controlled trial [9,11], 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% [19,33], 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 [35,36]. 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
[12,37,38]. 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 param-
eters 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
[40,41,42,43]. 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 enhance-
ments of vaccine efficacy associated with adjuvanted vaccines.
Enhanced durability of vaccine-derived immunity may further
enhance the economic attractiveness of this intervention.
File S1 Supplementary appendix.
Figure S1 Model calibration to average excess influen-
za-attributable mortality. Average influenza mortality was
estimated using a smoothed time-series of average influenza-
attributable mortality for the province of Ontario over seven
influenza seasons, as described in the Methods section. Average
reported age-specific vaccine uptake rates in Ontario for the time
period under study (1997–2004) were used.
Conceived and designed the experiments: ART DNF. Performed the
experiments: ART. Analyzed the data: ART DNF. Wrote the paper: ART
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PLoS ONE | www.plosone.org 8 November 2011 | Volume 6 | Issue 11 | e27420