A major event for new TB 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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    • "In all trials to date, MVA85A induces antigen-specific Th1 and Th17 cells, believed to be important in protection against tuberculosis [9-11]. If, as has been suggested [12], low T cell responses to vaccination in this trial contributed to the lack of vaccine efficacy, understanding the mechanisms determining the magnitude of the response to vaccination is important to the development of an improved vaccine. "
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    ABSTRACT: BackgroundTuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population.MethodsWe investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis.ResultsOne day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A.ConclusionThe results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies.Trial number NCT00953927
    BMC Infectious Diseases 06/2014; 14(1):314. DOI:10.1186/1471-2334-14-314 · 2.61 Impact Factor
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    • "These vaccines consistently induce strong Th1 responses [14,16,45] however the magnitude of these responses varies between individuals and populations with potential impact for the applicability of early clinical studies. For example, lack of enhanced efficacy in a recent trial in BCG-vaccinated infants may link to lower immunogenicity in this population compared to UK adults [6,46]. An understanding of the processes linking recognition of the vector and early immune events at a molecular level to the vaccine-elicited immune response will aid the future development of these vaccines. "
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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 · 3.23 Impact Factor
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