Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial.

RATIONALE: Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions. OBJECTIVES: To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB. METHODS: We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS: No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8+ and moderate CD4+ T-cell responses, mainly to Ag85B in both vaccine groups. CONCLUSIONS: Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

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

BACKGROUND: BCG 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. METHODS: In our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4­6 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 NCT00953927. FINDINGS: Between 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 19·2­28·1), 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). INTERPRETATION: MVA85A 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. FUNDING: Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).

A phase 2b, Randomized, double blinded comparison of the safety and efficacy of the monoclonal antibody mixture SYN023 and human rabies immune globulin in patients exposed to rabies.

BACKGROUND: SYN023 is an anti-rabies monoclonal antibody mixture administered as part of post-exposure prophylaxis regimens. The rabies virus neutralizing antibody (RVNA) concentration generally accepted as an adequate immune response to vaccination is ≥ 0.5 IU/mL. METHODS: Within 54 h of potential rabies exposure, 448 patients in two risk substrata of WHO Category III exposure were randomized to receive either 0.3 mg/kg SYN023 or 0.133 mL/kg human rabies immunoglobulin (HRIG) injected in and around the wound site(s) plus a course of rabies vaccination. Patients were followed for safety and absence of rabies for ≥ 365 days. RESULTS: GMT RVNA was higher with SYN023 throughout the 2-week post-treatment period. In the primary analysis group (n = 368), 99.4 % of SYN023 recipients versus 4.5 % of HRIG recipients had protective RVNA levels on Day 4. On Day 8, 98.1 % SYN023 versus 12.2 % HRIG recipients were protected. The SYN023:HRIG ratio of geometric mean titer of RVNA (RVNA GMTs) on Day 8 (19.42) exceeded the 10 % superiority margin (P < 0.0001) indicating higher Day 8 RVNA with SYN023. On Day 99, the SYN023:HRIG RVNA GMT ratio (0.66) was below the non-inferiority margin of 20 % (P = 0.9485) suggesting some moderation of vaccine immune response by SYN023 relative to HRIG. The ratio of percent SYN023:HRIG recipients achieving RVNA ≥ 0.5 IU/mL on Day 99 (0.98) met the non-inferiority margin of 20 % (P = 0.013) indicating anti-rabies immune response with SYN023 was non-inferior to HRIG despite this effect. There were no probable/confirmed rabies cases in any patient. Study regimens were well tolerated. CONCLUSIONS: SYN023 provided higher RVNA than HRIG soon after rabies exposure. By Day 99 post-treatment, GM RVNA with SYN023 was lower than HRIG, however, the percent of SYN023 recipients with a protective response was not inferior at this time point. No rabies cases were reported in the study. The SYN023 safety profile was acceptable. CLINICALTRIALS: gov ID: NCT03961555.

The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults.

RATIONALE: AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine. OBJECTIVES: We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a tuberculosis-endemic region of South Africa. METHODS: Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4(+) and CD8(+) T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells. MEASUREMENTS AND MAIN RESULTS: AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4(+) T-cell response dominated by cells coexpressing IFN-gamma, tumor necrosis factor-alpha, and IL-2 ("polyfunctional" cells). AERAS-402 also induced a potent CD8(+) T-cell response, characterized by cells expressing IFN-gamma and/or tumor necrosis factor-alpha, which persisted for the duration of the study. CONCLUSIONS: Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8(+) T cells are also important. AERAS-402 induced a robust and durable CD8(+) T-cell response, which appears extremely promising. Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381).

Safety, Pharmacokinetics, and Neutralizing Activity of SYN023, a Mixture of Two Novel Antirabies Monoclonal Antibodies Intended for Use in Postrabies Exposure Prophylaxis.

