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1.  Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults 
Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines.
Objectives: We investigated a novel TB vaccine candidate, M72/AS01, in a phase IIa trial of bacille Calmette-Guérin–vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)–infected and -uninfected adults in South Africa.
Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry.
Measurements and Main Results: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67+ T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants.
Conclusions: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals.
Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).
doi:10.1164/rccm.201208-1385OC
PMCID: PMC3778736  PMID: 23306546
tuberculosis; vaccine; T cell; cytokine; proliferation
2.  A Phase IIa Trial of the New Tuberculosis Vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis–infected Adults 
Rationale: Novel tuberculosis (TB) vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control.
Objective: To determine the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic.
Methods: An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 107 plaque-forming units of MVA85A. Specific T-cell responses were characterized by IFN-γ enzyme-linked immunospot and whole blood intracellular cytokine staining assays.
Measurements and Main Results: MVA85A was well tolerated and no vaccine-related serious adverse events were recorded. MVA85A induced robust and durable response of mostly polyfunctional CD4+ T cells, coexpressing IFN-γ, tumor necrosis factor-α, and IL-2. Magnitudes of pre- and postvaccination T-cell responses were lower in HIV-infected, compared with HIV-uninfected, vaccinees. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed.
Conclusions: MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations.
doi:10.1164/rccm.201108-1548OC
PMCID: PMC3326425  PMID: 22281831
tuberculosis; HIV-1; vaccine; MVA85A; clinical trial
3.  Advances in childhood immunisation in South Africa: where to now? Programme managers’ views and evidence from systematic reviews 
BMC Public Health  2012;12:578.
Background
The Expanded Programme on Immunisation (EPI) is one of the most powerful and cost-effective public health programmes to improve child survival. We assessed challenges and enablers for the programme in South Africa, as we approach the 2015 deadline for the Millennium Development Goals.
Methods
Between September 2009 and September 2010 we requested national and provincial EPI managers in South Africa to identify key challenges facing EPI, and to propose appropriate solutions. We collated their responses and searched for systematic reviews on the effectiveness of the proposed solutions; in the Health Systems Evidence, Cochrane Library, and PubMed electronic databases. We screened the search outputs, selected systematic reviews, extracted data, and assessed the quality of included reviews (using AMSTAR) and the quality of the evidence (using GRADE) in duplicate; resolving disagreements by discussion and consensus.
Results
Challenges identified by EPI managers were linked to healthcare workers (insufficient knowledge of vaccines and immunisation), the public (anti-immunisation rumours and reluctance from parents), and health system (insufficient financial and human resources). Strategies proposed by managers to overcome the challenges include training, supervision, and audit and feedback; strengthening advocacy and social mobilisation; and sustainable EPI funding schemes, respectively. The findings from reliable systematic reviews indicate that interactive educational meetings, audit and feedback, and supportive supervision improve healthcare worker performance. Structured and interactive communication tools probably increase parents’ understanding of immunisation; and reminders and recall, use of community health workers, conditional cash transfers, and mass media interventions probably increase immunisation coverage. Finally, a national social health insurance scheme is a potential EPI financing mechanism; however, given the absence of high-quality evidence of effects, its implementation should be pilot-tested and the impacts and costs rigorously monitored.
Conclusion
In line with the Millennium Development Goals, we have to ensure that our children’s right to health, development and survival is respected, protected and promoted. EPI is central to this vision. We found numerous promising strategies for improving EPI performance in South Africa. However, their implementation would need to be tailored to local circumstances and accompanied by high-quality monitoring and evaluation. The strength of our approach comes from having a strong framework for interventions before looking for systematic reviews. Without a framework, we would have been driven by what reviews have been done and what is easily researchable; rather than the values and preferences of key immunisation stakeholders.
doi:10.1186/1471-2458-12-578
PMCID: PMC3418205  PMID: 22849711
4.  Specific T Cell Frequency and Cytokine Expression Profile Do Not Correlate with Protection against Tuberculosis after Bacillus Calmette-Guérin Vaccination of Newborns 
Rationale: Immunogenicity of new tuberculosis (TB) vaccines is commonly assessed by measuring the frequency and cytokine expression profile of T cells.
Objectives: We tested whether this outcome correlates with protection against childhood TB disease after newborn vaccination with bacillus Calmette-Guérin (BCG).
Methods: Whole blood from 10-week-old infants, routinely vaccinated with BCG at birth, was incubated with BCG for 12 hours, followed by cryopreservation for intracellular cytokine analysis. Infants were followed for 2 years to identify those who developed culture-positive TB—these infants were regarded as not protected against TB. Infants who did not develop TB disease despite exposure to TB in the household, and another group of randomly selected infants who were never evaluated for TB, were also identified—these groups were regarded as protected against TB. Cells from these groups were thawed, and CD4, CD8, and γδ T cell–specific expression of IFN-γ, TNF-α, IL-2, and IL-17 measured by flow cytometry.
