Prof Helen McShane
|Scientific Themes:||Immunology & Infectious Disease|
|Keywords:||Tuberculosis, Vaccine, Immunisation and Clinical Trial|
The HIV epidemic and the emergence of multi and extensively drug-resistant strains of Mycobacterium tuberculosis (M.tb) mean that global control of tuberculosis (TB), particularly adult pulmonary TB, remains inadequate. There is an urgent need for better control measures, and the most cost effective way to control any infectious disease epidemic is with effective vaccination. The current vaccine, BCG confers protection against disseminated disease in childhood, but does not reliably protect against pulmonary disease. A strong cell mediated immune response is essential for protective immunity. It is known that Class II-restricted CD4+ T cells are essential for protective immunity and that class I-restricted CD8+ T lymphocytes may play a role in maintaining the latent state. Other cell types, including gamma delta cells and Th17 cells may also play a role. Antibodies may have some role, particularly in prevention of infection.
Since 2002, my group has conducted a series of clinical trials in the UK, The Gambia, South Africa, Senegal and Uganda, to investigate the safety, immunogenicity and efficacy of candidate TB vaccines, including MVA85A (recombinant modified vaccinia Ankara expressing antigen 85A) and ChAdOx1 85A (chimp adenovirus expressing antigen 85A) (both developed at the Jenner), and a number of industry partners’ vaccines. MVA85A and ChAdOx1 85A are used as boost vaccines for BCG-primed subjects; heterologous prime-boost vaccination regimens provide an effective way to induce high levels of cellular immunity, while the inclusion of BCG in a new regimen allows the retention of the protective effects of BCG in childhood against severe disease. Both vaccines have been shown to be safe and immunogenic in healthy adult volunteers. MVA85A has been further studied in M.tb latently infected individuals, and HIV-infected individuals, and the vaccine is safe and immunogenic in these groups. Successful healthy adult clinical trials were followed by age de-escalation studies that demonstrated safety in children and infants.
MVA85A was the first new TB candidate vaccine to be evaluated in an efficacy trial since BCG was last tested in infants in the 1960s. The first efficacy trial, conducted from 2009-2012 in collaboration with the South African TB Vaccine Initiative (SATVI) and supported by Aeras and the Wellcome Trust, enrolled 2797 South African infants who were randomised to receive BCG alone at birth or BCG followed by MVA85A boost at 4-6 months of age. MVA85A vaccination was safe but did not improve upon BCG-induced protection.
A second randomised, double-blind, placebo-controlled, efficacy trial has taken place in South Africa and Senegal in HIV-infected adults, with the collaboration of the University of Cape Town and CHU Le Dantec and support from Aeras and EDCTP. This trial started in 2011 and the 650 adults completed follow up in late 2014. Results are expected shortly.
A current area of interest to our group is whether delivering a TB vaccine via the aerosol route (through nebulisation directly into the lungs) is a more effective method of vaccination. In the last few years we have started clinical trials investigating aerosol delivery of MVA85A and have shown this route to be both safe and immunogenic. Other current projects within my group include the development of a BCG challenge model in humans, evaluating the effect of helminth infection on vaccine induced immune responses, and the evaluation of the protective efficacy of new antigens in viral vectors.
|Dr Henry Bettinson||Respiratory Medicine||Churchill Hospital||United Kingdom|
|Prof Keith Channon FMedSci FRCP (RDM)||Cardiovascular Medicine||University of Oxford||United Kingdom|
|Prof Hazel Dockrell||London School of Hygeine and Tropical Medicine||United Kingdom|
|Prof Alexander (Hal) Drakesmith (RDM)||Investigative Medicine Division||University of Oxford||United Kingdom|
|Prof Alison Elliott||MRC Laboratories, Entebbe||Uganda|
|Dr Tom Evans||Aeras||United States|
|Dr Helen A Fletcher||University of Oxford||United Kingdom|
|Prof Mark Hatherill||South African TB Vaccine Initiative (SATVI), Cape Town||South Africa|
|Prof Glyn Hewinson||Jenner Institute||University of Oxford||United Kingdom|
|Prof Adrian VS Hill||Jenner Institute||University of Oxford||United Kingdom|
|Dr Kris Huygen||Belgian Scientific Institute for Public Health||Belgium|
|Prof David Lewinsohn||University of Oregon||United States|
|Prof Souleymane MBoup||University of Dakar||Senegal|
|Prof Paul Moss||University of Birmingham||United Kingdom|
|Prof Tom Ottenhoff||Department of Infectious Diseases||Leiden University||Netherlands|
|Dr Ann Rawkins||Public Health England, Porton Down||United Kingdom|
|Dr Sally Sharpe||Public Health England, Porton Down||United Kingdom|
|Dr Martin Vordermeier||Jenner Institute||University of Oxford||United Kingdom|
|Prof Robert Wilkinson||University of Cape Town||South Africa|
RATIONALE: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. OBJECTIVES: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. METHODS: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNgamma and IL-2 ELISpot assays and FACS. MEASUREMENTS AND MAIN RESULTS: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-gamma and IL-2 response that was durable for 52 weeks. The magnitude of IFN-gamma response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4(+) T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. CONCLUSIONS: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183). Hide abstract
BACKGROUND: Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection. METHODS AND FINDINGS: Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60). CONCLUSIONS: Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates. Hide abstract
Interferon gamma (IFNgamma) is a critical component of the pro-inflammatory immune response that provides protection against Mycobacterium tuberculosis. In the absence of an immunological correlate of protection, antigen-specific production of IFNgamma is a commonly used marker of a protective immune response. To facilitate the evaluation of tuberculosis candidate vaccines three different IFNgamma detection methods were compared. The cultured whole blood ELISA, ex vivo IFNgamma ELISpot and whole blood ex vivo intracellular cytokine staining (ICS) assays were performed head-to-head during a Phase I clinical trial using the candidate vaccine MVA85A. Whilst all three assays detected significant increases in IFNgamma production immediately following vaccination, distinctions between the assays were apparent. Higher baseline IFNgamma responses were detected using the cultured whole blood ELISA, whereas the ex vivo ELISpot assay was the most sensitive in detecting long-term (52 weeks) post-vaccination responses. The whole blood ex vivo ICS assay provided novel information by dissecting the IFNgamma response into responding CD4, CD8 and gamma/delta T cell subsets. Future tuberculosis vaccine trials and immunology studies should ideally include a combination of ex vivo and cultured assays to ensure a thorough and multifaceted evaluation of the immune response is achieved. Hide abstract