SYN023 is a mixture of 2 humanized monoclonal antirabies antibodies (CTB011, CTB012). Two first-in-human studies evaluated ascending intramuscular (IM) injected doses (Study SYN023-001; N = 15) and IM vs subcutaneous (SC) administration (Study SYN023-003; N = 35) in healthy adults. In both studies, end points were safety, pharmacokinetics (PK), pharmacodynamics/rabies virus neutralizing activity (RVNA), and immunogenicity (anti-SYN023 antibodies). Adverse events were mild and infrequent at all doses tested by IM injection (0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg), or by SC injection (0.3 mg/kg). There were no apparent trends in adverse event frequency or nature with increased dose or with administration route. Serum PK of SYN023 component antibodies appeared comparable to each other at each dose tested and when administered IM versus SC with serum exposure doubling over the second week after administration. At the lowest dose tested (0.3 mg/kg) by either IM or SC injection, RVNA levels exceeded the concentration generally accepted as protective against rabies (≥0.5 IU/mL) by day 1 after administration. Supra-inhibitory levels persisted >42 days. RVNA increased with higher doses. Anti-CTB011 and anti-CTB012 antibodies occurred with no apparent effect on PK or safety. These data support the potential use of SYN023 in antirabies postexposure prophylaxis.

Rabies virus neutralizing activity, pharmacokinetics, and safety of the monoclonal antibody mixture SYN023 in combination with rabies vaccination: Results of a phase 2, randomized, blinded, controlled trial.

BACKGROUND: SYN023-002 is a randomized, blinded, controlled study comparing rabies virus neutralizing activity (RVNA) and safety of SYN023, a monoclonal anti-rabies antibody mixture, to human-serum derived anti-rabies immunoglobulin (RIG) when administered with commercially available vaccines to healthy adult volunteers. METHODS: Participants were randomized among 4 treatment groups (SYN023 + Imovax, SYN023 + RabAvert, HyperRab + Imovax, HyperRab + RabAvert). On Day 0, subjects received 1 dose of RIG (0.3 mg/kg SYN023 or 20 IU/mL HyperRab) and their first of 5 vaccine doses. The primary objective was to compare cumulative RVNA between SYN023 and HyperRab recipients. Secondary objectives were to compare safety and to assess SYN023 pharmacokinetics and immunogenicity. RESULTS: All 164 randomized subjects initiated treatment and were included in safety analyses. At least 34 subjects/treatment group received all treatment and had complete RVNA results, thus were included in the primary endpoint analysis. Mean RVNAs were approximately ten-fold higher in SYN023 recipients compared to HyperRab recipients until Day 14. From Day 14 onwards, mean RVNA was lower in SYN023 recipients, but remained above the RVNA level widely considered adequate (≥0.5 IU/mL) through Day 112 (study end). The point estimate of the cumulative RVNA (83.22% SYN023/HyperRab), but not the lower CI bound (90% CI: 66.06%, 104.83%), fell within the protocol-defined similarity margin. Each RIG + vaccine regimen appeared safe with mostly mild AEs and no serious or severe related events observed. Except injection site pain (22% HyperRab recipients vs. 6% SYN023 recipients), treatment-related AEs incidences were similar between RIGs. Anti-SYN023 antibodies were observed but had no apparent effects on PK or safety. CONCLUSIONS: SYN023 administered with commercially available vaccines provides adequate antibody coverage beginning earlier than other commercially available RIGs with an acceptable safety profile. Some suppression of vaccine response occurred, but RVNA levels ≥ 0.5 IU/mL were maintained throughout the relevant period. REGISTRATION: ClinicalTrials.gov #NCT02956746. FUNDING: Synermore biologics.

Cytomegalovirus infection is a risk factor for tuberculosis disease in infants.

Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first 2 years of life, and 129 healthy matched controls, we found the cytomegalovirus-stimulated (CMV-stimulated) IFN-γ response to be associated with CD8+ T cell activation (Spearman's rho, P = 6 × 10-8). A CMV-specific IFN-γ response was also associated with increased risk of developing TB disease (conditional logistic regression; P = 0.043; OR, 2.2; 95% CI, 1.02-4.83) and shorter time to TB diagnosis (Log Rank Mantel-Cox, P = 0.037). CMV+ infants who developed TB disease had lower expression of NK cell-associated gene signatures and a lower frequency of CD3-CD4-CD8- lymphocytes. We identified transcriptional signatures predictive of TB disease risk among CMV ELISpot-positive (area under the receiver operating characteristic [AUROC], 0.98, accuracy, 92.57%) and -negative (AUROC, 0.9; accuracy, 79.3%) infants; the CMV- signature was validated in an independent infant study (AUROC, 0.71; accuracy, 63.9%). A 16-gene signature that previously identified adolescents at risk of developing TB disease did not accurately classify case and control infants in this study. Understanding the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study.

