Article

Estimation of the Health Impact and Cost-Effectiveness of Influenza Vaccination with Enhanced Effectiveness in Canada

Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e27420. DOI: 10.1371/journal.pone.0027420
Source: PubMed

ABSTRACT

The propensity for influenza viruses to mutate and recombine makes them both a familiar threat and a prototype emerging infectious disease. Emerging evidence suggests that the use of MF59-adjuvanted vaccines in older adults and young children enhances protection against influenza infection and reduces adverse influenza-attributable outcomes compared to unadjuvanted vaccines. The health and economic impact of such vaccines in the Canadian population are uncertain.
We constructed an age-structured compartmental model simulating the transmission of influenza in the Canadian population over a ten-year period. We compared projected health outcomes (quality-adjusted life years (QALY) lost), costs, and incremental cost-effectiveness ratios (ICERs) for three strategies: (i) current use of unadjuvanted trivalent influenza vaccine; (ii) use of MF59-adjuvanted influenza vaccine adults ≥65 in the Canadian population, and (iii) adjuvanted vaccine used in both older adults and children aged < 6.
In the base case analysis, use of adjuvanted vaccine in older adults was highly cost-effective (ICER = $2111/QALY gained), but such a program was "dominated" by a program that extended the use of adjuvanted vaccine to include young children (ICER = $1612/QALY). Results were similar whether or not a universal influenza immunization program was used in other age groups; projections were robust in the face of wide-ranging sensitivity analyses.
Based on the best available data, it is projected that replacement of traditional trivalent influenza vaccines with MF59-adjuvanted vaccines would confer substantial benefits to vaccinated and unvaccinated individuals, and would be economically attractive relative to other widely-used preventive interventions.

Full-text

Available from: Ashleigh R Tuite
Estimation of the Health Impact and Cost-Effectiveness
of Influenza Vaccination with Enhanced Effecti veness in
Canada
David N. Fisman*, Ashleigh R. Tuite
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Abstract
Introduction:
The propensity for influenza viruses to mutate and recombine makes them both a familiar threat and a
prototype emerging infectious disease. Emerging evidence suggests that the use of MF59-adjuvanted vaccines in older
adults and young children enhances protection against influenza infection and reduces adverse influenza-attributable
outcomes compared to unadjuvanted vaccines. The health and economic impact of such vaccines in the Canadian
population are uncertain.
Methods:
We constructed an age-structured compartmental model simulating the transmission of influenza in the Canadian
population over a ten-year period. We compared projected health outcomes (quality-adjusted life years (QALY) lost), costs,
and incremental cost-effectiveness ratios (ICERs) for three strategies: (i) current use of unadjuvanted trivalent influenza
vaccine; (ii) use of MF59-adjuvanted influenza vaccine adults $65 in the Canadian population, and (iii) adjuvanted vaccine
used in both older adults and children aged , 6.
Results:
In the base case analysis, use of adjuvanted vaccine in older adults was highly cost-effective (ICER = $2111/QALY
gained), but such a program was ‘‘dominated’’ by a program that extended the use of adjuvanted vaccine to include young
children (ICER =
$1612/QALY). Results were similar whether or not a universal influenza immunization program was used in
other age groups; projections were robust in the face of wide-ranging sensitivity analyses.
Interpretation:
Based on the best available data, it is projected that replacement of traditional trivalent influenza vaccines
with MF59-adjuvanted vaccines would confer substantial benefits to vaccinated and unvaccinated individuals, and would
be economically attractive relative to other widely-used preventive interventions.
Citation: Fisman DN, Tuite AR (2011) Estimation of the Health Impact and Cost-Effectiveness of Influenza Vaccination with Enhanced Effectiveness in
Canada. PLoS ONE 6(11): e27420. doi:10.1371/journal.p one.0027420
Editor: Benjamin J. Cowling, University of Hong Kong, Hong Kong
Received July 13, 2011; Accepted October 17, 2011; Published November 14, 2011
Copyright: ß 2011 Fisman, Tuite. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by Novartis, which manufactures an adjuvanted influenza vaccine. The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have read the journal’s policy and have the following conflicts: This research was supported by Novartis, which manufactures
an adjuvanted influenza vaccine. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: david.fisman@utoronto.ca
Introduction
Influenza is a contagious acute respiratory disease that is
responsible for an estimated 4000 deaths annually in Canada, due
both the influenza and its downstream complications [1], with
deaths mainly occurring in adults aged 65 and older. Although
most influenza infections are self-limiting, they result in increased
demands on health care services and are costly in terms of
morbidity and lost productivity [2,3,4,5].
