Skip to main content

Advertisement

SpringerLink
Log in

Lipid A adjuvanted Chylomicron Mimicking Solid Fat Nanoemulsions for Immunization Against Hepatitis B

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Traditional parenteral recombinant hepatitis B virus (HBV) vaccines have effectively reduced the disease burden despite being able to induce seroprotective antibody titers in 5–10% vaccinated individuals (non-responders). Moreover, an estimated 340 million chronic HBV cases are in need of treatment. Development of safe, stable, and more effective hepatitis B vaccine formulation would address these challenges. Recombinant hepatitis B surface antigen (rHBsAg) entrapped solid fat nanoemulsions (SFNs) containing monophosphoryl lipid A (MPLA) that was prepared and optimized by quality by design (QbD) using response surface methodology (RSM), i.e., central composite design (CCD). Its immune potential was evaluated with preset immunization protocol in a murine model. Dose escalation study revealed that formulation containing 1 μg of rHBsAg entrapped SFNs with MPLA-induced significant higher humoral, and cellular response compared to the marketed vaccine (Genvac B) administered intramuscularly. SFNs with nanometric morphology and structural similarity with chylomicrons assist in improved uptake and processing to lymphatics. Moreover, the presence of an immunogenic component in its structure further augments delivery of rHBsAg to immune cells with induction of danger signals. This multi-adjuvant based approach explores new prospect for the dose sparing. Improved cellular immune response induced by this vaccine formulation suggests that it could be tested as an immunotherapeutic vaccine as well.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Dormitzer PR, Ulmer JB, Rappuoli R. Structure-based antigen design: a strategy for next generation vaccines. Trends Biotechnol. 2008;26(12):659–67. https://doi.org/10.1016/j.tibtech.2008.08.002.

    Article  CAS  PubMed  Google Scholar 

  2. Brito LA, Malyala P, O’Hagan DT. Vaccine adjuvant formulations: a pharmaceutical perspective. Semin Immunol. 2013;25(2):130–45. https://doi.org/10.1016/j.smim.2013.05.007.

    Article  CAS  PubMed  Google Scholar 

  3. Vanlandschoot P, Leroux-Roels G. Hepatitis B vaccines: accomplishments, shortcomings, and future developments. S Afr J Epidemiol Infect. 2008;23(1):33–7. https://doi.org/10.1080/10158782.2008.11441298.

    Google Scholar 

  4. Zehrung D, Jarrahian C, Wales A. Intradermal delivery for vaccine dose sparing. Vaccine. 2013;31(34):3392–5. https://doi.org/10.1016/j.vaccine.2012.11.021.

    Article  CAS  PubMed  Google Scholar 

  5. Manesis EK, Cameron CH, Gregoriadis G, Hepatitis B. Surface antigen-containing liposomes enhance humoral and cell-mediated immunity to the antigen. FEBS Lett. 1979;102(1):107–11. https://doi.org/10.1016/0014-5793(79)80939-4.

    Article  CAS  PubMed  Google Scholar 

  6. Damme PV, Oosterhuis-Kafeja F, Wielen MV, Almagor Y, Sharon O, Levin Y. Safety and efficacy of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults. Vaccine. 2009;27(3):454–9. https://doi.org/10.1016/j.vaccine.2008.10.077.

    Article  PubMed  Google Scholar 

  7. Anselem S, Lowell GH, Aviv H, Friedman D. Solid fat nanoemulsions as vaccine delivery vehicles. United States Patent no. 5,716,637, 10 February 1998

  8. Paliwal R, Paliwal SR, Mishra N, Mehta A, Vyas SP. Engineered chylomicron mimicking carrier emulsome for lymph targeted oral delivery of methotrexate. Int J Pharm. 2009;380(1-2):181–8. https://doi.org/10.1016/j.ijpharm.2009.06.026.

    Article  CAS  PubMed  Google Scholar 

  9. Kaviratna AS, Banerjee R. The effect of acids on dipalmitoyl phosphatidylcholine (DPPC) monolayers and liposomes. Colloids Surf A Physicochem Eng Asp. 2009;345(1-3):155–62. https://doi.org/10.1016/j.colsurfa.2009.04.051.

    Article  CAS  Google Scholar 

  10. Mady MM, Darwish MM. Effect of chitosan coating on the characteristics of DPPC liposomes. J Adv Res. 2010;1(3):187–91. https://doi.org/10.1016/j.jare.2010.05.008.