BACKGROUND: The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion. METHODS: We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18-24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35-4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6-24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test. FINDINGS: Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4-1·1]), children with QFT conversion at interferon-γ values between 0·35-4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4-9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4-15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9-45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2-99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35-4·00 IU/mL (IRR 11·4 [95% CI 2·4-107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61). INTERPRETATION: In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children. FUNDING: Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC) were the funders of the MVA85A 020 Trial. National Institute of Allergy and Infectious Diseases supported this analysis.

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.

BACKGROUND: Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. METHODS: BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150µg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. RESULTS: H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50µg of H4 in combination with the 500nmol IC31 adjuvant dose. CONCLUSIONS: The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50µg of H4 and 500nmol of IC31. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02066428 and NCT02074956.

Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy, BCG-vaccinated, QuantiFERON(®)-TB Gold (+) Kenyan adults without evidence of tuberculosis.

In a Phase 1 trial, we evaluated the safety of AERAS-402, an adenovirus 35-vectored TB vaccine candidate expressing 3 Mycobacterium tuberculosis (Mtb) immunodominant antigens, in subjects with and without latent Mtb infection. HIV-negative, BCG-vaccinated Kenyan adults without evidence of tuberculosis, 10 QuantiFERON(®)-TB Gold In-Tube test (QFT-G)(-) and 10 QFT-G(+), were randomized 4:1 to receive AERAS-402 or placebo as two doses, on Days 0 and 56, with follow up to Day 182. There were no deaths, serious adverse events or withdrawals. For 1 AERAS-402 QFT-G(-) and 1 AERAS-402 QFT-G(+) subject, there were 3 self-limiting severe AEs of injection site pain: 1 after the first vaccination and 1 after each vaccination, respectively. Two additional severe AEs considered vaccine-related were reported after the first vaccination in AERAS-402 QFT-G(+) subjects: elevated blood creatine phosphokinase and neutropenia, the latter slowly improving but remaining abnormal until study end. AERAS-402 was not detected in urine or throat cultures for any subject. In intracellular cytokine staining studies, curtailed by technical issues, we saw modest CD4+ and CD8+ T cell responses to Mtb Ag85A/b peptide pools among both QFT-G(-) and (+) subjects, with trends in the CD4+ T cells suggestive of boosting after the second vaccine dose, slightly more so in QFT-G(+) subjects. CD4+ and CD8+ responses to Mtb antigen TB10.4 were minimal. Increases in Adenovirus 35 neutralizing antibodies from screening to end of study, seen in 50% of AERAS-402 recipients, were mostly minimal. This small study confirms acceptable safety and tolerability profiles for AERAS-402, in line with other Phase 1 studies of AERAS-402, now to include QFT-G(+) subjects.

T-cell activation is an immune correlate of risk in BCG vaccinated infants.

Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case-control analysis to identify immune correlates of TB disease risk in Bacille Calmette-Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR(+) CD4(+) T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25-2.68, P=0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis-infected adolescents, activated HLA-DR(+) CD4(+) T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068-1.801, P=0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29-0.86, P=0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations.

The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV-infected, BCG-vaccinated adults with CD4(+) T cell counts >350 cells/mm(3).

