Determining the cost–effectiveness of adult pneumococcal vaccination strategies

Abstract

The 23-valent pneumococcal polysaccharide vaccine is known to be economically reasonable in adults. With the 13-valent pneumococcal conjugate vaccine (PCV13) now available, the question is whether 23-valent pneumococcal polysaccharide vaccine offers sufficient protection in adults compared with PCV13. Our cost–effectiveness analyses favor adult PCV13 use, but results depend largely on assumptions regarding PCV13 effectiveness in preventing non-bacteremic pneumococcal pneumonia and on herd immunity effects from childhood PCV13 use, neither of which are well characterized at present. An ongoing randomized trial of adult PCV13 use and future surveillance data should clarify these issues for some population groups, but in others, such as the immunocompromised, modeling that rigorously accounts for uncertainty can and should be used to assist policymakers in their decisions.

Keywords::

• adults
• cost–effectiveness analysis
• immunocompromising conditions
• invasive pneumococcal disease
• pneumococcal pneumonia
• pneumococcal vaccination

In the USA, Streptococcus pneumoniae may cause 250,000 hospitalizations and 30,000 deaths annually [101], and occurs more frequently among the elderly and among persons with immunocompromising conditions or other comorbid conditions [1]. Major pneumococcal illness is classified as invasive pneumococcal disease (IPD) or non-bacteremic pneumococcal pneumonia (NPP). IPD is infection in a normally sterile site, with a <1% risk in the remaining lifetime of US 50 year olds [2]. NPP is pneumonia without bacteremia and more common; its risk is 5–10% from age 50 onward [3].

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) remains the only vaccine recommended by the US Centers for Disease Control and Prevention (CDC) for use in non-immunocompromised adults [1]. PPSV23 prevents IPD; however, effectiveness against NPP is unproven, with trials suggesting no convincing efficacy [4]. In addition, PPSV23 may not protect against IPD in the immunocompromised, with many experts doubting its effectiveness in this high-risk group [2]. The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in the USA for use in children in 2010, superseding the 7-valent vaccine (PCV7) [1]. Through direct effects (i.e., in vaccinees), conjugate vaccines prevent IPD and NPP in children [1] and IPD in immunocompromised adults [5]. Perhaps more importantly, PCV7 and PCV13, unlike PPSV23, have indirect (herd immunity) effects; vaccinating children has decreased disease in all ages [6]. This success of childhood vaccination has raised questions whether adult PCV13 will have any effect [7]. However, indirect effects are less in the immunocompromised, with illness still frequently caused by vaccine serotypes [8].

Pneumococcal vaccination in children is cost-effective, due largely to herd immunity [9]. This paper concentrates on the cost–effectiveness of adult vaccination.

Prior to PCV13 availability, PPSV23 was economically reasonable when used as recommended in the USA [2]. Prior to the recent modification (see below), all US adults aged ≥65 years were recommended to receive PPSV23 unless a comorbid condition was present, in which case PPSV23 was recommended at condition diagnosis and again 5 years later [4]. Due to suboptimal PPSV23 uptake in high-risk groups, the higher prevalence of high-risk conditions in persons aged ≥50 years, and greater pneumococcal illness risk in persons this age without high-risk conditions, universal PPSV23 use at age 50 was examined and found to be economically reasonable [2,10]. With adult PCV13 now available, the question is whether PPSV23 use alone offers sufficient protection for adults compared with strategies using PCV13 [3,11].

Beyond herd immunity effects from childhood vaccination, the other major consideration is whether PCV13 prevents adult NPP. CAPITA, a randomized controlled trial of PCV13 in 85,000 persons in The Netherlands aged ≥65 years, is designed to answer this question, with final results expected in July 2015 [102].

Until trial results are available and childhood PCV13 indirect effects become clear, estimating the cost–effectiveness of adult PCV13 use is challenging. Factors to be considered include: changes in disease frequency and serotype distributions due to herd immunity, vaccine effectiveness and uptake and differential risks and indirect effects among population subgroups. Pneumococcal serotype epidemiology is complex, and predicting epidemiologic responses to vaccines is a daunting task. Herd immunity due to adult vaccination will likely be insignificant when compared with that of childhood vaccination. Replacement disease, increases in illness due to non-vaccine serotypes, occurred after childhood PCV7 introduction [6]. The impact of replacement disease post PCV13 is unclear [12].

In our analysis, we used estimates of PCV13 effectiveness and of future indirect and replacement disease effects, varying them widely in sensitivity analyses [3]. Differences in these estimates drive the differences in analysis results [13]. In our work, we used an expert panel to estimate PCV13 effectiveness in preventing vaccine serotype illness and a prior expert panel’s estimates for PPSV23 effectiveness [2]. We projected increasing future PCV13 indirect effects and replacement disease based on observed effects after PCV7 introduction.

We found [3] that PCV13 strategies would likely be cost-effective under base case assumptions regarding vaccine efficacy and childhood vaccination herd immunity effects. However, results were sensitive to variation of PCV13 vaccine effectiveness against NPP, with PPSV23 being favored if PCV13 effectiveness against NPP was low. Results were also sensitive to assumptions regarding PCV13 indirect effects: if greater future effects were seen, adult PCV13 use became unfavorable.