When the vaccine is well matched with circulating influenza
strains, immunization is an effective preventive measure for
reducing influenza-attributable morbidity and mortality. Unadju-
vanted trivalent influenza vaccine (TIV), containing three specific
subtypes of influenza expected to dominate during the upcoming
influenza season (two influenza A strains and one influenza B
strain), is currently used in Canada. The composition of the
vaccine is updated annually to reflect changes in the dominant
circulating subtypes, due to antigenic drift or antigenic shift.
Efficacy of unadjuvanted vaccine in older adults ($65) is
typically lower than that observed in healthy adults [6]; this
reduced efficacy may be due to a lowered antibody response to the
vaccine in the elderly [7]. To overcome this reduced efficacy,
influenza vaccines containing an adjuvant to enhance immune
response have been used in older adults in some European
countries [8]. Additionally, during the recent pH1N1 pandemic,
adjuvanted vaccine was adopted as an antigen-sparing measure by
many countries, where its use was not restricted to older adults. In
the elderly and young children, there is emerging evidence that
adjuvanted trivalent influenza vaccines (ATIV) result in enhanced
protection against influenza infection or adverse outcomes
following infection [9,10,11]. It has also been proposed that these
vaccines may provide protection against viral drift, thereby
enhancing the duration of immunity against infection [12,13,14].
Given the evidence of both enhanced vaccine efficacy and
enhanced duration of immunity associated with ATIV, we sought
to evaluate the effect of using a seasonal adjuvanted vaccine in the
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Canadian population. We used an age-structured mathematical
model to evaluate the impact of seasonal influenza vaccination on
expected influenza transmission over a 10-year period. Model
projections were used to perform an economic evaluation to
estimate projected health outcomes and costs associated with the
use of adjuvanted vaccine compared to the currently used
unadjuvanted vaccine in the Canadian population.
Methods
Model Construction
We constructed an age-structured compartmental model that
simulates the transmission of influenza in the Canadian popula-
tion, as described in detail in [15,16]; this model was modified to
include births and non-influenza deaths, in order to examine
multi-year influenza dynamics. The model structure is presented
in Figure 1 and additional model details are provided in File S1.
Natural history assumptions (Table 1) were derived from
epidemiologic studies and by model calibration. The population
was divided into five compartments representing different disease
states: susceptible (S), vaccinated (V), exposed (E; i.e., infected but
not infectious), infectious (I), and recovered (R).
Vaccination was modeled by removing individuals from the
susceptible compartment during a three-month period each year,
beginning approximately 4 months prior to peak influenza activity.
The model was calibrated to reproduce average excess seasonal
influenza-attributable mortality rates observed in the Canadian
province of Ontario over seven influenza seasons (1997–2004)
[17].
Vaccine Uptake and Strategies
Ontario introduced a Universal Influenza Immunization
Program (UIIP) in 2000, which theoretically removes barriers to
vaccination in the population. As this program has been projected
to be cost-effective in the Canadian context [18] our base-case
analysis included immunization with TIV for individuals aged 6–
64 at rates observed in the Ontario UIIP. We regarded rates of
vaccine uptake observed in the UIIP as those expected with ATIV.
Vaccine efficacy estimates were derived from trials and observa-
tional studies for ATIV, and from both published estimates and
model calibration for TIV [9,10,11,19,20,21]. Approaches to
estimates of relative efficacy are presented in File S1.
We assumed the population was immunized at UIIP rates.
