Beyond the BCG vaccine: Novel approaches to tuberculosis prevention and control in Africa

Study design

This study was conducted as a structured narrative review to synthesize evidence on TB prevention and control strategies beyond the BCG vaccine in African contexts. The approach combined narrative synthesis with systematic transparency to enhance reproducibility.

Sources of evidence

Peer-reviewed journal articles, global health reports, and case-based evidence published between 2005 and 2025 were considered. Databases searched included PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, along with official reports from the WHO, Centers for Disease Control and Prevention, Global Fund, and national TB programs in Africa.

Search strategy

Keywords and MeSH terms were combined using Boolean operators (AND/OR). Search strings included: “Tuberculosis” OR “TB,” “BCG vaccine” OR “BCG efficacy,” “novel TB vaccines” OR “M72/AS01E” OR “VPM1002,” “diagnostics” OR “GeneXpert” OR “AI screening” OR “LAM test,” “preventive therapy” OR “3HP” OR “1HP,” “drug-resistant TB” OR “BPaL regimen” OR “BPaLM,” “community-based TB care” OR “digital adherence,” “One Health” OR “zoonotic tuberculosis,” and “Africa” OR “sub-Saharan Africa.”

Eligibility criteria

Data extraction

Key data extracted included

• Vaccine candidate characteristics, trial phases, and efficacy outcomes.

• Diagnostic innovations and performance metrics (sensitivity, specificity, turnaround time).

• Preventive and therapeutic regimens, adherence rates, and WHO recommendation status.

• Socio-economic and health system interventions (nutrition, housing, digital tools).

• One Health approaches and zoonotic TB burden estimates.

Data synthesis

Findings were synthesized thematically into five domains: (i) biomedical innovations, (ii) diagnostic advancements, (iii) therapeutic regimens, (iv) socio-economic/structural interventions, and (v) OH frameworks. Contradictions and uncertainties across studies were highlighted, and African-specific constraints (e.g., HIV prevalence, health system fragility, resource limitations) were integrated into the analysis. Where available, quantitative estimates (incidence, prevalence, efficacy percentages, completion rates, cost-effectiveness ratios) were incorporated to strengthen analytical depth.

The shortcomings of the BCG vaccine

BCG vaccine, which was first made available in 1921, is still the only vaccine that is approved for use against TB. However, even though it has been important in the past, its effectiveness varies greatly across age groups, populations, and geographic areas. Studies have shown strong protection against severe pediatric forms of TB, such as miliary and meningeal disease, but limited or inconsistent efficacy against pulmonary TB in adults, the most common and transmissible form of the disease.^[15,16] Several factors, including host genetics, exposure to environmental mycobacteria, and regional differences in immune priming, influence this variable efficacy. The reported efficacy of BCG varies widely: approximately 60-80% protection against severe pediatric TB, but only 0-50% against adult pulmonary TB, depending on geography and population.^[13,17] This variability highlights the need for age-specific interpretation and underscores the limited utility of BCG in reducing adult transmission.

The masking and blocking hypotheses suggest that previous exposure to environmental mycobacteria may diminish the immune response elicited by BCG, a phenomenon observed in tropical regions of Africa.^[18] Another major problem is that immunity does not last long; it starts to fade after 10-15 years, leaving most teens and adults unprotected.^[19] Since BCG is given mostly at birth, this decline in long-term protection undermines its ability to reduce transmission in adult populations. Furthermore, the ineffectiveness of BCG against pulmonary TB in adults is a significant limitation. Clinical trials conducted in Africa and Asia have consistently indicated negligible protection among adults.^[20] Attempts at re-vaccination have not significantly increased immunity, with a New England Journal of Medicine trial showing no major protective effect of BCG revaccination against M. tuberculosis infection [Table 1].^[20]

Novel TB vaccine candidates

M72/AS01E vaccine: Promising results from clinical trials and potential for widespread use.

