68 research outputs found
Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers
No full textIncludes bibliographical references.Tuberculosis (TB) remains a global health burden, with an estimated 1.3 million people dying from the disease in 2012. Protective immunity against TB is thought to depend on specific T cells. However, exactly which T cell characteristics are required for immunological protection is unknown. To gain a better understanding of M. tuberculosis (M.tb)-specific memory T cell immunity, we studied longevity and function of M.tb-specific memory T cells. We reasoned that such knowledge would facilitate rational vaccine design of a TB vaccine. We designed and developed a set of new HLA class II tetramers to perform in-depth studies of M.tb-specific CD4 T cell responses. We studied persons vaccinated with a novel TB vaccine, MVA85A, as well as persons naturally infected with M.tb. Antigen-specific CD4 T cells were detected with HLA class II tetramers and functional and phenotypic attributes of these T lymphocytes characterised by standard flow cytometric techniques. Comprehensive transcriptional analyses of M.tb-specific CD4 T cells, which were also sorted by FACS, were performed by microfluidic quantitative real-time PCR. Early after intradermal vaccination with MVA85A a large proportion of Ag85Aspecific CD4 T cells were highly activated, expressed skin homing markers and displayed an effector T cell phenotype. This effector response waned rapidly and gave way to antigen-specific central memory CD4 T cells with high proliferative potential, which we proposed may be desirable for protection. However, recent results from the first efficacy trial of MVA85A in infants suggested that these cells are not sufficient to enhance protection beyond that induced by BCG vaccination at birth. Further, we characterised surface marker expression and transcriptional signatures of a newly detected and described population of M.tb-specific CD4 T cells, that displayed a CD45RA+CCR7+CD27+ naïve-like T cell phenotype. We hypothesised that these unique M.tb-specific naïve-like CD4 T cells had a transcriptional profile distinct from truly naïve, central memory and effector bulk CD4 T cells, as well as other M.tb-specific memory CD4 T cell subsets. Gene expression of CFP10-specific naïve-like CD4 T cells reflected an mRNA profile that was very distinct from truly naïve bulk CD4 T cells. Rather, naïvelike CD4 T cells clustered with bulk effector CD4 T cells in unsupervised analysis methods such as hierarchical clustering and principle component analyses. Further analyses revealed that naïve-like CFP10-specific CD4 cells expressed mRNAs coding for effector cytokines, cytotoxic molecules and chemokine receptors consistent with effector memory T cells. However, the overall transcriptional profile was more similar to CFP10-specific central memory CD4 T cells than that of the effector CD4 T cells. We concluded that M.tb-specific naïve-like CD4 T cells may possess an ability to traffic to sites of infection or inflammation, where they may contribute to effector function. These hypotheses need confirmation on a protein level. The HLA class II tetramers developed in this thesis are valuabe tools for assessing direct ex vivo M.tb-specific CD4 T cell responses without activation and cell perturbation. Our findings contribute to a more comprehensive understanding of T cell immunity induced by vaccines and/or natural M.tb infection
PLOS Pathogens publication: A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates.
No full textTuberculosis (TB) causes more deaths than any other single infectious disease, and a new, improved vaccine is needed to control the epidemic. Many new TB vaccine candidates are in clinical development, but only one or two can be advanced to expensive efficacy trials. In this study, we compared magnitude and functional attributes of memory T cell responses induced in recently conducted clinical trials by six TB vaccine candidates, as well as BCG. The results suggest that these vaccines induced CD4 and CD8 T cellresponses with similar functional attributes, but that one vaccine, M72/AS01 E , induced the largest responses. This finding may indicate a lack of diversity in T cell responses induced by different TB vaccine candidates. A repertoire of vaccine candidates that induces more diverse immune response characteristics may increase the chances of finding a protective vaccine against TB.</div
Safety and immunogenicity of a subtype C ALVACHIV vCP2438 vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV HVTN 107 A phase 12a randomized trial
No full textAnalysis of the HIV Vaccine Trials Network 702 Phase 2b–3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk
No full textThis is the accepted manuscript version of the work published in its final form as Moodie, Z., Dintwe, O., Sawant, S., Grove, D., Huang, Y., Janes, H., Heptinstall, J., Omar, F. L., Cohen, K., Stephen C De Rosa., Zhang, L., Yates, N. L., Sarzotti-Kelsoe, M., Seaton, K. E., Laher, F., Bekker, L. G., Malahleha, M., Innes, C., Kassim, S., ... McElrath, M. J. (2022). Analysis of the HIV Vaccine Trials Network 702 Phase 2b3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk. The Journal of Infectious Diseases, 226(2), 246-257. https://doi.org/10.1093/infdis/jiac260
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Non-HIV Vaccine-Induced Immune Responses as Potential Baseline Immunogenicity Predictors of ALVAC-HIV and AIDSVAX B/E-Induced Immune Responses