    Article  Google Scholar 

  11. Chong CSW, Cao M, Wong WW, Fischer KP, Addison WR, Kwon GS, et al. Enhancement of T helper type 1 immune responses against hepatitis B virus core antigen by PLGA nanoparticles vaccine delivery. J Control Release. 2005;102(1):85–99. https://doi.org/10.1016/j.jconrel.2004.09.014.

    Article  CAS  PubMed  Google Scholar 

  12. Lionberger RA, Lee SL, Lee LM, Raw A, Yu LX. Quality by design: concepts for ANDAs. AAPS J. 2008;10(2):268–73. https://doi.org/10.1208/s12248-008-9026-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83. https://doi.org/10.1208/s12248-014-9598-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Riley BS, Li X. Quality by design and process analytical Technology for Sterile Products—Where are we now? AAPS PharmSciTech. 2011;12(1):114–8. https://doi.org/10.1208/s12249-010-9566-x.

    Article  PubMed  Google Scholar 

  15. Cook J, Cruañes MT, Gupta M, Riley S, Crison J. Quality-by-design: are we there yet? AAPS PharmSciTech. 2014;15(1):140–8. https://doi.org/10.1208/s12249-013-0043-1.

    Article  PubMed  Google Scholar 

  16. Sangshetti JN, Deshpande M, Zaheer Z, Shinde DB, Arote R. Quality by design approach: Regulatory need. Arab J Chem. 2017;10(2):S3412–25. https://doi.org/10.1016/j.arabjc.2014.01.025.

    Article  CAS  Google Scholar 

  17. Minz S, Kaurav M, Sahu KK, Mandal V, Pandey RS. Development and validation of TLC-densitometric method for determination of lipid A adjuvant as a bulk and in solid fat nanoemulsions. Biomed Chromatogr. 2015;29(10):1473–9. https://doi.org/10.1002/bmc.3444.

    Article  CAS  PubMed  Google Scholar 

  18. Gonzalez-Mira E, Egea M, Souto E, Calpena A, García M. Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery. Nanotechnology. 2011;22(4):045101. https://doi.org/10.1088/0957-4484/22/4/045101.

    Article  CAS  PubMed  Google Scholar 

  19. Hao J, Wang F, Wang X, Zhang D, Bi Y, Gao Y, et al. Development and optimization of baicalin-loaded solid lipid nanoparticles prepared by coacervation method using central composite design. Eur J Pharm Sci. 2012;47(2):497–05. https://doi.org/10.1016/j.ejps.2012.07.006.

    Article  CAS  PubMed  Google Scholar 

  20. Pradhan M, Singh D, Singh MR. Development characterization and skin permeating potential of lipid based novel delivery system for topical treatment of psoriasis. Chem Phys Lipids. 2015 Feb;186:9–16. https://doi.org/10.1016/j.chemphyslip.2014.11.004.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang JA, Anyarambhatla G, Ma L, Ugwu S, Xuan T, Sardone T, et al. Development and characterization of a novel Cremophor® EL free liposome-based paclitaxel (LEP-ETU) formulation. Eur J Pharm Biopharm. 2005;59(1):177–87. https://doi.org/10.1016/j.ejpb.2004.06.009.

    Article  CAS  PubMed  Google Scholar 

  22. Maheshwari C, Pandey RS, Chaurasiya A, Kumar A, Selvam DT, Prasad GBKS, et al. Non-ionic surfactant vesicles mediated transcutaneous immunization against hepatitis B. Int Immunopharmacol. 2011;1:1516–22.

    Article  Google Scholar 

  23. Morton RE, Evans TA. Modification of the Bicinchoninic acid protein assay to eliminate lipid interference in determining lipoprotein protein content. Anal Biochem. 1992;204(2):332–4. https://doi.org/10.1016/0003-2697(92)90248-6.

    Article  CAS  PubMed  Google Scholar 

  24. Gupta PN, Mahor S, Rawat A, Khatri K, Goyal A, Vyas SP. Lectin anchored stabilized biodegradable nanoparticles for oral immunization, development and in vitro evaluation. Int J Pharm. 2006;318(1-2):163–73. https://doi.org/10.1016/j.ijpharm.2006.03.017.

    Article  CAS  PubMed  Google Scholar 

  25. Pandey RS, Babbar AK, Kaul A, Mishra AK, Dixit VK. Evaluation of ISCOM matrices clearance from rabbit nasal cavity by gamma scintigraphy. Int J Pharm. 2010;398(1-2):231–6. https://doi.org/10.1016/j.ijpharm.2010.07.051.