In one trial of the M72/AS01E-4 vaccine in people living with HIV, a two-dose regimen of the M72/AS01E-4 vaccine, which was administered 1 month apart, was well tolerated, with an acceptable safety profile, and was immunogenic in antiretroviral-treated participants aged 16-35 years with well-controlled HIV. The M72/AS01E-4 vaccine reactogenicity profile, as assessed by solicited adverse events, was consistent with previous M72 trials in people living with or without HIV, including the phase 2b efficacy trial of 3500 adults without HIV. In summary, a two-dose regimen of the M72/AS01E-4 vaccine, which was administered 1 month apart, was well tolerated, had an acceptable safety profile, and was immunogenic in virally suppressed, ART-treated people living with HIV aged 16-35 years. The timely completion of this trial supported the decision to include a larger number of people living with HIV in the M72/AS01E-4 global registration phase 3 trial.^[21]

In another trial, it was found that the M72/AS01E scenarios could avert approximately 12.7 (11.0-14.6) million cases and 2.0 (1.8-2.4) million deaths, and the BCG re vaccination scenarios could avert approximately 9.0 (7.8-10.4) million cases and 1.5 (1.3-1.8) million deaths among the 72.2 (63.3-79.7) million cases and 13.8 (6.1-13.2) million deaths predicted by the Status Quo baseline between 2025 and 2050. Although modeling studies from India suggest that M72/AS01E vaccination could avert millions of TB cases, extrapolation to African contexts requires caution. The epidemiological landscape in Africa is characterized by high HIV prevalence, diverse genetic backgrounds, and fragile health systems, all of which may influence vaccine performance. Current evidence is limited to phase IIb data in HIV-negative adults, with Africa-specific phase III trials only now underway in South Africa and other sub-Saharan countries.^[22] Similarly, VPM1002 has demonstrated safety and immunogenicity in African neonates, including HIV-exposed infants, but adult efficacy data remain inconclusive.^[23] Therefore,while these candidates are promising, definitive conclusions about their capacity to substantially reduce TB burden in Africa await region-specific phase III outcomes.

The cost-effectiveness ratios for the base case M72/AS01E scenario were approximately seven times higher than those for the base case BCG revaccination scenario, but regardless of the realized product characteristics, nearly all vaccine characteristics and coverage scenarios were cost-effective at the most conservative country-level threshold compared to the new vaccine baseline. The average annual cost of M72/AS01E vaccination was four times greater than that of BCG revaccination. Introducing the vaccine could lead to an annual incremental program cost of US$190 million for M72/AS01E and US$23 million for BCG revaccination, accounting for vaccination costs as well as savings in diagnostic and treatment costs. Our modeling demonstrated a 40% greater health impact from M72/AS01E than from BCG revaccination. The difference in impact was due to assumptions about vaccine characteristics and delivery. On the basis of clinical trial data and expert opinions, we assumed that the base case, the M72/AS01E vaccine, would prevent disease and be efficacious in everyone without active disease at vaccination. M72/AS01E and BCG revaccination may substantially reduce the TB burden in India over future decades and would be cost-effective regardless of the assumed product characteristics. Using clinical trial data to assess vaccine characteristics, researchers identified variability in the vaccine profile as a significant source of uncertainty.^[24,25]

VPM1002: A genetically modified BCG with improved safety and efficacy.

One study showed that VPM1002 was less likely to cause reactions than the BCG vaccine. Both vaccines were able to make the body immune, but the immune responses caused by BCG were stronger than those caused by VPM1002 starting at week six. This study revealed the non-inferiority of VPM1002 to the BCG vaccine in terms of the incidence of grade 3 or higher local adverse reactions or vaccine-related ipsilateral or generalized lymphadenopathy of 10 mm or greater. This finding is important because of the difference in the local percentage of multifunctional CD4+ T cells (95% CI), p-value, and percentage of multifunctional CD8+ T cells (95% CI), p-value. The statistical analysis demonstrated a substantial improvement in the functionality of both CD4+ and CD8+ T cells within the VPM1002 group. These findings indicate that VPM1002 not only aligns with the safety profile of the BCG vaccine but also has the potential to generate a more vigorous immune response, necessitating further exploration of its clinical applications. BCG VPM1002 Day 0: n=37. VPM1002 and BCG elicited similar immunological responses in both HIV-unexposed and HIV-exposed infants, as assessed by variations in IFNγ concentrations in whole blood assays and cytokine expression in CD4+ and CD8+ T cells.^[26,27]