This analysis used a 50-year-old cohort, preventing analysis of population effects or of effects in other age groups. To partially remedy this, we also examined PCV13 in 65- and 75-year-old cohorts [14], finding PCV13 use likely to be economically favorable, but again limited by sensitivity to assumptions regarding NPP effectiveness and herd immunity due to childhood PCV13 [14].

The US FDA approved PCV13 use in adults aged ≥50 years, conditional on a clinical trial to examine NPP prevention performed during the post-approval marketing period, that is, the previously mentioned CAPITA trial. A CDC recommendation for PCV13 in the adult general population is also hampered by the lack of adult effectiveness data, which the CAPITA trial will likely fill.

However, the CAPITA sample of non-immunocompromised elderly will not provide data on effectiveness in the immunocompromised [15]. Additionally, few data support PPSV23 effectiveness in the immunocompromised, and small studies suggest that pneumococcal conjugate vaccines could prevent IPD in the immunocompromised, leading to interest in PCV13 use in this group [1].

We and others estimated PCV13 cost–effectiveness in the immunocompromised [16,17,103]. Our work incorporated updated CDC recommendations for the immunocompromised: use of both PCV13 and PPSV23 [1]. However, vaccine effectiveness in the immunocompromised is quite uncertain, specifically PPSV23 effectiveness against IPD and PCV13 effectiveness against IPD and NPP. We modeled PPSV23 effectiveness in preventing IPD relative to expert estimates of PCV13 effectiveness against IPD and PCV13 effectiveness against NPP relative to its estimated IPD effectiveness.

Our base case results assumed 50% relative IPD effectiveness of PPSV23 compared with PCV13. The prior CDC recommendation for the immunocompromised, using only PPSV23, was dominated (more costly and less effective) by strategies using PCV13. In HIV-infected individuals, both a single PCV13 dose and the newly recommended strategy using both PCV13 and PPSV23 cost less than $100,000/QALY gained over the model’s 15-year time horizon. Individuals with other immunocompromising conditions, and shorter life expectancy, had greater incremental cost–effectiveness ratios for these strategies. Overall, PCV13 use in the immunocompromised was supported, with uncertainty regarding the incremental value of adding PPSV23 to PCV13, particularly in immunocompromised persons with relatively shorter life expectancy [17].

Two other analyses had different results. The CDC performed a cost–effectiveness analysis; they found the new recommendation for the immunocompromised cost saving and more effective than the prior recommendation [103]. A UK analysis [16], on the other hand, found PCV13 unlikely to be cost-effective, costing £90,720 (or ∼$145,000) per QALY gained. However, differing modeling choices drove the differences in results. The CDC analysis did not examine strategies using only PCV13, as ours did, and modeled greater PCV13 effectiveness and boosting of its effectiveness after subsequent PPSV23 doses [103]. The UK analysis assumed that PCV13 was ineffective against NPP; when PCV13 was modeled as fully effective against NPP, it cost approximately $39,000 per QALY [16]. The lesson here is that when analysis results differ, exploration of the models and their assumptions will often explain those differences [13].

However, the question remains: is pneumococcal vaccination in adults economically reasonable? Prior work suggests PPSV23 use in general population groups aged ≥50 or ≥65 years is economically favorable. The cost–effectiveness of switching to or adding PCV13 depends, in part, on its NPP effectiveness, which is, as yet, unproven in adults. The CAPITA trial is poised to answer this question for non-immunocompromised persons aged ≥65 years. CAPITA may also supply information on PCV13 effectiveness in persons at high risk for pneumococcal disease due to non-immunocompromising comorbid conditions, such as chronic heart and lung disease. However, other studies will need to supply information on NPP effectiveness duration (CAPITA plans 2 years follow-up), effectiveness in the immunocompromised and on the generalizability of CAPITA results to more diverse (non-Dutch) populations.

Indirect effects of childhood PCV13 use are probably more important, but will become clearer with time. IPD caused by PCV7 serotypes rapidly decreased after childhood PCV7 use in most groups, but not in the immunocompromised [8]. Whether PCV13 serotypes will respond similarly should be apparent soon; recent data suggest they will [18]. If PCV13 serotypes become insignificant in causing disease, PCV13 use in general adult population groups may not be economically reasonable [3,7]. Interactions of childhood PCV13 use and time since such use began will impact adult PCV13 cost–effectiveness, as herd immunity effects increase with time [16].

Given this uncertainty, the CDC and others have deferred decisions regarding PCV13 in most adults until data become available. In subgroups where data are scant and not as predictably forthcoming, such as the immunocompromised, more speculative data and analyses can and should be used to assist policymakers. Well-performed cost–effectiveness analyses incorporating new data as they become available while rigorously accounting for uncertainty could play a role in PCV13 policy recommendations in other groups, such as adults younger than 65 or having non-immunocompromising high-risk conditions.

Financial & competing interests disclosure

KJ Smith receives National Institute of Health funding. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.