Cost-effectiveness of novel vaccines for tuberculosis control: a decision analysis study

Nearly a third of the world's population harbors the Mycobacterium tuberculosis bacillus, and about 1.7 million people die of tuberculosis (TB) each year [1]. Since the early 1990s, inconsistent treatment and the consequent emergence of drug resistance, and widespread HIV infection have contributed to the global epidemic. Other major challenges include limited diagnostic tools, and suboptimal provider/patient adherence with recommended diagnostic and treatment interventions [2]. The World Health Organization's recommended strategy of directly observed treatment, short course (DOTS) has reduced incidence in most world regions; however, TB control in sub-Saharan Africa and in the former Soviet Union continues to be a particular concern [3, 4]. In response to these challenges, the World Health Organization (WHO) has broadened its approach to TB control, for example by considering HIV-TB co-infection, smear-negative TB and treatment for latent infection [5]. In addition, there is intensive research into novel diagnostic, therapeutic, and preventive interventions. The development of an effective TB vaccine holds great appeal; by preventing TB infection and/or disease, it would circumvent limitations of current diagnostic and treatment strategies.

The only currently licensed TB vaccine, bacille Calmette-Guérin (BCG), has proven at least modestly efficacious in preventing tuberculous meningitis and disseminated disease in young children, although estimates of protection vary [6, 7]. It has very limited efficacy in preventing adult pulmonary disease, the form of disease that is contagious, and hence fuels the continuing epidemic. Based on current development timelines, next-generation TB vaccines may become available in the next 5-7 years [8, 9]. Because a suboptimal vaccine is already in widespread use, an improved vaccine is likely to attain the same or even better population coverage. However, costs for development, testing, and implementation may be substantial. Given the limited resources available for TB control, it is relevant to consider likely costs and public health benefits of a novel vaccine, based on currently available information. If vaccine development is likely to prove very expensive, with public health benefits accruing only in the distant future, then other interventions may be accorded higher priority.

Using a simulation model, we aimed to predict health outcomes and costs with different scenarios for the introduction of a novel TB vaccine in a sub-Saharan African country. We were particularly interested in the impact of varying scenarios for vaccine efficacy, and for the mechanism and timing of vaccine effect. As a case study, we estimated TB-related morbidity, mortality, and costs of a novel TB vaccine introduced in Zambia, a country with high HIV prevalence (9.4%) and very high annual TB incidence (247 smear positive cases/100,000) [1, 10]. We projected changes in TB morbidity, mortality, and cost when an improved vaccine replaces the current BCG vaccination program, and supplements the current DOTS program, over a range of scenarios for vaccine efficacy.

With the status quo, the model projected 25,557 active TB cases and 18,379 TB-related deaths over a period of 30 years, among 468,073 Zambians born in Year 1. The associated direct costs were $11.4 million and indirect costs were $45.1 million. Relative to current TB control measures, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to prevent 932 active TB cases and 422 TB-related deaths over the same period. This corresponds to a reduction of 199 cases and 90 deaths per 100,000 vaccinated. The prevention of these active TB cases and TB-related deaths would decrease direct costs by $0.2 million, and indirect costs by $3.4 million, resulting in a net reduction of $3.6 million in societal costs. Hence a new vaccine is predicted to result in cost savings as well as reduced morbidity and mortality.

The addition of a booster vaccine dose would avert 1,863 active TB cases and 1,011 TB-related deaths as compared to the status quo--a further reduction of 931 TB cases and 589 TB-related deaths beyond a single neonatal dose of the new vaccine. However, this would increase total direct costs to $11.9 million, reflecting larger investment in research, development, distribution, and vaccine administration. Substantial indirect cost savings of $6.2 million however, would produce net societal cost savings of $5.6 million compared to the status quo, or $2.0 million compared to a single dose of the new vaccine at birth.

Tables 4 and 5 summarize TB related costs, TB morbidity and mortality for each strategy over varying time horizons, for the entire group of newborns (Table 4), and per 100,000 newborns (Table 5). With vaccination at birth alone, net savings for Zambia would begin within 1 year, whereas the prime-boost strategy would require an additional 5 years to realize savings - reflecting greater initial development costs (Figure 2). In the long run (>16 years), the prime-boost vaccination strategy would be the cheapest.