    Article  CAS  PubMed  Google Scholar 

  26. Pandey RS, Dixit VK. Evaluation of ISCOM vaccines for mucosal immunization against hepatitis B. J Drug Target. 2010;18(4):282–91. https://doi.org/10.3109/10611860903450015.

    Article  CAS  PubMed  Google Scholar 

  27. Pandey RS, Sahu S, Sudheesh MS, Madan J, Kumar M, Dixit VK. Carbohydrate modified ultrafine ceramic nanoparticles for allergen immunotherapy. Int Immunopharmacol. 2011;11(8):925–31. https://doi.org/10.1016/j.intimp.2011.02.004.

    Article  CAS  PubMed  Google Scholar 

  28. Greiner VJ, Ronzon F, Larquet E, Desbat B, Esteves C, Bonvin J, et al. The structure of HBsAg particles is not modified upon their adsorption on aluminium hydroxide gel. Vaccine. 2012;30(35):5240–55. https://doi.org/10.1016/j.vaccine.2012.05.082.

    Article  CAS  PubMed  Google Scholar 

  29. Pandey RS, Dixit VK. Evaluation of ISCOMs for immunization against hepatitis B. Curr Pharm Biotechnol. 2009;10(7):709–16. https://doi.org/10.2174/138920109789542093.

    Article  CAS  PubMed  Google Scholar 

  30. Chittasupho C, Lirdprapamongkol K, Kewsuwan P, Sarisuta N. Targeted delivery of doxorubicin to A549 lung cancer cells by CXCR4antagonist conjugated PLGA nanoparticles. Eur J Pharm Biopharm. 2014;88(2):529–38. https://doi.org/10.1016/j.ejpb.2014.06.020.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang J, Chen XG, Peng WB, Liu CS. Uptake of oleoyl-chitosan nanoparticles by A549 cells. Nanomedicine. 2008;4(3):208–14. https://doi.org/10.1016/j.nano.2008.03.006.

    Article  CAS  PubMed  Google Scholar 

  32. Sarti F, Perera G, Hintzen F, Kotti K, Karageorgiou V, Kammona O, et al. Vivo evidence of oral vaccination with PLGA nanoparticles containing the immunostimulant monophosphoryl lipid a. Biomaterials. 2011;32(16):4052–7. https://doi.org/10.1016/j.biomaterials.2011.02.011.

    Article  CAS  PubMed  Google Scholar 

  33. Mishra D, Dubey V, Asthana A, Saraf DK, Jain NK. Elastic liposomes mediated transcutaneous immunization against hepatitis B. Vaccine. 2006;24(22):4847–55. https://doi.org/10.1016/j.vaccine.2006.03.011.

    Article  CAS  PubMed  Google Scholar 

  34. Borges O, Silva M, de Sousa A, Borchard G, Junginger HE, Cordeiro-da-Silva A. Alginate coated chitosan nanoparticles are an effective subcutaneous adjuvant for hepatitis B surface antigen. Int Immunopharmacol. 2008;8(13-14):1773–80. https://doi.org/10.1016/j.intimp.2008.08.013.

    Article  CAS  PubMed  Google Scholar 

  35. Madan J, Kaushik D, Sardana S, Ali A, Sudheesh MS, Pandey RS. Effect of levofloxacin and pefloxacin on humoral immune response elicited by bovine serum albumin docked in gelatin microparticles and nanoparticles. Pharmazie. 2010;65:1–6.

    Google Scholar 

  36. Lason E, Sikora E, Ogonowski J. Influence of process parameters on properties of nanostructured lipid carriers (NLC) formulation. Acta Biochim Pol. 2003;60:773–7.

    Google Scholar 

  37. Greiner VJ, Manin C, Larquet E, Ikhelef N, Gréco F, Naville S, et al. Characterization of the structural modifications accompanying the loss of HBsAg particle immunogenicity. Vaccine. 2014;32(9):1049–54. https://doi.org/10.1016/j.vaccine.2014.01.012.

    Article  CAS  PubMed  Google Scholar 

  38. Hemling ME, Carr SA, Capiau C, Petre J. Structural characterization of recombinant hepatitis B surface antigen protein by mass spectrometry. Biochemistry. 1988;27(2):699–05. https://doi.org/10.1021/bi00402a031.

