Genetic immunization in the lung induces potent local and systemic immune responses.
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.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kaimei
K
Song
Diane L
DL
Bolton
Chih-Jen
CJ
Wei
Robert L
RL
Wilson
Jeremy V
JV
Camp
Saran
S
Bao
Joseph J
JJ
Mattapallil
Leonore A
LA
Herzenberg
Leonard A
LA
Herzenberg
Charla A
CA
Andrews
Jerald C
JC
Sadoff
Jaap
J
Goudsmit
Maria Grazia
MG
Pau
Robert A
RA
Seder
Pamela A
PA
Kozlowski
Gary J
GJ
Nabel
Mario
M
Roederer
Srinivas S
SS
Rao
D000256:Adenoviridae; D000281:Administration, Intranasal; D000336:Aerosols; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005289:Ferrets; D005822:Genetic Vectors / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000276:immunology; D007114:Immunization / Q000379:methods*; D007070:Immunoglobulin A / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology*; D008168:Lung; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*
D000336:Aerosols; D007070:Immunoglobulin A; D007074:Immunoglobulin G