BACKGROUND: The safety and immunogenicity of a replication deficient adenovirus serotype 35 tuberculosis (TB) vaccine containing gene inserts for Antigens (Ag) 85A, Ag85B and TB10.4 (AERAS-402/AD35.TB-S) was evaluated in previously BCG vaccinated, HIV-infected South African adults with baseline CD4 counts >350 cells/mm(3). METHODS: Subjects were randomized (1:1) to receive two doses of either intramuscular AERAS-402/AD35.TB-S or placebo at month 0 and at month 1. Participants were monitored for adverse events 28 days after each vaccination and for serious adverse events over 12 months. CD4(+) and CD8(+) T-cell and antibody responses to vaccine antigens were evaluated post first and second vaccination. RESULTS: 26 subjects were randomly assigned to receive AERAS-402/AD35.TB-S (N=13) or placebo (N=13). The mean age was 29.0 years, all were Black-African, 88.5% were female, 46.2% were QuantiFERON Test (QFT) positive at baseline, and the median CD4 count was 559.5 cells/mm(3), all similar by treatment group. All subjects received their first vaccination and 24 subjects received their second vaccination. Injection site reactions and some systemic reactions were reported more commonly in the AERAS-402/AD35.TB-S versus placebo recipients. AERAS-402/AD35.TB-S did not appear to influence CD4 counts and HIV-1 viral load over the course of study follow-up. AERAS-402/AD35.TB-S induced a mixed CD4(+) T-cell and CD8(+) T-cell responses to Ag85B. The CD4(+) T-cell responses peaked to Ag85A and Ag85B 14 days after the second vaccination and had declined by Day 182. AERAS-402/AD35.TB-S predominantly induced CD4(+) T-cells expressing three (IFN-γ, TNF, IL-2) or two (IL-2 and TNF) cytokines, two weeks after the last vaccination, which did not differ by baseline Quantiferon test status. AERAS-402/AD35.TB-S induced strong Ag85A and Ag85B specific antibody responses, particularly after the second vaccination. CONCLUSION: AERAS-402/AD35.TB-S was well tolerated, safe and induced predominantly polyfunctional CD4(+) and CD8(+) T-cell responses to vaccine.

Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG.

BACKGROUND: New tuberculosis (TB) vaccines are being developed to combat the global epidemic. A phase IIb trial of a candidate vaccine, MVA85A, was conducted in a high burden setting in South Africa to evaluate proof-of-concept efficacy for prevention of TB in infants. OBJECTIVE: To describe the study design and implementation lessons from an infant TB vaccine efficacy trial. METHODS: This was a randomised, controlled, double-blind clinical trial comparing the safety and efficacy of MVA85A to Candin control administered to 4-6-month-old, BCG-vaccinated, HIV-negative infants at a rural site in South Africa. Infants were followed up for 15-39 months for incident TB disease based on pre-specified endpoints. RESULTS: 2797 infants were enrolled over 22 months. Factors adversely affecting recruitment and the solutions that were implemented are discussed. Slow case accrual led to six months extension of trial follow up. CONCLUSION: The clinical, regulatory and research environment for modern efficacy trials of new TB vaccines are substantially different to that when BCG vaccine was first evaluated in infants. Future infant TB vaccine trials will need to allocate sufficient resources and optimise operational efficiency. A stringent TB case definition is necessary to maximize specificity, and TB case accrual must be monitored closely.

A recombinant adenovirus expressing immunodominant TB antigens can significantly enhance BCG-induced human immunity.

BACKGROUND: Despite the availability of Bacille Calmette Guérin (BCG) vaccines, Mycobacterium tuberculosis currently infects billions of people and millions die annually from tuberculosis (TB) disease. New TB vaccines are urgently needed. METHODS: We studied the ability of AERAS-402, a recombinant, replication-deficient adenovirus type 35 expressing the protective M. tuberculosis antigens Ag85A, Ag85B, and TB10.4, to boost BCG immunity in an area of low TB endemicity. RESULTS: In volunteers primed with BCG 3 or 6 months prior to AERAS-402 boosting, significant CD4(+) and CD8(+) T cell responses were induced. Ag85-specific responses were more strongly boosted than TB10.4-specific responses. Frequencies of TB-specific CD8(+) T cells reached>50 fold higher than pre-AERAS boosting levels, remarkably higher than reported in any previous human TB vaccine trial. Multiparameter flow cytometric assays demonstrated that AERAS-402-boosted CD4(+) and CD8(+) T cells were multifunctional, producing multiple cytokines and other immune effector molecules. Furthermore, boosted T cells displayed lymphoproliferative capacity, and tetramer analyses confirmed that antigen-specific CD8(+) T cells were induced. BCG and AERAS-402 vaccinations given 3 and 6 months apart appeared equivalent. CONCLUSIONS: Our results indicate that AERAS-402 is a promising TB vaccine candidate that can significantly enhance both CD4(+) and CD8(+) TB-specific T cell responses after BCG priming. ClinicalTrials.gov Identifier: NCT01378312.