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

Lead Research Organisation: University of Oxford
Department Name: Paediatrics

Abstract

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.

Technical Summary

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

Planned Impact

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.

Publications

10 25 50
 
Description -VaxCelerate: Development of a T Cell-Based Vaccine for Q Fever
Amount $163,000 (USD)
Organisation Massachusetts General Hospital 
Sector Hospitals
Country United States
Start 08/2018 
End 07/2019
 
Description Confidence in concept Oxford
Amount £45,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 06/2018
 
Description Development of a novel vaccine to protect against Q fever epidemics: late stage preclinical formulation and progression to clinical trial
Amount £1,000,000 (GBP)
Funding ID 971619 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 09/2018 
End 08/2020
 
Description Jenner Institute Investigator
Amount £3,000 (GBP)
Organisation University of Oxford 
Department Jenner Institute
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 12/2019
 
Description Jenner Institute Investigator
Amount £3,000 (GBP)
Organisation University of Oxford 
Department Jenner Institute
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 12/2018
 
Description Jenner Institute Investigator
Amount £3,000 (GBP)
Organisation University of Oxford 
Department Jenner Institute
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 12/2017
 
Description Jenner Institute Investigator
Amount £3,000 (GBP)
Organisation University of Oxford 
Department Jenner Institute
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2016
 
Description Jenner Institute Investigator
Amount £3,000 (GBP)
Organisation University of Oxford 
Department Jenner Institute
Sector Academic/University
Country United Kingdom
Start 01/2015 
End 12/2015
 
Description Jenner Investigator award
Amount £2,000 (GBP)
Organisation University of Oxford 
Department Jenner Institute
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 03/2020
 
Description SBRI
Amount £360,000 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2017
 
Description SBRI Vaccines against outbreak diseases
Amount £470,000 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 05/2017 
End 04/2018
 
Description SBRI Vaccines against outbreak diseases
Amount £3,000,000 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description UCSF
Amount £36,000 (GBP)
Organisation University of Oxford 
Department Oxford University Innovation
Sector Private
Country United Kingdom
Start 11/2017 
End 02/2019
 
Title Evaluation of in vitro antigen expression as a correlate of immunogenicity 
Description We have developed an in vitro assay intending to measure antigen expression achieved in cell lines after infection by viral vectored vaccine candidate, in order to replace some of the mouse immunogenicity studies. The number of vaccine candidate developed with modifications, for example of the promoter, signal sequences or vector backbone, is high, and implies that a lot of mice are used to compare the immunogenicity of these vaccines. We believe that this approach could be refined, by measuring the level of antigen expressed by each vaccine in mice and human cells. We hypothesise that the level of antigen expression is a main driver of immunogenicity (albeit not the only one). Therefore screening of new vectors can be performed in cells rather than in animal experiment, in particular in the case of comparing vector backbones, as this is more likely to influence immunogenicity in a specie-specific manner. Therefore screening in cells, in particular human cells rather than mouse is highly relevant. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2015 
Provided To Others? Yes  
Impact In our group this technology has allowed understanding of mechanisms driving antigen expression fro viral vaccine candidates, as well as selection of vectors with optimal antigen expression for further testing in in vivo experiments. 
 
Title T and B-cell responses to vaccines using small samples 
Description Method to detect several cytokines produced by T-cell against a target, or several types of B-cell responses, using limited cell numbers (Fluorospot) 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2018 
Provided To Others? No  
Impact Saving precious samples from clinical trials while obtaining more outcome measures 
 
Title adenovirus-based vaccine technology 
Description . Our adenovirus-based vaccine technology is the first vaccine to our knowledge that uses human cells as the expression system for an outer membrane protein from extracellular bacteria, using the adjuvant properties of a viral vector. This is innovative as bacterial outer membrane proteins might not be expected to fold properly or to undergo the correct post-translational modifications in a mammalian cell, and our findings with a MenB antigen are innovative and promising. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Progress to GMP for phase I study 
 
Description BP project 
Organisation National Institute for Biological Standards and Control (NIBSC)
Country United Kingdom 
Sector Public 
PI Contribution Concept, design and production of novel vaccine candidates against BP
Collaborator Contribution Expertise in measuring immune response to BP vaccines, and efficacy in models
Impact Application for joint D.Phil studentship
Start Year 2016
 
Description Collaboration for development of novel Q fever vaccine 
Organisation Massachusetts General Hospital
Country United States 
Sector Hospitals 
PI Contribution Exoertise in preclinical vaccine development, previous data demonstrating the suitability of the vaccine platform and expertise
Collaborator Contribution Antiegn design and funding to develop a novel vaccine candidate against Q fever
Impact Results are used for a grant application with DTRA to progress the vaccine candidate to clinical development
Start Year 2017
 
