Health and economic impacts of Vaccae vaccination incorporating active case finding in India and South Africa: a modelling study

Dynamic transmission modeling

We adapted the dynamic transmission models from our earlier study,5 using R software V.4.2.1 (R Foundation for Statistical Computing, Vienna, Austria). The model for India characterised the natural TB progression through five distinct states (compartments): susceptible (S), latently infected (L), infectious active TB disease showing bacteriologically positivity (I), noninfectious active disease despite bacteriological negativity (NI) and those recovered from active disease (R). The entry point for newborns within the model was the susceptible (S) compartment. For South Africa, these states were integrated with three additional HIV-related strata: HIV-negative individuals (HIV^- stratum), HIV-positive individuals not undergoing antiretroviral therapy (HIV⁺ stratum) and HIV-positive individuals engaged in antiretroviral therapy (ART stratum), with progression visualised in a supplementary flowchart (online supplemental figure S3).

The model tracked several key transmissions, including (1) the acquisition of TB infection (categorised by fast or slow progression); (2) the emergence of active disease (from fast progression or through reactivation, reinfection or relapse); (3) the detection, treatment and recovery; and (4) TB-related mortality (as illustrated in online supplemental figure S3 and table S3). The simulation of TB dynamics encompassed the entire population demographic, ranging from newborns to centenarians, and spanned across 150 years from 1900 to 2050, applying age-adjusted contact patterns based on predictive matrices.9 In the model, individuals within the HIV⁺ and ART strata were predisposed to an increased risk of active TB development and faced higher mortality rates than those in the HIV^- stratum.

Initial population structures, birth rates and death rates (online supplemental tables S4–S7) for both countries drew from the United Nations Population Prospects.10 Comprehensive literature reviews yielded parameters for TB transmission and disease progression (online supplemental tables S8 and S9), while the trajectory of the South African HIV epidemic was modelled through HIV-specific incidence rates, AIDS-related mortality and ART coverage (outlined in online supplemental tables S10–S12). The model presumed ART to diminish the additional TB risk associated with HIV by 65% in adults and 70% in children.11 12

Calibration was conducted with the directed-search Nelder-Mead (NM) method within the ‘dfoptim’ R package,13 considering uncertainties through a hundred best-fitting simulations (online supplemental table S13). The calibration focused on specific demographic and epidemic benchmarks in online supplemental tables S14 and S15, ensuring it aligned with estimated figures for TB prevalence, incidence, mortality and TB-HIV coinfection statistics specific to South Africa. The calibration intrinsically included the impacts of existing TB control interventions, operating under the presumption that related variables would remain consistent.

Vaccination strategies and health outcomes

The following age-specific vaccination strategies were evaluated for implementation in India: (1) the adolescent (aged 15 years) strategy, (2) the adolescent and young adult (AYA, 15–34 years) strategy, (3) the adult (18–55 years) strategy and (4) the elderly (60+ years) strategy. In contrast, the proposed strategies for South Africa were structured with an emphasis on HIV status: (1) the HIV-targeted strategy, (2) the non-HIV strategy and (3) the general population strategy. The assumptions underlying the strategies were displayed in table 1. It was anticipated that the vaccination rollout, complemented with ACF approaches, would commence in 2024. The transmission models were designed to forecast health outcomes spanning from 2024 to 2050—a 27-year evaluation window. We assumed vaccine coverage would increase from 30% to 80% over 5 years. Achieving 80% is ambitious but feasible, given the 91% pneumococcal vaccine coverage in India and 90% human papillomavirus vaccine coverage in South Africa.14 15

The vaccine efficacy (VE) was set as 54.7% (95% UI: 29.8%–70.8%) against active TB (see online supplemental table S2 for case definition). The duration of protection was set at 20 years, after which immunity was completely lost. For the South Africa setting, a 20% (5%–30%) reduction in VE was anticipated for HIV⁺ individuals relative to their HIV^- counterparts, as referenced in sources.16–18 TST screening sensitivity was reported as 77.2%.19 The Centers for Disease Control and Prevention of USA recommends a ≥5 mm cut-off to define a positive TST in PLHIV,20 with sensitivity of 78.2%.19 Our study assumed consistent TST sensitivity for individuals with or without HIV, with different cut-offs. The ACF component is modelled using a mechanistic approach simulating sequential screening processes (TST and CXR). We assumed ACF interventions could increase the case detection rate by 25% (0%–30%) compared with the status quo.21

