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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. In 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 NCT00953927 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 19·2–28·1), 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). 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. Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).

Mycobacterium tuberculosis remains a major global health threat. In this report, the M72/AS01 E vaccine provided approximately 50% protection against progression to active tuberculosis disease in adults.

Mycobacterium tuberculosis is a major global pathogen. In this trial in sub-Saharan Africa, a new vaccine was found to have 54% efficacy against the development of active pulmonary M. tuberculosis in infected adults.

Abstract Rationale Global tuberculosis (TB) control requires effective vaccines in TB-endemic countries, where most adults are infected with Mycobacterium tuberculosis (M.tb). Objectives We sought to define optimal dose and schedule of H56:IC31, an experimental TB vaccine comprising Ag85B, ESAT-6, and Rv2660c, for M.tb-infected and M.tb-uninfected adults. Methods We enrolled 98 healthy, HIV-uninfected, bacillus Calmette-Guérin–vaccinated, South African adults. M.tb infection was defined by QuantiFERON-TB (QFT) assay. QFT-negative participants received two vaccinations of different concentrations of H56 in 500 nmol of IC31 to enable dose selection for further vaccine development. Subsequently, QFT-positive and QFT-negative participants were randomized to receive two or three vaccinations to compare potential schedules. Participants were followed for safety and immunogenicity for 292 days. Measurements and Main Results H56:IC31 showed acceptable reactogenicity profiles irrespective of dose, number of vaccinations, or M.tb infection. No vaccine-related severe or serious adverse events were observed. The three H56 concentrations tested induced equivalent frequencies and functional profiles of antigen-specific CD4 T cells. ESAT-6 was only immunogenic in QFT-negative participants who received three vaccinations. Conclusions Two or three H56:IC31 vaccinations at the lowest dose induced durable antigen-specific CD4 T-cell responses with acceptable safety and tolerability profiles in M.tb-infected and M.tb-uninfected adults. Additional studies should validate applicability of vaccine doses and regimens to both QFT-positive and QFT-negative individuals. Clinical trial registered with www.clinicaltrials.gov (NCT01865487).

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. BCG vaccine confers only partial protection against tuberculosis. Here the authors show that the risk of tuberculosis infection and progression to disease in BCG-immunized children positively correlates with the frequency of activated HLA-DR + CD4 + T cells.

H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis (M.tb) infection. Low dose (15μg H56 protein in 500nmol IC31) or high dose (50μg H56, 500nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA. One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4+ T cells. M.tb-infected vaccinees had higher frequencies of H56-induced CD4+ T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ+TNF-α+IL-2+) and higher frequencies of H56-specific CD4+ T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4+ T cells, displaying a CD45RA−CCR7− effector memory phenotype, emerged after the second high-dose vaccination in M.tb-infected vaccinees. TNF-α+IL-2+ H56-specific memory CD4+ T cells were detected mostly after low-dose H56 vaccination in M.tb-infected vaccinees, and predominantly expressed a CD45RA−CCR7+ central memory phenotype. Our results support further clinical testing of H56:IC31.

Human breath contains trace amounts of non-volatile organic compounds (NOCs) which might provide non-invasive methods for evaluating individual health. In previous work, we demonstrated that lipids detected in exhaled breath aerosol (EBA) could be used as markers of active tuberculosis (TB). Here, we advanced our analytical platform for characterizing small metabolites and lipids in EBA samples collected from participants enrolled in clinical trials designed to identify molecular signatures of active TB. EBA samples from 26 participants with active TB and 73 healthy participants were processed using a dual-phase extraction method, and metabolites and lipids were identified via mass spectrometry database matching. In total, 13 metabolite and 9 lipid markers were identified with statistically different optimized relative standard deviation values between individuals diagnosed with active TB and the healthy controls. Importantly, EBA lipid profiles can be used to separate the two sample types, indicating the diagnostic potential of the identified molecules. A feature ranking algorithm reduced this number to 10 molecules, with the membrane glycerophospholipid, phosphatidylinositol 24:4, emerging as the top driver of segregation between the two groups. These results support the use of this approach to identify consistent NOC signatures from EBA samples in active TB cases. This suggests the potential to apply this method to other human diseases which alter respiratory NOC release.

