Cost-effectiveness of seasonal quadrivalent versus trivalent influenza vaccination in the United States: A dynamic transmission modeling approach

Figures & data

Table 1. Ten-year average annual results for the base-case analysis (2012–2022): IIV4 versus IIV3.

Outcomes^a	IIV3	IIV4	Difference: IIV4–IIV3 (%)
Health outcomes
Number of people vaccinated	125,479,086	125,479,086	0
Cases of influenza	16,066,932	14,093,083	−1,973,849 (−12.3)
Type A	13,419,031	13,419,031	0
Type B	2,647,901	674,052	−1,973,849 (−74.5)
Influenza-related complications	2,040,773	1,792,822	−247,951 (−12.1)
Influenza-related deaths	10,577	9,181	−1,396 (−13.2)
Life years accrued	251,124,881	251,130,886	6,005 (+0.002)
QALYs accrued	232,293,904	232,312,389	18,485 (+0.008)
Cost outcomes (2013/2014 $)
Total direct medical costs	16,277,026,239	16,176,911,683	−100,114,557 (−0.6)
Vaccine-related costs	10,565,287,914	11,163,818,974	598,531,060 (+5.7)
Acquisition	1,430,420,828	2,028,951,888	598,531,060 (+41.8)
Administration	9,125,758,120	9,125,758,120	0
Vaccine-related AE management	9,108,966	9,108,966	0
Influenza treatment costs	5,711,738,326	5,013,092,709	−698,645,617 (−12.2)
Inpatient	3,563,010,255	3,129,491,214	−433,519,041 (–12.2)
Outpatient	2,107,708,964	1,847,588,081	−260,120,883 (−12.3)
Non-medically attended	41,019,107	36,013,414	−5,005,693 (−12.2)
Total indirect costs	109,568,786,671	102,615,203,315	−6,953,583,357 (−6.3)
Time lost for vaccination	49,420,957,469	49,420,957,469	0
Caregiver time lost for cases	7,737,050,813	6,682,377,821	−1,054,672,992 (−13.6)
Patient time lost for cases	21,046,749,319	18,491,117,241	−2,555,632,078 (−12.1)
Time lost for influenza-related death	31,364,029,070	28,020,750,783	−3,343,278,287 (−10.7)
Total costs	125,845,812,911	118,792,114,997	−7,053,697,913 (−5.6)
ICERs (2013/2014 $)
Incremental direct medical costs per QALY gained	−	−	−5,416^b
Incremental direct medical costs and indirect costs (for time lost for vaccination and for caregiver time lost for cases of influenza) per QALY gained^c	−	−	−62,472^b

AE, adverse event; ICER, incremental cost-effectiveness ratio; IIV3, trivalent inactivated influenza vaccine; IIV4, quadrivalent inactivated influenza vaccine; QALY, quality-adjusted life year.

^a All health and cost outcomes were discounted to 2012 using an annual discount rate of 3%.⁵⁴

^b Negative ICERs shown here indicate that vaccination with IIV4 yielded lower total costs and more QALYs than vaccination with IIV3.

^c Costs for patient time lost for cases of influenza and for influenza-related death were not included in the numerator as these time losses are assumed to be captured in the QALY loss estimates; it would therefore be considered double counting to also include the costs of patient time lost in the numerator.¹⁷

Table 2. Ten-year average annual scenario analyses results (2012–2022)^a.

Scenario settings	Cases avoided (IIV4 versus IIV3)	ICER (2013/2014 $ per QALY gained)^b
Base case	1,973,849	−62,472
Higher infectivity^c (β = 0.000529, R0 = 3.5)	3,593,862	−50,598
Lower infectivity^c (β = 0.000256, R0 = 1.69)	563,795	+19,678
Increased duration of natural immunity to type A influenza (Upper 95% CL [2.52 years])	1,973,849	−62,469
Decreased duration of natural immunity to type A influenza (Lower 95% CL [2.38 years])	1,973,849	−62,484
Increased duration of natural immunity to type B influenza (Upper 95% CL [15.44 years])	1,834,046	−60,710
Decreased duration of natural immunity to type B influenza (Lower 95% CL [13.94 years])	2,130,249	−64,058
Increased natural cross-protection (Upper 95% CL [Type A = 52.2%, Type B = 52.0%])	1,938,301	−61,964
Decreased natural cross-protection (Lower 95% CL [Type A = 44.3%, Type B = 48.3%])	2,012,049	−62,993
Increased amplitude of season variation factor (Upper 95% CL [0.472])	2,103,013	−64,232
Decreased amplitude of season variation factor (Lower 95% CL [0.443])	1,857,467	−60,605
Increased probability of selecting the correct B lineage (Upper 95% CL [71.2%])	1,925,708	−62,269
Decreased probability of selecting the correct B lineage (Lower 95% CL [65.3%])	1,973,849	−62,472
Fixed vaccine coverage projections^d (at 2012 levels)	2,489,427	−70,708
Increased percentage of children receiving 2 doses of IIV3 or IIV4^e	1,973,849	−62,368
Increased inpatient costs per case (base case +50%)	1,973,849	−74,198
Decreased inpatient costs per case (base case −50%)	1,973,849	−50,745
Lower vaccine administration cost (nurse setting; $20.06 visit + $25.08 administration)	1,973,849	−62,472

