Type 1 and 2 Immunity Following Vaccination Is Influenced by Nanoparticle Size: Formulation of a Model Vaccine for Respiratory Syncytial Virus
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- 作者：Patricia L. Mottram ; David Leong ; Blessing Crimeen-Irwin ; Simone Gloster ; Sue D. Xiang ; Jayesh Meanger ; Reena Ghildyal ; Nicholas Vardaxis ; Magdalena Plebanski
- 刊名：Molecular Pharmaceutics
- 出版年：2007
- 出版时间：February 2007
- 年：2007
- 卷：4
- 期：1
- 页码：73 - 84
- 全文大小：636K
- 年卷期：v.4,no.1(February 2007)
- ISSN：1543-8392
文摘
Previous studies compared uptake by dendritic cells (DC) of 20, 40, 100, 200, 500, 1000,and 2000 nm beads in vivo. When beads were used as antigen carriers, bead size influenced antibodyresponses and induction of IFN-
-producing CD4 and CD8 T cells. Beads of 40-50 nm were takenup preferentially by DC and induced particularly strong immunity. Herein, we examine immunity inducedby minute differences in nanobead size, specifically within a narrow viral-sized range (20, 40, 49, 67,93, 101, and 123 nm), to see if bead carrier size influenced the induction of type 1 or type 2 cells asdemonstrated by the production of IFN- or IL-4. In vivo uptake by DC was assessed for selectedsizes in this range. Responses to whole ovalbumin (OVA) or the OVA-derived CD8 T cell peptideepitope (SIINFEKL) were tested. After one immunization with beads-OVA, IFN- responses to bothOVA and SIINFEKL were significantly better with 40 and 49 nm beads than other sizes, while, incontrast, IL-4 responses to OVA were higher after immunization with OVA conjugated to larger beads(93, 101, and 123 nm). Thus IFN- induction from CD8 T cells was limited to 40-49 nm beads, whileCD4 T cell activation and IL-4 were induced by 93-123 nm beads-OVA. After two immunizations,there were comparable high levels of IFN- produced with 40 and 49 beads and IL-4 reactivity wasstill higher for larger beads (93, 101, 123 nm). Production of IgG1 was seen across the full range ofbead sizes, increasing after two immunizations. Since protection against respiratory syncytial virus(RSV) depends on strong IFN responses, while IL-4 responses are reported to cause asthma-likesymptoms, immunization with RSV antigens on the 49 nm carrier beads could provide the basis for asuitable vaccine. When the 49 nm beads were conjugated to RSV proteins G88 (surface) or M2.1(internal capsid), one immunization with G88 induced high levels of IFN- and low levels of IL-4. IL-4increased with two immunizations. Beads-M2.1 induced only moderate levels of IFN- and low titerantibody after two immunizations. Mice vaccinated once with G88-conjugated 49 nm beads andchallenged intranasally with RSV strain A2 subtype showed reduced viral titers and recovered fromweight loss more rapidly than mice immunized with M2.1-conjugated 49 nm beads or naive controlmice. These results show that precise selection of nanobead size for vaccination can influence thetype 1/type 2 cytokine balance after one immunization, and this will be useful in the development ofeffective vaccines against common human pathogens such as RSV.
-producing CD4 and CD8 T cells. Beads of 40-50 nm were takenup preferentially by DC and induced particularly strong immunity. Herein, we examine immunity inducedby minute differences in nanobead size, specifically within a narrow viral-sized range (20, 40, 49, 67,93, 101, and 123 nm), to see if bead carrier size influenced the induction of type 1 or type 2 cells asdemonstrated by the production of IFN- or IL-4. In vivo uptake by DC was assessed for selectedsizes in this range. Responses to whole ovalbumin (OVA) or the OVA-derived CD8 T cell peptideepitope (SIINFEKL) were tested. After one immunization with beads-OVA, IFN- responses to bothOVA and SIINFEKL were significantly better with 40 and 49 nm beads than other sizes, while, incontrast, IL-4 responses to OVA were higher after immunization with OVA conjugated to larger beads(93, 101, and 123 nm). Thus IFN- induction from CD8 T cells was limited to 40-49 nm beads, whileCD4 T cell activation and IL-4 were induced by 93-123 nm beads-OVA. After two immunizations,there were comparable high levels of IFN- produced with 40 and 49 beads and IL-4 reactivity wasstill higher for larger beads (93, 101, 123 nm). Production of IgG1 was seen across the full range ofbead sizes, increasing after two immunizations. Since protection against respiratory syncytial virus(RSV) depends on strong IFN responses, while IL-4 responses are reported to cause asthma-likesymptoms, immunization with RSV antigens on the 49 nm carrier beads could provide the basis for asuitable vaccine. When the 49 nm beads were conjugated to RSV proteins G88 (surface) or M2.1(internal capsid), one immunization with G88 induced high levels of IFN- and low levels of IL-4. IL-4increased with two immunizations. Beads-M2.1 induced only moderate levels of IFN- and low titerantibody after two immunizations. Mice vaccinated once with G88-conjugated 49 nm beads andchallenged intranasally with RSV strain A2 subtype showed reduced viral titers and recovered fromweight loss more rapidly than mice immunized with M2.1-conjugated 49 nm beads or naive controlmice. These results show that precise selection of nanobead size for vaccination can influence thetype 1/type 2 cytokine balance after one immunization, and this will be useful in the development ofeffective vaccines against common human pathogens such as RSV.