Use of adjuvanted trivalent influenza vaccine in older-age adults: a systematic review of economic evidence

Figures & data

Figure 1. Study selection process.

Table 1. Main characteristics of the included studies.

Authors, year [Ref]	Country, currency (year)	Population	Evaluation type	Model type	Prospective	Time horizon	Strategies	Uncertainty analysis
Piercy et al., 2004^Citation31	France, € (Unclear)	Elderly^a at high risk (with heart or lung disease)	CEA	Static	Payer	1 year	TIV; aTIV	One-way deterministic
Baio et al., 2006^Citation32	Italy, € (2003–2004)	Elderly^a	CEA	Static	Payer	1 year	TIV; aTIV; non-vaccination	Probabilistic
Iannazzo et al., 2009^Citation33	Italy, € (Unclear^b)	Elderly^a	CEA	Static	Payer	1 year	TIV; aTIV; non-vaccination	One-way deterministic; scenario
Lee et al., 2009^Citation34	US, $ (2007)	Elderly^a	CUA	Static	Societal; payer	1 year	TIV; aTIV	Probabilistic
Fisman et al., 2011^Citation35	Canada, C$ (2009)	All ages	CUA	Dynamic	Payer	10 years	TIV to all age-classes; TIV to children (<6 years), while aTIV to the elderly; aTIV to both children and the elderly. Each strategy could include or not TIV for people aged 6–64 years.	One-way deterministic; best-worst case scenario
Iannazzo, 2011^Citation36	Italy, € (Unclear^c)	Elderly^a	BIA	Static	Payer	1 year	TIV; aTIV; non-vaccination	One-way deterministic; scenario
Mullikin et al., 2015^Citation37	US, $ (Unclear)	All ages	CUA	Dynamic	Societal; payer	1 year	QIV to people aged <65 years, while aTIV to the elderly; QIV to all age-classes; TIV to all age-classes	One-way deterministic; scenario
Ruiz-Aragón et al., 2015^Citation38	Spain, € (Unclear^d)	Elderly^a	BIA	Static	Payer	1 year	TIV; aTIV	One-way deterministic
Garlapati, 2016^Citation39	Canada, C$ (Unclear)	Elderly^a	CCA	Static	Unclear^e	Unclear^f	TIV; aTIV; non-vaccination	None
Raviotta et al., 2016^Citation40	US, $ (2014)	Elderly^a	CUA	Static	Societal	Unclear^f	Non-vaccination; TIV; QIV, hdTIV; aTIV^g	One-way deterministic; probabilistic
Barbieri et al., 2017^Citation41	Italy, € (2017)	Elderly^a	BIA	Static	Payer	1 year	TIV, aTIV, idTIV, QIV at actual and hypothetical market shares	Scenario
Perez-Rubio et al., 2018^Citation42	Spain, € (Different^d)	Elderly^a	BIA	Static	Payer	1 year	TIV; aTIV	One-way deterministic
Capri et al., 2018^Citation43	Italy, € (2017)	Elderly^a	CUA	Static	Payer	1 year	TIV; aTIV; idTIV; QIV; non-vaccination	One-way deterministic; probabilistic

Notes

a: Defined here as ≥65 years old; b: The vaccine price was a 3-year (2006–2008) average; c: The vaccine price was a 4-year (2006–2009) average; d: It is likely that different reference years were used; adjustment methods were not reported; e: Probably, payer; f: Probably 1 year; g: aTIV was considered only in the secondary analysis

TIV: trivalent inactivated vaccines;

aTIV: adjuvanted trivalent inactivated vaccines;

QIV: quadrivalent inactivated vaccines;

hd-TIV: high-dose trivalent inactivated vaccines;

idTIV: intradermal trivalent inactivated vaccines;

CEA: cost-effectiveness analysis;

CUA: cost-utility analysis;

BIA: budget impact analysis;

CCA: cost-consequences analysis.