The primary outcomes were the numbers of prevented TB cases and deaths relative to a ‘no vaccination’ strategy (status quo). In addition, secondary outcomes included the incidence rate reduction, mortality rate reduction, as well as the number needed to vaccinate (NNV) to avert a single case or death.

Economic evaluation

A detailed overview of key cost assumptions can be found in table 1. The pricing for Vaccae was established at US$120 in 2021 for a complete course of six doses, which was roughly one-third of the market price observed in China, reflecting efforts to make it more affordable. We discussed these price assumptions with Jiang Pu, senior director at ZhiFei Biological Products Co. Ltd.5 The cost analysis included considerations from both healthcare sector (direct medical costs) and societal (direct medical costs, direct non-medical costs and indirect costs) perspectives. The costs for LTBI screening (ACF) were tabulated at US$1.12 (95% UI: 0.99–1.25) per TST and US$4.2 (3.3–5.0) per CXR in India.22 23 In South Africa, these costs were higher, at US$3.90 (3.32–7.27) for the TST and US$14.0 (11.2–16.8) for the CXR.24 25 TB diagnosis and treatment expenses in India were calculated to be US$14.82 (11.86–17.78) and US$538.6 (447.9–623.7) respectively.26 27 Comparable costs in South Africa were US$25.90 (20.72–31.08) for diagnosis and US$440.9 (205.7–723.9) for treatment.27 28 Additionally, the analysis took into account the costs associated with ART in South Africa. We calculated the costs of vaccination programme (C_vaccination) as the combined total of the vaccine-associated cost (C_vaccine) and the screening cost (C_screening).

Disability-adjusted life years (DALYs) were calculated using the standard equation of years of life lost (YLLs)+years lived with disability (YLDs) derived from simulation outputs. Calculation for YLLs was based on annual TB mortality rates and corresponding life expectancies with specific details available in online supplemental tables S16 and S17. The YLDs were determined annually by multiplying the total number of TB cases by an appropriate disability weight (DW). DW, provided by the Global Burden of Disease, for TB without HIV (0.333) and with HIV (0.408), were incorporated.29 Both costs and DALYs were discounted annually at a 3% rate.

A systematic evaluation approach was applied to evaluate strategies for Vaccae vaccination programme. The process began with the budget impact analysis to ascertain the costs involved, including those related to the vaccine and screening (C_vaccination). Subsequently, the cost-effectiveness analysis was conducted. Critical indicators included the average cost-effectiveness ratio (ACER), measuring the cost per TB case or death prevented, and the incremental cost-effectiveness ratio (ICER), focusing on the cost per DALY averted (△C/△E). The willingness-to-pay (WTP, λ) threshold was established according to the WHO’s criteria, set at the gross domestic product (GDP) per capita for 2021: US$ 2257 for India and US$ 7055 for South Africa, as reported by the World Bank Open Data (https://data.worldbank.org/indicator/NY.GDP.PCAP.CD). The third step entailed the cost-benefit analysis to evaluate the economic benefits of each strategy comprehensively, considering not just healthcare outcomes but broader economic effects. The benefit-cost ratio (BCR) was computed by comparing the total benefits—comprising both reduced direct medical costs (△C_treatment) and the monetised value of DALYs (λ△E)—with the cost of the vaccination programme. A BCR exceeding one indicates that benefits surpass costs, signifying monetary savings.

Following the analyses, the strategies were prioritised based on their rankings of vaccination programme budget (C_vaccination), ICER and BCR. A lower C_vaccination or ICER corresponded to a higher priority; whereas, a higher BCR denoted a higher priority rank. After prioritising the above three items, we summed up the total priority. By implementing this methodical approach, policymakers can allocate resources to the optimal strategy that are both economically sustainable and have the highest potential for positive impact.

