Simultaneous parenteral and pulmonary immunisation against tuberculosis

Lead Research Organisation: The Pirbright Institute
Department Name: Livestock Viral Diseases

Abstract

Two million individuals die each year from tuberculosis infection, which is an increasing problem because HIV/AIDS makes individuals highly susceptible and because antibiotic resistant strains of Mycobacterium tuberculosis are appearing. The present tuberculosis vaccine, BCG, is only partially effective, so development of a better vaccine is an urgent health care priority. Up to now, most new tuberculosis vaccines have been designed to be given after BCG, in order to boost the weak immunity provided by BCG. This is called prime boost immunisation. However, it is becoming clear that prime boost immunisation may not be sufficiently effective to control tuberculosis.
In this project we will establish an alternative novel immunisation strategy called Simultaneous Immunisation (SIM). We have already shown that giving one tuberculosis vaccine by injection and simultaneously spraying another into the lungs is highly effective in mice. The lung vaccine establishes local immunity, which combats tuberculosis infection immediately after infection, and the injected vaccine has a slower effect, but the two work very effectively together. We now want to test several different SIM regimes in mice to find the most effective one and test its safety. We will also study how different white cells combine to protect the lungs against tuberculosis, in order to make even more effective vaccines in the future. At the same time we will study humans infected with tuberculosis to develop better tests to assess immunity to tuberculosis. This will help in testing new immunisation procedures, including SIM, in man. A better tuberculosis vaccine will have major health benefits for humans and can also be used to control bovine tuberculosis, which is currently widespread in the UK and causes considerable economic losses.

Technical Summary

Tuberculosis vaccinology is dominated by the prime boost paradigm. In this project we will establish the novel concept of simultaneous immunisation (SIM) against Mycobacterium tuberculosis (Mtb). We will determine the roles of different lung and peripheral lymphocyte populations in protective immunity induced by SIM in mice, and develop assays for protective pulmonary immunity in man.
In mice intranasal immunisation with the subunit Mtb vaccine, Ad85A, generates pulmonary immunity. Importantly, Mtb growth is inhibited immediately after challenge. In contrast, parenteral BCG or subunit vaccines only inhibit Mtb growth late after challenge. The additive effect of parenteral/pulmonary immunisation does not depend on prime/boosting but on targeting early and late Mtb growth. Therefore SIM should be possible. We have demonstrated in practice that it is highly effective.
We will determine the efficacy, duration and mechanism of protection of SIM. SIM safety will be tested by assessing immune responses and pathology after coincident infection with influenza virus or induction of allergic lung responses.
Expression of the chemokine/receptor pair CXCL16/CXCR6 in the lungs after pulmonary immunisation is a correlate of protective pulmonary immunity. CXCR6+ cells are recoverable in bronchoalveolar lavage (BAL) unlike antigen specific cells induced by parenteral vaccines. However, three cell populations take part in pulmonary protection against Mtb, BAL cells, interstitial lung cells and extrapulmonary lymphocytes, but their roles in early and late inhibition of Mtb growth after challenge are ill-defined, as is the function of CXCL16/CXCR6 in intrapulmonary localization of cells. We shall use in vivo antibody depletion/blocking or transfer of purified cells to determine the function of different cells in early or late growth inhibition and the migration inhibitor, fingolimod, to dissect the contribution of intrapulmonary and extrapulmonary cells. CXCL16/CXCR6 deficient mice will illuminate the role of these molecules.
We will develop assays for human pulmonary immunity by quantifying immune mediators in nasal and bronchial fluid or supernatants of cultured nasal epithelial cells, BAL or peripheral blood lymphocytes from Mtb un-exposed, Mtb exposed, latently infected subjects or Tb patients.
This project will establish SIM as a highly effecive and safe method, which would require only a single clinic visit. We will determine the roles of different Tb-immune populations in protective lung immunity and the roles of CXCL16/CXCR6 in localization of cells within the lung. We will identify candidate assays for future assessment of immunity after pulmonary immunisation in man.