Other vaccine candidates in development: Current pipeline of TB vaccines.

There are currently 19 types of new TB vaccines in different stages of clinical trials. Four are in phase I (AdHu5Ag85A, GX-70, TB/FLU-01 L, and TB/FLU-04 L), three are in phase IIa (ID93+GLA-SE, AEC/BC02, and ChAdOx1.85A), five are in phase IIb (RUTI, DAR-901, H56:IC31, H4:IC31, and MVA85A), and five are in phase III (MIP, SRL172, MTBVAC, VPM1002, and M72/AS01E). While advancements have occurred in the investigation of novel TB vaccines, the integration of innovative technologies has introduced new avenues for research, including the use of mRNA vaccines and deep learning methodologies. Despite the numerous challenges facing the field of TB vaccine development, including economic, policy, and social constraints, it is essential to recognize that the development of novel TB vaccines is a public health endeavor that promotes the well-being of humanity. Governments and international organizations should provide robust support and actively promote international collaboration and exchange in this endeavor.^[28] Future TB vaccine adoption in Africa should be guided by a structured decision framework that balances evidence strength, feasibility in HIV-endemic contexts, and equity of access. Comparative analysis highlights distinct profiles: M72/AS01E targets adolescents and adults with latent TB infection, demonstrating robust T-cell responses but with unresolved questions regarding durability and generalizability beyond trial populations.^[22] VPM1002, a recombinant BCG, shows a favorable safety profile and potential for neonatal use, including HIV-exposed infants, but its adult efficacy remains uncertain.^[23] Kaufmann et al. emphasize that African health systems must weigh these differences against infrastructural realities, cost-effectiveness, and integration into existing immunization platforms.^[29] Such a framework ensures that vaccine adoption is evidence-based, context-appropriate, and equitable [Table 2].^[30-34]

Improvements in TB diagnosis and early detection

Early detection of TB is essential to prevent its spread and reduce mortality, particularly in high-burden regions of Africa.^[35] Conventional diagnostic methods, such as sputum smear microscopy, are cost-effective; however, they exhibit limited efficacy and frequently overlook numerous cases, particularly individuals with HIV and pediatric patients.^[36,37]Recent technological advancements have greatly improved the speed and accuracy of testing, which has led to new ways to manage The GeneXpert Mycobacterium tuberculosis/rifampicin resistance (MTB/RIF) assay is a highly useful diagnostic tool that can detect M. tuberculosis and rifampicin resistance within two hours using molecular techniques.^[38,39]In several African countries, it has reduced the time required to obtain test results and initiate treatment.^[40]However, the high cost of equipment, the need for regular maintenance, and the need for a reliable power supply have made it difficult for people in areas with few resources to access them.

Researchers are developing cost-effective, portable, and user-friendly point-of-care diagnostics to address these issues in rural and remote regions.^[41] Lateral flow urine lipoarabinomannan (LAM) tests have demonstrated efficacy in HIV-positive patients with advanced disease, in which traditional sputum-based testing is less dependable.^[42]Emerging technologies include the utilization of artificial intelligence (AI) and digital health platforms to enhance TB screening. AI-enhanced interpretation of chest X-rays and mobile applications for contact tracing are improving surveillance and broadening diagnostic capabilities.^[43,44]These enhancements represent significant advancements in ensuring prompt TB diagnosis for all individuals. To reduce diagnostic delays and enhance TB control in African nations, ensuring the equitable utilization of these devices is crucial. Despite encouraging advances, AI-based TB screening is constrained by several limitations. False positives remain common, particularly in populations with a high prevalence of non-TB lung disease. Algorithmic bias is a concern when models are trained predominantly on non-African datasets, potentially reducing accuracy in local contexts. Regulatory uncertainty regarding clinical validation and integration into national TB programs further complicates adoption.^[45] These challenges underscore the need for rigorous African-specific validation before large-scale deployment [Figure 1].

