Summary
Gonorrhoea is a sexually transmitted infection which can cause severe disease, including pelvic inflammatory disease, ectopic pregnancy and infertility in women. It disproportionally affects women in low- and middle-income countries. Increasing antibiotic resistance among isolates threatens a global public health catastrophe.
We are currently developing a vaccine candidate against gonorrhoea consisting of bacterial surface blebs known as native outer membrane vesicles (NOMVs) ready for clinical trials. With the proposed project, we aim to improve our NOMVs by genetically modifying the strain of gonococcus used to produce them in two ways and thereby improve levels of possible protection.
First, we will perform targeted deletion of the Rmp surface protein which is thought to be the focus of non-protective immune responses, to prevent the development of unhelpful immunity. Second, we will stabilise the production of lipo-oligosaccharide O-antigen surface sugars thought to be the target of protective immune responses, to increase protective immunity.
The new strains will be tested for their fitness and ability to produce NOMVs. Purified NOMVs will be characterised in a series of lab tests and used to test vaccinate mice. The antibodies produced through immunisation will be assessed for their ability to bind and kill a range of representative global gonococcal strains. At the end of the study, further support will be applied for to test the ability of promising new NOMVs to increase clearance of gonococcal infection in an animal model.
Project Outcomes:
The project objectives were to develop novel vaccines against gonorrhoea based on native outer membrane vesicles (NOMVs), which are naturally released from some bacteria. Not much is known about the antigens involved in protection against gonorrhoea. 2C7 is a specific part of the bacteria causing gonorrhoea, and antibodies against 2C7 can protect against gonorrhoea infection in a mouse model. The expression of 2C7 is not stable in gonorrhoea. We successfully introduced mutations into gonorrhoea bacteria which stabilised the presence of 2C7. We demonstrated that 2C7 was indeed stabilised, and from these mutants, we were able to produce vaccine candidate NOMVs, and evaluate their ability to generate an immune response in a mouse model.
Gonorrhoea also expresses a protein called Rmp, which acts as a decoy for the bacteria by stimulating antibodies in infected people that block the function of protective antibodies against gonorrhoea. It may be beneficial to avoid having Rmp in the vaccine candidates. We successfully mutated the gene rmp, and were able to obtain seven new mutants with rmp mutated in different ways. We produced the resulting vaccine candidates, and investigated their capacity to induce immune responses in mice. The sera from these mice were tested for antibody quantity and quality.
Dr Thomas Belcher
Post-doctoral Scientist
University of Oxford, UK
Collaborators:
Professor Calman MacLennan, Professor of Vaccine Immunology, University of Oxford, UK
Professor Peter Beernink, Associate Professor in Residence, University of California San Francisco, USA
Professor Lisa Lewis, Associate Professor, UMass Chan Medical School, USA
Professor Christine Rollier, Professor of Vaccinology, University of Surrey, UK
Professor Magnus Unemo, Professor and Director, WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Sweden
Professor Andrew Gorringe, Professor UK Health Security Agency, UK
Dr Seanette Wilson, Senior Project Manager, Biovac Institute, South Africa