Polysorbitol Transporter as Novel Vaccine Carrier and Adjuvant Elicits Prolonged Antibody Response

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Cheol-Heui YUN
농업생명과학대학 농생명공학부
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서울대학교 대학원
학위논문 (박사)-- 서울대학교 대학원 : 농생명공학부, 2015. 2. 윤철희.
Effective delivery together with the action of adjuvant is essential for enhanced, long lasting and protective efficacy of the vaccine. Thus, the interest to develop such strategy (i.e., delivery tools and adjuvants) for the vaccination is getting a great attention in the public as well as private sectors. In the present study, I evaluated polysorbitol transporter (PST), a polysaccharide-based polymer as a delivery system and an adjuvant in terms of the induction of long-lasting antigen-specific antibody response.
In the first approach, I demonstrated PST for its application as both a potential adjuvant system and polymeric delivery tool for respiratory syncytial virus (RSV) glycoprotein antigen. RSV is one of the most common causes of viral deaths in infants worldwide, yet there are no effective vaccines available. PST is prepared from sorbitol diacrylate and low molecular weight polyethylenimine (PEI). Unlike PEI and the pre-existing experimental mucosal adjuvant, cholera toxin (CT), PST showed no toxicity in vitro and in vivo. The osmotically active PST formed nano-sized complexes with RGp by simple mixing, retained the antigenic stability and exhibited negative surface charges made them highly effective for the activation of phagocytic cells and enhancement of phagocytosis-mediated uptake. This resulted in an improved cytokine expression and the significant augmentation of RGp-specific antibody production with long-term persistency over 200 days. Interestingly, PST/RGp enhanced phagocytic cell-mediated uptake owing to the osmotic property of PST and negative zeta potential, suggesting that PST could specifically stimulate phagocytic cells for long-lived antigen-specific immune response, where the polysaccharide properties of PST might also play a role in the induction of prolonged memory response.
In the second approach, I have investigated a mechanism on PST-mediated long-lasting antibody response using a model protein, ovalbumin (OVA). The result showed that PST/OVA targeted mainly APCs and mostly the B cells in mediastinal lymph node (MdLN) after intranasal delivery. As secondary lymphoid organ, this draining lymph node is providing a site for iNKT cell activation at germinal center in response to higher number of CD1d expressed cells specially macrophage, dendritic cells, B cells and neutrophils. Interestingly, a significant number of CD1d+ cells were also found OVA positive i.e. antigen specific.
In the third approach, the existence of OVA-specific antibody secreting cells were investigated thoroughly in bone marrow, lung, spleen, MdLN and other lymph nodes Interestingly, PST/OVA system showed persisted antibody response for a long period of time (over 90 days and up to 500 days after the last immunization) The results showed that PST continuously maintained OVA-specific plasma cells in MdLN as well as in bone marrow from days 7 to 90 after the last immunization. OVA-specific germinal center B cells were also appeared in the MdLN from soon after the last immunization throughout the experimental period. On the other hand, the germinal center B cells showed a significantly increased number and characteristic of antigen specific plasma cells at days 60 and 90 after the last immunization in MdLN of PST/OVA-immunized mice upon OVA restimulation ex vivo. Furthermore, higher OVA-specific IgG was found in the supernatant in which they were cultured. Interestingly, in MdLN, potential OVA-specific B cells were maintained up to day 90 from the last immunization. It is worthy to mention that, PST exhibited long-term antigen-specific antibody response without showing any polymer-specific antibody response, which is particularly one of the necessary properties for vaccine delivery to improve the efficacy of antigen-specific immunity.
In conclusion, all of the results indicate that PST is a promising adjuvant and functional delivery material for vaccine, devoid of side effects, able to stimulate innate immune system and most importantly induces the long-lasting antibody response with some unique mechanisms, especially with CD1d-mediated iNKT cell activation.
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College of Agriculture and Life Sciences (농업생명과학대학)Dept. of Agricultural Biotechnology (농생명공학부)Theses (Ph.D. / Sc.D._농생명공학부)
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