Publications

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Beverley P (2016) Selective presentation of MVA85A tuberculosis booster vaccine preclinical animal data. in International journal of epidemiology

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

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Bolinger B (2013) A new model for CD8+ T cell memory inflation based upon a recombinant adenoviral vector. in Journal of immunology (Baltimore, Md. : 1950)

 
Description DEFRA policy advice on bovine TB
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description BBSRC Newton Fund Swine and Poultry Research Initiative
Amount £865,623 (GBP)
Funding ID BB/R01275X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 06/2021
 
Title MCMV85A 
Description novel vaccine vector for tuberculosis 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact novel vaccine vector for TB which offers persistence and long term protection. Microrarray analysis after MCMV infection. 
 
Title microarray analysis 
Description performed microarray analysis of lungs lymphocytes from MCMV infected mice 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Information of genes expression in the lungs of MCMV infected mice, which will have an impact on the design of CMV vaccine vectors and mechanisms of vaccine induced protection 
 
Description TB antigens for vaccine testing and diagnostics 
Organisation Leiden University Medical Center
Department Department of Infectious Diseases
Country Netherlands 
Sector Academic/University 
PI Contribution We provide the mouse model and the SIM strategy.
Collaborator Contribution Partners provide TB antigens for vaccine testing and diagnostics.
Impact Two joint publications.
Start Year 2008
 
Description To explore the use of MCMV as a vaccine vector for TB 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Max von Pettenkofer-Institute of Hygiene and Medical Microbiology
Country Germany 
Sector Academic/University 
PI Contribution We perform all of the in vivo work to test the efficacy of the MCMV constructs as TB vaccine vectors.
Collaborator Contribution Partners provide the viral constructs and provide help and advice on the virology.
Impact One joint publication.
Start Year 2011
 
Description To test novel immunisation strategy SIM in cows 
Organisation Animal Health And Veterinary Laboratories Agency (AHVLA)
Country United Kingdom 
Sector Public 
PI Contribution Our contribution - discovery of the new immunisation strategy SIM.
Collaborator Contribution Partners - they will carry out simultaneous immunisation (SIM) in cows administering BCG by pulmonary and parenteral routes.
Impact Testing of SIM in cows, showed increased protection compared to parenteral BCG alone. Joint publication.
Start Year 2011
 
Description To test novel immunisation strategy SIM in cows 
Organisation Animal and Plant Health Agency
Country United Kingdom 
Sector Public 
PI Contribution Our contribution - discovery of the new immunisation strategy SIM.
Collaborator Contribution Partners - they will carry out simultaneous immunisation (SIM) in cows administering BCG by pulmonary and parenteral routes.
Impact Testing of SIM in cows, showed increased protection compared to parenteral BCG alone. Joint publication.
Start Year 2011
 
Description To test novel immunisation strategy SIM in guinea pigs 
Organisation University of Colorado
Country United States 
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 guinea pigs administering BCG or recombinant antigen 85A by pulmonary and parenteral routes.
Impact Testing of SIM in guinea pigs did not show increased protection over parenteral BCG alone. Not yet published
Start Year 2011
 
Description To test novel immunisation strategy SIM in mouse model 
Organisation Aeras
Department Aeras Global TB Vaccine Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution Our contribution - discovery of the new immunisation strategy SIM.
Collaborator Contribution Partners - they will carry out simultaneous immunisation (SIM) in mice administering BCG or recombinant antigen 85A by pulmonary and parenteral routes.
Impact Experiment completed, but not yet published.
Start Year 2011
 
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
 
Description To test the common respiratory mucosal concept by examining nasal and lung immune responses to TB antigen 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide the mouse model and SIM strategy.
Collaborator Contribution Partners will test human lung and nasal immune responses to BCG.
Impact Colleagues at Imperial continue to work on human immune responses to MTb. Two joint publications.
Start Year 2011
 
Title CXCR6 
Description The use of CXCR6 and CXC16 for diagnosis of the effectiveness of pulmonary immunisation or treatment of pulmonary infection. 
IP Reference WO2012025759 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact N/A
 
Title SIM 
Description An immunisation strategy, comprising simultaneous parenteral and lung administration of an antigen, against Mycobacterium Tuberculosis or Mycobacterium bovis. 
IP Reference WO2012052748 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact N/A
 
Description work experience for school children 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact provided work experience for 5 school children

The pupils performed very well in their A level exams and went on to further education.
Year(s) Of Engagement Activity 2010,2011,2012,2013