To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in lowand middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middleincome countries, respectively. Increased investments in adulttargeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies. mathematical modeling | epidemiology | threshold analysis T he bacterium Mycobacterium tuberculosis was responsible for ∼8.6 million cases of tuberculosis (TB) disease and ∼1.3 million deaths in 2012 (1), of which over 80% were in lowincome countries (LICs) and middle-income countries. This burden remains despite the widespread use of the infant TB vaccine, bacille Calmette-Guérin (bacillus Calmette-Guérin) (2). Dramatic levels of control are required to reach the World Health Organization (WHO) targets of TB elimination as a public health problem by 2050 (3). Previous mathematical modeling has suggested elimination can only be achieved through the use of new vaccines (4-7).In 2013, there were more than a dozen new TB vaccines in clinical trials, using a large range of antigens and adjuvants (8). A variety of modes of action and target populations are being researched (9, 10). The most recent TB vaccine tested in a largescale phase II trial reported a nonsignificant impact on TB disease of 17.3% [95% confidence interval (CI): −31.9 to 48.2] (11). However, such an undertaking highlights the progress that has been made in TB vaccine clinical trials, as well as the need for a reevaluation of the potential impact and need for increased investment in new TB vaccines (12).Estimates of the likely impact and cost-effectiveness of new products before and during development are useful for informing target product profiles and guiding produc...

The potential impact of COVID-19-related disruption on tuberculosis burden To the Editor: Before the coronavirus disease 2019 (COVID-19) pandemic, over 4000 people were dying from tuberculosis (TB) every day [1]. As with past emergencies [2], the impact of COVID-19 on TB outcomes is a serious cause for concern [3] but is currently unknown. Health system overload, due to high numbers of COVID-19 cases, as well as interventions necessary to limit the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could result in severe reductions in health service availability and access for the detection and treatment of TB cases [4]. However, physical distancing interventions could also limit Mycobacterium tuberculosis transmission outside of households, where most transmission occurs [5]. This has not been adequately explored in concurrent work [6-8], and it is currently unclear whether social distancing could compensate for disruptions in TB services, and what the impact of these combined COVID-19 disruption effects on TB burden is likely to be.

Bill and Melinda Gates Foundation.

Mathematical models are useful for assessing the potential epidemiological impact of future tuberculosis (TB) vaccines. We conducted a systematic review of mathematical models estimating the epidemiological impact of future human TB vaccines. PubMed, Embase and WHO Global Health Library were searched, 3-stage manual sifted, and citation- and reference-tracked, identifying 23 papers. An adapted quality assessment tool was developed, with a resulting median study quality score of 20/28. The literature remains divided as to whether vaccines effective pre- or post-infection would provide greatest epidemiological impact. However, all-age or adolescent/adult targeted prevention of disease vaccines achieve greater and more rapid impact than neonatal vaccines. Mass campaigns alongside routine neonatal vaccination can have profound additional impact. Economic evaluations found TB vaccines overwhelmingly cost-effective, particularly when targeted to adolescents/adults. The variability of impact by setting, age group and vaccine characteristics must be accounted for in the development and delivery of future TB vaccines.

Summary Background Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Methods Adult volunteers aged 18–59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov , NCT02735590 . Findings 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25–6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3H...

More effective tuberculosis vaccines are needed to help reach World Health Organization tuberculosis elimination goals. Insufficient evidence exists on the potential impact of future tuberculosis vaccines with varying characteristics and in different epidemiological settings. To inform vaccine development decision making, we modeled the impact of hypothetical tuberculosis vaccines in three high-burden countries. We calibrated Mycobacterium tuberculosis (M.tb) transmission models to age-stratified demographic and epidemiological data from China, South Africa, and India. We varied vaccine efficacy to prevent infection or disease, effective in persons M.tb uninfected or infected, and duration of protection. We modeled routine early-adolescent vaccination and 10-yearly mass campaigns from 2025. We estimated median percentage population-level tuberculosis incidence rate reduction (IRR) in 2050 compared to a no new vaccine scenario. In all settings, results suggested vaccines preventing disease in M.tb-infected populations would have greatest impact by 2050 (10-year, 70% efficacy against disease, IRR 51%, 52%, and 54% in China, South Africa, and India, respectively). Vaccines preventing reinfection delivered lower potential impact (IRR 1, 12, and 17%). Intermediate impact was predicted for vaccines effective only in uninfected populations, if preventing infection (IRR 21, 37, and 50%) or disease (IRR 19, 36, and 51%), with greater impact in higher-transmission settings. Tuberculosis vaccines have the potential to deliver substantial population-level impact. For prioritizing impact by 2050, vaccine development should focus on preventing disease in M.tb-infected populations. Preventing infection or disease in uninfected populations may be useful in higher transmission settings. As vaccine impact depended on epidemiology, different development strategies may be required.

