Clinical Development of New TB Vaccines: Recent Advances and Next Steps.

Mycobacterium tuberculosis (Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release assay (IGRA) negative adolescents provided 45% protection against sustained Mtb infection defined by IGRA conversion; and the protein-subunit vaccine M72/AS01 E provided 50% protection against progression from Mtb infection to tuberculosis disease in IGRA-positive adults. These findings provide encouraging evidence for pre-exposure and post-exposure approaches to vaccination against tuberculosis, both of which may be necessary to rapidly interrupt the cycle of Mtb transmission and sustain long-term impact on global tuberculosis control. New trials are needed to demonstrate efficacy of M72/AS01 E with greater precision, in a wider age range, in diverse epidemic settings, and in populations that include Mtb-uninfected and HIV-infected persons. Modeling the impact of mass campaigns with M72/AS01 E and other fast-follower vaccine candidates will be crucial to make the use case and demonstrate public health value for TB endemic countries. The size and scope of the next generation of efficacy trials, and the need to expand and accelerate the existing clinical development pipeline, will require public and private consortium funding and concerted political will

Guest Editorial

A novel blood test for tuberculosis prevention and treatmen

Comparison of Mantoux and Tine Tuberculin Skin Tests in BCG-Vaccinated Children Investigated for Tuberculosis

BACKGROUND:Tuberculin skin tests (TSTs) are long-established screening methods for tuberculosis (TB). We aimed to compare agreement between the intradermal Mantoux and multipuncture percutaneous Tine methods and to quantify risk factors for a positive test result. METHODOLOGY/PRINCIPAL FINDINGS:1512 South African children younger than 5 years of age who were investigated for tuberculosis (TB) during a Bacille Calmette Guerin (BCG) trial were included in this analysis. Children underwent both Mantoux and Tine tests. A positive test was defined as Mantoux >or=15 mm or Tine >or= Grade 3 for the binary comparison. Agreement was evaluated using kappa (binary) and weighted kappa (hierarchical). Multivariate regression models identified independent risk factors for TST positivity. The Mantoux test was positive in 430 children (28.4%) and the Tine test in 496 children (32.8%, p<0.0001), with observed binary agreement 87.3% (kappa 0.70) and hierarchical agreement 85.0% (weighted kappa 0.66). Among 173 children culture-positive for Mycobacterium tuberculosis, Mantoux was positive in 49.1% and Tine in 54.9%, p<0.0001 (kappa 0.70). Evidence of digit preference was noted for Mantoux readings at 5 mm threshold intervals. After adjustment for confounders, a positive culture, suggestive chest radiograph, and proximity of TB contact were risk factors for a positive test using both TST methods. There were no independent associations between ethnicity, gender, age, or over-crowding, and TST result. CONCLUSIONS/SIGNIFICANCE:The Tine test demonstrated a higher positive test rate than the Mantoux, with substantial agreement between TST methods among young BCG-vaccinated children. TB disease and exposure factors, but not demographic variables, were independent risk factors for a positive result using either test method. These findings suggest that the Tine might be a useful screening tool for childhood TB in resource-limited countries

Systematic review of diagnostic and prognostic host blood transcriptomic signatures of tuberculosis disease in people living with HIV [version 2; peer review: 2 approved]

Background HIV-associated tuberculosis (TB) has high mortality; however, current triage and prognostic tools offer poor sensitivity and specificity, respectively. We conducted a systematic review of diagnostic and prognostic host-blood transcriptomic signatures of TB in people living with HIV (PLHIV). Methods We systematically searched online databases for studies published in English between 1990-2020. Eligible studies included PLHIV of any age in test or validation cohorts, and used microbiological or composite reference standards for TB diagnosis. Inclusion was not restricted by setting or participant age. Study selection, quality appraisal using the QUADAS-2 tool, and data extraction were conducted independently by two reviewers. Thereafter, narrative synthesis of included studies, and comparison of signatures performance, was performed. Results We screened 1,580 records and included 12 studies evaluating 31 host-blood transcriptomic signatures in 10 test or validation cohorts of PLHIV that differentiated individuals with TB from those with HIV alone, latent Mycobacterium tuberculosis infection, or other diseases (OD). Two (2/10; 20%) cohorts were prospective (29 TB cases; 51 OD) and 8 (80%) case-control (353 TB cases; 606 controls) design. All cohorts (10/10) were recruited in Sub-Saharan Africa and 9/10 (90%) had a high risk of bias. Ten signatures (10/31; 32%) met minimum WHO Target Product Profile (TPP) criteria for TB triage tests. Only one study (1/12; 8%) evaluated prognostic performance of a transcriptomic signature for progression to TB in PLHIV, which did not meet the minimum WHO prognostic TPP. Conclusions Generalisability of reported findings is limited by few studies enrolling PLHIV, limited geographical diversity, and predominantly case-control design, which also introduces spectrum bias. New prospective cohort studies are needed that include PLHIV and are conducted in diverse settings. Further research exploring the effect of HIV clinical, virological, and immunological factors on diagnostic performance is necessary for development and implementation of TB transcriptomic signatures in PLHIV

Systematic review of diagnostic and prognostic host blood transcriptomic signatures of tuberculosis disease in people living with HIV [version 1; peer review: 2 approved]