Individuals aged 6–64 were immunized with TIV, with an efficacy
of 0.9 in all scenarios. We evaluated three strategies: (i)
immunization of children and older adults with TIV; (ii)
immunization of children with TIV and older adults with ATIV;
and (iii) immunization of children and older adults with ATIV. We
repeated the same scenarios in the absence of vaccination in the 6–
64 age group.
Estimation of Burden of Disease and Costs
The age-specific impact of influenza on healthcare utilization
and cost was estimated using the approach of Sander et al. [18,22]
and based on event probabilities as described by Kwong et al.
[17]. Details are presented in File S1, and costs are presented in
Table 2 and File S1. A ten-year time horizon was used in the
analysis and we did not include pandemic years in the analysis.
Sensitivity Analyses
To determine the sensitivity of our base case findings to
assumptions around the costs and consequences of influenza
infection and vaccine costs, we conducted a one-way sensitivity
analysis, with parameters varied one at a time across the range of
plausible values outlined in Table 2 and File S1. We also
calculated ICERs for best and worst case sets of parameters (i.e.,
simultaneously setting all parameters to their extreme values).
Given the uncertainly surrounding vaccine efficacy (for both
TIV and ATIV) and model assumptions, we conducted sensitivity
analyses to determine the robustness of our base case findings. We
estimated the vaccine efficacy values at which use of ATIV was no
longer cost effective for different willingness-to-pay thresholds
(ranging from
$1000 to $50,000 per QALY).
In base case analyses, we assumed that the duration of immunity
to influenza infection was 1.3 years following natural infection and
1 year following vaccination. It has been suggested that
immunization with adjuvanted vaccine results in enhanced
duration of immunity, due to the induction of a broader immune
response than that observed with TIV [23]. We assessed the
impact of enhanced durability of immunity following vaccination
(up to 2 years) with ATIV.
Results
Model Calibration
Model projected estimates of average influenza-attributable
mortality were comparable to those observed in Ontario, assuming
reported UIIP vaccination rates (Figure S1). Because the model
assumed constant influenza transmissibility and vaccine efficacy
over time, it did not reproduce the observed year-to-year
variability in influenza incidence and mortality.
Enhanced Vaccine Efficacy with Adjuvanted Vaccine
Use of ATIV in children under 6 and adults aged $65 in the
Canadian population, with continued use of TIV in the population
aged 6–64, was projected to provide substantial health benefits,
including aversion of deaths and hospitalizations, relative to
currently used TIV (Figure 2). In the base case analysis, use of
ATIV in adults aged $65 was highly cost effective, with an
incremental cost-effectiveness ratio (ICER) of
$2111 per QALY
gained, relative to use of TIV. While the cost of using ATIV was
substantially higher than TIV (
$837.0 versus $730.5 million over
Figure 1. Outline of model structure, showing population flows
between compartments. Each compartment is further stratified by
age category.
doi:10.1371/journal.pone.0027420.g001
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Table 1. Transmission model parameter values.
Variable Age group Value (range) Source
Total population size All 31,612,905 [44]
Life expectancy (years) All 75.3 [45]
Latent period (days) All 2.5 [46]
Duration of infectiousness (days) All 3.5 [46]
Basic reproductive number All 1.6 (1.4–1.9) Model calibration
Duration of immunity (years) Model calibration and assumption
Following infection All 1.3 (1–2)
Following vaccination All 1 (1–2)
Proportion vaccinated ,1 0.12 [17,47]
1–5 0.28
6–19 0.30
20–64 0.33
$65 0.75
Vaccine efficacy [9,10,19,20,21] and model calibration
Trivalent influenza vaccine (TIV) ,6 0.5 (0–0.83)
6–64 0.9 (0.7–0.9)
$65 0.2 (0–0.2)
Adjuvanted influenza vaccine (ATIV) ,6 0.9 (0–0.9)
$65 0.4 (0.2–0.4)
doi:10.1371/journal.pone.0027420.t001
Table 2. Parameter values used in the economic evaluation.
