The challenge: to develop good and cheap phage-based vaccines against animal diseases at scale required for mass vaccination of agricultural animals.
Bacteriophages are the most abundant biological entity on the planet, with 1031 in the biosphere. Despite being a natural part of the human microbiome, naturally occurring bacteriophages are known to induce adaptive immune responses. It is this natural response that we plan to exploit to use phages as a vaccine. Furthermore, phages are very cheap to produce in large quantities. There is a large diversity of phage types, with several having been previously used for vaccine applications, including phages T4, M13, MS2, and T7[1]. We will utilise phage T7, which has previously been used to develop vaccines against viruses causing influenza, Foot & mouth disease and mononucleosis. In all cases vaccination with recombinant T7 displaying antigens from the pathogenic viruses has resulted in the production of neutralising antibodies [1].
It is well established that proteins can be displayed on the capsid of T7 by fusing the antigen to the minor capsid protein of T7 (10B). By displaying on the capsid head in a repetitive and organised manor (as a result of the structure of the capsid) a higher immunogenicity of foreign antigens to B cells is thought to occur. A limiting factor in the modification of the capsid head is the ability to rapidly alter and engineer the genome of T7 to display these antigens. We are uniquely positioned to do this after having now optimised the ability to rapidly engineer the genome of phage T7 [2]. Possible disadvantages of using phages as vaccines are the introduction of a biological entity that can potentially replicate uncontrollably, if it finds a suitable E. coli host and phages do not always have strong adjuvant characteristics.
Proposed Work:
Objective 1: Produce a non-replicate version of phage T7 with the DNA polymerase replaced by a large CpG island
Objective 2: Engineer the non-replicative, strong adjuvant form of T7 with (in first instance) fragments of structural antigens from the MDV virus, a causative agent of Marek’s disease, expressed on the capsid and perform preliminary characterisation of the phage and levels of MDV’s peptides exposed on its surface. Normally ~45 10B subunits are incorporated on the capsid, so similar number of MDV’s peptides would be expected to be displayed.
Objective 3. To assess safety, immunogenicity and protectivity of the T7 MDV vaccine prototype in vitro and relevant animal systems.
We have already produced non-replicative forms of T7 by alteration of the tail fibres and can easily adjust this to remove the T7 DNA-polymerase. We will introduce a large CpG island into the carrier phage genome as it is known CpG islands can act as adjuvants that are known to boost the immune response [3].We will then construct a non-replicative adjuvant version T7 phage with multiple copies of peptides from the MDV displayed on its capsid.
Objective 4. Develop a suite of plasmids that rapidly allows different antigens to be displayed in multiple combinations on phage T7.
Potential Impact:
Unlike most of subunit vaccines, a phage-based vaccine will be stable and very cheap to manufacture, and the technology easily transferable to multiple users. It will use a highly stable carrier base and will not require adjuvant. It will be likely recognised by the immune system as a “virus” thus eliciting broad humoral and cellular immune responses that are essential for protectivity.
Entry requirements:
• Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.
• Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.
• Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.
• Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.
• Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above
• University English language requirementsapply. https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs/ielts-65
For further information please contact [Email Address Removed]
Application advice:
To apply please refer the application instructions at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
You will need to apply for the PhD place and also submit your online application notification to MIBTP. Links for both are on the above web page.
Project / Funding Enquiries: For further information please contact [Email Address Removed]
Application enquiries to [Email Address Removed]
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