Impact of COVID-19 Disruptions on Global BCG Coverage and Paediatric TB Mortality: A Modelling Study.

The impact of COVID-19 disruptions on global Bacillus Calmette-Guérin (BCG) coverage and paediatric tuberculosis (TB) mortality is still unknown. To fill this evidence-gap and guide mitigation measures, we estimated the impact of COVID-19 disruptions on global BCG coverage and paediatric TB mortality. First, we used data from multiple sources to estimate COVID-19-disrupted BCG vaccination coverage. Second, using a static mathematical model, we estimated the number of additional paediatric TB deaths in the first 15 years of life due to delayed/missed vaccinations in 14 scenarios-varying in duration of disruption, and magnitude and timing of catch-up. We estimated a 25% reduction in global BCG coverage within the disruption period. The best-case scenario (3-month disruption, 100% catch-up within 3 months) resulted in an additional 886 (0.5%) paediatric TB deaths, and the worst-case scenario (6-month disruption with no catch-up) resulted in an additional 33,074 (17%) deaths. The magnitude of catch-up was found to be the most influential variable in minimising excess paediatric TB mortality. Our results show that ensuring catch-up vaccination of missed children is a critical priority, and delivery of BCG alongside other routine vaccines may be a feasible way to achieve catch-up. Urgent action is required to support countries with recovering vaccination coverages to minimise paediatric deaths

Potential implementation strategies, acceptability, and feasibility of new and repurposed TB vaccines

Recently, two Phase 2B tuberculosis vaccine trials reported positive efficacy results in adolescents and adults. However, experience in vaccinating these age groups is limited. We identified potential implementation strategies for the M72/AS01E vaccination and BCG-revaccination-like candidates and explored their acceptability and feasibility. We conducted in-depth semi-structured interviews among key decision makers to identify implementation strategies and target groups in South Africa, India, and China. Thematic and deductive analysis using a coding framework were used to identify themes across and within settings. In all three countries there was interest in novel TB vaccines, with school-attending adolescents named as a likely target group. In China and India, older people were also identified as a target group. Routine vaccination was preferred in all countries due to stigma and logistical issues with targeted mass campaigns. Perceived benefits for implementation of M72/AS01E were the likely efficacy in individuals with Mycobacterium tuberculosis (Mtb) infection and efficacy for people living with HIV. Perceived challenges for M72/AS01E included the infrastructure and the two-dose regimen required. Stakeholders valued the familiarity of BCG but were concerned about the adverse effects in people living with HIV, a particular concern in South Africa. Implementation challenges and opportunities were identified in all three countries. Our study provides crucial information for implementing novel TB vaccines in specific target groups and on country specific acceptability and feasibility. Key groups for vaccine implementation in these settings were identified, and should be included in clinical trials and implementation planning

Feasibility of novel adult tuberculosis vaccination in South Africa: a cost-effectiveness and budget impact analysis.

Early trials of novel vaccines against tuberculosis (TB) in adults have suggested substantial protection against TB. However, little is known about the feasibility and affordability of rolling out such vaccines in practice. We conducted expert interviews to identify plausible vaccination implementation strategies for the novel M72/AS01E vaccine candidate. The strategies were defined in terms of target population, coverage, vaccination schedule and delivery mode. We modelled these strategies to estimate long-term resource requirements and health benefits arising from vaccination over 2025-2050. We presented these to experts who excluded strategies that were deemed infeasible, and estimated cost-effectiveness and budget impact for each remaining strategy. The four strategies modelled combined target populations: either everyone aged 18-50, or all adults living with HIV, with delivery strategies: either a mass campaign followed by routine vaccination of 18-year olds, or two mass campaigns 10 years apart. Delivering two mass campaigns to all 18-50-year olds was found to be the most cost-effective strategy conferring the greatest net health benefit of 1.2 million DALYs averted having a probability of being cost-effective of 65-70%. This strategy required 38 million vaccine courses to be delivered at a cost of USD 507 million, reducing TB-related costs by USD 184 million while increasing ART costs by USD 79 million. A suitably designed adult TB vaccination programme built around novel TB vaccines is likely to be cost-effective and affordable given the resource and budget constraints in South Africa