Our comparison of two vaccination strategies with the current DOTS and BCG vaccination strategy for tuberculosis control in Zambia suggest that improved vaccines could reduce TB-related mortality and morbidity, and produce cost savings over a 30-year time horizon. The projections were generally robust in sensitivity analyses, even with assumed protective efficacy of 60% with a novel vaccine. Not surprisingly, neonatal vaccines which target initial infection or rapid progression will be more cost-effective in the short-term than those which target late re-activation. The current pipeline for novel vaccines predominantly focuses on these mechanisms of action [8, 35].

A previous analysis examined the public health impact of new tuberculosis vaccines and predicted that a pre-exposure vaccine, targeting the acquisition of infection or primary progression would be effective at preventing a substantial proportion of active TB cases. Although such a vaccine would not benefit persons who have already become infected with Mycobacterium tuberculosis, it would nonetheless provide important public health gains with respect to tuberculosis-related morbidity and mortality. The authors predicted that a pre-exposure vaccine that acts solely by reducing later reactivation of latent infection would not have the same impact, even if the vaccine were highly efficacious [36]. Our findings are similar and concordant with another recent analysis that used different modeling methods [37]. Over the long term, any vaccine that reduces late reactivation will decrease the annual risk of TB infection and therefore decrease disease incidence. However, the low annual risk of re-activation in HIV-negative persons, combined with finite vaccine duration of action make such a vaccine less cost-effective in the short or medium term.

The cost-effectiveness of a vaccine targeting late reactivation will be enhanced if it provides longer lasting immunity, and potentially if it is administered only after the acquisition of latent infection. One report estimated that a pre-exposure vaccine with efficacy of 50% - 90%, with a single mechanism of action, may only be capable of reducing TB morbidity by one third over the long term [36]. However, a more recent analysis concluded that a neonatal vaccine could reduce TB incidence by 39-55% in the long term, while a mass pre-exposure vaccine campaign could reduce incidence by 67%, in the absence of HIV infection [38]. The same analysis suggested that the combination of pre- and post- exposure vaccines could reduce TB incidence by 79% in Southeast Asia by 2050, in the absence of HIV infection. Hence, a TB control strategy that combines the DOTS program with vaccines targeting both early infection/progression and late reactivation may ultimately be considered.

The duration of vaccine-induced immunity remains unclear for the current BCG vaccine [6, 39, 40], so no concrete estimates exist for novel BCG replacement vaccines. For a vaccine with waning efficacy, a prime-boost strategy would be more cost-effective in the long term (Figure 2); however, the time lag to net savings may present a barrier to investment by both the public and private sectors.

A limitation of our analysis was the prorated attribution of the initial vaccine development, research, and production costs to Zambia, in proportion to its current share of global BCG vaccination coverage (0.398%). At this point in vaccine development there remains great uncertainty about the ultimate cost of research, pre-clinical and clinical trials, and vaccine rollout. It is quite conceivable that these costs will exceed the estimates used in our primary analysis. However, sensitivity analyses suggested cost savings for the neonatal replacement vaccine, even if the initial investment and vaccine unit costs were both quadrupled. Our prorating of development costs to a single cohort of newborns is also conservative, as it tends to underestimate the cost-effectiveness of TB vaccines over time.

In fact, high-incidence low- and middle- income countries which will use novel TB vaccines may bear little of their initial development costs. The funds may be provided primarily by governments of high-income countries, non-governmental organizations and research grants. This means that from the perspective of high-incidence countries and their populations, novel tuberculosis vaccines will be even more cost-effective. On the other hand, from the broader global TB control perspective, which includes costs to funders, these costs are relevant to the present analysis.

We did not model potential adverse events related to the administration of tuberculosis vaccines in neonates. An open-label, phase I trial of a novel vaccine candidate has demonstrated safety and high immunogenicity in individuals with latent tuberculosis infection [41]. The frequency of disseminated BCG has been reported to be less than five per million, and is mainly associated with congenital immunocompromised states [42]. A recent revision to the WHO guidelines on BCG vaccination recommends the immunization of asymptomatic infants whose HIV status is unknown, but advises against immunization of 1) infants whose HIV status is unknown, but display signs or symptoms suggestive of HIV infection; and 2) HIV positive infants, regardless of signs or symptoms [43]. A previous study showed that the risk of disseminated BCG disease is increased several hundredfold in HIV-infected infants compared to the documented risk in HIV-uninfected infants [44]. Unfortunately, due to the transplacental passage of maternal HIV antibodies, accurate diagnosis in the neonatal period requires the demonstration of HIV DNA, or HIV RNA and p24 antigen. Furthermore, signs of HIV infection are uncommon prior to BCG vaccine administration in the first weeks of life. For these reasons, the current program for BCG vaccination may have reduced efficacy in a particularly high-risk group, and increased morbidity, mortality, and added costs may result from BCG-related adverse events in countries with high HIV prevalence such as Zambia. Conversely, safety in HIV-infected neonates is considered a prerequisite for any future neonatal TB vaccine.