Uncertainty analyses

The sensitivity analyses included both deterministic (DSA) and probabilistic sensitivity analysis (PSA). The one-way DSA was presented as a tornado diagram, underscoring the 10 variables with the greatest impact. For example, we adopted a conservative assumption that individuals in the pre-symptomatic stage were not detectable by ACF (0%), and an optimistic assumption that ACF could enhance case detection by 30%, based on the findings in the ZAMSTAR study.30 For the PSA, 100 simulations were conducted, drawing each parameter from its specified probability distribution. The outcomes were illustrated using scatter plots and cost-effectiveness acceptability curves to demonstrate variability.

Furthermore, scenario analyses took into consideration a variety of factors to assess different potential outcomes. These factors included variations in VE (considering both 29.8% and 70.8% rates), the duration of vaccine protection (spanning from 10 years to lifelong protection), the potential introduction year of the programme (envisioned as 2034) and the speed of programme implementation (examining an instant scale-up to 80% coverage).

Health impacts of Vaccae vaccination in India and South Africa

Our examination of the demographic and epidemiological data produced well-fitted models for India and South Africa, as depicted in figure 1A,B and E,F and elaborated on in online supplemental figures S4–S7 respectively. In India, the temporal scope from 2024 to 2050 under a ‘no vaccination’ strategy forecasted 83.74 (95% UI: 65.86–99.19) million TB cases and approximately 5.97 (4.19–7.50) million TB-related fatalities. For South Africa, within the same timeframe, we anticipate 5.33 (3.43–7.22) million TB cases and 1.58 (1.22–1.91) million TB-associated deaths (online supplemental figure S8).

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For India, data indicated that the adult vaccination strategy could forestall 8.70 (95% UI: 6.86–11.13) million TB cases and prevent 0.61 (0.39–0.91) million related deaths (presented in table 2), slashing the TB incidence and mortality rates by 20.1% (18.7%–23.5%) and 19.0% (17.5%–22.5%), respectively, by the year 2050 (figure 1C and online supplemental table S18). This effect dwarfed that of alternative strategies. The higher number of vaccine doses used in the elderly scenario can be attributed to the fact that the elderly strategy was a combination of routine and campaign vaccination; whereas, the adult strategy was purely a campaign strategy (table 1). The age-specific LTBI carriers and corresponding TB incidence are presented in online supplemental figure S9.

In South Africa, on the other hand, the general population strategy was predicted to avert 0.67 (95% UI: 0.45–0.99) million TB cases and 0.21 (0.15–0.28) million TB-related deaths (table 2). There would be an associated decline in TB incidence and mortality rates by 28.1% (26.1%–30.3%) and 27.0% (23.5%–30.0%), respectively, by the year 2050 (figure 1G and online supplemental table S18). Comparatively, the HIV-targeted strategy was poised to be most efficacious, with the model reflecting the smallest NNV per case or death averted, at 2 (1–5) and 5 (3–16), respectively (online supplemental table S19).

Figure 1D and H showed per cent reductions in TB cases in India and South Africa under different intervention strategies. When ACF was implemented independently, it avoided 0.7% to 2.5% of TB cases in India and 0.6% to 1.7% in South Africa. With the implementation of Vaccae vaccination strategies, the incremental impact of ACF was diminished. This reduction occurred because the Vaccae vaccine itself caused a substantial decrease in TB cases, thereby, lessening the additional impact that ACF could provide. Online supplemental figure S10 presented the estimated TB-associated DALYs with and without Vaccae vaccination and ACF strategies in India and South Africa.

Optimal strategy of Vaccae vaccination in India

The cost of the adolescent vaccination strategy was the lowest, reaching approximately US$5.27 (95% UI: 3.86–9.00) billion (table 3), followed by the AYA strategy, estimated at US$14.01 (10.14–23.29) billion. These immunisation approaches have facilitated a decrease in TB incidence, and consequently, have contributed to reductions in diagnoses and treatment expenses (table 2).

