2024-25 Project (Groppelli & Ma)

Development of a novel and affordable vaccine against hepatitis A virus

SUPERVISORY TEAM

Supervisor

Dr Elisabetta Groppelli at SGUL
Email: e.groppelli@sgul.ac.uk

Co-Supervisor

Professor Julian Ma at SGUL
Email: jma@sgul.ac.uk

PROJECT SUMMARY

Project Summary

The project aims to develop a novel and affordable Hepatis A Virus vaccine to be deployed globally and strongly contribute to the WHO Global Health Sector Strategies 2022-2030 that promote the end of epidemics of viral hepatitis by 2030.   

The novel HAV vaccine is based on virus-like particles that  are structurally identical to the virus, but because they do not contain any genome, they are not infectious. Crucially, HAV VLPs are generated independently of the infectious virus, so are not affected by the low-yield and high costs of the current inactivated vaccines. Initially, HAV VLPs are developed in a mammalian system, the natural environment of the virus. Then, focus will shift to a high-yield low-cost plant system. The project relies on molecular biology, virus-like-particle expression and purification and immunoassays.

Project Key Words

vaccine development; virus-like-particles; viral hepatitis; molecular pharming

MRC LID Themes

  • Global Health = Yes
  • Health Data Science = No
  • Infectious Disease = Yes
  • Translational and Implementation Research = Yes

Skills

MRC Core Skills

  • Quantitative skills = Yes
  • Interdisciplinary skills = Yes
  • Whole organism physiology = No

Skills we expect a student to develop/acquire whilst pursuing this project

1. Laboratory: Molecular virology, Virus-Like-Particle expression, immunoassays 
2. Research: project design and delivery 
3. Research data presentation (written and oral)

Routes

Which route/s is this project available for?

  • 1+4 = Yes
  • +4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

  • SGUL – MRes Biomedical Science – Infection and Immunity

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? No

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

  • SGUL’s standard institutional eligibility criteria for doctoral study.
  • MRes in a relevant discipline would be advantageous

Other useful information

  • Potential CASE conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

Background 
The WHO Global Health Sector Strategies 2022-2030 promote the end of epidemics of viral hepatitis by 2030. This ambitious goal reflects the crucial standing of viral hepatitis amongst global health challenges and relies on the right tools, including vaccines, to be developed and deployed.  Hepatitis A is caused by the Hepatitis A virus (HAV). The clinical manifestations include malaise, fatigue, anorexia, vomiting, abdominal discomfort, diarrhoea. HAV is a leading cause of fulminant hepatic failure that can be associated with up to 50% of all cases in children.  WHO estimates 40,000,000  to 100,000,000 cases globally yearly and ~ 80,000 deaths. HAV infection in adolescents and adults shows higher rate of severe clinical manifestations, with hospitalisation required. Although most cases are self-limiting, full recovery takes 3-6 months and relapses are frequent.        

HAV is mainly transmitted by the faecal/oral route, via ingestion of contaminated food or water. However, objects and direct contact between people (including during sexual intercourse) are becoming equally important. Crucially, climate change-induced flooding, water scarcity, water quality deterioration are increasing the burden of HAV globally.  

Currently, three inactivated vaccines are available but, despite WHO recommendations, they are not deployed globally due to their high price and stock shortages. In fact, manufacturing costs are high due to the slow growth of the virus in cell culture, its poor yield and the need for safety containment.   

Project objectives 
The project aims to develop an affordable HAV Virus-like particle vaccine. VLPs are structurally identical to the virus, but because they do not contain any genome, they are not infectious. Initially, the VLP design is tested in a mammalian system, the natural environment of the virus. Then, attention will focus to a high-yield plant system.    1. Mammalian system:   1.1 Expression of HAV structural proteins and assembly into VLP   1.2 Assessment of VLP antigenicity with ELISA and Cryo-EM   2. Plant system  2.1 VLP optimisation in N. benthamiana   2.2 Assessment of VLP antigenicity with ELISA and Cryo-EM   3. Assessment of VLP immunogenicity in an animal model      

Techniques  
1. Molecular biology: cloning; PCR; sequencing 
2. Mammalian system: cell culture, protein expression 
3. Plant system: growth of N. benthamiana, protein expression (Agrobacterium infiltration), Prof Julian Ma, SGUL 
4. Density gradients; Western Blotting; ELISA 
5. T-EM and Cryo-EM, in collaboration with Prof David Stuart, University of Oxford   

Confirmed availability of specialist materials 
The project stems from work led by Dr Elisabetta Groppelli (Medical Research Foundation funding) . Project resumed in late 2022 after the forced hiatus of the pandemic.
Reagents are available and validated; first generation expression constructs have been generated and provide evidence of HAV VLP expression.      

Potential risks and their mitigation. 
HAV is a mammalian virus and generation of VLPs in plants requires assessment. However, VLPs for Picornaviridae have been successfully generated.
HAV VLPs must show native antigenicity to be a valid vaccine candidate. It is anticipated that the unique structural stability of HAV will be transferred to its VLPs. However, should VLP structural stabilisation be required, mutagenesis will be assessed and informed by work on Picornaviridae.

Further reading

(Relevant preprints and/or open access articles)

Additional information from the supervisory team

  • The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.
    Groppelli-Ma Recording
  • DOI: 10.1038/s41467-017-00090-w  Plant-made polio type 3 stabilized VLPs-a candidate synthetic polio vaccine

MRC LID LINKS