Enhancing DNA vaccination by sequential injection of lymph nodes with plasmid vectors and peptides.
DNA vaccines or peptides are capable of inducing specific immunity; however, their translation to the clinic has generally been problematic, primarily due to the reduced magnitude of immune response and poor pharmacokinetics. Herein, we demonstrate that a novel immunization strategy, encompassing sequential exposure of the lymph node milieu to plasmid and peptide in a heterologous prime-boost fashion, results in considerable MHC class I-restricted immunity in mice. Plasmid-primed antigen expression was essential for the generation of a population of central memory T cells, expressing CD62L and low in PD-1, with substantial capability to expand and differentiate to peripheral memory and effector cells, following subsequent exposure to peptide. These vaccine-induced T cells dominated the T cell repertoire, were able to produce large amounts of chemokines and pro-inflammatory cytokines, and recognized tumor cells effectively. In addition to outlining a feasible and effective method to transform plasmid DNA vaccination into a potentially viable immunotherapeutic approach for cancer, this study sheds light on the mechanism of heterologous prime-boost and the considerable heterogeneity of MHC class I-restricted T cell responses.
Division of Translational Medicine, MannKind Corporation, 28903 North Avenue Paine, Valencia, CA 91355, USA.
Kent A
KA
Smith
Victor L
VL
Tam
Raymond M
RM
Wong
Robb R
RR
Pagarigan
Brenna L
BL
Meisenburg
Diljeet K
DK
Joea
Xiping
X
Liu
Christiana
C
Sanders
David
D
Diamond
Thomas M
TM
Kündig
Zhiyong
Z
Qiu
Adrian
A
Bot
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory; D008168:Lung / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology
D019496:Cancer Vaccines; D016207:Cytokines; D019444:Vaccines, DNA; D022223:Vaccines, Subunit