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Selection and evaluation of new universal influenza vaccine candidates using monoclonal antibodies and digitally designed HA and NA libraries & pseudotype virus screens


Medway School of Pharmacy

Canterbury United Kingdom Bioinformatics Epidemiology Immunology Microbiology Molecular Biology Structural Biology Virology

About the Project

Universal influenza vaccines are a major global R&D vaccine priority. The Temperton (ORCID: https://orcid.org/0000-0002-7978-3815) lab at Kent is currently funded by the Bill & Melinda Gates Foundation and Innovate UK (in partnership with the University of Cambridge and spin-out vaccine company DIOSynVax) to develop universal vaccine candidates for Influenza A and B viruses. The vaccine platform being used is based on computationally designed synthetic antigens downselected by highly sensitive pseudotype virus screens (https://diosvax.com/technology).

Pseudotype neutralisation assays for influenza have been shown by us to be exquisitely sensitive for the measurement of functional antibody responses to the surface HA glycoprotein head and stalk, the latter being one of the primary targets of many new ‘universal influenza vaccine’ approaches.

The antibody responses directed against the HA stalk can be separated from those against the more antigenically variable head by making use of a chimeric HA pseudotype assay. One such chimeric pseudotype virus that has been created in our lab has an HA stalk (Group 1) derived from the 2009 pandemic H1N1 strain, and an HA globular head derived from an H11 strain which is found in wild birds. Humans have negligible serological reactivity to H11, so if a neutralisation assay is undertaken with this hybrid HA pseudotype, one can readily measure the response directed against the HA stalk only. The traditional HI assay (for which a correlate of immunity exists) used by the regulators only measures responses against the globular HA head and thus is not fit for purpose for the licensing of many new ‘universal vaccines’. HA stalk serological assays, such as those based on pseudotypes or HA2 ELISA, have gained prominence as many of these new vaccines move down the clinical pipeline.

For neuraminidase (NA) another essential universal vaccine target, we have developed a pseudotype-based enzyme-linked lectin assay (PV-ELLA) for N1, which allows the quantification of antibody responses against NA. This assay innovatively uses NA-only pseudotypes as a source of NA. The availability of this PV-ELLA to the R&D community is instrumental as it means that ELLA assays can be performed without requiring access to reverse genetic (RG) viruses, which often have IP attached. Also, there are moves towards standardising the amount of NA in next generation vaccines, making PV-ELLA assays increasingly important for influenza vaccine R&D.

The student will;

1. Construct a comprehensive library of HA pseudotypes spanning all 18 subtypes of influenza. This will be a world-class resource for seasonal, pandemic and universal influenza vaccine immunogenicity studies.
2. Construct a chimeric HA pseudotype (in silico followed by molecular cloning) with a Group 2 influenza A stalk and an influenza B stalk such that full coverage of stalk-centric cross-reactive immunity can be studied.
3. Construct a complete panel of NA pseudotypes that allow maximum coverage of circulating types and integrate these into PV-ELLA assays.
4. Use these pseudotype HA and NA assay platforms in parallel with ELISA and FACS to identify and characterise the most broadly neutralising monoclonal antibodies from available panels including mouse, human and nanobodies.
5. After immunisation experiments (Cambridge) with the most cross-reactive sequences identified above, identify potential antigens to be incorporated into universal vaccine designs.

This is a cutting-edge research project where you will be part of a highly dynamic team of virologists, immunologists and bioinformaticians at Kent, Cambridge and Regensburg (Germany). Both the Kent lab and the consortium partner labs are very well resourced and staffed giving PhD students all opportunities to flourish academically and professionally in a blended academic/industrial environment.

Entry requirements:

Applicants should have or expect to obtain a first or upper second class honours degree (or equivalent) in an appropriate subject and a Masters (at Merit or above) in Pharmaceutical Science or closely related subject.

How to Apply:

To apply please go to https://msp.ac.uk/postgraduate/?course_id=785&course_level=postgraduate

You will need to apply through the online application form on the main University website. Please note that you will be expected to provide personal details, education and employment history and supporting documentation (curriculum vitae, transcript of results, two academic

We welcome applications from people with disabilities and Black, Asian and Minority Ethnic (BAME) backgrounds.

Funding Notes

This project is a self-funded opportunity available to both Home/EU and International students.

Applicant must have access to funding to cover tuition fees, living costs and any related project costs (i.e. bench fees).

References

Science (2012) doi:10.1126/science.1205669.

Nature Communications (2019) doi:10.1038/s41467-018-06228-8

Frontiers in Immunology (2020) doi:10.3389/fimmu.2020.00627

TEMPERTON research portfolio: https://europepmc.org/search?query=temperton%20n

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