Potential implementation strategies, acceptability, and feasibility of new and repurposed TB vaccines

Recently, two Phase 2B tuberculosis vaccine trials reported positive efficacy results in adolescents and adults. However, experience in vaccinating these age groups is limited. We identified potential implementation strategies for the M72/AS01 vaccination and BCG-revaccination-like candidates and explored their acceptability and feasibility. We conducted in-depth semi-structured interviews among key decision makers to identify implementation strategies and target groups in South Africa, India, and China. Thematic and deductive analysis using a coding framework were used to identify themes across and within settings. In all three countries there was interest in novel TB vaccines, with school-attending adolescents named as a likely target group. In China and India, older people were also identified as a target group. Routine vaccination was preferred in all countries due to stigma and logistical issues with targeted mass campaigns. Perceived benefits for implementation of M72/AS01 were the likely efficacy in individuals with Mycobacterium tuberculosis (Mtb) infection and efficacy for people living with HIV. Perceived challenges for M72/AS01 included the infrastructure and the two-dose regimen required. Stakeholders valued the familiarity of BCG but were concerned about the adverse effects in people living with HIV, a particular concern in South Africa. Implementation challenges and opportunities were identified in all three countries. Our study provides crucial information for implementing novel TB vaccines in specific target groups and on country specific acceptability and feasibility. Key groups for vaccine implementation in these settings were identified, and should be included in clinical trials and implementation planning

Bridging the gap: evaluating high TB burden country data needs to support the potential introduction of TB vaccines for adolescents and adults: a workshop report

High tuberculosis (TB) burden countries (HBCs) need to prepare for TB vaccine implementation alongside licensure, to ensure rapid rollout. WHO policy/implementation frameworks have been created to support this effort. Using WHO frameworks, we convened a workshop to ask HBC experts about what epidemiological, impact, feasibility and acceptability data they anticipated they would need to guide TB vaccine introduction. For required data, we asked HBC and global experts which data were already available, data collection planned, or gaps. HBC experts expressed high demand for epidemiological, impact, feasibility and acceptability data, reported variable availability of existing epidemiological data, and low availability for impact, feasibility, and acceptability data. Global experts reported additional knowledge of existing data on impact, upcoming collection of infection prevalence, acceptability and feasibility data, and potential epidemiological data collection on adolescents, adults, people living with HIV, and underweight individuals. HBC and global experts made key recommendations for: a coordinated data collation, collection, analysis and sharing system; updating existing HBC health and economic impact estimates and extending impact analyses to other HBCs; demand/market forecasting; resource gap mapping; aligning delivery strategies; addressing manufacturing, procurement, delivery, and regulatory barriers; sharing potential vaccine licensure timing; incorporating TB vaccine introduction strategies into NSPs, immunization programs, and health services; collecting vaccine hesitancy, mistrust, and misinformation data; collecting adolescent/adult vaccine demand generation data, and identifying funding. Experts recommended expanding this analysis to other areas of the WHO frameworks, including more HBC stakeholders, and repeating this analysis after country and community advocacy and socialization around different vaccine candidates

BCG vaccination protects against infection with Mycobacterium tuberculosis ascertained by tuberculin skin testing

