Comparative evaluation of the potential impact of rotavirus versus hpv vaccination in GAVI-eligible countries: A preliminary analysis focused on the relative disease burden

Several new vaccines have recently become available, including those against rotavirus, human papillomavirus (HPV), and pneumococcus. To set new policies for optimum use of these vaccines in different settings, participating entities including international agencies (e.g., World Health Organization [WHO]), domestic policymakers, financing coordination mechanisms (e.g., GAVI Alliance), and donors [1, 2] will need new information on which to base their decisions.

Unfortunately, given the complexity of many vaccine-preventable diseases [3], the impact and inevitable tradeoffs associated with a particular vaccine program are never fully known until well after implementation. To help resolve this uncertainty for policymakers, a decision analytic approach using a disease-specific model can be used to organize, synthesize and integrate the available clinical, epidemiologic, and economic information and to estimate the cost-effectiveness of a prospective vaccine program [4, 5]. Furthermore, such model-based analyses can also be useful for generating other outcomes such as intermediate (e.g., infections averted and cases averted) and long-term outcomes (e.g., deaths prevented and disability-adjusted life years [DALYs] averted) as well as the timing of those outcomes (e.g., immediate, within a few years, or decades later). Finally, a model-based analysis can help to identify the more influential determinants of a vaccine's expected impact and value in a given setting.

Recently, economic evaluation studies using a modeling approach have reported that many of the new vaccines would substantially reduce disease-specific mortality and provide good value for money in low- to middle-income country settings [6‐9]. However, these vaccines also tend to be far more expensive than the traditional childhood vaccines previously introduced into these countries, many of which now face growing populations and unprecedented budget constraints. It is in this context that immunization policy makers at both global and local levels need to establish priorities among the new vaccines competing for limited resources [10, 11]. Even for countries wishing to adopt multiple new vaccines, there are inevitable questions about which programs should be implemented earlier and whether some should be implemented more aggressively than others. Such priority decisions would entail various considerations (e.g., cost-effectiveness, affordability, and equity), and there has been an increasing attention paid to how best to achieve a balance between these considerations [12, 13].

However, comprehensive comparison of prospective vaccine programs in low- to middle-income country settings is difficult. There have been few economic evaluations of new vaccines in resource-poor settings, for which important data is often lacking. Additionally, the cost-effectiveness profiles derived for individual vaccines from separate studies make for problematic comparison, as the analyses use different data sources and assumptions. Furthermore, independent analyses conducted for a single vaccine are often presented in different formats making it more challenging to compare results.

Nevertheless, since policymakers will likely have to make early and comprehensive priority decisions in the context of incomplete information, even a preliminary comparison based on the available data would be useful to inform deliberative dialogue among stakeholders [14]. Indeed, there recently has been an increasing demand for this type of information among international agencies and immunization financing mechanisms.

Motivated to provide early insight into how the comparative impact of different new vaccines could be assessed across different resource-poor settings (where most benefits from the vaccines would be realized), we leverage our previously conducted analyses for rotavirus and HPV (conducted for each disease separately) [6, 15‐19]. Given that new vaccine prices are often unknown at the early stages of vaccine arrival, and that data on country-specific program delivery costs are highly uncertain and rarely available in resource-poor settings, we take a composite cost approach that assumes the same level of plausible, collective program costs across the countries for each of the two vaccines. We thus compare the health, economic, and financial impact of introducing these two vaccines in 72 GAVI support-eligible low-income countries, with a primary focus on relative disease burden. In doing so, we standardize a simple modeling approach and analytic framework in order to facilitate comparison. We also identify and highlight methodologic challenges and influential uncertainties that should be considered as discussions about vaccine prioritization unfold.

A brief summary of the key features of the diseases caused by the two pathogens--rotavirus and HPV--and the characteristics of the two new vaccines follows:

Our findings show that the number of lives saved in a head-to-head comparison of a single-age cohort of infants and pre-adolescent girls, with the rotavirus and HPV vaccines, respectively, in the GAVI countries are very similar even though the two vaccines target different populations in terms of size and gender, and even though the diseases the vaccines target have different epidemiological features. The target population for rotavirus vaccines is approximately twice as large as the target population for HPV vaccines (~76 million versus ~32 million for a single cohort) since the former includes both genders while the latter only includes girls. However, the absolute number of deaths averted within each age cohort over their lifetime is slightly lower for rotavirus vaccines than for HPV vaccines (~274,000 versus ~286,000); partly, this is due to the higher disease-specific mortality (i.e., case fatality rate) of cervical cancer compared to that of rotavirus gastroenteritis.

We found 5.2 lives were saved per 1,000 children vaccinated against rotavirus, and 12.6 lives were saved per 1000 pre-adolescent girls vaccinated against HPV 16,18. The timing of the lives saved, however, drastically differs since the deaths attributable to rotavirus occur in close proximity to the acute infection, while deaths attributable to HPV-related cervical cancer occur in the girl's adult life largely after the age of 30.