    Article  CAS  PubMed  Google Scholar 

  39. Peng J, Tong Y, Ying L, Jie X, Ying Z, Yanna H, et al. Naringenin-loaded solid lipid nanoparticles: preparation, controlled delivery, cellular uptake, and pulmonary pharmacokinetics. Drug Des Devel Ther. 2016;10:911–25.

    Article  Google Scholar 

  40. Win KY, Feng SS. Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials. 2005;26(15):2713–22. https://doi.org/10.1016/j.biomaterials.2004.07.050.

    Article  CAS  PubMed  Google Scholar 

  41. Desai MP, Labhasetwar V, Walter E, Levy RJ, Amidon GL. The mechanism of uptake of biodegradable microparticles in Caco-2 cells is size dependent. Pharm Res. 1997;14(11):1568–73. https://doi.org/10.1023/A:1012126301290.

    Article  CAS  PubMed  Google Scholar 

  42. Foster KA, Yazdanian M, Audus KL. Microparticulate uptake mechanisms of in-vitro cell culture models of the respiratory epithelium. J Pharm Pharmacol. 2001;53(1):57–66. https://doi.org/10.1211/0022357011775190.

    Article  CAS  PubMed  Google Scholar 

  43. Couvreur P, Puisieux F. Nano- and microparticles for the delivery of polypeptides and proteins. Adv Drug Deliv Rev. 1993;10(2-3):141–62. https://doi.org/10.1016/0169-409X(93)90046-7.

    Article  CAS  Google Scholar 

  44. Kanchan K, Panda AK. Interactions of antigen-loaded polylactide particles with macrophages and their correlation with the immune response. Biomaterials. 2007;28(35):5344–57. https://doi.org/10.1016/j.biomaterials.2007.08.015.

    Article  CAS  PubMed  Google Scholar 

  45. Sanyal G, Shi LA. Review of multiple approaches towards an improved hepatitis B vaccine. Expert Opin Ther Pat. 2009;19(1):59–72. https://doi.org/10.1517/13543770802587226.

    Article  CAS  PubMed  Google Scholar 

  46. Ucisik MH, Sleytr UB, Schuster B. Emulsomes Meet S-layer proteins: an emerging targeted drug delivery system. Curr Pharm Biotech. 2015;16:392–05.

    Article  CAS  Google Scholar 

  47. Guldur T, Karabulut AB, Bayraktar N, Kaynar O. Hydrophobic nature of rat lymph chylomicrons. Clini Chem Acta. 2004;342(1-2):161–9. https://doi.org/10.1016/j.cccn.2003.12.018.

    Article  CAS  Google Scholar 

  48. Kretschmar M, Amselem S, Zawoznik E, Mosbach K, Dietz A, Hof H, et al. Efficient treatment of murine systemic infection with Candida albicans using amphotericin B incorporated in nanosize range particles (emulsomes). Mycoses. 2001;44(7–8):281–6. https://doi.org/10.1111/j.1439-0507.2001.00654.x.

    Article  CAS  PubMed  Google Scholar 

  49. Gavilanes F, Gomez-gutierrez J, Aracil M, Gonzalez-ros JM, Ferragut JA, Guerrero E, et al. Hepatitis B surface antigen role of lipids in maintaining the structural and antigenic properties of protein components. Biochem J. 1990;265(3):857–64. https://doi.org/10.1042/bj2650857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tleugabulova D. Sodium dodecylsulfate polyacrylamide gel electrophoresis of recombinant hepatitis B surface antigen particles. J Chromatogr B Biomed Sci Appl. 1998;707(1-2):267–73. https://doi.org/10.1016/S0378-4347(97)00567-7.

    Article  CAS  PubMed  Google Scholar 

  51. Saraf S, Mishra D, Asthana A, Jain R, Singh S, Jain NK. Lipid microparticles for mucosal immunization against hepatitis B. Vaccine. 2006;24(1):45–56. https://doi.org/10.1016/j.vaccine.2005.07.053.

    Article  CAS  PubMed  Google Scholar 

  52. Chen D, Tyagi A, Carpenter J, Perkins S, Sylvester D, Guy M, et al. Characterization of the freeze sensitivity of a hepatitis B vaccine. Hum Vaccin. 2009;5:6–32.

    Article  CAS  Google Scholar 

  53. Anderson RC, Fox CB, Dutill TS, Shaverdian N, Evers TL, Poshusta GR, et al. Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations. Colloids Surf B: Biointerfaces. 2010;75(1):123–32. https://doi.org/10.1016/j.colsurfb.2009.08.022.

