Giuseppe
Emeritus
Genetic immunization in the lung induces potent local and systemic immune responses (PNAS, abstract, edited)
[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/107/51/22213.short?rss=1">Genetic immunization in the lung induces potent local and systemic immune responses ? PNAS</cite>. Abstract, edited.]
Genetic immunization in the lung induces potent local and systemic immune responses
1. Kaimei Song a, 1, 2. Diane L. Bolton a,1, 3. Robert L. Wilson b,c, 4. Jeremy V. Camp b,c, 5. Saran Bao a, 6. Joseph J. Mattapallil d, 7. Leonore A. Herzenberg e, 8. Leonard A. Herzenberg e,2, 9. Charla A. Andrews a, 10. Jerald C. Sadoff f, 11. Jaap Goudsmit g, 12. Maria Grazia Pau g, 13. Robert A. Seder a, 14. Pamela A. Kozlowski b,c, 15. Gary J. Nabel a, 16. Mario Roederer a,1,2, and 17. Srinivas S. Rao a,1
Author Affiliations
1. a Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
2. b Gene Therapy Program and
3. c Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70803;
4. d Uniformed Services University for Health Sciences, Bethesda, MD 20814;
5. e Department of Genetics, Stanford University, Stanford, CA 94305;
6. f AERAS Global TB Foundation, Rockville, MD 20850; and
7. g Crucell Holland BV, Leiden, The Netherlands
1. Contributed by Leonard A. Herzenberg, October 20, 2010 (sent for review October 8, 2010)
2. ↵1K.S., D.L.B., M.R., and S.S.R contributed equally to this work.
Abstract
Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens.
* mucosal responses
* tuberculosis
* platform immunization
Footnotes
* 2 To whom correspondence may be addressed. E-mail: lenherz@darwin.stanford.edu or roederer@nih.gov.
* Author contributions: D.L.B., J.J.M., C.A.A., J.C.S., J.G., M.G.P., R.A.S., G.J.N., M.R., and S.S.R. designed research; K.S., D.L.B., R.L.W., J.V.C., S.B., J.J.M., P.A.K., and S.S.R. performed research; J.C.S., J.G., M.G.P., P.A.K., and M.R. contributed new reagents/analytic tools; K.S., D.L.B., J.J.M., P.A.K., and M.R. analyzed data; and K.S., D.L.B., Leonore A. Herzenberg, Leonard A. Herzenberg, C.A.A., M.R., and S.S.R. wrote the paper.
* Conflict of interest statement: A patent application for the use of aerosolized adenoviruses as a vaccine has been filed with S.S.R., C.A.A., G.J.N., and M.R. as inventors.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1015536108/-/DCSupplemental.
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[Source: Proc Natl Acad Sci USA, full text: <cite cite="http://www.pnas.org/content/107/51/22213.short?rss=1">Genetic immunization in the lung induces potent local and systemic immune responses ? PNAS</cite>. Abstract, edited.]
Genetic immunization in the lung induces potent local and systemic immune responses
1. Kaimei Song a, 1, 2. Diane L. Bolton a,1, 3. Robert L. Wilson b,c, 4. Jeremy V. Camp b,c, 5. Saran Bao a, 6. Joseph J. Mattapallil d, 7. Leonore A. Herzenberg e, 8. Leonard A. Herzenberg e,2, 9. Charla A. Andrews a, 10. Jerald C. Sadoff f, 11. Jaap Goudsmit g, 12. Maria Grazia Pau g, 13. Robert A. Seder a, 14. Pamela A. Kozlowski b,c, 15. Gary J. Nabel a, 16. Mario Roederer a,1,2, and 17. Srinivas S. Rao a,1
Author Affiliations
1. a Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
2. b Gene Therapy Program and
3. c Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70803;
4. d Uniformed Services University for Health Sciences, Bethesda, MD 20814;
5. e Department of Genetics, Stanford University, Stanford, CA 94305;
6. f AERAS Global TB Foundation, Rockville, MD 20850; and
7. g Crucell Holland BV, Leiden, The Netherlands
1. Contributed by Leonard A. Herzenberg, October 20, 2010 (sent for review October 8, 2010)
2. ↵1K.S., D.L.B., M.R., and S.S.R contributed equally to this work.
Abstract
Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens.
* mucosal responses
* tuberculosis
* platform immunization
Footnotes
* 2 To whom correspondence may be addressed. E-mail: lenherz@darwin.stanford.edu or roederer@nih.gov.
* Author contributions: D.L.B., J.J.M., C.A.A., J.C.S., J.G., M.G.P., R.A.S., G.J.N., M.R., and S.S.R. designed research; K.S., D.L.B., R.L.W., J.V.C., S.B., J.J.M., P.A.K., and S.S.R. performed research; J.C.S., J.G., M.G.P., P.A.K., and M.R. contributed new reagents/analytic tools; K.S., D.L.B., J.J.M., P.A.K., and M.R. analyzed data; and K.S., D.L.B., Leonore A. Herzenberg, Leonard A. Herzenberg, C.A.A., M.R., and S.S.R. wrote the paper.
* Conflict of interest statement: A patent application for the use of aerosolized adenoviruses as a vaccine has been filed with S.S.R., C.A.A., G.J.N., and M.R. as inventors.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1015536108/-/DCSupplemental.
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