In clinical trials recombinant-modified vaccinia virus Ankara expressing the Mycobacterium tuberculosis antigen 85A (MVA85A) induces approximately 10 times more effector T cells than any other recombinant MVA vaccine. We have found that in BCG primed subjects MVA85A vaccination reduces transforming growth factor beta 1 (TGF-beta1) mRNA in peripheral blood lymphocytes and reduces TGF-beta1 protein in the serum, but increases IFN-gamma ELISPOT responses to the recall antigen SK/SD. TGF-beta1 is essential for the generation of regulatory T cells and we see a correlation across vaccinees between CD4+CD25hiFoxP3+ cells and TGF-beta1 serum levels. This apparent ability to counteract regulatory T cell effects suggests a potential use of MVA85A as an adjuvant for less immunogenic vaccines. Hide abstract
BACKGROUND: The efficacy of bacille Calmette-Guérin (BCG) may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A (where "MVA" denotes "modified vaccinia virus Ankara"), has shown promising safety and immunogenicity in human trials performed in the United Kingdom. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed--but Mycobacterium tuberculosis-uninfected--healthy adults from a region of South Africa where TB is endemic. METHODS: Twenty-four adults were vaccinated with MVA85A. All subjects were monitored for 1 year for adverse events and for immunological assessment. RESULTS: MVA85A vaccination was well tolerated and induced potent T cell responses, as measured by interferon (IFN)-gamma enzyme-linked immunospot assay, which exceeded prevaccination responses up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A were comprised of multiple populations expressing combinations of IFN-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and IL-17, as measured by polychromatic flow cytometry. IFN-gamma-expressing and polyfunctional IFN-gamma+TNF-gamma+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response, which occurred 7 days after vaccination. CONCLUSION: The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials assessing the efficacy of MVA85A as a boosting vaccine in countries where TB is endemic. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00460590. Hide abstract
In the search for effective vaccines against intracellular pathogens such as HIV, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed T cell responses. Published data have shown prime-boost vaccination with BCG-MVA85A (modified vaccinia virus Ankara expressing antigen 85A) to be highly immunogenic in humans as measured by ex vivo IFN-gamma ELISPOT. Here, we used polychromatic flow cytometry to investigate the phenotypic and functional profile of these vaccine-induced Mycobacterium tuberculosis (M.tb) antigen 85A-specific responses in greater detail. Promisingly, antigen 85A-specific CD4(+) T cells were found to be highly polyfunctional, producing IFN-gamma, TNF-alpha, IL-2 and MIP-1beta. Surface staining showed the responding CD4(+) T cells to be relatively immature (CD45RO(+) CD27(int)CD57(-)); this observation was supported by the robust proliferative responses observed following antigenic stimulation. Furthermore, these phenotypic and functional properties were independent of clonotypic composition and epitope specificity, which was maintained through the different phases of the vaccine-induced immune response. Overall, these data strongly support the use of MVA85A in humans as a boosting agent to expand polyfunctional M.tb-specific CD4(+) T cells capable of significant secondary responses. Hide abstract
Tuberculosis remains a substantial global health problem despite effective drug treatments. The efficacy of BCG, the only available vaccine, is variable, especially in tuberculosis-endemic regions. Recent advances in the development of new vaccines against tuberculosis mean that the first of these are now entering into early clinical trials. A recombinant modified vaccinia virus Ankara expressing a major secreted antigen from Mycobacterium tuberculosis, antigen 85A, was the first new tuberculosis vaccine to enter into clinical trials in September 2002. This vaccine is known as MVA85A. In a series of phase I clinical trials in the UK, MVA85A had an excellent safety profile and was highly immunogenic. MVA85A was subsequently evaluated in a series of phase I trials in The Gambia, a tuberculosis-endemic area in west Africa. This vaccine is the only new subunit tuberculosis vaccine to enter into clinical trials in Africa to date. Here, we discuss some of the issues that were considered in the protocol design of these studies including recruitment, inclusion and exclusion criteria, reimbursement of study participants, and HIV testing. These issues are highly relevant to early clinical trials with all new tuberculosis vaccines in the developing world. Hide abstract
Protective immunity against Mycobacterium tuberculosis depends on the generation of a T(H)1-type cellular immune response, characterized by the secretion of interferon-gamma (IFN-gamma) from antigen-specific T cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4(+) and CD8(+) T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-gamma-secreting T cells when used alone in bacille Calmette-Guerin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-gamma-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas. Hide abstract
Identifying new protective antigens for TB subunit vaccines
One leading approach to TB vaccine development is to develop a subunit booster vaccine, designed to boost the effects of the current vaccine, BCG. The selection of antigen(s) to include in such a vaccine has been rather limited to date. We are collaborating with two antigen discovery groups within the field to select potential antigens to include in our viral vector delivery systems, and have some extremely promising results with the first four antigens tested. We are also exploring new ...