a
Age group Value (range) Source
Total costs per infection (
$)
[18]
0–5 13.76 (3.56–86.17)
6–19 8.30 (2.33–33.21)
20–64 11.33 (2.59–63.50)
$65 23.85 (4.37–165.57)
Total cost per vaccine dose (
$)
Trivalent influenza vaccine All 7.55 [18]
Adjuvanted All 11.59 (8.59–18.59) [22]
QALY lost per influenza infection [18]
0–5 0.015 (0.0065–0.022)
6–19 0.015 (0.0065–0.022)
20–64 0.017 (0.0097–0.025)
$65 0.029 (0.023–0.035)
QALY lost per death due to influenza (discounted at 5%) [22]
0–5 18.530
6–19 18.150
20–64 15.140
$65 2.410
Discount rate (%) All 5.0 [39]
The range indicates the minimum and maximum values used in sensitivity analyses.
a
Additional details provided in Table S1.
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10 years), part of this cost was offset by reducing the number of
cases, and consequently, health care resource use due to influenza
treatment, from
$501.76 to $473.50 million. Expanding ATIV
coverage to include young children weakly dominated the strategy
that included vaccination of older adults only, with an ICER of
$386 per QALY gained. As such, a program that covered both
young children and older adults with ATIV would be preferred to
one that covered only older adults, with an ICER of
$1612 per
QALY. Discounted costs and benefits, and incremental cost-
effectiveness ratios for the alternate strategies are shown in
Table 3.
Qualitatively similar results were observed when the scenarios
were repeated excluding immunization of the population aged 6–
64, with vaccination of older adults and young children weakly
dominating vaccination of older adults only and both strategies
being highly cost-effective compared to use of unadjuvanted
vaccine in the these groups (Table 4).
Sensitivity Analysis
The projected cost-effectiveness of introducing an adjuvanted
vaccine in older adults (Figure 3(a)) or older adults and young
children (Figure 3(b)) was most sensitive to estimates of the cost
of adjuvanted vaccine and QALYs lost per infection, but still
remained a highly cost-effective intervention in all scenarios. Using
the best case set of parameter values, introduction of adjuvanted
vaccine was projected to be cost-saving, saving
$3350 and $3153
per QALY gained with use of ATIV older adults or older adults
and young children, respectively, compared to use of TIV in the
entire population. In the worst case scenario, use of ATIV was
projected to cost
$10,647 and $9472 per QALY gained with the
older adults only and older adults and young children strategies,
respectively, compared to the use of TIV only.
We estimated the vaccine efficacy in older adults at which use of
adjuvanted vaccine was no longer a cost-effective strategy. When
ATIV efficacy in older adults was 0.21 or greater (compared to the
baseline estimate of 0.2 for TIV), use of ATIV was cost-effective,
costing less than
$50,000 per QALY gained. Similarly, when
ATIV efficacy in children was greater than 0.51 (versus 0.5 for
TIV), expanding the use of ATIV to include children was cost-
effective (ICER
$38,748.34) relative to the use of adjuvanted
vaccine in older adults only. Similar results were observed when
we excluded immunization of the population aged 6–64.
Vaccine efficacy values at which use of ATIV was no longer the
preferred strategy were evaluated for different willingness-to-pay
thresholds. We calculated these thresholds for different assumed
vaccine efficacies for TIV in older adults (Figure 4(a)) and young
children (Figure 4(b)).
Assuming no difference in vaccine efficacy but enhanced
duration of immunity following immunization with ATIV
compared to TIV, use of ATIV was projected to be highly cost-
effective when used in children and older adults. Specifically, when
duration of vaccine-induced immunity with ATIV was 1.3 years
(equivalent to that conferred by natural infection) compared to 1
year with TIV, the ICER was
$6665 per QALY. When ATIV-
induced immunity was modeled as more durable (1.3 years) and
more effective than TIV in older adults and young children, the
ICER was reduced to
$882 per QALY.
Discussion
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
Figure 2. Projected health benefits of using adjuvanted influenza vaccine. Health benefits are estimated for a strategy in which adults .65
or adults $65 and children ,6 years are vaccinated with adjuvanted influenza vaccine. Projected number of infections, hospitalizations, and deaths
averted, by age, over a 10-year period were calculated relative to the use of unadjuvanted trivalent influenza vaccine in the entire population over
this time period.
doi:10.1371/journal.pone.0027420.g002
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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 [24,25].