Table 2. Key findings of the included studies (full papers): adjuvanted trivalent inactivated vaccine (aTIV) vs non-vaccination.

Authors, year [Ref]	Key assumptions	Key findings: base case	Key findings: uncertainty analysis
Baio et al., 2006^Citation32	ILI attack rate: 16.6%. Vaccination coverage: 52.6%. Reduction in cases generated by aTIV: pharmacological treatments (62.6%); GP visits (50.9%); hospitalization for influenza/pneumonia (44.2%), chronic heart failure (31.7%), respiratory disease (35.4%); mortality (54.8%). aTIV price (with administration): €14.12 (2017$19.81).	Results were reported graphically with no explicitly stated base case. For example, at the WTP threshold of €500 (2017$702) per death avoided, the probability aTIV produces a positive incremental net benefit was approximately 80%.	The probability of having a positive incremental net benefit was >50% at WTP thresholds of up to €6,000 (2017$8,418) per death avoided.
Iannazzo et al., 2009^Citation33	ILI attack rate: 16.8%. Vaccination coverage: 64.9%. Reduction in cases generated by aTIV in the elderly: H1N1 (11.8%); H3N2 (23.8%); B (19.6%). Reduction in cases generated by aTIV in the elderly at high risk: H1N1 (10.4%); H3N2 (26.6%); B (23.8%). aTIV price: €5.59 (2017$7.25).	In terms of both €/ILI avoided and €/death avoided aTIV was dominant. aTIV would produce €83.7 (2017$108.5) million (−7.9%) of savings in terms of total direct costs.	In the scenario analysis (complete mismatch) aTIV remained the dominant strategy: it would produce a net saving of €35.6 (2017$46.1) million (−3.4%) in front of health gains. In the one-way sensitivity analysis ICER aTIV vs non-vaccination was constantly negative (aTIV dominant strategy).
Iannazzo, 2011^Citation36	ILI attack rate: 16.8%. Vaccination coverage: 64.9%. aTIV effectiveness against ILI in the low- and high-risk elderly of 53% and 55%, respectively. aTIV price: €5.58 (2017$6.99).	aTIV would produce €74.0 (2017$92.7) million (−6.8%) of savings in terms of total direct costs.	In the scenario analysis (complete mismatch) aTIV would still produce a net saving of €14.6 (2017$18.3) million (−1.3%). In the one-way sensitivity analysis aTIV was constantly associated with net savings in terms of total costs.
Garlapati, 2016^Citation39	Unclear attack rate. aTIV effectiveness: 40%. aTIV price: C$12.59 (2017$10.30).	The benefit-cost ratio of aTIV vs non-vaccination was 49.8.	–
Capri et al, 2018^Citation43	Influenza attack rate: 5.4%. Vaccination coverage in the low- and high-risk elderly of 55.1% and 66.0%, respectively. aTIV effectiveness against laboratory-confirmed influenza: 72.5%. aTIV price: €6.99 (2017$7.88).	ICUR: €12,305 (2017$13,866)/QALY	In the one-way analysis, the major ICUR drivers were: influenza attack rate, aTIV effectiveness, aTIV price, aTIV administration cost and QALY loss due to influenza; the min-max variation [from €5,104 (2017$5,752)/QALY to €19,358 (2017$21,814)/QALY] of these parameters were below the adopted ICUR threshold of €30,000 (2017$33,807)/QALY. In the probabilistic sensitivity analysis (10,000 Monte Carlo rounds) aTIV was cost-effective (ICUR<€30,000/QALY) in 80.9% of simulations, dominant in 1.8%, likely not cost-effective (ICUR>€30,000/QALY) in 17.3% of simulations.

aTIV: adjuvanted trivalent inactivated vaccines;

ICUR: incremental cost-utility ratio;

ICER: incremental cost-effectiveness ratio;

QALY: Quality Adjusted Life Years

ILI: Influenza-like illness;

Table 3. Key findings of the included studies (full papers): adjuvanted trivalent inactivated vaccine (aTIV) vs non-adjuvanted trivalent inactivated vaccine (TIV).

