Oral Vaccine Delivery: The Coming Age of Particulate Vaccines to Elicit Mucosal Immunity

  • Rikhav P. Gala
  • Lotika Bajaj
  • Amit Bansal
  • Keegan Braz Gomes
  • Devyani Joshi
  • Ipshita Menon
  • Rokon Uz Zaman
  • Susu M. Zughaier
  • Marissa D’Souza
  • Carmen Popescu
  • Nigel D’Souza
  • Gregory T. Knipp
  • Martin J. D’SouzaEmail author
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 41)


With the evolution of different challenging diseases, there is an urgent need of vaccine development against them to save millions of lives around the world. Particlulate delivery system plays an important role by acting as self-adjuvant in form of particles and thus assisting the immunogenicity of vaccines. Particulate vaccines have shown to have improved uptake by antigen presenting cells as compared to the soluble antigen. Traditional injectable vaccines are generally poor inducers of mucosal immunity and are therefore less effective against infections at the mucosal site. Mucosal vaccines have been reported to provide additional secretory antibody mediated protection at the mucosal site of entry of the pathogen. In this chapter, we discuss the benefits of particulate drug delivery systems for oral delivery, the role of immune system in the gut, and a case study ofa novel particulate vaccine formulated into oral dissolving film for immunization via the buccal route. Key formulation components, process parameters and their biophysical characterizations have been discussed as well.


Microparticles Spray dry Oral dissolving films Mucosal immunity Buccal immunization 



Antigen-Presenting Cells


Blood-Brain Barrier


Bovine Serum Albumin


Dendritic Cells


Enhanced Permeability and Retention


Gut Associated Lymphoid Tissue


Interferon Gamma




Major Histocompatibility Complex


Mesenteric Lymph Nodes


Mucosal Associate Lymphoid Tissues


Mucosal Immune System


Nasopharynx-Associated Lymphoid Tissue


Oral Dissolving Film


Peyer’s Patches


Poly(lLactic-cCo-gGlycolic aAcid)


