A novel lipid nanoparticle adjuvant significantly enhances B cell and T cell responses to sub-unit vaccine antigens

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• 作者：Gokul Swaminathan^a ; Elizabeth A. Thoryk^a ; Kara S. Cox^a ; Steven Meschino^c ; Sheri A. Dubey^a ; Kalpit A. Vora^a ; Robert Celano^b ; Marian Gindy^b ; Danilo R. Casimiro^a ; Andrew J. Bett^a ; ^{andrew_bett@merck.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Lipid nanoparticle ; TLR9 agonist ; Adjuvant ; Subunit vaccine ; CD8 T cell response
• 刊名：Vaccine
• 出版年：2016
• 出版时间：2 January 2016
• 年：2016
• 卷：34
• 期：1
• 页码：110-119
• 全文大小：1439 K

文摘

Sub-unit vaccines are primarily designed to include antigens required to elicit protective immune responses and to be safer than whole-inactivated or live-attenuated vaccines. But their purity and inability to self-adjuvant often result in weaker immunogenicity. Emerging evidence suggests that bio-engineered nanoparticles can be used as immunomodulatory adjuvants. Therefore, in this study we explored the potential of novel Merck-proprietary lipid nanoparticle (LNP) formulations to enhance immune responses to sub-unit viral antigens. Immunization of BALB/c and C57BL/6 mice revealed that LNPs alone or in combination with a synthetic TLR9 agonist, immune-modulatory oligonucleotides, IMO-2125 (IMO), significantly enhanced immune responses to hepatitis B virus surface antigen (HBsAg) and ovalbumin (OVA). LNPs enhanced total B-cell responses to both antigens tested, to levels comparable to known vaccine adjuvants including aluminum based adjuvant, IMO alone and a TLR4 agonist, 3-O-deactytaled monophosphoryl lipid A (MPL). Investigation of the quality of B-cell responses demonstrated that the combination of LNP with IMO agonist elicited a stronger Th1-type response (based on the IgG2a:IgG1 ratio) than levels achieved with IMO alone. Furthermore, the LNP adjuvant significantly enhanced antigen specific cell-mediated immune responses. In ELISPOT assays, depletion of specific subsets of T cells revealed that the LNPs elicited potent antigen-specific CD4⁺ and CD8⁺T cell responses. Intracellular FACS analyses revealed that LNP and LNP + IMO formulated antigens led to higher frequency of antigen-specific IFNγ⁺TNFα⁺IL-2⁺, multi-functional CD8⁺T cell responses, than unadjuvanted vaccine or vaccine with IMO only. Overall, our results demonstrate that lipid nanoparticles can serve as future sub-unit vaccine adjuvants to boost both B-cell and T-cell responses in vivo, and that addition of IMO can be used to manipulate the quality of immune responses.