Authors, year [Ref]	Key assumptions	Key findings: base case	Key findings: uncertainty analysis
Piercy et al., 2004^Citation31	Relative vaccine effectiveness of aTIV vs TIV was 6.0%, 15.0% and 18.2% against H1N1, H3N2 and B, respectively. Relative price increase of aTIV vs TIV: 50%.	ICERH1N1: €17,496 (2017$24,752)/LYG or €87,040 (2017$122,243)/DA; ICERH3N2: €3,759 (2017$5,279)/LYG or €18,701 (2017$26,265)/DA; ICERB: €4,821 (2017$6,671)/LYG or €23,985 (2017$33,686)/DA.	In the sensitivity analysis aTIV was constantly cost-effective or cost-saving. In particular, the influenza attack rate was a strong driver of ICER: at the attack rate of 10% ICERB became negative in terms of both CPLYG and CPDA (aTIV was dominant), while at the attack rate, while it was €19,435 (2017$27,296)/LYG or €96,686 (2017$135,791)/DA at the attack rate of 2%. Variations in life expectancy (from 1 to 7 years) produced a ranger of ICERB of €3,426 (2017$4,812) to €26,383 (2017$37,054) per LYG, while different discount rates (0–10%) did not change ICER significantly.
Baio et al., 2006^Citation32	aTIV was associated with a greater relative reduction than TIV: pharmacological treatments (18.0%); GP visits (13.4%); hospitalization for influenza/pneumonia (20.1%), chronic heart failure (32.6%), respiratory disease (22.0%); mortality (10.0%). Relative price increase of aTIV vs TIV: 9.7%.	Results were reported graphically with no explicitly stated base case. For example, at the WTP threshold of €0 per death avoided, the probability aTIV produces a positive incremental net benefit was >90%.	The probability of having a positive incremental net benefit was >50% at WTP thresholds of up to €6,000 (2017$8,418) per death avoided.
Iannazzo et al., 2009^Citation33	Relative vaccine effectiveness of aTIV vs TIV against ILI: 29.3% and 34.1% in the low- and high-risk elderly, respectively. Relative price increase of aTIV vs TIV: 46.5%.	In terms of both €/ILI avoided and €/death avoided aTIV was dominant. A total replacement of TIV with aTIV would produce €129.5 (2017$167.8) million (−11.7%) of savings in terms of total direct costs.	In the scenario analysis (complete mismatch) aTIV remained the dominant strategy: it would produce a net saving of €123.3 (2017$159.8) million (−10.7%) in front of health gains. In the one-way sensitivity analysis ICER aTIV vs TIV was constantly negative (aTIV dominant strategy). In the breakeven analysis aTIV remained dominant with a relative price increase of up to 473.5%.
Lee et al., 2009^Citation34	Use of the adjuvant overcomes the imunnosenescence, i.e. the elderly had the same vaccine effectiveness as non-elderly adults. Cost of adjuvant varied from $15.75 (2017$18.61), which is the average TIV price, to $100.00 (2017$118.17).	From both the societal and payer perspective, aTIV was a dominant strategy with a price increase of up to $30 (2017$35). From the societal perspective, replacement of TIV with aTIV would save $824 (2017$974) million, $595 (2017$703) million, $369 (2017$436) million and $167 (2017$197) million at an extra price of aTIV of $0, $10 (2017$12), $20 (2017$24) and $30 (2017$35), respectively. From the payer perspective, replacement of TIV with aTIV would save $842 (2017$995) million, $614 (2017$726) million, $394 (2017$466) million and $167 (2017$197) million at an extra price of aTIV of $0, $10, $20 and $30, respectively.	aTIV was always the dominant strategy as long as the extra price over TIV was >$20 (2017$24). When aTIV had an extra price of $40 (2017$47), it ceased to be a favourable strategy when the WTP was >$750 (2017$886)/QALY.