Rabies Virus Glycoprotein


Toll-Like Receptors


Type 1 Helper T Cells


Type 2 Helper T Cells


Virus-Like Particles


  1. 1.
    De Temmerman M-L, Rejman J, Demeester J, Irvine DJ, Gander B, De Smedt SC. Particulate vaccines: on the quest for optimal delivery and immune response. Drug Discov Today. 2011 Jul 1;16(13):569–82.CrossRefGoogle Scholar
  2. 2.
    Oberg AL, Kennedy RB, Li P, Ovsyannikova IG, Poland GA. Systems biology approaches to new vaccine development. Curr Opin Immunol. 2011 Jun;23(3):436–43.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rappuoli R, Mandl CW, Black S, De Gregorio E. Vaccines for the twenty-first century society. Nat Rev Immunol. 2011 04;11(12):865–872.Google Scholar
  4. 4.
    Zhao L, Seth A, Wibowo N, Zhao C-X, Mitter N, Yu C, et al. Nanoparticle vaccines. Vaccine. 2014 Jan 9;32(3):327–37.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bramwell VW, Perrie Y. The rational design of vaccines. Drug Discov Today. 2005 Nov 15;10(22):1527–34.CrossRefGoogle Scholar
  6. 6.
    Hubbell JA, Thomas SN, Swartz MA. Materials engineering for immunomodulation. Nature. 2009 Nov 26;462(7272):449–60.CrossRefGoogle Scholar
  7. 7.
    Storni T, Kündig TM, Senti G, Johansen P. Immunity in response to particulate antigen-delivery systems. Adv Drug Deliv Rev. 2005 Jan 10;57(3):333–55.CrossRefGoogle Scholar
  8. 8.
    Scheerlinck J-PY, Greenwood DLV. Particulate delivery systems for animal vaccines. Methods. 2006 Sep 1;40(1):118–24.CrossRefGoogle Scholar
  9. 9.
    Bachmann MF, Jennings GT. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol. 2010 Nov;10(11):787–96.CrossRefGoogle Scholar
  10. 10.
    Gregory AE, Titball R, Williamson D. Vaccine delivery using nanoparticles. Front Cell Infect Microbiol. 2013;3:13.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jahraus A, Storrie B, Griffiths G, Desjardins M. Evidence for retrograde traffic between terminal lysosomes and the prelysosomal/late endosome compartment. J Cell Sci. 1994 Jan;107(Pt 1):145–57.PubMedGoogle Scholar
  12. 12.
    Pitt A, Mayorga LS, Stahl PD, Schwartz AL. Alterations in the protein composition of maturing phagosomes. J Clin Invest. 1992 Nov;90(5):1978–83.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Garin J, Diez R, Kieffer S, Dermine JF, Duclos S, Gagnon E, et al. The phagosome proteome: insight into phagosome functions. J Cell Biol. 2001 Jan 8;152(1):165–80.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Tacken PJ, Torensma R, Figdor CG. Targeting antigens to dendritic cells in vivo. Immunobiology. 2006;211(6–8):599–608.CrossRefGoogle Scholar
  15. 15.
    Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S-I, Soares H, et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med. 2004 Mar 15;199(6):815–24.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gieseler RK, Marquitan G, Hahn MJ, Perdon LA, Driessen WHP, Sullivan SM, et al. DC-SIGN-specific liposomal targeting and selective intracellular compound delivery to human myeloid dendritic cells: implications for HIV disease. Scand J Immunol. 2004 May;59(5):415–24.CrossRefGoogle Scholar
  17. 17.
    Agarwal R, Jurney P, Raythatha M, Singh V, Sreenivasan SV, Shi L, et al. Effect of shape, size, and aspect ratio on nanoparticle penetration and distribution inside solid tissues using 3D spheroid models. Adv Healthc Mater. 2015 Oct 28;4(15):2269–80.CrossRefGoogle Scholar
  18. 18.
    Shima F, Uto T, Akagi T, Baba M, Akashi M. Size effect of amphiphilic poly(γ-glutamic acid) nanoparticles on cellular uptake and maturation of dendritic cells in vivo. Acta Biomater. 2013 Nov;9(11):8894–901.CrossRefGoogle Scholar
  19. 19.
