10.1016/j.carbpol.2016.12.034
  38. Imanishi KI. Aloctin A, an active substance of Aloe arborescens Miller as an immunomodulator. Phytother Res 1993;7:S20-S22. https://doi.org/10.1002/ptr.2650070708
  39. Yoshimoto R, Kondoh N, Isawa M, Hamuro J. Plant lectin, ATF1011, on the tumor cell surface augments tumor-specific immunity through activation of T cells specific for the lectin. Cancer Immunol Immunother 1987;25:25-30. https://doi.org/10.1007/BF00199297
  40. Reynolds T, Dweck AC. Aloe vera leaf gel: a review update. J Ethnopharmacol 1999;68:3-37. https://doi.org/10.1016/S0378-8741(99)00085-9
  41. Radha MH, Laxmipriya NP. Evaluation of biological properties and clinical effectiveness of Aloe vera: a systematic review. J Tradit Complement Med 2014;5:21-26. https://doi.org/10.1016/j.jtcme.2014.10.006
  42. Chang WC, White MR, Moyo P, McClear S, Thiel S, Hartshorn KL, Takahashi K. Lack of the pattern recognition molecule mannose-binding lectin increases susceptibility to influenza A virus infection. BMC Immunol 2010;11:64.
  43. Alonso M, Tambara Y, Lopez M, Aguilar JC, Mayo O, Prieto E, Cremata J, Gerwig G, Kamerling H, Hardy E. On the isolation of immunostimulatory active acemannan from Aloe barbadensis. Biotecnol Apl 2012;29:87-101.