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作者 Greenland, John Richard
書名 Vaccine antigen expression and immune responses
說明 177 p
附註 Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 6873
Adviser: Norman Letvin
Thesis (Ph.D.)--Harvard University, 2006
Control of the HIV pandemic will require novel vaccination strategies. Although plasmid DNA immunization can elicit both cellular and humoral immune responses in experimental animals, these immunogens have often induced disappointing immune responses in human volunteers. Understanding the relationship between vaccine antigen expression and immunogenicity should facilitate the development of adjuvants for plasmid DNA immunogens and improve their clinical viability
We screened polymers from a library of beta-amino esters for their ability to augment plasmid DNA expression and cellular immune responses in vivo. Among the candidate polymers identified in this screen, poly [(1,6-di(acryloxyethoxy)-hexane)-co-(4-aminobutanol)] enhanced plasmid DNA transgene expression by seven-fold (p=0.0001) and its immunogenicity by seventy percent (p=0.03). We also observed a log-linear correlation (R 2=0.93) between peak cellular immune responses and transgene expression in all evaluated polymer-plasmid DNA formulations, clarifying the relationship between immunogenicity and the quantity of expressed antigen
A number of novel vaccination strategies are based the assumption that long-term, high-level antigen expression may be required for eliciting potent and durable immune responses. However, little is known about host factors that might restrict long-term vaccine antigen expression in vivo. We have demonstrated that vaccine antigen-elicited T lymphocytes limit vaccine antigen expression. This damping of vaccine antigen expression occurs coincident with the emergence of cellular immune responses, is associated with the presence of strong cellular immune responses, and is dependent on the Fas receptor
Finally, we have demonstrated that the innate immune system limits early antigen expression from plasmid DNA immunogens. Pretreatment of mice with plasmid GM-CSF decreases in vivo antigen expression from those vaccine constructs. This suppression is associated with the recruitment of innate immune cells to the site of inoculation and local increases in levels of certain cytokines, including IFNbeta. Coadministration of a monoclonal antibody that neutralizes IFNbeta activity with plasmid DNA immunogens relieves the cytokine-mediated suppression of plasmid DNA expression
In summary, adjuvants that augment antigen expression by plasmid DNA vaccine constructs can enhance their immunogenicity, while adaptive and innate immune responses can reduce vaccine antigen expression. A transient and selective inhibition of these immune responses may represent a novel approach for enhancing the potency of vaccines
School code: 0084
Host Item Dissertation Abstracts International 67-12B
主題 Biology, Microbiology
Health Sciences, Immunology
Alt Author Harvard University
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