    Fifis T, Gamvrellis A, Crimeen-Irwin B, Pietersz GA, Li J, Mottram PL, et al. Size-dependent immunogenicity: therapeutic and protective properties of nano-vaccines against tumors. J Immunol Baltim Md 1950. 2004 Sep 1;173(5):3148–54.Google Scholar
  20. 20.
    Mathaes R, Winter G, Siahaan TJ, Besheer A, Engert J. Influence of particle size, an elongated particle geometry, and adjuvants on dendritic cell activation. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Verfahrenstechnik EV. 2015 Aug;94:542–9.CrossRefGoogle Scholar
  21. 21.
    Sun J, Zhang L, Wang J, Feng Q, Liu D, Yin Q, et al. Tunable rigidity of (polymeric core)-(lipid shell) nanoparticles for regulated cellular uptake. Adv Mater Deerfield Beach Fla. 2015 Feb 25;27(8):1402–7.CrossRefGoogle Scholar
  22. 22.
    Kaur R, Henriksen-Lacey M, Wilkhu J, Devitt A, Christensen D, Perrie Y. Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses. Mol Pharm. 2014 Jan 6;11(1):197–207.CrossRefGoogle Scholar
  23. 23.
    Benne N, van Duijn J, Kuiper J, Jiskoot W, Slütter B. Orchestrating immune responses: how size, shape and rigidity affect the immunogenicity of particulate vaccines. J Control Release. 2016 Jul 28;234:124–34.CrossRefGoogle Scholar
  24. 24.
    Chablani L, Tawde SA, D’souza MJ. Spray-dried microparticles: a potential vehicle for oral delivery of vaccines. J Microencapsul. 2012 Jun 1;29(4):388–97.CrossRefGoogle Scholar
  25. 25.
    Kumar M, Mani P, Pratheesh P, Chandra S, Jeyakkodi M, Chattopadhyay P, et al. Membrane fusion mediated targeted cytosolic drug delivery through scFv engineered Sendai viral envelopes. Curr Mol Med. 2015;15(4):386–400.CrossRefGoogle Scholar
  26. 26.
    Bolhassani A, Javanzad S, Saleh T, Hashemi M, Aghasadeghi MR, Sadat SM. Polymeric nanoparticles. Hum Vaccines Immunother. 2014 Feb 1;10(2):321–32.CrossRefGoogle Scholar
  27. 27.
    Basu A, Kunduru KR, Katzhendler J, Domb AJ. Poly(α-hydroxy acid)s and poly(α-hydroxy acid-co-α-amino acid)s derived from amino acid. Adv Drug Deliv Rev. 2016 15;107:82–96.Google Scholar
  28. 28.
    Foged C, Hansen J, Agger EM. License to kill: formulation requirements for optimal priming of CD8+ CTL responses with particulate vaccine delivery systems. Eur J Pharm Sci. 2012 Mar 12;45(4):482–91.CrossRefGoogle Scholar
  29. 29.
    Harding CV. Song R Phagocytic processing of exogenous particulate antigens by macrophages for presentation by class I MHC molecules. J Immunol Baltim Md 1950. 1994 Dec 1;153(11):4925–33.Google Scholar
  30. 30.
    McCraw DM, Gallagher JR, Torian U, Myers ML, Conlon MT, Gulati NM, et al. Structural analysis of influenza vaccine virus-like particles reveals a multicomponent organization. Sci Rep. 2018 Jul 9;8(1):1–16.CrossRefGoogle Scholar
  31. 31.
    Xiang SD, Scholzen A, Minigo G, David C, Apostolopoulos V, Mottram PL, et al. Pathogen recognition and development of particulate vaccines: does size matter? Methods San Diego Calif. 2006 Sep;40(1):1–9.CrossRefGoogle Scholar
  32. 32.
    Singh B, Maharjan S, Cho K-H, Cui L, Park I-K, Choi Y-J, et al. Chitosan-based particulate systems for the delivery of mucosal vaccines against infectious diseases. Int J Biol Macromol. 2018 Apr 15;110:54–64.CrossRefGoogle Scholar
  33. 33.
    Bansal A, Wu X, Olson V, D’Souza MJ. Characterization of rabies pDNA nanoparticulate vaccine in poloxamer 407 gel. Int J Pharm. 2018 Jul 10;545(1–2):318–28.CrossRefGoogle Scholar
  34. 34.
    Akalkotkar A, Chablani L, Tawde SA, D’Souza C, D’Souza MJ. Development of a microparticulate prostate cancer vaccine and evaluating the effect of route of administration on its efficacy via the skin. J Microencapsul. 2015 Apr 3;32(3):281–9.CrossRefGoogle Scholar
  35. 35.
    D’Souza MJ, Tawde SA, Akalkotkar A, Chablani L, D’Souza M, Chiriva-Internati M. Nanotechnology in Vaccine Delivery. In: Giese M, editor. Molecular vaccines: from prophylaxis to therapy - Volume 2 [Internet]. Cham: Springer International Publishing; 2014 [cited 2018 Oct 2]. p. 727–741. Available from: doi:
