Correlates of protection against Mycobacterium tuberculosis infection

Lead Research Organisation: University of Oxford
Department Name: Unknown

Abstract

Tuberculosis is an increasing health problem because HIV increases individuals? susceptibility to the disease. Furthermore the bacteria are now often resistant to antibiotics, making treatment difficult. An improved vaccine would therefore be a major contribution to world health. Because Bacille Calmette-Guerin (BCG) the current vaccine, provides partial protection it is likely that any new vaccine will be used to boost the protection afforded by BCG. Several candidate booster vaccines are currently entering clinical trials to test their safety and ability to boost the immune response to tuberculosis. However, proving that a booster increases protection will require a very large, expensive and long clinical trial. A test that could indicate which vaccine candidates can boost protection, would allow a rational selection from among the available candidates and save a great deal of time, money and effort.
In our project we will study the lymphocytes from mice given BCG and then booster vaccines that are already known to increase protection or have no effect. This will allow us to compare the properties of protective and non-protective lymphocytes and identify a ?signature? of protection. We shall then use this in cows immunised against bovine tuberculosis, a disease that is very similar to human tuberculosis, to predict whether different booster immunisations are protective. Finally we shall study human volunteers given a candidate booster vaccine and predict whether this is a good candidate to go on to efficacy trials.

Technical Summary

A number of vaccine candidates aimed at boosting protective immunity to M. tuberculosis (Mtb) above the level afforded by BCG, have entered or are close to, early phase clinical trials. Thus a test that would allow identification of effective booster vaccines without the need for efficacy trials would be extremely valuable. We have established an aerosol challenge mouse model in which BCG priming and intra-nasal boosting with a recombinant adenovirus expressing Mtb antigen 85A (Ad85A), induces strong protection against Mtb. We will study in detail the properties of T lymphocytes that are present in the lungs after this immunisation regime. Our hypothesis is that these cells are responsible for increased protection, are part of an endothoracic recirculating pool of memory and effector T cells and exhibit a distinct lung homing and functional signature, which will provide a correlate of increased protection. We will use multi-colour flow cytometry to analyse in detail the phenotype of lung resident 85A-specific T cells, identify their functional properties and perform gene expression analysis using microarrays. These properties will be compared to 85A-specific cells in the spleen induced by intra-nasal Ad85A or splenic 85A-specific cells induced by non-protective immunisation regimes, to identify a signature for lung homing protective cells. We shall then show that the protective signature can be detected in the blood following protective but not non-protective immunisation in mice. We shall go on to examine pre-challenge blood samples from cows immunised with BCG or prime boost regimes that provide increased protection over BCG alone. Finally we shall examine blood samples from human volunteers immunised with BCG followed by modified vaccinia Ankara containing antigen 85A. This project will identify a correlate of increased protection above that afforded by BCG alone in mice and show whether this can be used to provide predictive information in cows and humans.

Publications

10 25 50

publication icon
Beverley PC (2014) A novel murine cytomegalovirus vaccine vector protects against Mycobacterium tuberculosis. in Journal of immunology (Baltimore, Md. : 1950)

publication icon
Beverley PC (2008) Lessons for tuberculosis vaccines from respiratory virus infection. in Expert review of vaccines

 
Description BCG Transmission Study Working Group
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Chairman Vaccine policy advisory group
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://randd.defra.gov.uk/Default.aspx?Module=More&Location=None&ProjectID=13843
 
Description Project Grant
Amount £992,214 (GBP)
Funding ID G1100085 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 06/2014
 
Title Ad85A 
Description We have constructed a human adenovirus type 5 recombinant virus expressing Mycobacterium tuberculosis antigen 85A. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact We have used this virus to immunise mice intranasally and shown that it induces protective immunity inhibiting the early growth of Mycobacterium tubcerculosis in the lungs after aerosol challenge. 
 
Title Local immunity inhibiting early growth of Mycobacterium tuberculosis 
Description In pulmonary Mycobacterium tuberculosis (Mtb) infection, immune responses are delayed compared to other respiratory infections, so that antigen specific cells are not detected in the lungs earlier than day 14. Even after parenteral immunization with Bacille Calmette Guerin (BCG) or a subunit vaccine, the immune response after Mtb challenge is only slightly accelerated and the kinetics of pulmonary Mtb growth do not differ between naïve and immunised animals up to day 14. In contrast, intranasal immunization with Ad85A can inhibit early growth of Mtb because it establishes a lung antigen depot and maintains an activated lung-resident lymphocyte population. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2010 
Provided To Others? Yes  
Impact Two publications. 
 
Title Microarray data 
Description Microarray data has been obtained from CD8 T cells in the lungs of mice immunised intranasally with a recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A and compared to lung CD8 T cells from mice immunised with the same recombinant intradermally. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Several genes are under investigation as correlates of effective local protective immunity to Mycobacterium tuberculosis. Two publications. 
 