CL, confidence limit; ICER, incremental cost-effectiveness ratio; IIV3, trivalent inactivated influenza vaccine; IIV4, quadrivalent inactivated influenza vaccine; QALY, quality-adjusted life year.

^a All health and cost outcomes were discounted to 2012 using an annual discount rate of 3%.⁵⁴

^b ICER includes direct medical costs, the cost for time lost for vaccination, and the cost for caregiver time lost for cases of influenza. Negative ICERs shown here indicate that vaccination with IIV4 yielded lower total costs and more QALYs than vaccination with IIV3.

^c Infectivity was varied from the base-case value of β = 0.000287 (R₀ = 1.9).²²

^d Vaccination coverage values for 2012–2022 were assumed to remain fixed at 2012–2013 values¹⁴ rather than following a projected increase over time.

^e Using age-specific estimates of percentages of children <9 years old who received 2 doses of vaccine.¹¹

Figure 1. Simplified model structure for cost-effectiveness of IIV4 versus IIV3 (the full structure can be found in Thommes et al.²²). *A proportion of individuals were vaccinated with either IIV3 or IIV4 according to the vaccine coverage parameters shown in Figure. 2. †Case of influenza type A or B. ‡ED cases were set to zero due to a lack of robust data. [+] indicates clinical pathway is the same as above. ED, emergency department; IIV3, trivalent inactivated influenza vaccine; IIV4, quadrivalent inactivated influenza vaccine; LRTC, lower respiratory tract complication; OM, otitis media.

Figure 2. Historical^10-14 and projected influenza vaccine coverage by age group. Historical vaccine coverage data were available through 2012, and data were not available for every year for children aged <18 years; therefore, vaccination coverage estimates for future years and for years without historical estimates were projected using regression techniques and available historical data. Exponential and logarithmic functions were tested, and best-fit functions were selected for each age group.

Table 3. Vaccine-related inputs.

	Age range (years)
	0–2	3–4	5–17	18–49	50–64	65–74	≥75	Sources
Vaccine acquisition cost per dose ($)^a								^37
IIV3, public cost	7.75	7.75	7.75	7.52	7.52	7.52	7.52
IIV3, private sector cost	10.69	11.30	11.30	11.90	11.90	11.90	11.90
IIV4, public cost	15.29	13.65	13.65	12.22	12.22	12.22	12.22
IIV4, private sector cost	18.62	16.15	16.15	16.15	16.15	16.15	16.15
Vaccine administration cost ($)								^38
Visit cost^b	46.57	46.57	46.57	46.57	46.57	46.57	46.57
Administration cost^c	25.08	25.08	25.08	25.08	25.08	25.08	25.08
Cost per vaccine-related AE ($)^d								^39,41,43
Anaphylaxis	3,864	3,864	3,864	592	636	629	629
Guillain-Barre syndrome	33,427	33,427	33,427	86,237	86,237	86,237	86,237
Vaccine efficacies (IIV3 and IIV4) (%)								^8,9,16,44-46
Type A	59.0	59.0	59.0	61.0	61.0	58.0	58.0
Type B included in vaccine	66.0	66.0	77.0	77.0	73.0	69.0	66.0
Type B not included in vaccine	44.0	44.0	52.0	52.0	49.0	47.0	44.0

AE, adverse event; IIV3, trivalent inactivated influenza vaccine; IIV4, quadrivalent inactivated influenza vaccine.