Measurements and Main Results: A total of 5,662 infants were enrolled; 29 unprotected and two groups of 55 protected infants were identified. There was no difference in frequencies of BCG-specific CD4, CD8, and γδ T cells between the three groups of infants. Although BCG induced complex patterns of intracellular cytokine expression, there were no differences between protected and unprotected infants.
Conclusions: The frequency and cytokine profile of mycobacteria-specific T cells did not correlate with protection against TB. Critical components of immunity against Mycobacterium tuberculosis, such as CD4 T cell IFN-γ production, may not necessarily translate into immune correlates of protection against TB disease.
doi:10.1164/rccm.201003-0334OC
PMCID: PMC2970848  PMID: 20558627
mycobacteria immunity; pediatric settings
5.  Association of Human TLR1 and TLR6 Deficiency with Altered Immune Responses to BCG Vaccination in South African Infants 
PLoS Pathogens  2011;7(8):e1002174.
The development of effective immunoprophylaxis against tuberculosis (TB) remains a global priority, but is hampered by a partially protective Bacillus Calmette-Guérin (BCG) vaccine and an incomplete understanding of the mechanisms of immunity to Mycobacterium tuberculosis. Although host genetic factors may be a primary reason for BCG's variable and inadequate efficacy, this possibility has not been intensively examined. We hypothesized that Toll-like receptor (TLR) variation is associated with altered in vivo immune responses to BCG. We examined whether functionally defined TLR pathway polymorphisms were associated with T cell cytokine responses in whole blood stimulated ex vivo with BCG 10 weeks after newborn BCG vaccination of South African infants. In the primary analysis, polymorphism TLR6_C745T (P249S) was associated with increased BCG-induced IFN-γ in both discovery (n = 240) and validation (n = 240) cohorts. In secondary analyses of the combined cohort, TLR1_T1805G (I602S) and TLR6_G1083C (synonymous) were associated with increased IFN-γ, TLR6_G1083C and TLR6_C745T were associated with increased IL-2, and TLR1_A1188T was associated with increased IFN-γ and IL-2. For each of these polymorphisms, the hypo-responsive allele, as defined by innate immunity signaling assays, was associated with increased production of TH1-type T cell cytokines (IFN-γ or IL-2). After stimulation with TLR1/6 lipopeptide ligands, PBMCs from TLR1/6-deficient individuals (stratified by TLR1_T1805G and TLR6_C745T hyporesponsive genotypes) secreted lower amounts of IL-6 and IL-10 compared to those with responsive TLR1/6 genotypes. In contrast, no IL-12p70 was secreted by PBMCs or monocytes. These data support a mechanism where TLR1/6 polymorphisms modulate TH1 T-cell polarization through genetic regulation of monocyte IL-10 secretion in the absence of IL-12. These studies provide evidence that functionally defined innate immune gene variants are associated with the development of adaptive immune responses after in vivo vaccination against a bacterial pathogen in humans. These findings could potentially guide novel adjuvant vaccine strategies as well as have implications for IFN-γ-based diagnostic testing for TB.
Author Summary
Tuberculosis (TB) is one of the leading infectious causes of death worldwide. The current vaccine for TB, BCG, is widely used but it is not highly effective in preventing disease. We investigated the role of host genetics in the immune response to BCG vaccination. We found that variants of innate immunity genes (TLR1 and TLR6) were associated with BCG-induced immune responses after vaccination. These findings may guide new strategies for vaccine development as well as diagnosis of TB.
doi:10.1371/journal.ppat.1002174
PMCID: PMC3154845  PMID: 21852947
6.  The Novel Tuberculosis Vaccine, AERAS-402, Induces Robust and Polyfunctional CD4+ and CD8+ T Cells in Adults 
Rationale: AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine.
Objectives: We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis–uninfected BCG-vaccinated adults from a tuberculosis-endemic region of South Africa.
Methods: Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4+ and CD8+ T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells.
Measurements and Main Results: AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4+ T-cell response dominated by cells coexpressing IFN-γ, tumor necrosis factor-α, and IL-2 (“polyfunctional” cells). AERAS-402 also induced a potent CD8+ T-cell response, characterized by cells expressing IFN-γ and/or tumor necrosis factor-α, which persisted for the duration of the study.
Conclusions: Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8+ T cells are also important. AERAS-402 induced a robust and durable CD8+ T-cell response, which appears extremely promising.
Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381).
doi:10.1164/rccm.200910-1484OC
PMCID: PMC2894413  PMID: 20167847
tuberculosis; vaccine; immunity; CD4; CD8
7.  MVA85A, a novel TB vaccine, is safe in adolescents and children, and induces complex subsets of polyfunctional CD4+ T cells 
European journal of immunology  2010;40(1):279-290.
Summary
MVA85A is a new tuberculosis vaccine aimed at enhancing immunity induced by BCG. We investigated the safety and immunogenicity of MVA85A in healthy adolescents and children from a tuberculosis endemic region, who received BCG at birth.
Twelve adolescents and 24 children were vaccinated and followed up for 12 or 6 months, respectively. Adverse events were documented and vaccine-induced immune responses assessed by IFN-γ ELISpot and intracellular cytokine staining.
The vaccine was well tolerated and there were no vaccine-related serious adverse events. MVA85A induced potent and durable T cell responses. Multiple CD4+ T cell subsets, based on expression of IFN-γ, TNF-α, IL-2, IL-17 and GM-CSF, were induced. Polyfunctional CD4+ T cells co-expressing IFN-γ, TNF-α and IL-2 dominated the response in both age groups. A novel CD4+ cell subset co-expressing these three Th1 cytokines and IL-17 was induced in adolescents, while a novel CD4+ T cell subset co-expressing Th1 cytokines and GM-CSF was induced in children. Antigen-specific CD8+ T cells were not detected.
We conclude that in adolescents and children MVA85A safely induces the type of immunity thought to be important in protection against tuberculosis. This includes induction of novel Th1 cell populations which have not been previously described in humans.
doi:10.1002/eji.200939754
PMCID: PMC3044835  PMID: 20017188
MVA85A; tuberculosis; vaccine; polyfunctional; IL-17
8.  Bacille Calmette Guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles 
The immune response to vaccination with Bacillus Calmette-Guerin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-week old infants, routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 hours induced expression of predominantly IFN-γ, IL-2 and TNF-α in CD4+ T cells, in 7 distinct cytokine combinations. IL-4 and IL-10 expression were detected in CD4+ T cells at low frequencies, and only in cells that did not co-express Type 1 cytokines. Specific CD8+ T cells were less frequent than CD4+ T cells, and produced mainly IFN-γ and/or IL-2, and less TNF-α, IL-4 and IL-10. Importantly, many mycobacteria-specific CD4+ and CD8+ T cells did not produce IFN-γ. The predominant phenotype of BCG-specific Type 1 T cells was that of effector cells, i.e., CD45RA–CCR7–CD27+, which may reflect persistence of M. bovis BCG in infants until 10 weeks of age. Among 5 phenotypic patterns of CD4+ T cells, central memory cells were more likely to be IL-2+, and effector cells more likely to be IFN-γ+. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN-γ production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination, and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.
PMCID: PMC2842001  PMID: 18292584
Human; Th1/Th2 Cells; T cells; Cytokines; Memory; Vaccination
9.  Significantly skewed memory CD8+ T cell subsets in HIV-1 infected infants during the first year of life1 
Clinical immunology (Orlando, Fla.)  2008;130(3):280-289.
HIV-1 infection causes a severe T cell compromise; however, little is known about changes in naïve, memory, effector and senescent T cell subsets during the first year of life. T cell subsets were studied over the first year of life in blood from 3 infant cohorts: untreated HIV-infected, HIV-exposed but uninfected, and HIV-unexposed. In HIV-infected infants, the frequency of CCR7+CD45RA+ naïve CD8+ T cells was significantly decreased, whilst the frequency of CCR7−CD45RA− effector memory CD8+ T cells was increased, compared with the control cohorts. A larger population of CD8+ T cells in HIV-infected infants displayed a phenotype consistent with senescence. Differences in CD4+ T cell subset frequencies were less pronounced, and no significant differences were observed between exposed and unexposed HIV-uninfected infants. We concluded that the proportion of naïve, memory, effector and senescent CD8+ T cells during the first year of life is significantly altered by HIV-1 infection.
doi:10.1016/j.clim.2008.09.006
PMCID: PMC2722743  PMID: 18996749
CD4; CD8; memory; HIV-1; infants
10.  Infant HIV-1 Infection Severely Impairs the Bacille Calmette-Guerin Vaccine-Induced Immune Response1 
The Journal of infectious diseases  2009;199(7):982-990.
Background
World-wide, most infants born to HIV-infected mothers receive BCG. Tuberculosis is a major cause of death of HIV-infected infants in sub-Saharan Africa, and should be prevented. However, BCG may itself cause disease (BCGosis) in these infants. Information regarding the immunogenicity of BCG is imperative for the risk/benefit assessment of BCG vaccination in HIV-infected infants; however, no such data exists.