BACKGROUND The End TB Strategy sets global goals of reducing TB incidence and mortality by 50% and 75% respectively by 2025. We assessed resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS We examined intervention scenarios developed in consultation with country stakeholders, which scaled-up existing interventions to high but feasible coverage by 2025. Nine independent TB modelling groups collaborated to estimate policy outcomes, and we costed each scenario by synthesizing service utilization estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health impact and resource implications for 2016–2035, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios to a base case representing continued current practice. FINDINGS Incremental TB service costs differed by scenario and country, and in some cases more than doubled current funding needs. In general, expanding TB services substantially reduced patient-incurred costs; and in India and China this produced net cost-savings for most interventions under a societal perspective. In all countries, expanding TB care access produced substantial health gains. Compared to current practice, most intervention approaches appeared highly cost-effective when compared to conventional cost-effectiveness thresholds. INTERPRETATION Expanding TB services appears cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, though funding needs challenge affordability. Further work is required to determine the optimal intervention mix for each country.

Background Tuberculosis is the leading single-pathogen cause of death worldwide, and China has the third largest number of cases worldwide. New tools, such as new vaccines, are needed to meet WHO tuberculosis goals. Tuberculosis vaccine development strategies mostly target infants or adolescents, but given China's ageing epidemic, vaccinating older people might be important. We modelled the potential impact of new tuberculosis vaccines in China targeting adolescents (15-19 years) or older adults (60-64 years) with varying vaccine characteristics to inform strategic vaccine development. Methods A Mycobacterium tuberculosis transmission model was calibrated to age-stratified demographic and epidemiological data from China. Varying scenarios of vaccine implementation (age targeting [adolescents or older adults] and coverage [30% or 70%]) and characteristics (efficacy [40%, 60%, or 80%], duration of protection [10 years or 20 years], and host infection status required for efficacy [pre-infection, post-infection in latency, post-infection in latency or recovered, or pre-infection and post-infection]) were assessed. Primary outcomes were tuberculosis incidence and mortality rate reduction in 2050 in each vaccine scenario compared with the baseline (no new vaccine) scenario and cumulative number needed to vaccinate (NNV) per case or death averted, 2025-50. Findings By 2050, results suggest that 74•5% (uncertainty interval [UI] 70•2-78•6) of incident tuberculosis cases in China would occur in people aged 65 years or older, and 75•1% (66•8-80•7) of all cases would be due to reactivation, rather than new infection. All vaccine profiles delivered to older adults had higher population-level impact (reduction of incidence and mortality rates) and lower NNV per case and per death averted than if delivered to adolescents. For an intermediate vaccine scenario of 60% efficacy, 10-year protection, and 70% coverage, the reduction of tuberculosis incidence rates with older adult vaccination was 1•9 times (UI 1•5-2•6) to 157•5 times (119•3-225•6) greater than with adolescent vaccination, and the NNV was 0•011 times (0•008-0•014) to 0•796 times (0•632-0•970) lower. Furthermore, with older adult vaccination, post-infection vaccines provided substantially greater mortality and incidence rate reductions than pre-infection vaccines. Interpretation Adolescent-targeted tuberculosis vaccines, the focus of many development plans, would have only a small impact in ageing, reactivation-driven epidemics such as those in China. Instead, an efficacious post-infection vaccine delivered to older adults will be crucial to maximise population-level impact in this setting and would provide an important contribution towards achieving WHO goals. Older adults should be included in tuberculosis vaccine clinical development and implementation planning. Funding Aeras and UK MRC.