Evaluation of Intranasal Vaccine Delivery Using Anatomical Replicas of Infant Nasal Airways



Nasal delivery is a favorable route for vaccination against most respiratory infections, as antigen deposited in the nasal turbinate and Waldeyer’s ring areas induce mucosal and systemic immune responses. However, little is known about the nasal distribution of the vaccines, specifically for infants.


Anatomical nasal replicas of five subjects, 3–24 months, were developed to assess local intranasal vaccine delivery using MAD Nasal™ device, and understand impact of breathing conditions and administration parameters. High performance liquid chromatography was used to quantify the deposition pattern and determine the delivery efficiency.


The delivery efficiency on average for all models was found to be 86.57±14.23%. There were no significant differences in the total delivery efficiency between the models in all cases. However, the regional deposition pattern was altered based on the model and subsequent administration. Furthermore, removing the foam tip from the MAD Nasal™ device, to study the impact of insertion length, did not significantly increase the efficiency within the two models tested, 5- and 16-month.


Incorporating nasal replicas in testing provided a benchmark to determine the efficiency of a common intranasal vaccine delivery combination product. This proposed platform would allow comparing other potential nasal vaccine delivery devices.

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Fig. 5



Computed topography


Deposition efficiency


High performance liquid chromatography


Tukey’s honest significant difference test


Internal nasal valve


Mucosal atomization device


Nasal-associated lymphoid tissue


Regional deposition efficiency

RDP Ad :

Adenoid regional deposition percentage

RDP An :

Anterior regional deposition percentage


Nasal cavity regional deposition percentage

RDP Ol :

Olfactory regional deposition percentage


Paranasal sinuses regional deposition percentage


Throat and filter regional deposition percentage


  1. 1.

    Yusuf H, Kett V. Current prospects and future challenges for nasal vaccine delivery. Hum Vaccines Immunother. 2017;13:34–45.

    Article  Google Scholar 

  2. 2.

    Sharma S, Mukkur TKS, Benson HAE, Chen Y. Pharmaceutical aspects of intranasal delivery of vaccines using particulate systems. J Pharm Sci. 2009;98:812–43.

    CAS  Article  Google Scholar 

  3. 3.

    Zaman M, Chandrudu S, Toth I. Strategies for intranasal delivery of vaccines. Drug Deliv Transl Res. 2013;3:100–9.

    CAS  Article  Google Scholar 

  4. 4.

    Yuki Y, Kiyono H. Mucosal vaccines: novel advances in technology and delivery. Expert Rev Vaccines. 2009;8:1083–97.

    CAS  Article  Google Scholar 

  5. 5.

    Jabbal-Gill I. Nasal vaccine innovation. J Drug Target. 2010;18:771–86.

    CAS  Article  Google Scholar 

  6. 6.

    Giudice EL, Campbell JD. Needle-free vaccine delivery. Adv Drug Deliv Rev. 2006;58:68–89.

    CAS  Article  Google Scholar 

  7. 7.

    Illum L. Nasal drug delivery - possibilities, problems and solutions. J Control Release. 2003;87:187–98.

    CAS  Article  Google Scholar 

  8. 8.

    Tlaxca JL, Ellis S, Remmele RL. Live attenuated and inactivated viral vaccine formulation and nasal delivery: potential and challenges. Adv Drug Deliv Rev. 2015;93:56–78.

    CAS  Article  Google Scholar 

  9. 9.

    Riese P, Sakthivel P, Trittel S, Guzmán CA. Intranasal formulations: promising strategy to deliver vaccines. Expert Opin Drug Deliv. 2014;11:1619–34.

    CAS  Article  Google Scholar 

  10. 10.

    O’Hagan DT, Rappuoli R. Novel approaches to vaccine delivery. Pharm Res. 2004;21:1519–30.

    Article  Google Scholar 

  11. 11.

    Davis SS. Nasal vaccines. Adv Drug Deliv Rev. 2001;51:21–42.

    CAS  Article  Google Scholar 

  12. 12.

    Slütter B, Hagenaars N, Jiskoot W. Rational design of nasal vaccines. J Drug Target. 2008;16:1–17.

    Article  Google Scholar 

  13. 13.

    Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Deliv Transl Res. 2013;3:42–62.

    CAS  Article  Google Scholar 

  14. 14.

    Scherließ R. Nasal administration of vaccines. In: Foged C, Rades T, Perrie Y, Hook S, editors. Subunit vaccine Deliv Adv Deliv Sci Technol. New York: Springer; 2015.

    Google Scholar 

  15. 15.

    Bryant ML, Brown P, Gurevich N, McDougall IR. Comparison of the clearance of radiolabelled nose drops and nasal spray as mucosally delivered vaccine. Nucl Med Commun. 1999;20:171–4.

    CAS  Article  Google Scholar 

  16. 16.

    Laube BL, Sharpless G, Vikani AR, Harrand V, Zinreich SJ, Sedberry K, et al. Intranasal deposition of Accuspray™ aerosol in anatomically correct models of 2-, 5-, and 12-year-old children. J Aerosol Med Pulm Drug Deliv. 2015;28:320–33.

    CAS  Article  Google Scholar 

  17. 17.

    Sosnowski TR, Rapiejko P, Sova J, Dobrowolska K. Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model. Int J Pharm. Elsevier; 2020;574:118911.

  18. 18.

    Tripp RA, Hanson JM. Inhaled countermeasures for respiratory tract viruses. In: Kwok PCL, Chan H-K, editors. Adv Pulm Drug Deliv. Boca Raton: Taylor & Francis Group; 2016. p. 93–129.

    Google Scholar 

  19. 19.

    Kundoor V, Dalby RN. Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast. Pharm Res. 2011;28:1895–904.

    CAS  Article  Google Scholar 

  20. 20.

    Xi J, Yuan JE, Zhang Y, Nevorski D, Wang Z, Zhou Y. Visualization and quantification of nasal and olfactory deposition in a sectional adult nasal airway cast. Pharm Res. 2016;33:1527–41.

    CAS  Article  Google Scholar 

  21. 21.

    Foo MY, Cheng YS, Su WC, Donovan MD. The influence of spray properties on intranasal deposition. J Aerosol Med. 2007;20:495–508.

    CAS  Article  Google Scholar 

  22. 22.

    Hosseini S, Wei X, Wilkins JV, Fergusson CP, Mohammadi R, Vorona G, et al. In vitro measurement of regional nasal drug delivery with Flonase,® Flonase® Sensimist,™ and MAD Nasal™ in anatomically correct nasal airway replicas of pediatric and adult human subjects. J Aerosol Med Pulm Drug Deliv. 2019;32:374–85.

    CAS  Article  Google Scholar 

  23. 23.

    Storey-Bishoff J, Noga M, Finlay WH. Deposition of micrometer-sized aerosol particles in neonatal nasal airway replicas. J Aerosol Sci. 2008;39:1055–65.

    CAS  Article  Google Scholar 

  24. 24.

    Zhou Y, Guo M, Xi J, Irshad H, Cheng Y-S. Nasal deposition in infants and children. J Aerosol Med Pulm Drug Deliv. 2014;27:110–6.

    Article  Google Scholar 

  25. 25.

    Tavernini S, Church TK, Lewis DA, Noga M, Martin AR, Finlay WH. Deposition of micrometer-sized aerosol particles in neonatal nasal airway replicas. Aerosol Sci Technol 2017;0.

  26. 26.

    Laube BL, Sharpless G, Shermer C, Sullivan V, Powell K. Deposition of dry powder generated by Solovent in Sophia anatomical infant nose-throat (SAINT) model. Aerosol Sci Technol. 2011;46:514–20.

    Article  Google Scholar 

  27. 27.

    Hosseini S, Golshahi L. An in vitro evaluation of importance of airway anatomy in sub-regional nasal and paranasal drug delivery with nebulizers using three different anatomical nasal airway replicas of 2-, 5- and 50-year old human subjects. Int J Pharm. 2019;563:426–36.

    CAS  Article  Google Scholar 

  28. 28.

    Neutra MR, Kozlowski PA. Mucosal vaccines: the promise and the challenge. Nat Rev Immunol. 2006;6:148–58.

    CAS  Article  Google Scholar 

  29. 29.