    Article  CAS  PubMed  Google Scholar 

  54. Bungener L, Huckriede A, Wilschut J, Daemen T. Delivery of Protein Antigens to the Immune System by Fusion-active Virosomes: A Comparison with Liposomes and ISCOMs. Biosci Rep. 2002;22(2):323–38. https://doi.org/10.1023/A:1020198908574.

    Article  CAS  PubMed  Google Scholar 

  55. Harding CV, Collins DS, Slot JW, Geuze HJ, Unanue ER. Liposome-encapsulated antigens are processed in lysosomes, recycled, and presented to T cells. Cell. 1991;64(2):393–01. https://doi.org/10.1016/0092-8674(91)90647-H.

    Article  CAS  PubMed  Google Scholar 

  56. Peachman KK, Rao M, Alving CR, Palmer DR, Sun W, Rothwell SW, et al. Macrophages exhibit different intracellular processing pathways for soluble and liposome-encapsulated antigens. Immunobiology. 2005;201:321–33.

    Article  Google Scholar 

  57. Reddy ST, Swartz MA, Hubbell AJ. Targeting dendritic cells with biomaterials: developing the next generation of vaccines. Trends Immunol. 2006;27(12):573–9. https://doi.org/10.1016/j.it.2006.10.005.

    Article  CAS  PubMed  Google Scholar 

  58. Nishioka Y, Yoshino H. Lymphatic targeting with nanoparticulate system. Adv Drug Deliv Rev. 2001;47(1):55–64. https://doi.org/10.1016/S0169-409X(00)00121-6.

    Article  CAS  PubMed  Google Scholar 

  59. Temmerman MD, Rejman J, Demeester J, Irvine DJ, Gander B, Smedt SCD. Particulate vaccines: on the quest for optimal delivery and immune response. Drug Discov Today. 2011;16(13-14):569–82. https://doi.org/10.1016/j.drudis.2011.04.006.

    Article  PubMed  Google Scholar 

  60. Steinhagen F, Kinjo T, Bode C, Klinman DM. TLR-based immune adjuvants. Vaccine. 2011;29(17):3341–55. https://doi.org/10.1016/j.vaccine.2010.08.002.

    Article  CAS  PubMed  Google Scholar 

  61. Vosika GJ, Barr C, Gilbertson D. Phase-I study of intravenous modified lipid A. Cancer Immunol Immunother. 1984;18(2):107–12.

    Article  CAS  PubMed  Google Scholar 

  62. Baldridge JR, Crane RT. Monophosphoryl lipid a (MPL) formulations for the next generation of vaccine. Methods. 1999;19(1):103–7. https://doi.org/10.1006/meth.1999.0834.

    Article  CAS  PubMed  Google Scholar 

  63. Heppner DG, Gordon DM, Gross M, Wellde B, Leitner W, Krzych U, et al. Safety, immunogenicity, and efficacy of Plasmodium falciparum repeatless circumsporozoite protein vaccine encapsulated in liposomes. J Infect Dis. 1996;174(2):361–6. https://doi.org/10.1093/infdis/174.2.361.

    Article  CAS  PubMed  Google Scholar 

  64. Steer NJ, Alving CR, Rao M. Modulation of immunoproteasome subunits by liposomal lipid A. Vaccine. 2008;26(23):2849–59. https://doi.org/10.1016/j.vaccine.2008.03.065.

    Article  Google Scholar 

  65. Leuridan E, Damme PV, Hepatitis B. The need for a booster dose. Clin Infect Dis. 2011;53(1):68–75. https://doi.org/10.1093/cid/cir270.

    Article  PubMed  Google Scholar 

  66. Khajuria A, Gupta A, Malik F, Singh S, Singh J, Gupta BD, et al. A new vaccine adjuvant (BOS 2000) a potent enhancer mixed Th1/Th2 immune responses in mice immunized with HBsAg. Vaccine. 2007;25(23):4586–94. https://doi.org/10.1016/j.vaccine.2007.03.051.

    Article  CAS  PubMed  Google Scholar 

  67. Isaka M, Yasuda Y, Mizokami M, Kozuka S, Taniguchi T, Matano K, et al. Mucsal immunization against hepatitis B virus by intranasal co-administration of recombinant hepatitis B surface antigen and recombinant cholera toxin B subunit as an adjuvant. Vaccine. 2001;19(11-12):1460–6. https://doi.org/10.1016/S0264-410X(00)00348-0.