We incorporated costs and health utility weights, which have
been used in prior published health economic analyses [18,22],
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 [26], 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 [17]. 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
[9,11,27,28]. 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
[29,30,31,32]. 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 [10]. Pediatric
effectiveness data, being derived from a well-designed randomized
Table 3. Incremental cost-effectiveness of influenza vaccination strategies targeting children and older adults implemented in the
Canadian population: base case, with trivalent influenza vaccination in individuals aged 6–64.
Strategy Vaccine efficacy
Cost
($ billion)
a
QALY lost
(million)
b
Incremental cost
per QALY gained (
$)
Immunization with TIV 0.5 in children; 0.9 in persons
6–64; 0.2 in older adults
1.232 0.749
Immunization of children and
persons aged 6–64 with TIV
and older adults with ATIV
0.5 in children; 0.9 in persons
6–64; 0.4 in older adults
1.310 0.712 Weakly dominated
c
Immunization of children and
older adults with ATIV and
persons 6–64 with TIV
0.875 in children; 0.9 in 6–64;
0.4 in older adults
1.316 0.697 1612
Abbreviations: TIV, trivalent inactivated vaccine; ATIV, adjuvanted trivalent inactivated vaccine.
a
2009 Canadian dollars, discounted at 5% annually over a 10-year time horizon.
b
Quality-adjusted life years lost, discounted at 5% annual over a 10-year time horizon.
c
Immunization of older adults only with ATIV was economically attractive at $2111 per QALY, but the incremental cost-effectiveness ratio of immunizing both older
adults and young children with ATIV was ,
$500 per QALY, indicating ‘‘extended dominance’’.
doi:10.1371/journal.pone.0027420.t003
Table 4. Incremental cost-effectiveness of influenza vaccination strategies targeting children and older adults implemented in the
Canadian population: no immunization of individuals aged 6–64.
Strategy Vaccine efficacy
Cost
($ billion)
a
QALY lost
(million)
b
Incremental cost
per QALY gained (
$)
Immunization of children
and older adults with TIV
0.5 in children aged , 6;
0.2 in older adults
1.087 1.289
Immunization of children with
TIV and older adults with ATIV
0.5 in children aged , 6;
0.4 in older adults
1.157 1.241 Weakly dominated
c
Immunization of children and
older adults with ATIV
0.875 in children; 0.4 in
older adults
1.162 1.226 1190
Abbreviations: TIV, trivalent inactivated vaccine; ATIV, adjuvanted trivalent inactivated vaccine.
a
2009 Canadian dollars, discounted at 5% annually over a 10-year time horizon.
b
Quality-adjusted life years lost, discounted at 5% annual over a 10-year time horizon.
c
Immunization of older adults only with ATIV was economically attractive at $1424 per QALY, but the incremental cost-effectiveness ratio of immunizing both older
adults and young children with ATIV was ,
$300 per QALY, indicating ‘‘extended dominance’’.
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Figure 3. Tornado diagram comparing the relative importance of model parameters on estimated cost-effectiveness. Incremental
cost-effectiveness ratios (ICER) are calculated relative to the use of unadjuvanted vaccine in the entire population when adjuvanted vaccine is usedin
(a) older adults and (b) older adults and young children. The vertical line corresponds to the base case value for each parameter, with the width of the
bars indicating the uncertainty associated with each parameter. The blue segments of the bars correspond to parameter values that result in
decreased estimates of cost effectiveness (with negative values corresponding to projected cost savings), while red segments indicate values that
increase the base case cost effectiveness. The range of parameters considered in the analysis is described in Table 2 and File S1 .
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Figure 4. Vaccine efficacy values above which use of adjuvanted vaccine is no longer the preferred strategy. Thresholds were
determined for different assumed unadjuvanted vaccine efficacies in (a) older adults and (b) young children, assuming different willingness-to-pay
thresholds. Unadjuvanted vaccine efficacy used in base case scenarios is indicated by a dotted line.
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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 [20]. 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 [34]. 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 [10], 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 [39],
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.
Supporting Information
File S1 Supplementary appendix.
(TIFF)
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.
