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1.  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
2.  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
3.  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
4.  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
5.  Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response 
Vaccine  2009;27(40):5488-5495.
Background
In most tuberculosis (TB) endemic countries, bacillus Calmette Guérin (BCG) is usually given around birth to prevent severe TB in infants. The neonatal immune system is immature. Our hypothesis was that delaying BCG vaccination from birth to 10 weeks of age would enhance the vaccine-induced immune response.
Methods
In a randomized clinical trial, BCG was administered intradermally either at birth (n=25) or at 10 weeks of age (n=21). Ten weeks after vaccination, and at 1 year of age, vaccine-specific CD4 and CD8 T cell responses were measured with a whole blood intracellular cytokine assay.
Results
Infants who received delayed BCG vaccination demonstrated higher frequencies of BCG-specific CD4 T cells, particularly polyfunctional T cells co-expressing IFN-γ, TNF-α and IL-2, and most strikingly at 1 year of age.
Conclusions
Delaying BCG vaccination from birth to 10 weeks of age enhances the quantitative and qualitative BCG-specific T cell response, when measured at one year of age.
doi:10.1016/j.vaccine.2009.06.103
PMCID: PMC2745558  PMID: 19616494
BCG; vaccination; birth; delayed; polyfunctional CD4 T cells
6.  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
7.  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
8.  Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa1 
The Journal of infectious diseases  2008;198(4):544-552.
BACKGROUND
The efficacy of BCG may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A, has shown promising safety and immunogenicity in UK human trials. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed, but Mycobacterium tuberculosis-uninfected, healthy adults from a TB-endemic region of South Africa.
METHODS
Twenty-four adults were vaccinated with MVA85A. All subjects were followed up for one year for adverse events and for immunological assessment.
RESULTS
MVA85A vaccination was well tolerated and induced potent T cell responses, measured by IFN-γ ELISPOT assay, which exceeded pre-vaccination levels up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A comprised of multiple populations expressing combinations of IFN-γ, TNF-α, IL-2 and IL-17, as measured by polychromatic flow cytometry. IFN-γ expressing and polyfunctional IFN-γ+TNF-α+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response 7 days post-vaccination.
CONCLUSION
The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials to assess the efficacy of MVA85A as a boosting vaccine in TB endemic countries.
doi:10.1086/590185
PMCID: PMC2822902  PMID: 18582195
Vaccination; tuberculosis; T cells; MVA85A; South Africa
9.  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
10.  Distinct, specific IL-17 and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response1 
We investigated whether the pro-inflammatory T cell cytokines interleukin-17 (IL-17) and IL-22 are induced by human mycobacterial infection. Remarkably, >20% of specific cytokine-producing CD4+ T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17 and IL-22 producing CD4+ T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, while bronchoalveolar lavage fluid (BALF) contained higher levels of IL-22 protein, compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-γ in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17 and IL-22-producing CD4+ T cells may play important roles in the human immune response to mycobacteria.
PMCID: PMC2219462  PMID: 18209095
human; T cells; cytokines; bacterial infection
11.  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

Results 1-11 (11)