In the cost-effectiveness analysis (CEA) from the healthcare sector perspective, the adolescent, AYA and adult strategies were cost-effective, with the ICERs at US$1259 (95% UI: 823–1608), 1082 (927–1426) and 1416 (1091–2094) per DALY averted (table 3), when compared with status quo. The ACERs stood at US$3230 (2394–4179), US$2778 (2492–3181) and US$3021 (2339–3881) per case averted; and US$47 092 (29 702–63834), US$38 780 (31 883–56307) and US$42 921 (31 306–73221) per death averted for each respective strategy (online supplemental table S20). The AYA strategy stood out as most cost-effective. From the social perspective, the strategies maintain cost-effectiveness, with the adolescent and AYA strategies registering as cost-saving (online supplemental table S20).

The benefit-cost ratios from the healthcare sector perspective were favourable at 1.8 (95% UI: 1.4–2.6), 2.0 (1.6–2.4) and 1.6 (1.1–2.0) for adolescent, AYA and adult strategies, respectively (table 3). A compelling BCR of 3.2 (2.4–3.7) for the AYA strategy is observed from the societal perspective (online supplemental table S20).

In prioritising strategies for optimal epidemic control within India, the AYA strategy ranks as the optimal approach (table 3), balancing both economic benefits and feasibility.

Optimal strategy of Vaccae vaccination in South Africa

The financial allocation for the HIV-targeted Vaccae vaccination programme was the most modest of all strategies, with a budget estimation of merely US$0.09 (95% UI: 0.06–0.15) billion (table 3). Despite achieving reductions in TB management costs, ART expenditures witnessed an uptick. This paradoxical outcome arose from the vaccine’s effectiveness in prolonging the lifespan of HIV-infected individuals already on ART by curtailing TB-related mortalities, which subsequently inflated the demand for ART. Similarly, immunising HIV-positive individuals not already under ART slowed TB progression and deference in mortality, leading to an increment in the cohort that eventually commenced ART (table 2).

From the healthcare sector perspective, the CEA suggested that all three strategies—focusing on HIV⁺ population, HIV^- population and the general population—were cost-effective relative to the existing status quo. The ICERs were commendable at US$70 (95% UI: 53–123), US$468 (337–945) and US$312 (234–515) per DALY averted, respectively (table 3). The strategies also boasted ACERs of US$502 (382–923) per case averted and US$1702 (1292–2788) per death deferred for the HIV-targeted strategy (online supplemental table S20). From the societal perspective, each strategy achieved cost-saving milestones (online supplemental table S20).

The CBA revealed that the HIV-targeted strategy prevented 2.2 (95% UI: 1.4–3.1) million DALYs, amassing benefits approximating US$15.3 (9.5–22.0) billion, overwhelmingly surpassing the status quo (table 2). The BCR for this strategy stood at 176.0 (83.4–255.3), markedly surpassing the other two strategies which maintain BCRs of 14.7 (7.3–20.5) and 23.1 (13.8–30.6) (table 3). The societal perspective corroborated the substantial economic benefit that the HIV-targeted strategy provided, yielding a BCR of 264.4 (125.3–392.4) (online supplemental table S20). When considering the hierarchy of these three indicators, the HIV-targeted strategy emerged as the optimal candidate in South Africa.

Online supplemental tables S21 and S22 presented the costs, cost-effectiveness and cost-benefit of the vaccination strategies for the 10-year and lifelong protection scenarios.

Sensitivity and scenario analyses

A bedding of input parameters through one-way sensitivity analyses signified that the potency of the economic model was significantly influenced by factors such as vaccine price and efficacy in both India and South Africa, from the healthcare sector perspective (figure 2A and E). Notably, in South Africa, the factor of VE reduction in PLHIV had some impact on the economic model, located in the fifth place of the one-way sensitivity analysis, from the healthcare sector perspective. The PSA ascertained that, with a one-time GDP per capita threshold in India, the AYA strategy boasted a 92% likelihood of cost-effectiveness (figure 2B,C). The societal perspective authenticated the 100% probability of the AYA strategy’s economic viability (online supplemental figure S11). In South Africa, from both healthcare and societal perspectives, the HIV-targeted strategy overwhelmingly showed a 100% probability of being cost-effective compared with current practices (figure 2F,G and online supplemental figure S11).

