A new adenovirus based vaccine vector expressing an Eimeria tenella derived TLR agonist improves cellular immune responses to an antigenic target.
BACKGROUND
Adenoviral based vectors remain promising vaccine platforms for use against numerous pathogens, including HIV. Recent vaccine trials utilizing Adenovirus based vaccines expressing HIV antigens confirmed induction of cellular immune responses, but these responses failed to prevent HIV infections in vaccinees. This illustrates the need to develop vaccine formulations capable of generating more potent T-cell responses to HIV antigens, such as HIV-Gag, since robust immune responses to this antigen correlate with improved outcomes in long-term non-progressor HIV infected individuals.


RESULTS
In this study we designed a novel vaccine strategy utilizing an Ad-based vector expressing a potent TLR agonist derived from Eimeria tenella as an adjuvant to improve immune responses from a [E1-]Ad-based HIV-Gag vaccine. Our results confirm that expression of rEA elicits significantly increased TLR mediated innate immune responses as measured by the influx of plasma cytokines and chemokines, and activation of innate immune responding cells. Furthermore, our data show that the quantity and quality of HIV-Gag specific CD8(+) and CD8(-) T-cell responses were significantly improved when coupled with rEA expression. These responses also correlated with a significantly increased number of HIV-Gag derived epitopes being recognized by host T cells. Finally, functional assays confirmed that rEA expression significantly improved antigen specific CTL responses, in vivo. Moreover, we show that these improved responses were dependent upon improved TLR pathway interactions.


CONCLUSIONS
The data presented in this study illustrate the potential utility of Ad-based vectors expressing TLR agonists to improve clinical outcomes dependent upon induction of robust, antigen specific immune responses.
Appledorn
Daniel M
DM
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America.
Aldhamen
Yasser A
YA
Depas
William
W
Seregin
Sergey S
SS
Liu
Chyong-Jy J
CJ
Schuldt
Nathan
N
Quach
Darin
D
Quiroga
Dionisia
D
Godbehere
Sarah
S
Zlatkin
Igor
I
Kim
Sungjin
S
McCormick
J Justin
JJ
Amalfitano
Andrea
A
D016915:AIDS Vaccines / Q000737:chemistry; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016786:Eimeria tenella / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005822:Genetic Vectors; D015488:HIV Antigens / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016366:Open Reading Frames; D000091402:Prohibitins; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
D016915:AIDS Vaccines; D015488:HIV Antigens; C000717331:PHB2 protein, human; D000091402:Prohibitins; D051193:Toll-Like Receptors; D054301:gag Gene Products, Human Immunodeficiency Virus