Preliminary studies on the identification of vaccinal mimotopes of bovine viral diarrhoea virus using combinatorial peptide libraries
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- Tez No: 400690
- Danışmanlar: DR. PETER H. RUSSEL
- Tez Türü: Doktora
- Konular: Patoloji, Pathology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2006
- Dil: İngilizce
- Üniversite: Unıversıty Of London
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Patoloji Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
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Özet (Çeviri)
Preliminary studies on the identification of vaccinal mimotopes of bovine viral diarrhoea virus using combinatorial peptide libraries Bovine Viral Diarrhoea Virus (BVDV) can cause acute fatal hemorrhagic disease and fatal mucosal disease. Neutralising antibodies that are directed to the major envelope glycoprotein of BDVD E2 are the main protective mediators for BVDV infections. The aim. of this study was to screen combinatorial peptide libraries with neutralising BVDV E2 monoclonal antibodies to facilitate the development of a mimotope-based marker vaccine against BVDV. In the first part of the present study, a range of neutralising BVDV E2 monoclonal antibodies (Wbl66, Wb214, WM63, and Wbl 58) was used to select binding ligands (peptides) by using a 15-mer phage-display library. Four peptides (Al-1, A2-1, A2-2, and A2-3) were selected with the mAbWbl66. However, they were not considered to be mimotopes because they did not compete with BVDV by a competitive-inhibition ELISA and a neutralisation-inhibition test with the selecting mAb. An 8-mer solid phase library was then screened to select binding ligands to neutralising mAbs (Wbl66 and Wb214). The peptide WM66-P1 selected by the mAb Wbl 66 showed a high sequence homology to the BVDV E2, whereas peptides selected by the mAb Wb214 did not. Since testing the reactivity of these peptides in a SPOT scan assay did not confirm their binding to the selector mAbs and the first peptide Wb214-Pl failed to induce cross-reactive antibodies to BVDV in mice, the planned immunisation of mice with more peptides was cancelled. The neutralizing mAb Wbl66 used for mimotope selection with both a 15-mer phage-display and an 8-mer solid phase libraries had high relative affinity to the BVDV. This -^s generated the idea that high antibody affinity could be problematic for mimotope selection in using phage libraries. In order to validate our methods and to show the effect of antibody affinity on mimotope selection, a low and a high affinity 2-4 Dinitrophenol (DNP) mAbs (DNP Pa47 and DNP Pa41) were tested by a range of linear and constrained types of phage-display libraries. The low affinity DNP mAb DNP Pa47 selected bound peptides on phage with each library whereas the high affinity mAb gave no result. The most antigenic 8-mer regions of two 15-mer potential mimotopes of DNP, DA15-1 and DAI 5-2, were mapped to either amino or to the carboxyl terminus using a SPOT scan assay. This implies that both flexible ends of mimotopes can be antigenic when displayed on phage. Thus, combinatorial libraries and a SPOT scan ELISA can be used for the selection of the immune reactive regions of mimotopes. A new BVDV E2 mAM57 that neutralised to a wide range of BVDV-1 isolates was then successfully used to select two 8-mer peptides from an 8-mer solid phase library. The reactivity of two 8-mer peptides (157A1 and 157A2) was then confirmed by a SPOT scan assay. Peptides selected by the mAbs (Wbl 66 and Wb214) had not bound to their selector mAbs in a similar assay (see above). Future work with the second set of 8-mer peptides 157A1 and 157A2 including competition assays and immunisation studies in mice was not possible within the time of this work. This study highlighted the importance of using a large range of combinatorial peptide libraries to select discontinuous neutralising epitopes on the E2 of BVDV. Novel aspects of this study were the use of phage-display peptide libraries to select DNP-specific mimotopes from low affinity DNP mAb and the use of an 8-mer solid phase library for selecting potential mimotopes of BVDV E2. In addition, the applicability of a SPOT scan assay for confirmation of the reactivity of the potential mimotopes was also shown.
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