  36. 36.
    Singh MN, Hemant KSY, Ram M, Shivakumar HG. Microencapsulation: a promising technique for controlled drug delivery. Res Pharm Sci. 2010;5(2):65–77.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Kumar B, Jalodia K, Kumar P, Gautam HK. Recent advances in nanoparticle-mediated drug delivery. J Drug Deliv Sci Technol. 2017 Oct 1;41:260–8.CrossRefGoogle Scholar
  38. 38.
    Agnihotri SA, Mallikarjuna NN, Aminabhavi TM. Recent advances on chitosan-based micro- and nanoparticles in drug delivery. J Control Release. 2004 Nov 5;100(1):5–28.CrossRefGoogle Scholar
  39. 39.
    Singh R, Lillard JW. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009 Jun;86(3):215–23.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Zaman RU, Mulla NS, Braz Gomes K, D’Souza C, Murnane KS, D’Souza MJ. Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin. Int J Pharm. 2018 Sep 5;548(1):698–706.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mahapatro A, Singh DK. Biodegradable nanoparticles are excellent vehicle for site directed in-vivo delivery of drugs and vaccines. J Nanobiotechnology. 2011;9(1):55.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    El-Say KM, El-Sawy HS. Polymeric nanoparticles: promising platform for drug delivery. Int J Pharm. 2017 Aug 7;528(1):675–91.CrossRefGoogle Scholar
  43. 43.
    Borchard G, Audus KL, Shi F, Kreuter J. Uptake of surfactant-coated poly(methyl methacrylate)-nanoparticles by bovine brain microvessel endothelial cell monolayers. Int J Pharm. 1994 Sep 12;110(1):29–35.CrossRefGoogle Scholar
  44. 44.
    Bahrami B, Hojjat-Farsangi M, Mohammadi H, Anvari E, Ghalamfarsa G, Yousefi M, et al. Nanoparticles and targeted drug delivery in cancer therapy. Immunol Lett. 2017 Oct 1;190:64–83.CrossRefGoogle Scholar
  45. 45.
    Zaman RU, Mulla NS, Braz Gomes K, D’Souza C, Murnane KS, D’Souza MJ. Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin. Int J Pharm. 2018 Sep 5;548(1):698–706.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Chablani L, Tawde SA, Akalkotkar A, D’Souza C, Selvaraj P, D’Souza MJ. Formulation and evaluation of a particulate oral breast cancer vaccine. J Pharm Sci. 2012 Oct 1;101(10):3661–71.CrossRefGoogle Scholar
  47. 47.
    Stella B, Arpicco S, Peracchia MT, Desmaële D, Hoebeke J, Renoir M, et al. Design of folic acid-conjugated nanoparticles for drug targeting. J Pharm Sci. 2000 Nov 1;89(11):1452–64.CrossRefGoogle Scholar
  48. 48.
    D’Souza B, Bhowmik T, Shashidharamurthy R, Oettinger C, Selvaraj P, D’Souza M. Oral microparticulate vaccine for melanoma using M-cell targeting. J Drug Target. 2012 Feb 1;20(2):166–73.CrossRefGoogle Scholar
  49. 49.
    McGhee JR, Fujihashi K. Inside the mucosal immune system. PLoS Biol. 2012 Sep 25;10(9):e1001397.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Montilla NA, Blas MP, Santalla ML. Villa JMM. Mucosal immune system: a brief review. 2004;23(2):10.Google Scholar
  51. 51.
    O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006 Jul;7(7):688–93.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Peters BM, Shirtliff ME, Jabra-Rizk MA. Antimicrobial Peptides: Primeval Molecules or Future Drugs? PLoS Pathog. 2010 Oct 28;6(10):e1001067.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Charles A Janeway J, Travers P, Walport M, Shlomchik MJ. The mucosal immune system. 2001 [cited 2018 Mar 29]; Available from:
  54. 54.
    Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. Host-gut microbiota metabolic interactions. Science. 2012 Jun 8;336(6086):1262–7.CrossRefGoogle Scholar
  55. 55.
