Comparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal delivery

Meyer, Joel N.; Harris, Stephanie A.; Satti, Iman; Poulton, Ian; Poyntz, Hazel C.; Tanner, Rachel; Rowland, Rosalind; Griffiths, Kristin; Fletcher, Helen A.; McShane, Helen

doi:10.1016/j.vaccine.2012.12.042

Cited by 48 publications

(60 citation statements)

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“…Our results suggest that the CD4-positive T cells induced by MVA85A—at least at the modest frequencies noted in this trial—do not correlate with protection against tuberculosis or M tuberculosis infection. Frequencies of antigen-specific Th1 cells observed in infants with MVA85A were up to a tenth of the frequencies noted in adults 16, 25…”

Section: Discussionmentioning

confidence: 86%

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial

et al. 2013

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SummaryBackgroundBCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants.MethodsIn our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927FindingsBetween July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9).InterpretationMVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.FundingAeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).

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Section: Discussionmentioning

confidence: 86%

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial

et al. 2013

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“…Full details of the trial have been published [30]. Peripheral blood mononuclear cells (PBMC) from volunteers were cryopreserved on day of vaccination and at the following timepoints: day 2 and weeks 1, 2, 4 and 12 post-vaccination.…”

Section: Resultsmentioning

confidence: 99%

“…The median IFN-γ ELISpot responses to 85A peptides were not significantly different between the IM and ID groups at any time point [30] and, from a filtered list of 22,000 genes, no genes were differentially expressed between the two groups at any time point. Both groups were therefore combined for all subsequent analyses.…”

Section: Resultsmentioning

confidence: 99%

Roles for Treg Expansion and HMGB1 Signaling through the TLR1-2-6 Axis in Determining the Magnitude of the Antigen-Specific Immune Response to MVA85A

et al. 2013

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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.

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“…Finally, we compare these findings with previous work performed in UK adults receiving the same vaccine [23], in an effort to characterise some of the differences between these populations.…”

Section: Introductionmentioning

confidence: 81%

Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response

et al. 2014

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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 registrationClinicalTrials.gov number NCT00953927

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Comparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal delivery

Abstract: Highlights► Candidate TB vaccine MVA85A is well tolerated intramuscularly or intradermally. ► Both routes are highly immunogenic. ► MVA85A-induced CD4+ T cell cytokine production was similar between the two routes.

Cited by 48 publications

References 37 publications

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial

Roles for Treg Expansion and HMGB1 Signaling through the TLR1-2-6 Axis in Determining the Magnitude of the Antigen-Specific Immune Response to MVA85A

Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response

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