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The scenario analyses were performed to prognosticate the fiscal outcomes under different conditions. In India, scenarios with 70.8% VE, lifelong duration of protection and instant scale-up to 80% coverage prevented more TB cases than the base-case AYA strategy, with figures at 5.49 (95% UI: 3.87–9.31), 4.92 (3.5–8.23) and 7.97 (5.7–12.97) million (figure 2D). Moreover, these scenarios were more cost-effective than the base-case with ICERs of US$912 (776–1213), US$971 (825–1299) and US$1035 (875–1400) per DALY averted, respectively. For South Africa, similar scenarios outperformed the base-case HIV-targeted strategy, averting up to 0.59 (0.4–0.92) million TB cases and proffering lower ICERs across the board, indicating enhanced cost-effectiveness (figure 2H).

Primary findings

The examination of demographic and epidemiological data on the health impacts of Vaccae vaccination in India and South Africa revealed significant findings. In both countries, the vaccination strategies are projected to reduce TB incidence and mortality rates substantially by 2050. In India, without vaccination, TB cases and deaths are expected to reach 83.74 million and 5.97 million, respectively. The adult vaccination strategy could prevent 8.70 million cases and 0.61 million deaths, reducing incidence and mortality rates by 20.1% and 19.0%. However, the AYA strategy was notably cost-effective, requiring fewer vaccinations per case or death averted. In South Africa, the general population strategy could avert 0.67 million TB cases and 0.21 million deaths, with incidence and mortality rates dropping by 28.1% and 27.0%. In contrast, the HIV-targeted strategy proved most effective, with the lowest numbers needed to vaccinate per case or death averted. Economically, the AYA strategy in India and the HIV-targeted strategy in South Africa emerged as the optimal, providing significant health and economic benefits. Sensitivity analyses confirmed the robustness of these findings, with high probabilities of cost-effectiveness under various scenarios. The insights gained from the study hold the promise of being exceptionally informative and valuable for researchers and policymakers engaged in the fight against TB.

Comparison with other studies

Our study contributes to the literature on TB vaccination in India and South Africa but is not the first of its kind. For example, an earlier study demonstrated that routine adolescent vaccination would not be cost-effective if the vaccine only provided PSI efficacy. The divergence in findings may be due to the application of a substantially lower WTP threshold (US$264 per DALY averted).27 Similarly, in South Africa, a prior study suggested that the most cost-effective approach was to target the adult population aged 18–50 years, with secondary priority given to HIV-infected adults.28 Our study’s different conclusions can be attributed to our broader outcome metrics. Unlike the previous work, which centred solely around the ICER for gauging cost-effectiveness priority, our analysis employed a multidimensional set of evaluation criteria. Another study by Sumner et al demonstrated that the M72/AS01E vaccine in South Africa, targeting individuals aged 15–34, including both HIV-positive and HIV-negative individuals, was cost-effective.31 However, our study focused exclusively on vaccinating the HIV-positive population, aligning more closely with the higher HIV prevalence in South Africa.

Policy implications

India’s National Tuberculosis Elimination Programme (NTEP) has developed a structured approach organised around the four strategic pillars of Detect-Treat-Prevent-Build (DTPB).32 Introducing the Vaccae vaccination into this framework could significantly impact the effectiveness of NTEP, potentially sealing various gaps within the existing model. The immunisation could lead to a substantial decline in new TB cases, while ACF initiatives were expected to increase the case detection.33 Moreover, the findings are not confined to India alone but may resonate across other high-burden TB countries, such as Indonesia, the Philippines and Bangladesh.2 The lessons learnt regarding age-specific Vaccae vaccination might inform their own national programmes, adapted to reflect distinct epidemiological and socioeconomic circumstances.

