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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Available from: Christopher Dye, Nov 30, 2015
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    • "Osteomyelitis/osteitis is a rare but serious complication of BCG immunization, even in immunocompetent children [1] [2] [3] [4]. Because new TB vaccines in the pipeline have not shown promising results in human trials so far [5], understanding how to best treat BCG complications is extremely important. BCG osteomyelitis/osteitis, typically presents in children 1–2 years after BCG inoculation who develop insidious clinical symptoms/signs despite massive radiologic findings. "
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    ABSTRACT: Bacillus Calmette-Guérin (BCG) osteomyelitis/osteitis in immunocompetent children is a rare but serious complication of BCG immunization. Rationale for its treatment is unclear. Due to the rarity of this complication, no randomized control trials has ever been conducted to evaluate methods of intervention. As such, we searched the literature for any reported BCG vaccination-related osteomyelitis/osteitis among immune-competent children published before April 15, 2014. We summarized the data from different affected regions of the body by recording the number of reported cases, while noting outcomes and their medical and/or surgical interventions. From 34 eligible studies gleaned from a screening of 804 articles, a total of 331 cases were enrolled. Involvement of the lower limbs was present in 55.6%, followed by the axial skeleton (26.0%), the upper limbs (15.4%), and multiple bones (3.0%). Of the 64 patients having records of detailed chemotherapy regimens, 45 patients (70%) received two or fewer drugs. Among the 80 patients with detailed surgical records, 50 (62.5%) received surgical procedures for diagnostic purposes. While there were uneventful outcomes for those receiving diagnostic procedures, 7 of the 30 (23.3%) patients receiving surgical interventions had major complications (p=0.002, Fisher's exact test). The overall prognosis was good with a 97.6% cure rate. Nevertheless, eight patients (2.4%) suffered major complications. The rationale for treatment of BCG osteomyelitis/osteitis in immunocompetent children is highly subjective. However, patients receiving diagnostic procedures instead of surgical interventions may avoid major complications. Because only a few of the publications had detailed treatment information, further studies are needed to identify proper treatments, while infant BCG vaccination is still in use. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jul 2015 · Vaccine
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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).
    Full-text · Article · Jun 2014
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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
    Full-text · Article · Jun 2014 · BMC Infectious Diseases
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