    McNabb PC, Tomasi TB. Host defense mechanisms at mucosal surfaces. Annu Rev Microbiol. 1981;35:477–96.CrossRefGoogle Scholar
  56. 56.
    Lamichhane A, Azegamia T, Kiyonoa H. The mucosal immune system for vaccine development. Vaccine. 2014 Nov 20;32(49):6711–23.CrossRefGoogle Scholar
  57. 57.
    Shanahan F. The host-microbe interface within the gut. Best Pract Res Clin Gastroenterol. 2002 Dec;16(6):915–31.CrossRefGoogle Scholar
  58. 58.
    Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol. 2001 Apr;2(4):361–7.CrossRefGoogle Scholar
  59. 59.
    Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science. 2004 Mar 12;303(5664):1662–5.CrossRefGoogle Scholar
  60. 60.
    Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang Y-C, et al. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science. 2010 Aug 13;329(5993):849–53.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Azegami T, Yuki Y, Kiyono H. Challenges in mucosal vaccines for the control of infectious diseases. Int Immunol. 2014 Sep;26(9):517–28.CrossRefGoogle Scholar
  62. 62.
    Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005 Apr;11(4 Suppl):S45–53.CrossRefGoogle Scholar
  63. 63.
    Hieshima K, Kawasaki Y, Hanamoto H, Nakayama T, Nagakubo D, Kanamaru A, et al. CC chemokine ligands 25 and 28 play essential roles in intestinal extravasation of IgA antibody-secreting cells. J Immunol Baltim Md 1950. 2004 Sep 15;173(6):3668–3675.Google Scholar
  64. 64.
    Leung AK, Hon KL, Leong KF, Sergi CM. Measles: a disease often forgotten but not gone. Hong Kong Med J Xianggang Yi Xue Za Zhi. 2018 Sep;24Google Scholar
  65. 65.
    Department of Pediatrics, The University of Calgary, Calgary, Alberta, Canada, Leung AK, Hon K, Leong K, Sergi C. Measles: a disease often forgotten but not gone. Hong Kong Med J [Internet]. 2018 Sep 24 [cited 2018 Oct 4]; Available from:
  66. 66.
    Gala RP, Popescu C, Knipp GT, McCain RR, Ubale RV, Addo R, et al. Physicochemical and preclinical evaluation of a novel buccal measles vaccine. AAPS PharmSciTech. 2017 Feb;18(2):283–92.CrossRefGoogle Scholar
  67. 67.
    O’Hagan DT, Singh M, Ulmer JB. Microparticle-based technologies for vaccines. Methods San Diego Calif. 2006 Sep;40(1):10–9.CrossRefGoogle Scholar
  68. 68.
    Lin C-Y, Lin S-J, Yang Y-C, Wang D-Y, Cheng H-F, Yeh M-K. Biodegradable polymeric microsphere-based vaccines and their applications in infectious diseases. Hum Vaccines Immunother. 2015 Mar 4;11(3):650–6.CrossRefGoogle Scholar
  69. 69.
    Singh R, Lillard JW. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009 Jun;86(3):215–23.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Zhu M, Wang R, Nie G. Applications of nanomaterials as vaccine adjuvants. Hum Vaccines Immunother. 2014;10(9):2761–74.CrossRefGoogle Scholar
  71. 71.
    Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release Off J Control Release Soc. 2001 Jan 29;70:1–2):1–20.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2020

Authors and Affiliations

  • Rikhav P. Gala
    • 1
    • 2
  • Lotika Bajaj
    • 1
  • Amit Bansal
    • 1
  • Keegan Braz Gomes
    • 1
  • Devyani Joshi
    • 1
  • Ipshita Menon
    • 1
  • Rokon Uz Zaman
    • 1
  • Susu M. Zughaier
    • 3
  • Marissa D’Souza
    • 1
  • Carmen Popescu
    • 4
  • Nigel D’Souza
    • 1
  • Gregory T. Knipp
    • 5
  • Martin J. D’Souza
    • 1
    Email author
  1. 1.Vaccine Nanotechnology Laboratory, Center for Drug DeliveryMercer UniversityAtlantaUSA
  2. 2.Department of Pharmaceutical SciencesUniversity of New MexicoAlbuquerqueUSA
  3. 3.College of MedicineQatar UniversityDohaQatar
  4. 4.Roquette America Inc.GenevaUSA
  5. 5.Department of Industrial and Physical PharmacyCollege of Pharmacy, Purdue UniversityWest LafayetteUSA

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