Background HIV-associated tuberculosis (TB) has high mortality; however, current triage and prognostic tools offer poor sensitivity and specificity, respectively. We conducted a systematic review of diagnostic and prognostic host-blood transcriptomic signatures of TB in people living with HIV (PLHIV). Methods We systematically searched online databases for studies published in English between 1990-2020. Eligible studies included PLHIV of any age in test or validation cohorts, and used microbiological or composite reference standards for TB diagnosis. Inclusion was not restricted by setting or participant age. Study selection, quality appraisal using the QUADAS-2 tool, and data extraction were conducted independently by two reviewers. Thereafter, narrative synthesis of included studies, and comparison of signatures performance, was performed. Results We screened 1,580 records and included 12 studies evaluating 31 host-blood transcriptomic signatures in 10 test or validation cohorts of PLHIV that differentiated individuals with TB from those with HIV alone, latent Mycobacterium tuberculosis infection, or other diseases (OD). Two (2/10; 20%) cohorts were prospective (29 TB cases; 51 OD) and 8 (80%) case-control (353 TB cases; 606 controls) design. All cohorts (10/10) were recruited in Sub-Saharan Africa and 9/10 (90%) had a high risk of bias. Ten signatures (10/31; 32%) met minimum WHO Target Product Profile (TPP) criteria for TB triage tests. Only one study (1/12; 8%) evaluated prognostic performance of a transcriptomic signature for progression to TB in PLHIV, which did not meet the minimum WHO prognostic TPP. Conclusions Generalisability of reported findings is limited by few studies enrolling PLHIV, limited geographical diversity, and predominantly case-control design, which also introduces spectrum bias. New prospective cohort studies are needed that include PLHIV and are conducted in diverse settings. Further research exploring the effect of HIV clinical, virological, and immunological factors on diagnostic performance is necessary for development and implementation of TB transcriptomic signatures in PLHIV

Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.

Achieving the WHO End-Tuberculosis (TB) targets requires approaches to prevent progression to TB among individuals with Mycobacterium tuberculosis (M.tb) infection. Effective preventive therapy (PT) exists, but current tests have low specificity for identifying who, among those infected, is at risk of developing TB. Using mathematical models, we assessed the potential population-level impact on TB incidence of using a new more specific mRNA expression signature (COR) to target PT among HIV-uninfected adults in South Africa. We compared the results to the use of the existing interferon-γ release assay (IGRA). With annual screening coverage of 30% COR-targeted PT could reduce TB incidence in 2035 by 20% (95% CI 15-27). With the same coverage, IGRA-targeted PT could reduce TB incidence by 39% (31-48) but would require greater use of PT resulting in a higher number needed to treat per TB case averted (COR: 49 (29-77); IGRA: 84 (59-123)). The relative differences between COR and IGRA were not sensitive to screening coverage. COR-targeted PT could contribute to reducing total TB burden in high incidence countries like South Africa by allowing more efficient targeting of treatment. To maximise impact, COR-like tests may be best utilised in the highest burden regions, or sub-populations, within these countries

The impact of blood transcriptomic biomarker targeted tuberculosis preventive therapy in people living with HIV: a mathematical modelling study

Background Tuberculosis (TB) preventive therapy is recommended for all people living with HIV (PLHIV). Despite the elevated risk of TB amongst PLHIV, most of those eligible for preventive therapy would never develop TB. Tests which can identify individuals at greatest risk of disease would allow more efficient targeting of preventive therapy. Methods We used mathematical modelling to estimate the potential impact of using a blood transcriptomic biomarker (RISK11) to target preventive therapy amongst PLHIV. We compared universal treatment to RISK11 targeted treatment and explored the effect of repeat screening of the population with RISK11. Results Annual RISK11 screening, with preventive therapy provided to those testing positive, could avert 26% (95% CI 13–34) more cases over 10 years compared to one round of universal treatment. For the cost per case averted to be lower than universal treatment, the maximum cost of the RISK11 test was approximately 10% of the cost of preventive therapy. The benefit of RISK11 screening may be greatest amongst PLHIV on ART (compared to ART naïve individuals) due to the increased specificity of the test in this group. Conclusions Biomarker targeted preventive therapy may be more effective than universal treatment amongst PLHIV in high incidence settings but would require repeat screening

Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trial

Objective To compare the incidence of tuberculosis over two years in infants vaccinated at birth with intradermal BCG or with percutaneous BCG

The candidate TB vaccine, MVA85A, induces highly durable Th1 responses

BACKGROUND: Vaccination against tuberculosis (TB) should provide long-term protective immunity against Mycobacterium tuberculosis ( M.tb ). The current TB vaccine, Bacille Calmette-Guerin (BCG), protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone. METHODS: We describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011. RESULTS: Of 252 potential participants, 183 (72.6%) consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA−CCR7+ central memory or CD45RA−CCR7− effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3-5 years after vaccination. CONCLUSION: MVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not enhance BCG-induced protection against TB in infants

TB incidence in an adolescent cohort in South Africa

BACKGROUND: Tuberculosis (TB) is a major public health problem globally. Little is known about TB incidence in adolescents who are a proposed target group for new TB vaccines. We conducted a study to determine the TB incidence rates and risk factors for TB disease in a cohort of school-going adolescents in a high TB burden area in South Africa. METHODS: We recruited adolescents aged 12 to 18 years from high schools in Worcester, South Africa. Demographic and clinical information was collected, a tuberculin skin test (TST) performed and blood drawn for a QuantiFERON TB Gold assay at baseline. Screening for TB cases occurred at follow up visits and by surveillance of registers at public sector TB clinics over a period of up to 3.8 years after enrolment. RESULTS: A total of 6,363 adolescents were enrolled (58% of the school population targeted). During follow up, 67 cases of bacteriologically confirmed TB were detected giving an overall incidence rate of 0.45 per 100 person years (95% confidence interval 0.29-0.72). Black or mixed race, maternal education of primary school or less or unknown, a positive baseline QuantiFERON assay and a positive baseline TST were significant predictors of TB disease on adjusted analysis. CONCLUSION: The adolescent TB incidence found in a high burden setting will help TB vaccine developers plan clinical trials in this population. Latent TB infection and low socio-economic status were predictors of TB disease