Description Collaboration for new B. pertussis vaccine development 
Organisation Radboud University Nijmegen Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Base on our experience, we propose a similar program of research into novel vaccine development against another bacterial specie (B. pertussis). WE are bringing the use of viral vector and expertise in preclinical vaccine development
Collaborator Contribution The partner is bringing his expertise in B. pertussis immunology and also a selection of potential antigen targets.
Impact We have established a CDA
Start Year 2019
 
Description Collaboration on vaccine development against Coxiella 
Organisation Massachusetts General Hospital
Country United States 
Sector Hospitals 
PI Contribution Expertise in vaccine development against bacterial species, and in preclinical vacinology
Collaborator Contribution The partner designed the project, obtained funding, designed novel antigen targets and leads the scientific development with multiple partners
Impact Too early in the research
Start Year 2018
 
Description Collaboration on vaccine development against another Neisseria specie 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Our experience in Neisseria meningitidis vaccine development and in working with a Neisseria specie in the laboratory (design, production, immunogenicity studies in animals and analysis of protective effect, outer membrane production)
Collaborator Contribution The partner Prof. C M designed and conceived a project, secrued funding and led further grant applications.
Impact Grant application to Bactivac, successful Grant application to Welcome trust, result pending
Start Year 2018
 
Description Improvement of antigen design 
Organisation Children's Hospital Oakland Research Institute (CHORI)
Country United States 
Sector Hospitals 
PI Contribution Confidential
Collaborator Contribution Confidential
Impact Confidential
Start Year 2014
 
Description Providing standards 
Organisation National Institute for Biological Standards and Control (NIBSC)
Country United Kingdom 
Sector Public 
PI Contribution Capacity and running of a clinical trial on meningococcal vaccines
Collaborator Contribution Proposed and support judicious addition to a clinical trial
Impact In progress, multi-disciplinary (immunology, assay development and standardisation)
Start Year 2017
 
Description Public health England for YP project 
Organisation Public Health England
Department Public Health England Porton Down
Country United Kingdom 
Sector Public 
PI Contribution Development of a novel vaccine based on the the expertise developed during this grant.
Collaborator Contribution Capacity to assess the functionality and efficacy of the vaccine candidate
Impact Funding obtained for clinical development of the new vaccine
Start Year 2017
 
Description Vector impact on innate T cells 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide vaccine candidates and models to address fundamental immunology questions
Collaborator Contribution Provide expertise in fundamental immunology of innate T cells in relation to a vaccine modality
Impact In progress
Start Year 2017
 
Title Investigating a new Vaccine against Meningitis B in Oxford (VAMBOX) 
Description This is a Phase I/IIa single-site dose-escalation clinical trial to test the safety and immunogenicity of a new vaccine against capsular group B meningococcal disease (MenB). It will be administered alone and following primary immunization with Bexsero, an existing licensed vaccine currently in the UK immunisation schedule for babies. We have started recruiting clinical trial volunteers and are in the process of screening our first participants. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Work in progress. 
URL http://trials.ovg.ox.ac.uk/trials/vambox
 
Description AIMday Antimicrobial resistance 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact A workshop where businesses proposed their research questions to experts, creating a discussion, brainstorming and generation of novel ideas by academics / other attendees
Year(s) Of Engagement Activity 2019
 
Description Global health security (Welcome Trust) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact to take part in a filming event with the Wellcome Trust. The event is being run/coordinated with Barry Gibb who is a scientific multimedia producer for the WT.
The event is centred around a computer game called The Last of Us. The game is based on a pandemic which has infected 60% of humanity in several months. They would like our input for a 'vaccine' discussion. The game will be used as the fiction starting point for discussion.
Year(s) Of Engagement Activity 2016
URL https://mosaicscience.com/outbreak
 
Description Immunisation Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation of the project and its status to nurses attending the yearly Immunisation Seminar organized by the oxford Vaccine Group
Year(s) Of Engagement Activity 2017
 
Description Invited talk for the Translationnal Reserach Office 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact A information meeting / workshop to provide information to research scientists on translational funding schemes (application, difficulties, further funding)
Year(s) Of Engagement Activity 2019
 
Description Romney Street Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation and debate with the Romney Street Group,
Year(s) Of Engagement Activity 2020
 
Description School visit (St gabriels) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact A lecture at a secondary school, intended for years 13 and above (A levels). The intended purpose was to engage / teach about vaccines and how they work, how they are developped, and what is the typical job /career of a research scientist
Year(s) Of Engagement Activity 2019