A novel vaccine for broad protection against meningococcal disease: progression to phase I clinical trial

The aim of this project is to progress a novel vaccine against serogroup B meningococcal disease (MenB) to phase I clinical trial.
MenB disease is the leading infectious cause of death in children in the UK. Two vaccine candidates are under development or recently licensed, based on recombinant proteins and outer membrane vesicles. The recently licensed vaccine was not considered to be cost-effective for infant immunisation in one recent analysis, as it requires up to 4 injections, and the other one is being developed for use in adolescents only. Therefore both have serious limitations if protection is to be provided for the population at most risk: infants under one year of age. Ongoing development of alternative or improved vaccine candidates is therefore required to reduce the cost of vaccine production and delivery.
Our proposed solution is to use a novel vaccine platform to deliver a major meningococcal antigen-target to the immune system. This approach is new as the delivery platform has never been used before for inducing antibody responses against bacterial outer membrane proteins. The rational is that the novel vaccine delivery system induces both innate and adaptive immune responses in mammalian hosts, including robust IFN-gamma responses, thought to provide the ideal conditions for switching B cells to produce complement-fixing bactericidal antibody, unlike conventional unadjuvanted or aluminium-based adjuvanted vaccines. We have already demonstrated in pre-clinical models that a single dose of this vaccine candidate induces strong and rapid functional antibody responses including high serum bactericidal antibody titres. The next step of the development plan is thus to progress this promising vaccine candidate into a phase I clinical trial.

The aim of this project is to progress a novel vaccine against serogroup B meningococcal disease (MenB) to Phase I clinical trial.
The need we are addressing is prevention of MenB disease, the leading infectious cause of death in children in the UK. Two vaccine candidates are under development or recently licensed, based on recombinant proteins and outer membrane vesicles. The recently licensed vaccine may be not cost-effective as it requires up to 4 injections, and the other one was developed for adolescents only. Therefore both have serious limitations in the goal of cost-effective protection of the population at most risk, who are infants under one year of age. Ongoing development of alternative vaccine candidates is therefore required.
Our proposed solution is to use a vectored delivery platform expressing a major meningococcus antigen target. A vector which induces both innate and adaptive immune responses in mammalian hosts, including concomitant induction of robust IFN-gamma responses, could provide the ideal conditions for switching B cells to produce complement-fixing bactericidal antibody, unlike conventional unadjuvanted or aluminium-based adjuvanted vaccines. A single dose of such a vectored vaccine has been shown to induce strong and functional antibody responses. A vectored vaccine is also a versatile platform that allows rapid adaptation to changing epidemiology.
We have already demonstrated in pre-clinical models that the approach is feasible with a conserved antigen: a single dose induces a strong, functional and long-lived antibody responses, far exceeding those obtained with conventional outer membrane vesicle-based vaccines. Our development plan is now to progress this vaccine candidate to a Phase I clinical trial. We propose taking an optimized vectored vaccine, designed to induce broad protection against heterologous strain and suitable for human use, to GMP manufacture and obtain regulatory and ethical approval to carry out a phase I trial

The objective of this project is to assess the safety and immunogenicity of a novel vaccine against MenB, and both academic and non-academic beneficiaries are expected from this research.

Academic Impact: The proposed project is an investigation of a novel method delivery of transmembrane bacterial protein antigens and will provide data on the validity of the delivery system and immunological mechanisms in addition to specific information about the utility of this approach as a meningococcal vaccine. Beyond meningococcal vaccines, the development and use of such a delivery system creates the know-how for similar approaches to be used by those working on other infections and improvements in vaccine formulation. The project will open new research avenues on vaccines against bacterial infections, identifying new leads, demonstrating a unique preventive approach.

This project could also contribute to the identification of the supporting T-cell environment necessary for the immune system to induce functional bactericidal antibodies against MenB. This information would benefit research groups working on development of vaccines against MenB based on other types of formulations (OMVs, recombinant proteins).

The project will also serve as a training platform for a researcher aiming at vaccine development. An early career research scientist working on this project would become an expert in vectored vaccine technology for bacterial proteins, vaccine-related immunology and animal models and, thus, could lead his/her way to novel vaccine research.

Economic impact: This work could be used to accelerate development of new vaccines by providing a delivery system for other bacterial antigens. Such data could lead to funding by research councils and medical charities for further development of bacterial vaccines and may be of interest to major vaccine manufacturers. It is highly likely that this proposal will generate new data that will lead to further research investment from industry in addition to academic funders. In addition, insight into the T-cell responses required to support efficient induction of bactericidal antibodies could provide indications into the adjuvant qualities needed in vaccine formulations to support adequate functional antibody responses.

Maximising potential impacts:
Exploitation: The investment from funding in this proposal will build on research skills and infrastructure that has been developed in meningococcal and vectored studies in Oxford and build capacity in vaccinology and experimental medicine. There are potential innovations if novel vaccine constructs are developed through the approaches used in this application and commercial exploitation would be pursued by the University's innovation department ISIS innovation as appropriate.

Future research: The samples collected in this trial are a unique resource not readily replicated. For this reason we have established a biobank at the Oxford vaccine Centre for curation of serum and genetic samples. We have an established process for sharing of data and clinical material that protects the integrity of the samples/data and includes removal of all personal identifiers which are retained only at the clinical study site.

End-users: Should the approach be successful, it will still take up to 10 years before such a vaccine reaches licensure, but the ultimate beneficiaries of this research are the children and people who each year lose life, quality of life and health as a consequence of MenB infection in the UK, but also for the thousands cases and deaths around the world, as MenB outbreaks happen in many countries, irrespective of their socio-economic status.