Close

Figure 1:

Flowchart of diagnostic advancements and their impact on TB control. TB: Tuberculosis, WHO: World Health Organization, MTB/RIF: Mycobacterium tuberculosis/Rifampicin resistance (MTB/RIF) assay, TB-LAM: Tuberculosis lipoarabinomannan.

Export to PPT

Preventive therapy and treatment innovations

The problems with BCG indicate that more preventive and therapeutic measures are needed. Recent advances include shorter regimens for latent TB infection, new drug combinations, and community-based care models. Low adherence has long been a problem with traditional preventive therapy (6-9 months of isoniazid monotherapy). The 3 HP regimen (once weekly isoniazid + rifapentine for 3 months) has the same effectiveness and higher completion rates, especially among HIV-positive individuals.^[46] The 1 HP regimen (one month of daily isoniazid + rifapentine) also showed similar effectiveness and better adherence.^[47] These shorter, safer regimens are critical for large-scale preventive therapy programs in Africa.

New drug combinations for active TB, such as innovative multidrug regimens, such as BPaL (bedaquiline, pretomanid, linezolid) and BPaLM (adding moxifloxacin), have revolutionized the treatment of drug-resistant TB. The BPaL regimen has achieved approximately 90% favorable outcomes in clinical trials and has proven cost-effective in South African modeling studies.^[48] The reduced linezolid doses in the ZeNIX trial further minimized adverse effects. However, vigilance is necessary to prevent the emergence of resistance.^[49,50] Similarly, while the BPaL regimen has demonstrated ~90% success in controlled trials, real-world rollout in Africa has been hindered by linezolid-associated toxicity, including peripheral neuropathy and myelosuppression, as well as emerging resistance.^[51,52] Limited pharmacovigilance infrastructure and constrained laboratory capacity exacerbate these risks. Thus, although BPaL represents a major advance in MDR/XDR-TB therapy, its implementation in resource-limited African settings requires careful monitoring, dose optimization, and strengthened safety surveillance.

Treatment in community-decentralized, community-led TB care models improves access and adherence. Interventions such as home-based DOT, digital adherence technologies (e.g., SMS reminders, video DOT), and the integration of TB services within primary and HIV care platforms have improved outcomes in multiple African contexts.^[53] [Table 3].

Socio-economic and structural methodologies

Controlling TB effectively requires more than just medical tools. It is important for all African countries to address social determinants, gaps in the health system, and long-term policy frameworks. Poverty, malnutrition, overcrowding, and poor housing conditions constitute some of the factors that perpetuate high TB vulnerability. Malnutrition and food insecurity weaken host immunity and increase the likelihood of disease progression.^[54] Settlements that are too crowded cause diseases to spread through the air faster. Socio- economic interventions, cash transfers, nutritional assistance, and housing improvements have proven effective in lowering the risk of TB and improving treatment adherence.^[55]

To meet TB control goals, African health systems need better infrastructure, diagnostics (such as GeneXpert), supply chains, and people.^[56] Integrating TB care with HIV and primary-care services improves efficiency and continuity. Digital tools and e-health registries can strengthen surveillance and accountability. Achieving the End TB targets depends on political commitment and sustainable financing. Governments must prioritize domestic funding for TB research, training, and drug procurement while leveraging support from partners such as the Global Fund and WHO.^[57] To determine what causes TB, policies that encourage public-private partnerships (PPPs) and cooperation between different areas of housing, nutrition, and education are needed [Figure 2].

