Distribution of Droplets and Immune Responses After Aerosol and Intra-Nasal Delivery of Influenza Virus to the Respiratory Tract of Pigs

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2020 Nov 16

PMID 33193445

Citations 14

Authors

Veronica Martini

Michael Hinchcliffe

Elaine Blackshaw

Mary Joyce

Adam McNee

Peter Beverley

Alain Townsend

Ronan MacLoughlin

Elma Tchilian

Affiliations

Soon will be listed here.

Abstract

Recent evidence indicates that local immune responses and tissue resident memory T cells (T) are critical for protection against respiratory infections but there is little information on the contributions of upper and lower respiratory tract (URT and LRT) immunity. To provide a rational basis for designing methods for optimal delivery of vaccines to the respiratory tract in a large animal model, we investigated the distribution of droplets generated by a mucosal atomization device (MAD) and two vibrating mesh nebulizers (VMNs) and the immune responses induced by delivery of influenza virus by MAD in pigs. We showed that droplets containing the drug albuterol, a radiolabel (Tc-DTPA), or a model influenza virus vaccine (S-FLU) have similar aerosol characteristics. Tc-DTPA scintigraphy showed that VMNs deliver droplets with uniform distribution throughout the lungs as well as the URT. Surprisingly MAD administration (1ml/nostril) also delivered a high proportion of the dose to the lungs, albeit concentrated in a small area. After MAD administration of influenza virus, antigen specific T cells were found at high frequency in nasal turbinates, trachea, broncho-alveolar lavage, lungs, tracheobronchial nodes, and blood. Anti-influenza antibodies were detected in serum, BAL and nasal swabs. We conclude that the pig is useful for investigating optimal targeting of vaccines to the respiratory tract.

Citing Articles

Predicting airway immune responses and protection from immune parameters in blood following immunization in a pig influenza model.

Gubbins S, Paudyal B, Dema B, Vats A, Ulaszewska M, Vatzia E Front Immunol. 2025; 15:1506224.

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High-Flow Nasal Aerosol Therapy; Regional Aerosol Deposition and Airway Responsiveness.

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Aerosol immunization with influenza matrix, nucleoprotein, or both prevents lung disease in pig.

Vatzia E, Paudyal B, Dema B, Carr B, Sedaghat-Rostami E, Gubbins S NPJ Vaccines. 2024; 9(1):188.

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The delivery device of SARS-CoV-2 mucosal vaccine matters.

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Single-cell analysis reveals lasting immunological consequences of influenza infection and respiratory immunization in the pig lung.

Muir A, Paudyal B, Schmidt S, Sedaghat-Rostami E, Chakravarti S, Villanueva-Hernandez S PLoS Pathog. 2024; 20(7):e1011910.

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References

Hodge L, Simecka J . Role of upper and lower respiratory tract immunity in resistance to Mycoplasma respiratory disease. J Infect Dis. 2002; 186(2):290-4. DOI: 10.1086/341280. View

Tannock G, Paul J, BARRY R . Relative immunogenicity of the cold-adapted influenza virus A/Ann Arbor/6/60 (A/AA/6/60-ca), recombinants of A/AA/6/60-ca, and parental strains with similar surface antigens. Infect Immun. 1984; 43(2):457-62. PMC: 264316. DOI: 10.1128/iai.43.2.457-462.1984. View

Dugernier J, Hesse M, Vanbever R, Depoortere V, Roeseler J, Michotte J . SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized Cross-over Study. Pharm Res. 2016; 34(2):290-300. DOI: 10.1007/s11095-016-2061-7. View

Beverley P, Sridhar S, Lalvani A, Tchilian E . Harnessing local and systemic immunity for vaccines against tuberculosis. Mucosal Immunol. 2013; 7(1):20-6. DOI: 10.1038/mi.2013.99. View

Canini L, Holzer B, Morgan S, Hemmink J, Clark B, Woolhouse M . Timelines of infection and transmission dynamics of H1N1pdm09 in swine. PLoS Pathog. 2020; 16(7):e1008628. PMC: 7446876. DOI: 10.1371/journal.ppat.1008628. View

