| 1. |
- Grdic Eliasson, Dubravka, et al.
(författare)
-
A novel non-toxic combined CTA1-DD and ISCOMS adjuvant vector for effective mucosal immunization against influenza virus.
- 2011
-
Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 29:23, s. 3951-61
-
Tidskriftsartikel (refereegranskat)abstract
- Here we demonstrate that by using non-toxic fractions of saponin combined with CTA1-DD we can achieve a safe and above all highly efficacious mucosal adjuvant vector. We optimized the construction, tested the requirements for function and evaluated proof-of-concept in an influenza A virus challenge model. We demonstrated that the CTA1-3M2e-DD/ISCOMS vector provided 100% protection against mortality and greatly reduced morbidity in the mouse model. The immunogenicity of the vector was superior to other vaccine formulations using the ISCOM or CTA1-DD adjuvants alone. The versatility of the vector was best exemplified by the many options to insert, incorporate or admix vaccine antigens with the vector. Furthermore, the CTA1-3M2e-DD/ISCOMS could be kept 1 year at 4°C or as a freeze-dried powder without affecting immunogenicity or adjuvanticity of the vector. Strong serum IgG and mucosal IgA responses were elicited and CD4 T cell responses were greatly enhanced after intranasal administration of the combined vector. Together these findings hold promise for the combined vector as a mucosal vaccine against influenza virus infections including pandemic influenza. The CTA1-DD/ISCOMS technology represents a breakthrough in mucosal vaccine vector design which successfully combines immunomodulation and targeting in a safe and stable particulate formation.
|
|
| 2. |
- Helgeby, Anja, 1967, et al.
(författare)
-
The combined CTA1-DD/ISCOM adjuvant vector promotes priming of mucosal and systemic immunity to incorporated antigens by specific targeting of B cells.
- 2006
-
Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 176:6, s. 3697-706
-
Forskningsöversikt (refereegranskat)abstract
- The cholera toxin A1 (CTA1)-DD/QuilA-containing, immune-stimulating complex (ISCOM) vector is a rationally designed mucosal adjuvant that greatly potentiates humoral and cellular immune responses. It was developed to incorporate the distinctive properties of either adjuvant alone in a combination that exerted additive enhancing effects on mucosal immune responses. In this study we demonstrate that CTA1-DD and an unrelated Ag can be incorporated together into the ISCOM, resulting in greatly augmented immunogenicity of the Ag. To demonstrate its relevance for protection against infectious diseases, we tested the vector incorporating PR8 Ag from the influenza virus. After intranasal immunization we found that the immunogenicity of the PR8 proteins were significantly augmented by a mechanism that was enzyme dependent, because the presence of the enzymatically inactive CTA1R7K-DD mutant largely failed to enhance the response over that seen with ISCOMs alone. The combined vector was a highly effective enhancer of a broad range of immune responses, including specific serum Abs and balanced Th1 and Th2 CD4(+) T cell priming as well as a strong mucosal IgA response. Unlike unmodified ISCOMs, Ag incorporated into the combined vector could be presented by B cells in vitro and in vivo as well as by dendritic cells; it also accumulated in B cell follicles of draining lymph nodes when given s.c. and stimulated much enhanced germinal center reactions. Strikingly, the enhanced adjuvant activity of the combined vector was absent in B cell-deficient mice, supporting the idea that B cells are important for the adjuvant effects of the combined CTA1-DD/ISCOM vector.
|
|
| 3. |
- Helgeby, Anja, 1967
(författare)
-
The development of a new combined adjuvant vector for mucosal immunization CTA1-DD/ISCOM
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The CTA1-DD/ISCOMs vector is a rationally designed mucosal adjuvant that was developed to host the distinctive properties of either adjuvant alone or in a combination that hosted additive enhancing effects on mucosal immune responses. Here I demonstrate that CTA1-DD can be incorporated into the ISCOM with greatly augmented immunogenicity of both incorporated and admixed antigen. The combined vector was a highly effective enhancer of a broad range of immune responses including specific antibodies and CD4+ T cell immunity. In particular, mucosal specific IgA responses in the respiratory and the genital tracts were strongly augmented by the combined vector, a mechanism that was enzyme dependent since the presence of the enzymatically inactive CTA1R7K-DD component failed to enhance the response above that with ISCOMs alone. Antigen incorporated into the combined vector could be presented by B cells as well as dendritic cells (DC). I also found that B cells in the lymph node were indeed targeted by the combined vector, but not by ISCOMs alone. The CTA1-DD/ISCOMs vaccine vector combines properties from two distinctive adjuvant systems. The ISCOM targets DC while the CTA1-exerts ADP-ribosylating functions. Following subcutaneous injection the CTA1-DD/ISCOMs vector induced a substantial increase in the cellularity of the draining lymph node, which was particularly evident for B cells and even more for granulocytes. These effects were enzyme-dependent as the inactive mutant CTA1R7K-DD/ISCOMs did not elicit a similar pattern. Functional studies of highly enriched DC in vitro demonstrated that the combined vector was superior at stimulating pro-inflammatory cytokines and chemokines, notably IL-1β, MIP-1 and RANTES, compared with ISCOMs alone. These effects appeared not to be due to better binding/up-take of the combined vector in DC, rather they depended on an intact enzymatic activity of the CTA1-enzyme. These findings help explain which are the critical properties added by the CTA1-DD to the ISCOM adjuvant. In my final article I used an adoptive transfer system to investigate the specific induction of genital tract CD4+ T cells by using ovalbumin (OVA) as our model antigen. Transfer of OVA specific T cell receptor (TCR) transgenic CD4+ T cells to naïve normal mice allows for tracking these cells using a TCR-specific antibody, KJ.126, after immunizations with or without adjuvant vectors. I found that hormones play an important role in the priming of T cells, since estrogen-treated mice failed to respond and progesterone-treated mice greatly expanded their OVA-specific T cells following immunization. Progesterone treatment expanded the OVA-specific T cells in a dose dependent way in regional lymph nodes. I also investigated the role of local verses systemic immunization on activation of genital tract T cells and found that both vaginal and intranasal immunizations with cholera toxin conjugated to OVA (CT-OVA) strongly expanded KJ.126+ T cells in the draining lymph node (Para aortic lymph node). However, local immunization was significantly more effective and was also an absolute requirement to attract T cells to the genital tract mucosa. These results convincingly demonstrate that not only antibody responses, but also antigen-specific T cell responses are effectively primed and boosted by local genital tract immunizations.
|
|