Given this time difference of lives saved, when we translated the health outcomes into DALYs averted applying a 3% discount rate, the number of DALYs averted was much higher with rotavirus vaccines compared to HPV vaccines (~7.15 versus ~1.30 million). Recently, arguments to use 'slow discounting' are made on the basis of this large time effect when the health outcome of an intervention is far in the future from the time of the actual intervention [64].

When we used WHO's cost-effectiveness threshold based on GDP per capita, in most of the GAVI countries (68 for rotavirus and 66 for HPV, at the cost of I$25 per vaccinated individual) the incremental cost per DALY averted was lower than each country's GDP per capita - implying both vaccines would meet the criterion for being "very cost-effective" [44, 56, 64].

We emphasize that our analysis was intended to provide a broad comparative overview of the potential impact of the rotavirus and HPV vaccines in the GAVI-eligible countries, rather than to provide precise estimates of the cost-effectiveness profiles of the two vaccines. The comparison is not based on empiric data obtained from a head-to-head clinical trial where randomization can minimize the risk of introducing bias caused by differences in the two vaccination programs. Such clinical trials are incredibly difficult to design when the comparison is based on different populations and for different conditions. Our cost-effectiveness results should be considered preliminary since the composite costs for vaccine purchase and delivery were assumed to be the same for both vaccines and uniform across all GAVI-eligible countries, and thus the differences in the cost-effectiveness results primarily reflect the relative disease burden within and across each of the GAVI countries. We therefore caution that our base-case cost-effectiveness results should be interpreted carefully. We suggest that, for priority setting decisions at a country level, more rigorous comparisons should be performed as country-specific data become available. We hope our analysis would facilitate a more specific discussion about important issues (as will be discussed later in this section) that should be considered in setting priorities among different vaccination programs competing for limited resources.

Other limitations of our analysis include the following: First, our static models are not designed to capture potential herd immunity effects that might result from either vaccine intervention, thus likely underestimating the true impact of the two vaccines. From a comparative standpoint, our results do not reflect potential differences in level of herd immunity between the two vaccines, which in turn are dependent on multiple complex factors (e.g., the nature of disease transmission and contact pattern in a given setting) for each pathogen. Second, when country-specific data were severely lacking, our analysis relied on standardized assumptions that may skew our estimates for both absolute and relative vaccine benefits in different ways for each country. For example, similar to the case of the composite vaccination program costs described previously, we relied on standardized assumptions on medical utilization practices (e.g., one-time outpatient visit plus a 3-day admission for treating severe rotavirus gastroenteritis requiring hospitalization) when calculating the costs to treat diseases caused by the two pathogens in each country. Third, due to the scarcity of relevant data on rotavirus disease in older individuals, our rotavirus model focuses on the disease burden among children under age 5 with a time horizon of 5 years. While severe rotavirus diseases occur primarily in younger children and adult cases are usually not severe, it is known that individuals older than 5 years may also develop symptomatic rotavirus diseases. Our study therefore presents a likely, but moderate, underestimate of the health benefits of rotavirus vaccination. Finally, we did not take into account the potential impact of current supplementary or alternative interventions (e.g., cervical cancer screening) on vaccine cost-effectiveness or the technological changes that may affect the cost-effectiveness profiles of the vaccines in the long-term.

Despite the limitations, the present comparative analysis, coupled with our previously published analyses, highlight some key factors related to the comparative impact, affordability, cost-effectiveness, and distributional equity that decision-makers must consider when introducing new interventions in resource-limited settings. Moreover, the analysis provides insight into several uncertainties that should be considered when assessing these vaccines.

In conclusion, it would be desirable for policy makers to be able to make decisions about the timing of new vaccine introduction using country-specific information, taking into account various criteria that could affect priority-setting procedures, and considering the impact on other health sectors and systems [13, 80‐82]. While avertable burden and cost-effectiveness are among these criteria, other critical factors considered in decision making and prioritization include (but are not limited to) externalities, horizontal and generational equity, political criteria, and affordability. Our findings show that both rotavirus and HPV vaccines have potential to reduce mortality and be cost-effective investments in GAVI country settings, with very similar cost-effectiveness profiles in terms of cost per DALY averted. However, we note that the absolute avertable burden will vary with regional differences in disease-specific mortality, and that the comparative cost-effectiveness could very well vary with country-specific differences in programmatic delivery costs and pricing, if markedly different between the two vaccines. While the benefits of these two new vaccines will be realized at different times, the number of lives saved with these two vaccines over each target populations' lifetime will be quite similar. Our study illustrates that the use of comparable models, consistent assumptions, and standardized output that reports results similarly, allows for comparison of the two new vaccines on different dimensions; this approach can enrich the discussion about what attributes might be weighted most prominently in the priority-setting process. Nevertheless, we re-emphasize that our analysis was intended to provide an early insight on what aspects of vaccine impact should be considered in priority setting, using the examples of rotavirus versus HPV vaccines in the GAVI-eligible countries. Accordingly, for priority setting in an individual country, a more comprehensive analysis should be performed, considering all relevant vaccination programs and using country-specific data. In addition, given uncertainties surrounding the epidemiology of the diseases, the vaccines' target coverage, and the longer term vaccine effects (e.g., herd immunity effects or serotype replacement), iterative comparative evaluations will be prudent.