A major event for new tuberculosis vaccines

HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland. Electronic address: .
The Lancet (Impact Factor: 45.22). 02/2013; 381(9871). DOI: 10.1016/S0140-6736(13)60137-3
Source: PubMed
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    • "The trial found no protection [8] and led to a lively discussion as to the reasons and implications for this lack of protection [8] [9] [10]. Of particular timeliness, a better knowledge of the mechanism that causes variation in BCG vaccine efficacy might help to explain why MVA85A failed to add to BCG effectiveness in its first trial [8] [9]. The variation in BCG-induced protection cannot be explained by differences in the vaccines strains used or by ethnicity [11] [12]. "
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    ABSTRACT: BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7–53%, p = 0.017) but low in Manaus (8%, 95% CI t0 39–40%, p = 0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3–33%, p = 0.022) and absent in Manaus (1%, 95% CI to 27–23%, p = 0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22–54%, p < 0.001) and Manaus (36%, 95% CI 11–53%, p = 0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective. The Department of International Development, UK (DFID) and the National Health Foundation, Brazil (FUNASA) funded the trial. It is registered at Controlled Trials (ISRCTN07601391).
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    ABSTRACT: Heterologous prime-boost strategies hold promise for vaccination against tuberculosis (TB). However, the T-cell characteristics required for protection are not known. We proposed that boost vaccines should induce long-lived functional and phenotypic changes to T cells primed by BCG and/or natural exposure to mycobacteria. We characterized changes among specific CD4(+) T cells after vaccination with the MVA85A vaccine in adults, adolescents and children. CD4(+) T cells identified with Ag85A peptide-bearing HLA class II tetramers were characterized by flow cytometry. We also measured proliferative potential and cytokine expression of Ag85A-specific CD4(+) T cells. During the effector phase, MVA85A-induced specific CD4(+) T cells co-expressed IFN-γ and IL-2, skin homing integrins and the activation marker CD38. This was followed by contraction and a transition to predominantly IL-2-expressing, CD45RA(-) CCR7(+) CD27(+) or CD45RA(+) CCR7(+) CD27(+) specific CD4(+) T cells. These surface phenotypes were similar to Ag85A-specific T cells prior to MVA85A. However, functional differences were observed post-vaccination: specific proliferative capacity was markedly higher after 6-12 months than before vaccination. Our data suggest that MVA85A vaccination may modulate Ag85A-specific CD4(+) T-cell function, resulting in greater recall potential. Importantly, surface phenotypes commonly used as proxies for memory T-cell function did not associate with functional effects of vaccination. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2013; 43(9). DOI:10.1002/eji.201343454 · 4.52 Impact Factor
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    ABSTRACT: A better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.
    PLoS ONE 07/2013; 8(7):e67922. DOI:10.1371/journal.pone.0067922 · 3.53 Impact Factor
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