Close

Figure 2:

The impact of social factors on TB outcomes. TB: Tuberculosis, WHO: World Health Organization.

Export to PPT

One health and holistic approaches

OH is a broad, cross-disciplinary approach to public health that recognizes the health issues that affect people, animals, and ecosystems and promotes cooperation between the fields of human, animal, and environmental health.^[58] In Africa, effective TB control necessitates strategies that extend beyond human health, acknowledging its significant connections with animals and the environment. Zoonotic TB, which is caused mainly by Mycobacterium bovis, is a major public health concern at the human-animal interface in West Africa.^[59]M. tuberculosis is the bacterium that causes most cases of human TB. Zoonotic TB, on the other hand, shows how human, animal, and environmental health are linked.^[59] Zoonotic TB caused by Mycobacterium bovis contributes a minority of human TB cases in Africa, with prevalence estimates generally ranging from 1-2% depending on region and diagnostic methodology.^[60,61]While this burden is non-negligible in pastoralists and cattle-farming communities, it remains small compared to the overwhelming dominance of M. TB. Consequently, OH approaches should be framed as context-specific adjuncts that strengthen surveillance and control in high-risk populations, rather than as central pillars of TB control strategies continent-wide. This re-framing ensures proportional allocation of resources while acknowledging the importance of integrated human-animal-environmental health interventions. The OH framework emphasizes this interconnection, stating that zoonotic TB affects all three sectors simultaneously.^[62]Epidemiologists, veterinarians, ecologists, and public health officials must collaborate to identify disease hotspots and implement targeted interventions.^[63] Such integrated collaboration enhances surveillance, promotes data sharing, and increases collective preparedness for zoonotic threats.

TB is still most common in 30 countries with a high burden, and it affects more people who are at risk, such as refugees and migrants. This is because they have less access to healthcare and live in bad conditions.^[64] The National OH Strategic Plan for Rwanda is an example of working together across borders and sectors. It brings together the Ministries of Health, Agriculture, and Environment to improve surveillance and emergency response.^[63] This partnership has raised awareness in the community and lowered the spread of zoonotic diseases such as rabies and brucellosis. This shows how combining policy-driven initiatives can strengthen TB control efforts.

To make OH work, we need new technologies and rules. Digital health tools, such as electronic surveillance systems and mobile health (mHealth) apps, are changing the way TB services are provided and monitored.^[65,66] DOT is still the most common way to ensure that patients stick to their treatment, but video-observed therapy and digital adherence technologies make it even easier for patients to stay in touch and follow up.^[67] These actions show how technology, coordinated policies, and cross-sectoral collaboration can all work together to lower the spread of TB and improve health outcomes in Africa.

The framework shows how health systems for people, animals, and the environment work together to stop and control TB. It emphasizes the importance of collaboration and information sharing among health ministries, veterinary services, and environmental sectors. This is all about integrated surveillance, which is made possible by digital health platforms. It guides joint responses, policy harmonization, and community involvement to achieve long-term TB control [Figure 3].

Close

Figure 3:

Conceptual framework for One Health in TB prevention and control.

Export to PPT

Implications for clinical and public health

To turn TB research into real-world action, we need strong clinical and public health systems supported by good surveillance and response systems. Surveillance systems are very important in the OH framework because they help keep track of disease trends, find cases early, and ensure that data are always available for making smart decisions to lessen the effects of zoonotic outbreaks.^[65] These systems produce essential data that inform strategic measures designed to safeguard at-risk human and animal populations. An efficient early warning system must deliver prompt, precise, and sensitive data capable of identifying anomalous patterns in human, animal, or environmental health occurrences, thereby facilitating swift epidemiological response and containment strategies.^[68]

TB remains a significant global public health issue, prompting its inclusion in the Sustainable Development Goals (SDGs) for eradication by 2030.^[69] Nigeria has the sixth-highest number of people with TB in the world and the highest number in Africa. It is still a major focus for disease control.^[69,70]The National Tuberculosis Program (NTP) and its partners have worked hard, but there is still a large difference between the number of TB cases reported and the number that actually occur in the country. In 2020, there were an estimated 9.9 million cases of TB worldwide, but only 5.8 million cases were reported. Nigeria is a major part of this problem.^[69,71] These gaps are caused by poor diagnosis, weak reporting systems, and insufficient access to care.