Background COVID-19 vaccine hesitancy has threatened the ability of many countries worldwide to contain the pandemic. Given the severe impact of the pandemic in South Africa and disruptions to the roll-out of the vaccine in early 2021, slower-than-expected uptake is a pressing public health challenge in the country. We examined longitudinal changes in COVID-19 vaccination intent among South African adults, as well as determinants of intent to receive a vaccine. Methods We used longitudinal data from Wave 4 (February/March 2021) and Wave 5 (April/May 2021) of the National Income Dynamics Study: Coronavirus Rapid Mobile Survey (NIDS-CRAM), a national and broadly representative panel survey of adults in South Africa. We conducted cross-sectional analyses on aggregate and between-group variation in vaccination intent, examined individual-level changes between waves, and modeled demographic predictors of intent. Results We analysed data for 5629 (Wave 4; 48% male, mean age 41.5 years) and 5862 (Wave 5; 48% male, mean age 41.6 years) respondents. Willingness to get a COVID-19 vaccine significantly increased from 70.8% (95% CI: 68.5–73.1) in Wave 4 to 76.1% (95% CI: 74.2–77.8) in Wave 5. Individual-level analyses indicated that only 6.6% of respondents remained strongly hesitant between survey waves. Although respondents aged 18–24 years were 8.5 percentage points more likely to report hesitancy, hesitant respondents in this group were 5.6 percentage points more likely to change their minds by Wave 5. Concerns about rushed testing and safety of the vaccines were frequent and strongly-held reasons for hesitancy. Conclusions Willingness to receive a COVID-19 vaccine has increased among adults in South Africa, and those who were entrenched in their reluctance make up a small proportion of the country’s population. Younger adults, those in formal housing, and those who trusted COVID-19 information on social media were more likely to be hesitant. Given that stated vaccination intent may not translate into behaviour, our finding that three-quarters of the population were willing to accept the vaccine may reflect an upper bound. Vaccination promotion campaigns should continue to frame vaccine acceptance as the norm and tailor strategies to different demographic groups.

Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb , and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN- α 2, TNF- α , CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb . The identification of immune correlates of protection in humans would inform on the design and development of tuberculosis vaccine candidates. In this work, authors examine samples collected from South African infants, to determine whether the correlates of risk of tuberculosis disease, previously identified in this population, are also correlates of risk of M. tuberculosis infection.

We explored the underlying mechanisms that may drive post-tuberculosis (TB) lung disease, a multifactorial, heterogenous, and prevalent disease. Extensive clinical phenotyping through fluorine-18 Fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) scans, pulmonary function testing, and symptom and quality of life questionnaires, was performed on a cohort of 48 adults who completed TB treatment within 6 months prior. Immunological characteristics of paired blood- and bronchoalveolar lavage fluid (BALF)-derived immune cells were assessed by multiplex bead-based immunoassay, ELISA and flow cytometry. There was agreement between measures of inflammation on PET, the severity of anatomical abnormalities on CT, and pulmonary function testing. However, of these, only PET was associated with exercise tolerance and symptom scores. Measures of radiologic extent (total glycolytic activity and SUVmax on PET, and segments involved on CT) also correlated with proteins detected in blood that implicate type 1 (IFN-γ, TNFα, IL-12) and type 2 (IL-4, IL-33) responses, ongoing remodelling of lung tissue (MMPs), airways and vasculature (VEGF), as well as subsets of activated CD8 + and CD4 + T-cells. The radiologic extent of structural post-TB lung involvement is associated with a range of impaired lung function measures and immunological dysregulation. Our findings suggest that obstructive and restrictive lung pathology due to pulmonary TB do not occur in opposition but rather point towards a mixed pathology in most TB survivors.