Other potential limitations of the analysis included our assumptions of stability in population size and age distribution, and HIV parameters. Herd immunity was not modeled [45], but a reduction in the annual risk of TB infection resulting from any vaccine which prevents contagious pulmonary TB would further reduce TB morbidity and mortality. Similarly, we did not model transmission, since the primary analysis considered vaccine protection among children, in whom TB is rarely contagious. Again, this makes our model conservative in that it tends to underestimate potential vaccine benefits.

A challenge to TB vaccine development is the lack of proven immunological correlates of vaccine-induced immunity, although early animal studies suggest improved protection against a pulmonary TB challenge for several prime-boost approaches [46‐48]. We did not model the effects of M. tuberculosis strain diversity. A recent analysis suggests the efficacy of novel vaccines may differ against different strains of the bacteria [49], however, the precise impact on efficacy remains uncertain given our incomplete knowledge regarding how distinct strains interact and the strain specificity of current vaccine candidates.

Our findings remained consistent across different scenarios for HIV seroprevalence. Greater savings and reduction in TB-related morbidity and mortality would be achieved if HIV seroprevalence was higher, owing to the more frequent development of active TB following infection. An increase in the proportion of TB which is multi-drug resistant would yield greater cost savings for vaccination, because of increased treatment and patient/family costs for MDR-TB. We computed the annual risk of TB infection from the incidence of smear-positive cases using the Styblo formula, which has been criticized [50]. Furthermore, a recent study has shown that in the presence of a strong control program, the TB incidence is not necessarily reflective of the true annual risk of TB infection in a country with high HIV seroprevalence [51]. However, we substantially varied the assumed annual risk of TB infection, and demonstrated that both primary vaccination strategies considered would still result in cost savings. Any inaccuracy in estimating the annual risk of TB infection would apply equally to all strategies, and would not tend to favor one particular strategy over the others.

Health care system costs were approximated by previously published data in Haiti, where GNI per capita is similar to Zambia. Social, political, and economic differences between the two countries may affect the validity of these estimates. However, indirect costs, which were obtained from Zambia itself, accounted for the bulk of total societal costs, strengthening our cost estimates. As a case study, our results may not be directly applicable to other sub-Saharan African countries given variability in epidemiology and economics, but the flexibility of the decision analysis model suggests the potential for a similar approach.

Several strengths of the analysis deserve comment. We considered the effect of HIV infection on TB pathogenesis, and accounted for survival with asymptomatic HIV and clinical AIDS, since HIV prevalence is high in Zambia and other sub-Saharan African countries [10]. Published values were used for epidemiologic data, TB pathogenesis, HIV pathogenesis, and treatment outcomes whenever available, thereby reducing uncertainty. We evaluated costs from a societal perspective, and considered both direct and indirect costs from the standpoint of a low-income country with high TB incidence. Notably, indirect costs borne by patients and families constituted a substantial proportion of the total. The decision analysis model allowed us to manipulate key variables and test our underlying assumptions. Sensitivity analyses confirmed the robustness of the main findings. In particular, with an assumed efficacy of 60%, a novel vaccine that prevents rapid progression to active TB would still provide cost savings, as well as prevent TB cases and TB-related deaths. This strengthens the economic argument in favour of developing and implementing new vaccines. We recognize that the 70% efficacy estimate used for our primary analysis is speculative, as useful evidence must await the outcome of one or more large-scale clinical trials, still years away.

Novel TB vaccine development and deployment faces a number of obstacles. The lack of validated biomarkers for candidate vaccine selection, scarcity of suitable field sites, exclusion of at-risk populations from trials, regulatory issues, and complex ethical concerns at each stage of human testing are among the challenges [52‐54]. The continued expansion of the TB vaccine pipeline, however, remains reassuring. Recent years have renewed interest in TB vaccine development. By the end of 2009, at least nine novel TB vaccines were undergoing evaluation in humans, with at least two recombinant protein vaccines reaching phase II trials [54, 55].

This analysis suggests that a prime-boost strategy using a tuberculosis vaccine with moderate efficacy (>60%) which prevents initial infection or rapid primary progression to disease, will be the most cost-effective vaccine intervention over the short to medium term, in high-burden countries. We conclude that investment in an improved TB vaccine may result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when it enhances existing control strategies.