(DOC)
Author Contributions
Conceived and designed the experiments: ART DNF. Performed the
experiments: ART. Analyzed the data: ART DNF. Wrote the paper: ART
DNF.
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    • "As vaccines have not yet proven completely effective in eradication ([16,737475), dengue presents a natural case study for evaluating the effectiveness of combining clinical interventions with transgenic manipulation. Except where we state otherwise, we follow [76] in modeling the impact of the intervention strategies over time horizons of T H 2 (0,10] years, which corresponds to a reasonable timespan for public health decision makers ([77] ). Previous studies using biologically detailed models of urban Ae. "
    [Show abstract] [Hide abstract] ABSTRACT: Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short- and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences-consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies.
    Full-text · Article · Mar 2016 · PLoS Computational Biology
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    [Show abstract] [Hide abstract] ABSTRACT: Annual vaccination is the main mean of preventing influenza in the elderly. In order to evaluate the effectiveness of the adjuvanted seasonal influenza vaccines available in Italy in preventing hospitalization for influenza and pneumonia, a matched case-control study was performed in elderly subjects during the 2010–2011 season in Genoa (Italy). Cases and controls were matched in a 1:1 ratio according to gender, age, socio-economic status and type of influenza vaccine. Vaccine effectiveness was calculated as IVE = [(1-OR)x100] and crude odds ratios were estimated through conditional logistic regression models. Adjusted odds ratios were estimated through multivariable logistic models. In the study area, influenza activity was moderate in the 2010–2011 season, with optimal matching between circulating viruses and vaccine strains. We recruited 187 case-control pairs; 46.5% of cases and 79.1% of controls had been vaccinated. The adjuvanted influenza vaccines (Fluad® considered together with Inflexal V®) were associated with a significant reduction in the risk of hospitalization, their effectiveness being 94.8% (CI 77.1–98.8). Adjusted vaccine effectiveness was 95.2% (CI 62.8–99.4) and 87.8 (CI 0.0–98.9) for Inflexal V® and Fluad®, respectively. Both adjuvanted vaccines proved effective, although the results displayed statistical significance only for Inflexal V® (p = 0.004), while for Fluad® statistical significance was not reached (p = 0.09). Our study is the first to provide information on the effectiveness of Inflexal V® in terms of reducing hospitalizations for influenza or pneumonia in the elderly, and demonstrates that this vaccine yields a high degree of protection and that its use would generate considerable saving for the National Health Service.
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    [Show abstract] [Hide abstract] ABSTRACT: To determine if newer influenza vaccines can safely improve seroprotection rates of older adults, we compared three licensed trivalent inactivated vaccines (TIVs) in a randomized, controlled trial with evaluator blinding. Participants were non-frail adults ≥ 65 y old, annually TIV-immunized. Study vaccines included intradermal (IDV), MF59-adjuvanted (ADV) and subunit (TIV) formulations of equal potency and strain composition. Blood was obtained before vaccination (V1) and 21 (V2) and 180 d (V3) afterward and tested by hemagglutination inhibition (HAI) assay. Safety diaries were completed daily by participants and specific tolerability questions were posed regarding injections and symptoms. In total, 911 participants were immunized and 887 (97.4%) completed V3. Groups had similar demographics. General symptom rates post-vaccination were similar among groups. Rates of injection site redness after IDV/ADV/TIV were 75%/13%/13% and rates of pain were 29%/38%/20%, respectively, but each vaccine was well tolerated, with symptoms causing little bother. Baseline antibody titers did not differ significantly among groups but B/Brisbane titers were too high for meaningful response assessments. At V2, seroprotection rates (HAI titer ≥ 40) were highest after ADV, the rate advantage over IDV and TIV being significant at 11.8% and 11.4% for H3N2 and 10.2% and 12.5% for H1N1, respectively. At day 180, seroprotection rates had declined ~25% and no longer differed significantly among groups. While IDV and TIV were also well tolerated, ADV induced modestly higher antibody titers in seniors to influenza A strains at 3 weeks but not 6 mo post-vaccination. Immune responses to IDV and TIV were similar in this population.
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