Iannazzo, 2011^Citation36	Relative vaccine effectiveness of aTIV vs TIV against ILI: 29.3% and 34.1% in the low- and high-risk elderly, respectively. Relative price increase of aTIV vs TIV: 43.7%.	A total replacement of TIV with aTIV would produce €124.3 (2017$155.8) million (−10.9%) in savings in terms of total direct costs.	In the scenario analysis (complete mismatch) aTIV would still produce a net saving of €124.6 (2017$156.2) million (−10.4%). In the one-way sensitivity analysis ICER aTIV vs TIV was constantly negative (aTIV dominant strategy).
Ruiz-Aragón et al., 2015^Citation38	Relative vaccine effectiveness of aTIV vs TIV against ILI: 34.1%. Relative price increase of aTIV vs TIV: 14.7%.	A total replacement of TIV with aTIV would produce €76.1 (2017$87.8) million in savings in terms of total direct costs.	Replacing TIV with aTIV was a cost-saving strategy when varying vaccination coverage (from 32.9% to 70.9%, base case: 57%) with a range of €43.9–78.2 (2017$50.7–90.3) million of net savings. Diminishing the aTIV price by 10% did not produce significant changes [€78.2 (2017$90.3) million in net savings].
Garlapati, 2016^Citation39	Relative vaccine effectiveness of aTIV vs TIV: 100%. Relative price increase of aTIV vs TIV: 67.9%.	The benefit-cost ratio of aTIV vs TIV was 87.6.	–
Perez-Rubio et al., 2018^Citation42	Relative vaccine effectiveness of aTIV vs TIV against ILI: 34.1%. Relative price increase of aTIV vs TIV: 48.3%.	A total replacement of TIV with aTIV would produce €82.5 (2017$94.5) million in savings in terms of total direct costs with a benefit-cost ratio of 12.83.	In the one-way analysis the benefit-cost ratio was constantly >9.
Capri et al, 2018^Citation43	Relative vaccine effectiveness of aTIV vs TIV against laboratory-confirmed influenza: 25.0%. Relative price increase of aTIV vs TIV: 30.7%.	ICUR: €4,527 (2017$4,797)/QALY	In the one-way analysis, the major ICUR drivers were: TIV (from aTIV being dominant to dominated) and aTIV [from €222 (2017$250)/QALY to €119,477 (2017$134,638)/QALY] effectiveness and TIV price [from aTIV being dominant to €24,479 (2017$27,785)/QALY]. In the probabilistic sensitivity analysis (10,000 Monte Carlo rounds) aTIV was cost-effective [ICUR<€30,000 (2017$33,807)/QALY] in 58.3% of simulations, dominant in 18.1%, likely not cost-effective (ICUR>€30,000/QALY) in 13.1% and was dominated by TIV in 10.5% of simulations.

aTIV: adjuvanted trivalent inactivated vaccines;

ICUR: incremental cost-utility ratio;

ICER: incremental cost-effectiveness ratio;

QALY: Quality Adjusted Life Years

ILI: Influenza-like illness;

Figure 2. Quality appraisal of the included studies (Joanna Briggs Institute checklist).

Notes: Item 1, Is there a well-defined question?; Item 2, Is there comprehensive description of alternatives?; Item 3, Are all important and relevant costs and outcomes for each alternative identified?; Item 4, Has clinical effectiveness been established? Item 5, Are costs and outcomes measured accurately? Item 6, Are costs and outcomes valued credibly? Item 7, Are costs and outcomes adjusted for differential timing? Item 8, Is there an incremental analysis of costs and consequences? Item 9, Were sensitivity analyses conducted to investigate uncertainty in estimates of cost or consequences? Item 10, Do study results include all issues of concern to users? Item 11, Are the results generalizable to the setting of interest in the review?

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