Description Antigens for simultaneous immunisation 
Organisation Leiden University Medical Center
Department Department of Infectious Diseases
Country Netherlands 
Sector Academic/University 
PI Contribution Performance of tuberculosis challenge experiments in mice using antigens supplied by the collaborator.
Collaborator Contribution Supply of recombinant antigens for development of the novel simultaneous immunisation procedure against tuberculosis.
Impact Two joint publications.
Start Year 2009
 
Description Development of MCMV as a vaccine vector for tuberculosis 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Max von Pettenkofer-Institute of Virology
Country Germany 
Sector Academic/University 
PI Contribution We immunise mice with recombinant MCMVs, analyse immune responses and perform infectious challenge experiments with M. tuberculosis.
Collaborator Contribution Partner constructs recombinant MCMVs containing M. tuberculosis antigens.
Impact One joint publication.
Start Year 2012
 
Description Further development of simultaneous immunisation 
Organisation Animal Health And Veterinary Laboratories Agency (AHVLA)
Department Tuberculosis Research Unit
Country United Kingdom 
Sector Public 
PI Contribution Development of the simultaneous immunisation strategy for tuberculosis. Testing of recombinant antigens by infectious TB chellenge in mice.
Collaborator Contribution Supply of recombinant antigens and testing of simultaneous immunisation strategy in cattle.
Impact PMID: 21628524
Start Year 2010
 
Description Human pulmonary immune responses 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have developed the simultaneous immunisation procedure for tuberculosis which is the subject of the collaboration.
Collaborator Contribution The collaboration aims to define protective pulmonary immune responses to M. tuberculosis in man. It has resulted in a successful joint grant application to the MRC.
Impact We have obtained a joint MRC grant with this collaborator reference G1100085.
Start Year 2010
 
Description SIM in Primates 
Organisation Biomedical Primate Research Centre
Department Department of Parasitology
Country Netherlands 
Sector Academic/University 
PI Contribution Discovery of the SIM strategy for immunisation
Collaborator Contribution Collaborator carried out a SIM immunisation experiment in NHPs, which demonstrated the efficacy of mucosal immunisation with BCG..
Impact Manuscript in preparation.
Start Year 2011
 
Description Simultaneous immunisation in bovines 
Organisation Animal Health And Veterinary Laboratories Agency (AHVLA)
Department Tuberculosis Research Unit
Country United Kingdom 
Sector Public 
PI Contribution Development of the simultaneous immunisation strategy for vaccination against tuberculosis.
Collaborator Contribution Performance of a simultaneous immunisation experiment in cows to test the immunisation strategy.
Impact One joint publication
Start Year 2012
 
Description To test novel immunisation strategy SIM in non-human primates 
Organisation Biomedical Primate Research Centre
Country Netherlands 
Sector Academic/University 
PI Contribution Our contribution - discovery of the new immunisation strategy SIM.
Collaborator Contribution Partners - they will carry out simultaneous immunisation (SIM) in non-human primates administering BCG by pulmonary and parenteral routes.
Impact Testing SIM in NHP showed that pulmonary administration of BCG is highly effective. Manuscript in press (Tuberculosis): Variable BCG efficacy in rhesus populations: pulmonary BCG provides protection where standard intra-dermal vaccination fails. Frank Verreck, Elma Z. Tchilian, Richard A.W. Vervenne, Claudia C. Sombroek, Ivanela Kondova, Okke A. Eissen, Vinod Sommandas, Nicole M. van der Werff, Ernst Verschoor, Gerco Braskamp, Jaco Bakker, Jan A.M. Langermans, Peter J. Heidt, Tom H.M. Ottenhoff, Klaas W. van Kralingen, Alan W. Thomas, Peter C.L. Beverley, Clemens H.M. Kocken
Start Year 2011
 
Title CXCR6 as a correlate of lung protective immunity after vacination 
Description We have shown that CXCR6 is expressed on a subset lung lymphocytes, resident in the airways, after immunisation.The presence of CXCR6+ lymohocytes correlates with induction of protective immunity agains Mycobacterium tuberculosis. 
IP Reference WO2012025759 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact None
 
Title Simultaneous immunisation 
Description We have shown that simultaneous parenteral and pulmonary immunisation against Mycobacterium tuberculosis is more effective than immunisation by either route alone. 
IP Reference WO2012052748 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact None
 
Description Informing the public about tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A pop up shop in a shopping centre with games and information relating to tuberculosis in the UK.
Year(s) Of Engagement Activity 2015
 
Description Lecture on Zoonoses 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A talk as part of the Big Biology Day at Hills Road College Cambridge.
Year(s) Of Engagement Activity 2015