New and creative ways to solve these problems have been developed. KNCV Nigeria has rolled out the TB-LAMP diagnostic tool and made changes to the Early Warning Outbreak Recognition System to make it easier for people in the community to find case.^[69,72,73]. Strengthening laboratory networks, making GeneXpert analyzers more widely available, and ensuring that people can access important diagnostic tools are still top priorities. Similarly, strategies that improve health education, use social and local media to spread the word, and involve community leaders in advocacy are essential. Policy changes need to ensure that national TB strategies are in line with global goals by making funding better, encouraging PPPs, and addressing social factors such as poor nutrition and access to healthcare. The inclusion of gender-sensitive approaches will help close care gaps even more and bring us closer to ending TB by 2030 [Table 4].

Challenges in research and future prospects

Despite considerable progress in TB research, challenges remain that impede the eradication and management of the disease in African countries.^[74] A notable deficiency is the absence of adequate long-term evidence regarding new vaccine candidates.^[16] Even though clinical trials with M72/AS01E and VPM1002 show promise, there are still concerns about how well they will work in the long run, how well they will work in different African populations, and how easy they will be to use in places with few resources.^[22] Current research is often limited by its limited scope and geographic range, hindering the generalization of findings to regions with diverse epidemiological and genetic characteristics.^[75]

The subsequent challenges pertain to the factors that complicate execution, such as political instability, inadequate healthcare institutions, and disrupted supply chains, which persist in complicating the prevention and treatment of TB.^[76,77]Despite the availability of novel tests and treatments, accessibility remains limited owing to prohibitive costs, insufficient laboratory facilities, and the challenges associated with traveling to remote or difficult-to-reach locations.^[77-79]Health disparities resulting from poverty, malnutrition, and HIV co-infection hinder TB control initiatives and foster conditions conducive to continuous transmission.^[80]

Money problems also make it harder for people to get ahead in life. Research on TB does not yield enough money compared with the number of people who have the disease around the world, and most of the money is allocated to rich countries.^[81] This difference makes it harder for Africa to lead in innovation, makes it take longer to test new medicines in local settings, and keeps people dependent on research goals set by others. Additionally, regulatory hurdles and slow policy implementation may lead to delays in the integration of innovative technologies from clinical trials into the national program.^[81]

Moving forward, we need a clear plan for our research. Our top priorities should be to conduct large, multi-center vaccine trials among African populations, look at long-term effects, and add new vaccines to current immunization schedules. Research must concentrate on abbreviated and safer preventive protocols, innovative treatment combinations for multi-drug-resistant TB, and the integration of digital health tools into standard surveillance practice.^[82] Improving implementation research will be crucial for converting insights into practice, especially in rural areas and settings with limited resources.^[83,84] We need to ensure that people from different fields work together in the end. The OH Initiative focuses on the health of people, animals, and the environment. This approach offers ways to address zoonotic reservoirs and the spread of TB across borders.^[85] Policymakers, researchers, and communities must collaboratively formulate policies that reconcile innovation with accessibility, ensuring that scientific progress provides equitable benefits for the African population.^[86]

To solve problems with TB research in Africa, we need long-term funding, political will, and new ways of doing things that fit the situation. Africa can eliminate TB as a public health threat and surpass the limitations of the BCG vaccine through collaborative efforts [Figure 4].

Close

Figure 4:

Research and innovation road-map for TB elimination

Export to PPT