    Article  CAS  PubMed  Google Scholar 

  68. Warren HS, Chedid LA. Future prospects for vaccine adjuvants. Crit Rev Immunol. 1988;8(2):83–101.

    CAS  PubMed  Google Scholar 

  69. Gupta RK, Rost BE, Relyveld E, Siber G, Powell MF, Newmandand MK, et al. Adjuvant properties of aluminum and calcium compounds. Vaccine design. New York: Plenum press; 1995. p. 229.

  70. Ulrich JT, Myers KR. Monophosphoryl lipid a as an adjuvant. Past experiences and new directions. Pharm Biotechnol. 1995;6:495–24. https://doi.org/10.1007/978-1-4615-1823-5_21.

    Article  CAS  PubMed  Google Scholar 

  71. Bramwell VW, Perrie Y. Particulate delivery systems for vaccines: what can we expect? J Pharm Pharmacol. 2006;58(6):717–28. https://doi.org/10.1211/jpp.58.6.0002.

    Article  CAS  PubMed  Google Scholar 

  72. Brunner R, Jensen-Jarolim E, Pali-Schöll I. The ABC of clinical and experimental adjuvants—a brief overview. Immunol Lett. 2010;128(1):29–35. https://doi.org/10.1016/j.imlet.2009.10.005.

    Article  CAS  PubMed  Google Scholar 

  73. Singh M, O’Hagan DT. Recent advances in vaccine adjuvants. Pharm Res. 2002;19:6.

    Article  Google Scholar 

  74. Airhart CL, Rohde HN, Hovde CJ, Bohach GA, Deobald CF, Lee SS, et al. Mimetics are potent adjuvants for an intranasal pneumonic plague vaccine. Vaccine. 2008;26(44):5554–61. https://doi.org/10.1016/j.vaccine.2008.08.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zeng W, Eriksson E, Chua B, Grollo L, Jackson DC. Structural requirement for the agonist activity of the TLR2 ligand Pam2Cys. Amino Acids. 2010;39(2):471–80. https://doi.org/10.1007/s00726-009-0463-0.

    Article  CAS  PubMed  Google Scholar 

  76. Zeng W, Azzopardi K, Hocking D, Wonga CY, Robevsk GA, Tauschek M, et al. A totally synthetic lipopeptide-based self-adjuvanting vaccine induces neutralizing antibodies against heat-stable enterotoxin from enterotoxigenic Escherichia Coli. Vaccine. 2012;30(32):4800–6. https://doi.org/10.1016/j.vaccine.2012.05.017.

    Article  CAS  PubMed  Google Scholar 

  77. Diwan M, Elamanchili P, Cao M, Samuel J. Dose sparing of CpG oligodeoxynucleotide vaccine adjuvants by nanoparticle delivery. Curr Drug Deliv. 2004;1(4):405–12. https://doi.org/10.2174/1567201043334597.

    Article  CAS  PubMed  Google Scholar 

  78. O’Hagan DT, Singh M. Microparticles as vaccine adjuvants and deliverysystems. Expert Rev Vaccines. 2003;2(2):269–83. https://doi.org/10.1586/14760584.2.2.269.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

One of the authors Ms. Sunita Minz (SRF-RGNF) appreciates University Grants Commission, New Delhi, India for providing financial assistance. Authors are also grateful to Serum Institute of Pune, India for providing gift sample (rHBsAg). All India Institute of Medical Sciences (AIIMS, New Delhi, India) for providing electron microscopy facility and National Institute of Pharmaceutical Education and Research (NIPER, Mohali, India) for fluorescence spectroscopy and circular dichroism.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, MP, 484886, India

    Sunita Minz

  2. SLT Institute of Pharmaceutical sciences, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, CG, 495009, India

    Sunita Minz & Ravi Shankar Pandey

Authors
  1. Sunita Minz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ravi Shankar Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ravi Shankar Pandey.

Ethics declarations

The study was carried out as per guidelines issued by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA, Ministry of Social Empowerment and Justice, Government of India). The experimental protocol on animals was approved by the Institutional animal ethics committee (IAEC).

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Minz, S., Pandey, R.S. Lipid A adjuvanted Chylomicron Mimicking Solid Fat Nanoemulsions for Immunization Against Hepatitis B. AAPS PharmSciTech 19, 1168–1181 (2018). https://doi.org/10.1208/s12249-017-0932-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-017-0932-9

Key Words

Search

Navigation