Steinert E, Schenkel J, Fraser K, Beura L, Manlove L, Igyarto B . Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance. Cell. 2015; 161(4):737-49. PMC: 4426972. DOI: 10.1016/j.cell.2015.03.031. View

Newman S, Fleming J . Challenges in assessing regional distribution of inhaled drug in the human lungs. Expert Opin Drug Deliv. 2011; 8(7):841-55. DOI: 10.1517/17425247.2011.577063. View

Masopust D, Picker L . Hidden memories: frontline memory T cells and early pathogen interception. J Immunol. 2012; 188(12):5811-7. PMC: 3375618. DOI: 10.4049/jimmunol.1102695. View

Jiang X, Clark R, Liu L, Wagers A, Fuhlbrigge R, Kupper T . Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature. 2012; 483(7388):227-31. PMC: 3437663. DOI: 10.1038/nature10851. View

10.

Masic A, Pyo H, Babiuk S, Zhou Y . An eight-segment swine influenza virus harboring H1 and H3 hemagglutinins is attenuated and protective against H1N1 and H3N2 subtypes in pigs. J Virol. 2013; 87(18):10114-25. PMC: 3753983. DOI: 10.1128/JVI.01348-13. View

11.

Turner D, Farber D . Mucosal resident memory CD4 T cells in protection and immunopathology. Front Immunol. 2014; 5:331. PMC: 4094908. DOI: 10.3389/fimmu.2014.00331. View

12.

de Swart R, de Vries R, Rennick L, van Amerongen G, McQuaid S, Verburgh R . Needle-free delivery of measles virus vaccine to the lower respiratory tract of non-human primates elicits optimal immunity and protection. NPJ Vaccines. 2017; 2:22. PMC: 5627256. DOI: 10.1038/s41541-017-0022-8. View

13.

Wu T, Hu Y, Lee Y, Bouchard K, Benechet A, Khanna K . Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J Leukoc Biol. 2013; 95(2):215-24. PMC: 3896663. DOI: 10.1189/jlb.0313180. View

14.

Baz M, Boonnak K, Paskel M, Santos C, Powell T, Townsend A . Nonreplicating influenza A virus vaccines confer broad protection against lethal challenge. mBio. 2015; 6(5):e01487-15. PMC: 4620468. DOI: 10.1128/mBio.01487-15. View

15.

Bolton D, Song K, Tomaras G, Rao S, Roederer M . Unique cellular and humoral immunogenicity profiles generated by aerosol, intranasal, or parenteral vaccination in rhesus macaques. Vaccine. 2017; 35(4):639-646. PMC: 5241230. DOI: 10.1016/j.vaccine.2016.12.008. View

16.

Hemmink J, Morgan S, Aramouni M, Everett H, Salguero F, Canini L . Distinct immune responses and virus shedding in pigs following aerosol, intra-nasal and contact infection with pandemic swine influenza A virus, A(H1N1)09. Vet Res. 2016; 47(1):103. PMC: 5073419. DOI: 10.1186/s13567-016-0390-5. View

17.

Snyder M, Finlayson M, Connors T, Dogra P, Senda T, Bush E . Generation and persistence of human tissue-resident memory T cells in lung transplantation. Sci Immunol. 2019; 4(33). PMC: 6435356. DOI: 10.1126/sciimmunol.aav5581. View

18.

de Bree G, van Leeuwen E, Out T, Jansen H, Jonkers R, van Lier R . Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung. J Exp Med. 2005; 202(10):1433-42. PMC: 2212987. DOI: 10.1084/jem.20051365. View

19.

Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M . Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020; 369(6499):77-81. PMC: 7202686. DOI: 10.1126/science.abc1932. View

20.

Djupesland P, Skretting A . Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump. J Aerosol Med Pulm Drug Deliv. 2012; 25(5):280-9. DOI: 10.1089/jamp.2011.0924. View