No full textIdentifying correlations between immune responses elicited via HIV and non-HIV vaccines could aid the search for correlates of HIV protection and increase statistical power in HIV vaccine-efficacy trial designs. An exploratory objective of the HVTN 097 phase 1b trial was to assess whether immune responses [focusing on those supported as correlates of risk (CoR) of HIV acquisition] induced via the RV144 pox-prime HIV vaccine regimen correlated with those induced via tetanus toxoid (TT) and/or hepatitis B virus (HBV) vaccines. We measured TT-specific and HBV-specific IgG-binding antibody responses and TT-specific and HBV-specific CD4+ T-cell responses at multiple time points in HVTN 097 participants, and we assessed their correlations at peak time points with HIV vaccine (ALVAC-HIV and AIDSVAX B/E)-induced responses. Four correlations were significant [false discovery rate-adjusted p-value (FDR) ≤ 0.2]. Three of these four were with IgG-binding antibody responses to TT measured one month after TT receipt, with the strongest and most significant correlation [rho = 0.368 (95% CI: 0.096, 0.588; p = 0.008; FDR = 0.137)] being with IgG-binding antibody responses to MN gp120 gDneg (B protein boost) measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. The fourth significant correlation [(rho = 0.361; 95% CI: 0.049, 0.609; p = 0.021; FDR = 0.137)] was between CD4+ T-cell responses to a hepatitis B surface antigen peptide pool, measured 2 weeks after the third HBV vaccination, and IgG-binding antibody responses to gp70BCaseAV1V2 (B V1V2 immune correlate), measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. These moderate correlations imply that either vaccine, TT or HBV, could potentially provide a moderately useful immunogenicity predictor for the ALVAC-HIV and AIDSVAX B/E HIV vaccine regimen
A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates - Fig 3
No full textVaccine-induced memory CD4 (A) and CD8 (B) T cell responses by vaccine and M.tb infection status. Frequencies of antigen-specific Th1-cytokine expressing CD4 (a) or CD8 (B) responses at the final time point in each trial, relative to the pre-vaccination frequencies (i.e. memory response minus pre-vaccination response). Points denote sample trimmed means, and error bars 95% CI. Solid error bar lines indicate responses that significantly exceeded 0% after controlling the false discovery rate at 0.01. Dashed lines did not meet this significance criterion.</p
A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates - Fig 1
No full textPre-vaccination antigen-specific CD4 (A) and CD8 (B) T cell responses by vaccine and M.tb infection status. Frequencies of antigen-specific, Th1-cytokine expressing CD4 or CD8 T cells pre-vaccination. Points denote sample trimmed means and error bars denote 95% CI. Solid error bar lines indicate responses that significantly exceeded 0.005% after controlling the false discovery rate at 0.01. Dashed lines did not meet this significance criterion. “No vaccine” indicates the immune response to M.tb infection detected after megapool stimulation in unvaccinated, IGRA-positive individuals. Pre-vaccination responses to each individual antigen in each vaccine are shown in S1A Fig.</p
Vaccine-induced cytokine co-expression profiles for vaccine-induced memory CD4 T cells.
No full textCharacterization of vaccine-induced memory CD4 T cells response by their Th1 cytokine co-expression profiles for each vaccine in M.tb-uninfected (A) and -infected (B) individuals. Points denote sample trimmed means of the scaled vaccine-induced memory CD4 response for each vaccine for each cytokine-expressing subset, and error bars 95% CI (see Materials and Methods for details). Solid error bar lines indicate responses that significantly exceeded 0% after controlling the false discovery rate at 0.01. Dashed lines did not meet this significance criterion. G+2+T+, for example, refers to IFNγ+IL-2+TNF+.</p
PCA biplots of cytokine co-expression profiles for vaccine-induced memory CD4 T cells.
No full textCharacterization of vaccine-induced memory CD4 T cells responses by their Th1 cytokine co-expression profiles for each vaccine in M.tb-uninfected (A) and -infected (B) individuals. PCA biplots show principal components 1 and 2, computed from the scaled vaccine-induced memory T cell responses by cytokine-expressing subset. The scaled response indicates the relative proportions of cytokine co-expressing subsets of the induced response. It ranges from -1 to 1 and is independent of the overall vaccine-induced response magnitude (see Materials and Methods for details). Thick curves denote 95% bootstrap-based confidence areas for bivariate means for each vaccine-induced response. Thin curves represent contour lines of the bootstrap kernel density. The cytokine co-expression combinations displayed (G+2+T+, for example, refers to IFNγ+IL-2+TNF+) by biplot axes had high axis predictivity values relative to other cytokine combinations (S6 Fig). Percentages of total variation captured by principal components 1 and 2 are given on plot axes. Points denote observations; not all observations are shown to highlight the confidence areas. The legend item “No vaccine” indicates the group of M.tb-infected individuals that did not receive a vaccine, but whose blood was stimulated with megapool.</p
Functional, Antigen-Specific Stem Cell Memory (TSCM) CD4+ T Cells Are Induced by Human Mycobacterium tuberculosis Infection
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