Methods
We compared BCG-induced CD4 and CD8 T cell responses, assessed by flow cytometry, in HIV-infected (n = 20), HIV-exposed but uninfected (n = 25), and HIV-unexposed (n = 23) infants, over their first year of life.
Results
BCG vaccination of the 2 HIV-uninfected groups induced a robust response, characterized by IFN-γ, TNF-α, and/or IL-2-expressing CD4 T cells. In contrast, HIV-infected infants had a markedly lower response, throughout the first year of life. These infants also had significantly reduced numbers of IFN-γ, TNF-α and IL-2 co-expressing polyfunctional CD4 T cells, thought to indicate T cell quality.
Conclusions
HIV-1 infection severely impairs the BCG-specific T cell response during the first year of life. BCG may therefore provide little, if any, vaccine-induced benefit in HIV-infected infants. Considering the significant risk of BCGosis, these data strongly support not giving BCG to HIV-infected infants.
doi:10.1086/597304
PMCID: PMC2815505  PMID: 19236280
Tuberculosis; BCG; HIV; infants; T cells; immune response; polyfuntional; Th1; Th17
11.  Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trial 
Objective To compare the incidence of tuberculosis over two years in infants vaccinated at birth with intradermal BCG or with percutaneous BCG.
Design Randomised trial.
Setting South Africa.
Participants 11 680 newborn infants.
Interventions Infants were randomised by week of birth to receive Tokyo 172 BCG vaccine through the percutaneous route (n=5775) or intradermal route (n=5905) within 24 hours of birth and followed up for two years.
Main outcome measures The primary outcome measure was documented Mycobacterium tuberculosis infection or radiological and clinical evidence of tuberculosis disease. Secondary outcome measures were rates of adverse events, all cause and tuberculosis specific admissions to hospital, and mortality.
Results The difference in the cumulative incidence of definite, probable, and possible tuberculosis between the intradermal group and the percutaneous group, as defined using study definitions based on microbiological, radiological, and clinical findings was −0.36% (95.5% confidence interval −1.27% to 0.54%). No significant differences were found between the routes in the cumulative incidence of tuberculosis using a range of equivalence of “within 25%.” Additionally, no significant differences were found between the routes in the cumulative incidence of adverse events (risk ratio 0.98, 95% confidence interval 0.91 to 1.06), including deaths (1.19, 0.89 to 1.58).
Conclusion Equivalence was found between intradermal BCG vaccine and percutaneous BCG in the incidence of tuberculosis in South African infants vaccinated at birth and followed up for two years. The World Health Organization should consider revising its policy of preferential intradermal vaccination to allow national immunisation programmes to choose percutaneous vaccination if that is more practical.
Trial registration ClinicalTrials.gov NCT00242047.
doi:10.1136/bmj.a2052
PMCID: PMC2583390  PMID: 19008268
12.  Dose-Dependent Immune Response to Mycobacterium bovis BCG Vaccination in Neonates▿  
Clinical and Vaccine Immunology  2006;14(2):198-200.
In 10-week-old infants vaccinated at birth with Japanese Mycobacterium bovis BCG, the number of dermal needle penetrations correlated positively with frequency of proliferating CD4+ T cells in whole blood following BCG stimulation for 6 days but did not correlate with secreted cytokine levels after 7 h or interferon CD4+ T-cell frequency after 12 h of BCG stimulation.
doi:10.1128/CVI.00309-06
PMCID: PMC1797790  PMID: 17182761
13.  Childhood tuberculosis: progress requires an advocacy strategy now 
The European Respiratory Journal  2012;40(2):294-297.
Childhood tuberculosis (TB) is a preventable and curable infectious disease that remains overlooked by public health authorities, health policy makers and TB control programmes. Childhood TB contributes significantly to the burden of disease and represents the failure to control transmission in the community. Furthermore, the pool of infected children constitutes a reservoir of infection for the future burden of TB. It is time to prioritise childhood TB, advocate for addressing the challenges and grasp the opportunities in its prevention and control. Herein, we propose a scientifically informed advocacy agenda developed at the International Childhood TB meeting held in Stockholm, Sweden, from March 17 to 18, 2011, which calls for a renewed effort to improve the situation for children affected by Mycobacterium tuberculosis exposure, infection or disease. The challenges and needs in childhood TB are universal and apply to all settings and must be addressed more effectively by all stakeholders.
doi:10.1183/09031936.00187711
PMCID: PMC3409406  PMID: 22337859
Control; infectious disease; Mycobacterium tuberculosis; public health

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