Optimal control strategies for influenza continue to generate controversy among public health communicable disease control experts. To inform this debate, we developed a mathematical to project the impact and cost-effectiveness of a novel adjuvanted seasonal influenza vaccine in the Canadian population based on the best-available data. Use of ATIV in seniors and young children was projected to provide substantial health benefits, and to be cost effective, relative to currently used TIV. Although the impact of adjuvanted vaccine on absolute numbers of deaths was greatest in seniors at highest risk of fatal outcomes, we projected that it would also avert substantial numbers of hospitalizations in younger individuals. The incorporation of transmission into the model made it possible to project the gains in health and survival in age groups not receiving the adjuvanted vaccine; we projected that the use of adjuvanted vaccine in children, in particular, would markedly reduce hospitalizations in children and adults not targeted to receive adjuvanted vaccine. Such “herd effects” are consistent with effects demonstrated in recent randomized controlled trials, in which immunization of younger individuals protects the population as a whole 
We incorporated costs and health utility weights, which have been used in prior published health economic analyses 
, into our model to assess the economic attractiveness of replacing immunization of older Canadians and young children with adjuvanted vaccine. Proposed World Health Organization benchmarks suggest that programs be considered highly cost-effective if life years are purchased at a cost of less than per-capita gross domestic product 
, which in Canada is approximately $40,000. In our base case we projected that immunization of older adults with ATIV would be extremely cost-effective relative to the use of traditional TIV, even in the context of a universal influenza immunization program like that in effect in Ontario, which appears to have reduced mortality in the elderly indirectly, via prevention of transmission of influenza from younger to older individuals 
. Cost-effectiveness was further enhanced when we eliminated the Ontario-style UIIP from the model, with the direct protection provided to older individuals by adjuvanted vaccine counterbalancing the loss of indirect protection accrued via immunization of younger adults. The relative novelty of adjuvanted influenza vaccines makes modeling challenging, given that the true values of vaccine efficacy parameters are not yet known with certainty; however, there is a growing body evidence supporting the contention that these vaccines are more effective in children and older adults than traditional unadjuvanted vaccines 
. Given the uncertainty in data inputs in the model, we subjected our projections to extremely wide-ranging sensitivity analyses and found them to be extremely robust; the use of adjuvanted vaccine was preferred in older individuals even when “best case” values (efficacy
0.5) were used for TIV and “worst case” (efficacy 0.51) values were used for ATIV. While this may appear surprising, the health and economic toll of influenza in older adults in typical influenza seasons is extremely high 
. Consequently, the direct protection provided by ATIV in this group translates into large health gains at low economic costs, even when the gap in effectiveness between vaccine types in older individuals is modeled as far smaller than would be expected based on the best available data 
. Pediatric effectiveness data, being derived from a well-designed randomized controlled trial 
, are subject to less uncertainty, but our projections of cost-effectiveness are nonetheless robust in the face of substantial variation in estimated efficacy in children.
While we assigned an efficacy of 20% to TIV in older adults in our base case, evidence for effectiveness of TIV in older adults is conflicting, with some studies reporting effectiveness as high as 50–60% 
, while others fail to find any evidence of effectiveness when circulating strains do not match vaccine components, or when influenza epidemics are absent 
. Furthermore, estimates of the impact of influenza vaccine on all-cause mortality in older individuals are implausibly large given levels of vaccine coverage seen in countries such as the United States, and the relatively limited proportion of deaths which are excess deaths during influenza season 
. The apparent impact of influenza vaccination on mortality in non-influenza season has served to provide further evidence that effects attributed to influenza vaccination may in some cases represent a “healthy vaccinee effect”, with more robust elderly individuals being more likely to receive vaccination 
. Interestingly, the large observational study of ATIV that is the source of our base-case effectiveness estimates was subject to exactly the opposite limitation: in that study, older individuals with poor health status preferentially received ATIV (while their healthy counterparts received TIV), and the excess risk of hospitalization seen in these individuals was confined to the period outside
influenza season 
, suggesting that the true relative efficacy of ATIV may be higher than we estimate in our base-case analysis.
Emerging data suggest that MF59-adjuvanted vaccines appear to confer cross-strain immune protection sufficiently robust to provide protection against drifted influenza strains, via generation of antibody and B-cell responses against a broader range of influenza antigens than is the case with unadjuvanted vaccine 
. We project that enhanced durability of protection could make ATIV economically attractive even in the absence of increased effectiveness; further research is needed to evaluate the relative durability of effect of these vaccines.
Like any model-based evaluation of vaccine effectiveness and cost-effectiveness, our analysis has limitations. Our mathematical model includes simplifying assumptions and incorporates parameters values that are subject to uncertainty. Model calibration to existing data was used to reduce this uncertainty for some key parameters and wide-ranging sensitivity analyses were used to explore the impact of parameter uncertainty on our findings. We used a constant value for estimates of vaccine efficacy, although these values will vary from year-to-year, depending on match with circulating influenza strains. We excluded vaccine-related adverse events; although studies to date have not suggested elevated risks of serious adverse events associated with the MF59 adjuvant 
, immune adjuvants may result in unusual adverse event profiles 
. Ongoing surveillance and evaluation of vaccine-associated adverse event risks are warranted for this novel vaccine.
In summary, a mathematical model parameterized to represent the transmission of influenza in the Canadian population suggests that use of an adjuvanted trivalent influenza vaccine in seniors and young children is likely to be a highly cost-effective intervention, relative to the currently used unadjuvanted vaccine. These projections hold even under assumptions of very minor enhancements of vaccine efficacy associated with adjuvanted vaccines. Enhanced durability of vaccine-derived immunity may further enhance the economic attractiveness of this intervention.