^a The median public and median private cost for IIV3 and IIV4 indicated for each age group are shown. The model used the weighted average of public and private costs (2014 US dollars), assuming public costs were incurred for 63.2% of those aged <1 year, 55.8% for 1–2 years, 50.9% for 3–6 years, 41.7% for 7–17 years, and 0% for adults (personal communication [unpublished data]: 2010 VFC Eligible Children. Centers for Medicare & Medicaid Services. VFC Comparison of Regional Maximum Rate for Vaccine Administration to Current State Rate. “2010PES_final_8/18/09”).

^b Visit cost based on the average of CPT codes 99213 (physician, $73.08) and 99211 (nurse, $20.06).³⁸

^c Vaccine administration cost based on CPT codes 90460 (children) and 90471 (adults).³⁸

^d Inflated to 2013 US dollars.⁴³

Table 4. Influenza-related inputs (for type A and type B influenza).

	Age range (years)
	0–4	5–17	18–49	50–64	≥65	Sources
Complicated/uncomplicated influenza distribution (%)
Influenza with LRTC^a	2.12	1.02	13.19	17.30	20.94	^49,50
Influenza with OM	11.88	3.13	0.79	0.35	0.21	^49,50
Uncomplicated influenza	86.01	95.85	86.02	82.35	78.85	Complement of above
Influenza with LRTC: treatment setting distribution (%)
Outpatient^b	47.87	35.16	35.95	41.60	72.24	Calculated from Molinari et al.^4
ED	0	0	0	0	0	Assumption (no data)
Inpatient^c^,^d	0.82	0.34	1.24	2.84	6.18	^49,50
Non-medically attended	51.31	64.50	62.82	55.56	21.58	Complement of above^4
Influenza with OM or uncomplicated influenza: treatment setting distribution (%)
Outpatient^b	47.87	35.16	35.95	41.60	72.24	Calculated from Molinari et al.^4
ED	0	0	0	0	0	Assumption (no data)
Inpatient^c^,^e	0.82	0.34	0.46	0.82	2.21	^49,50
Non-medically attended	51.31	64.50	63.59	57.58	25.55	Complement of above^4
Inpatient cases resulting in death (%)^f	0.28	1.67	2.14	6.94	27.79	Calculated from Molinari et al.^4
QALYs lost per case						<18 years;^39 ≥18 years calculated
Influenza with LRTC, inpatient	0.076	0.076	0.0115	0.0115	0.0093	from Gold et al.^51 and Lee et al.^52
Influenza with LRTC, other	0.046	0.046	0.0115	0.0115	0.0093
Influenza with OM, all	0.042	0.042	0.0052	0.0052	0.0036
Uncomplicated influenza, inpatient	0.076	0.076	0.0115	0.0115	0.0093
Uncomplicated influenza, other	0.005	0.005	0.0052	0.0052	0.0036
Medical care costs per case ($)^g						^4,43
Outpatient^b	269	220	307	490	518
Inpatient^b	20,831	25,565	33,326	40,890	20,268
Non-medically attended (over-the-counter medication)	4.29	4.29	4.29	4.29	4.29
Patient/caregiver time lost per case (days)						^4,53
Outpatient	1.38	1.38	1.15	2.66	5.05
Inpatient	9.13	9.13	13.34	16.63	15.56
Non-medically attended	1.0	0.5	0.5	0.5	1.0

ED, emergency department; LRTC, lower respiratory tract complication; OM, otitis media; QALY, quality-adjusted life year.

^a For ages 0–17 years, complications rates were based on pneumonia diagnoses only.⁴⁹ For ages ≥18 years, complication rates were based on pneumonia and respiratory diagnoses.⁵⁰

^b Weighted average of high-risk and non-high risk individuals.⁴

^c For ages 0–17 years, hospitalization rates were based on “any hospitalization” (regardless of complications).⁴⁹

^d For ages ≥18 years, hospitalization rates were based on pneumonia and respiratory hospitalizations.⁵⁰

^e For ages ≥18 years, hospitalization rates were based on all-cause hospitalizations minus pneumonia and respiratory hospitalizations.⁵⁰

^f Values were converted from mortality rates among all cases of influenza⁴ to conditional probabilities among inpatient cases of influenza. Deaths among cases that are treated outside the hospital (or not medically attended) were assumed to be negligible.

^g Inflated to 2013 US dollars.⁴³

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