In South Africa, the National Tuberculosis Programme’s adoption of the Vaccae vaccine may be a major leap forward in realising its aspirational goals to ‘End TB’ and ‘End HIV’. This preventive strategy may notably curtail TB rates among PLHIV, who are particularly susceptible to contracting active TB. HIV and LTBI screening, when combined with the vaccine’s deployment, could enhance disease detection within the country. The vaccine’s seamless integration with existing protocols would bolster the push for a more encompassing strategy, in harmony with antimicrobial TB treatment and HIV antiretroviral therapy. Moreover, South Africa’s approach might serve as an influential model for other regions grappling with high HIV prevalence, such as Gabon, Kenya and Thailand.2 These nations may also benefit from a tailored TB vaccine strategy aimed at addressing the intertwined HIV-TB challenge and alleviating their substantial healthcare burdens.

Concerning LTBI management, the WHO endorses TB preventive treatment (TPT) as a pivotal tactic in the journey to eliminate TB. The current recommendation highlights three rifamycin-based regimens: 3 months of isoniazid combined with weekly rifapentine (3HP), 4 months of daily rifampin (4R) or 3 months of daily isoniazid plus rifampin (3HR).34 Japan, which is a TB middle-burden country, has made the notification of LTBI mandatory since 2006, with TPT offered based on risk assessment.35 Nonetheless, the potential for adverse reactions partly accounts for patient hesitancy, thereby, hindering the widespread adoption of TPT.36 Integrating Vaccae vaccination as an alternative to TPT could address these concerns by offering a potentially safer and more acceptable option for both patients and healthcare providers. This could lead to improved compliance with preventative measures and bolster the fight against TB in contexts where TPT encounters substantial barriers to implementation.

Vaccine price and payment mechanisms are crucial for scaling up TB vaccination programmes. Biopharmaceutical companies often adjust prices by region based on market demand, economic conditions and healthcare infrastructure, typically lowering prices outside their home countries. For instance, Gilead Sciences priced its hepatitis C drug in China at one-fifth of the US price.37 Similarly, we assumed that the Vaccae vaccine price in India and South Africa was one-third of its price in China to enhance affordability (personal communication with Dr. Jiang Pu, senior officer of the Vaccae manufacturer). The affordability of the vaccine impacts the ability of healthcare systems, particularly, in low-income and middle-income countries, to procure and distribute the vaccine widely. Sustainable funding models, including government budgets, international aid and public-private partnerships, can help ensure that the vaccine reaches the populations most at risk.38

Strength and limitations

Our study is characterised by several notable strengths that set it apart from other studies in the field. First, it is anchored by the employment of the first clinically approved next-generation tuberculosis vaccine, apart from other studies that have relied on hypothetical vaccines or vaccines still under trial. The utilisation of an actionable vaccine in real-world contexts provided more practical insights and direct applicability of our study’s findings, compared with those inferred from studies based on vaccines with uncertain futures. Second, our analysis extended to a thorough consideration of ACF as an integral component of the PSI vaccine strategy. In doing so, we avoided underestimation and provide a more accurate assessment of the full potential of the PSI vaccine; whereas, other studies overlooked the costs associated with and the significance of ACF screening. Last but not least, we adopted a comprehensive evaluative stance through the incorporation of budget analysis, cost-effectiveness analysis and cost-benefit analysis. This approach extends beyond merely focusing on the ICER or any other singular metric. Consequently, this broadens our capacity to make well-informed decisions regarding the practicality and the economic ramifications of TB vaccine rollouts, providing a more expansive selection of indicators for policymakers’ guidance.

Admittedly, this study has several limitations. The vaccine was assumed to provide ‘all-or-nothing’ protection, yet the alternative ‘degree/leaky’ (efficacy was implemented as a reduction in natural history) assumption might reduce effect estimates. Our model omitted the analysis of regional disparities throughout the nation, gender-related variation, the spectrum of immune response, patterns of drug resistance, along with the extent of vaccine receptivity and adherence. These elements present valuable opportunities for prospective research. Delving into these details can enrich future studies, leading to models that more accurately reflect the intricacies associated with the deployment of TB vaccines and their more extensive influence on public health.