    Borges O, Lebre F, Bento D, Borchard G, Junginger HE. Mucosal vaccines: recent progress in understanding the natural barriers. Pharm Res. 2010;27:211–23.

    CAS  Article  Google Scholar 

  30. 30.

    Si XA, Xi J, Kim JW, Zhou Y, Zhong H. Modeling of release position and ventilation effects on olfactory aerosol drug delivery. Respir Physiol Neurobiol. 2013;186:22–32.

    CAS  Article  Google Scholar 

  31. 31.

    Shang Y, Dong J, Inthavong K, Tu J. Comparative numerical modeling of inhaled micron-sized particle deposition in human and rat nasal cavities. Inhal Toxicol. 2015;27:694–705.

    CAS  Article  Google Scholar 

  32. 32.

    ICRP. Human Respiratory Tract Model for Radiological Protection. ICRP Publ 66. 1994;Ann. ICRP.

  33. 33.

    Debertin AS, Tschernig T, Tönjes H, Kleemann WJ, Tröger HD, Pabst R. Nasal-associated lymphoid tissue (NALT): frequency and localization in young children. Clin Exp Immunol. 2003;134:503–7.

    CAS  Article  Google Scholar 

  34. 34.

    Pabst R. Mucosal vaccination by the intranasal route. Nose-associated lymphoid tissue (NALT)-structure, function and species differences. Vaccine. Elsevier Ltd; 2015;33:4406–4413.

  35. 35.

    van Ginkel FW, Jackson RJ, Yuki Y, McGhee JR. Cutting edge: the mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J Immunol United States. 2000;165:4778–82.

    Google Scholar 

  36. 36.

    Fukuyama Y, Okada K, Yamaguchi M, Kiyono H, Mori K, Yuki Y. Nasal Administration of Cholera Toxin as a mucosal adjuvant damages the olfactory system in mice. PLoS One. 2015;10:e0139368.

    Article  Google Scholar 

  37. 37.

    Wewetzer K, Radtke C, Kocsis J, Baumgärtner W. Species-specific control of cellular proliferation and the impact of large animal models for the use of olfactory ensheathing cells and Schwann cells in spinal cord repair. Exp Neurol. Elsevier Inc.; 2011;229:80–7.

  38. 38.

    Brandes G, Khayami M, Peck CT, Baumgärtner W, Bugday H, Wewetzer K. Cell surface expression of 27C7 by neonatal rat olfactory ensheathing cells in situ and in vitro is independent of axonal contact. Histochem Cell Biol. 2011;135:397–408.

    CAS  Article  Google Scholar 

  39. 39.

    Amirav I, Borojeni AAT, Halamish A, Newhouse MT, Golshahi L. Nasal versus oral aerosol delivery to the “lungs” in infants and toddlers. Pediatr Pulmonol. 2015;50:276–83.

    Article  Google Scholar 

  40. 40.

    El Taoum KK, Xi J, Kim JW, Berlinski A. In vitro evaluation of aerosols delivered via the nasal route. Respir Care. 2015;60:1015–25.

    Article  Google Scholar 

  41. 41.

    Bergeson PS, Shaw JC. Are infants really obligatory nasal breathers? Clin Pediatr (Phila). 2001;40:567–9.

    CAS  Article  Google Scholar 

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Authors would like to acknowledge Yan-Ping Yang, Sebastien Carayol, and Scott Gallichan for their supports on this project. In addition, Sana Hosseini is acknowledged for her contributions to the development of the models and measurement of some anatomical dimensions. Dr. Joseph Turner is gratefully acknowledged for providing the analytical support through VCU Instrumentation Facility. The authors have no conflicts of interest to declare related to the subject of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the views of the sponsor and VCU.

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Correspondence to Laleh Golshahi or Lillian Li.

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Wilkins, J.V., Golshahi, L., Rahman, N. et al. Evaluation of Intranasal Vaccine Delivery Using Anatomical Replicas of Infant Nasal Airways. Pharm Res 38, 141–153 (2021). https://doi.org/10.1007/s11095-020-02976-9

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  • dose deposition
  • infant
  • intranasal vaccines
  • in vitro
  • nasal models