Objectives: There is conflicting evidence as to whether Bacillus Calmette–Guérin (BCG) vaccination offers protection against Mycobacterium tuberculosis infection ascertained by a positive tuberculin skin test (TST). We investigated the association between BCG vaccination status and TST results in a set of surveys at increasing TST cut-off values to take cross-reactions to BCG vaccination into account. Methods: Secondary analysis of data from three consecutive tuberculin surveys done among schoolchildren in Tanzania between 1990 and 2002. BCG vaccination status was ascertained by the presence of a typical scar. Results: We analyzed data of 277,588 children of whom 77.7% were BCG vaccinated and 8.5% had TST indurations ≥ 15 mm, 5.1% ≥ 17 mm and 2.8% ≥ 19 mm. In the combined analysis, odds ratios for a positive TST were > 1 for children with BCG up to TST cut-off values of 16 mm. For cut-off values > 17 mm crude and adjusted odds ratios were significantly < 1, and decreased with further increasing cut-off values. Conclusions: Using a methodology that makes use of the differences in TST reaction sizes between specific and non-specific responses, we showed that BCG vaccination was associated with reduced prevalence of M. tuberculosis infection as measured by the tuberculin skin test, suggesting a protective effect

Potential implementation strategies, acceptability, and feasibility of new and repurposed TB vaccines.

Recently, two Phase 2B tuberculosis vaccine trials reported positive efficacy results in adolescents and adults. However, experience in vaccinating these age groups is limited. We identified potential implementation strategies for the M72/AS01E vaccination and BCG-revaccination-like candidates and explored their acceptability and feasibility. We conducted in-depth semi-structured interviews among key decision makers to identify implementation strategies and target groups in South Africa, India, and China. Thematic and deductive analysis using a coding framework were used to identify themes across and within settings. In all three countries there was interest in novel TB vaccines, with school-attending adolescents named as a likely target group. In China and India, older people were also identified as a target group. Routine vaccination was preferred in all countries due to stigma and logistical issues with targeted mass campaigns. Perceived benefits for implementation of M72/AS01E were the likely efficacy in individuals with Mycobacterium tuberculosis (Mtb) infection and efficacy for people living with HIV. Perceived challenges for M72/AS01E included the infrastructure and the two-dose regimen required. Stakeholders valued the familiarity of BCG but were concerned about the adverse effects in people living with HIV, a particular concern in South Africa. Implementation challenges and opportunities were identified in all three countries. Our study provides crucial information for implementing novel TB vaccines in specific target groups and on country specific acceptability and feasibility. Key groups for vaccine implementation in these settings were identified, and should be included in clinical trials and implementation planning

Data_Sheet_1_Bridging the gap: evaluating high TB burden country data needs to support the potential introduction of TB vaccines for adolescents and adults: a workshop report.PDF

High tuberculosis (TB) burden countries (HBCs) need to prepare for TB vaccine implementation alongside licensure, to ensure rapid rollout. WHO policy/implementation frameworks have been created to support this effort. Using WHO frameworks, we convened a workshop to ask HBC experts about what epidemiological, impact, feasibility and acceptability data they anticipated they would need to guide TB vaccine introduction. For required data, we asked HBC and global experts which data were already available, data collection planned, or gaps. HBC experts expressed high demand for epidemiological, impact, feasibility and acceptability data, reported variable availability of existing epidemiological data, and low availability for impact, feasibility, and acceptability data. Global experts reported additional knowledge of existing data on impact, upcoming collection of infection prevalence, acceptability and feasibility data, and potential epidemiological data collection on adolescents, adults, people living with HIV, and underweight individuals. HBC and global experts made key recommendations for: a coordinated data collation, collection, analysis and sharing system; updating existing HBC health and economic impact estimates and extending impact analyses to other HBCs; demand/market forecasting; resource gap mapping; aligning delivery strategies; addressing manufacturing, procurement, delivery, and regulatory barriers; sharing potential vaccine licensure timing; incorporating TB vaccine introduction strategies into NSPs, immunization programs, and health services; collecting vaccine hesitancy, mistrust, and misinformation data; collecting adolescent/adult vaccine demand generation data, and identifying funding. Experts recommended expanding this analysis to other areas of the WHO frameworks, including more HBC stakeholders, and repeating this analysis after country and community advocacy and socialization around different vaccine candidates.</p