A Critical Literature Review of Health Economic Evaluations in Pertussis Booster Vaccination

Aurelie Millier; Samuel Aballea; Lieven Annemans; Mondher Toumi; Sibilia Quilici

Expert Rev Pharmacoeconomics Outcomes Res. 2012;12(1):71-94.

Five-year View

National health authorities have to consider not only health benefits, but also economic aspects when deciding to recommend and fund new vaccination programs. In this framework, health technology assessment of vaccination programs is performed. The latter give a statement/advice to policy decision makers on whether these new vaccination programs should be included in the current national immunization program and funded. Health economic evaluation is often an essential component of this health technology assessment, being a key decision tool in a context of rising budget constraint. Changes in health policy are hardly predictable, making future requirements for economic evaluations of vaccines difficult to anticipate.

In this review, all included analyses used assumptions for several inputs. However, more data will become available, whether from further models or from real-life assessments (data from countries with new vaccination programs). These estimates should be incorporated into new models, so that comparison of different strategies is more precisely performed. The results of clinical trials evaluating the efficacy of maternal immunization should become available by the end of 2012.^[101]

In the absence of pertussis booster vaccination, new disease outbreaks are likely to occur in the future, which may strengthen the economic case for vaccination in coming years.

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Next Section

Acknowledgements
We would like to thank Professor MJ Postma, Dr L Coudeville, Dr TJ Westra and Dr F Alvarez for comments on previous versions of this manuscript.

Financial & competing interests disclosure
This article was funded by Sanofi-Pasteur MSD. S Quilici is an employee of Sanofi Pasteur MSD. A Millier and S Aballea are employees of Creativ-Ceutical, which received funding from Sanofi Pasteur MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Table 1. Description of economic evaluations included in this review.
Study (year)	Journal	Sponsor	Country	Type of analysis	Strategies^†	Authors' conclusion(s)	Ref.
*European studies*
Edmunds et al. (2002)	Vaccine	Independent	UK and Wales	CEA	(0) no booster vaccination (1) booster vaccination at 4 years of age (2) booster vaccination at 15 years of age	Introduction of acellular boosters, particularly at 4 years of age, has the potential to be cost effective in the UK	[19]
Lee et al. (2008)	Vaccine	Independent	Germany	CEA + CUA + economic impact analysis	(0) no adult booster vaccination (1) one-time adult pertussis vaccination at 20–64 years of age, where TdaP is administered instead of Td (2) adult pertussis vaccination with decennial boosters	The one-time adult vaccination strategy resulted in CE ratios of €5800 per QALY saved, or €160 per pertussis case prevented. The decennial booster strategy cost €7200 per QALY saved, or €200 per case prevented	[20]
De Vries et al. (2010)	PLoS ONE	GlaxoSmithKline	The Netherlands	CUA + economic impact analysis	(0) no booster vaccination (1) vaccination at the age of 12 years, with duration of protection equal to 8 or 15 years	ICERs are below €10,000 per QALY saved, for both durations of protection considered. Adolescent pertussis vaccination is likely to be a cost-effective intervention for The Netherlands	[13]
Westra et al. (2010)	Clinical Therapeutics	GlaxoSmithKline	The Netherlands	CUA + economic impact analysis	(0) current Dutch vaccination schedule (five doses) using an acellular pertussis vaccine (1) immunization at birth (2) cocooning strategy (3) maternal immunization (4) combine (2) and (3)	Addition of cocooning or maternal immunization to the current Dutch national immunization program would likely be cost effective or even cost saving	[21]
*North American studies*
Purdy et al. (2004)	Clinical Infectious Diseases	GlaxoSmithKline	USA	Economic impact analysis^‡	(0) no booster vaccination (1) adolescents 10–19 years of age (2) adults >20 years of age (3) adults >50 years of age (4) individuals >18 years of age with COPD (5) adults >15 years of age who are the primary caretakers of infants <1 year of age (6) healthcare workers >20 years of age (7) all persons 10 years of age (i.e., universal immunization)	The most economical strategy would be to immunize adolescents 10–19 years of age	[23]
Iskedjian et al. (2004)	Vaccine	Sanofi-Pasteur	Canada	CEA + economic impact analysis	(0) no booster vaccination (1) combined vaccination program including tetanus, dTacp administered at age 12 years	Administering a booster dose of dTacp at 12 years of age to replace diphtheria and tetanus vaccination at 14 years of age may reduce the economic burden of pertussis treatment in the long term at a reasonable cost	[17]
Iskedjian et al. (2005)	Paediatric Drugs	Sanofi-Pasteur	Canada	CEA + economic impact analysis	(0) current practice (1) booster in adolescence at the age of 14 years	Administering a booster dose of dTacp at 14 years of age to replace diphtheria and tetanus vaccination will slightly increase the economic burden from MOH and societal perspectives; however, the number of pertussis cases and the number of hospital admissions will decrease	[18]
Caro et al. (2005)	The Pediatric Infectious Disease Journal	Independent	USA	CEA + economic impact analysis	(0) no booster vaccination (1) adolescent booster	Although there is considerable uncertainty surrounding key inputs, the results indicate that the conditions required for adolescent immunization to be economically warranted are realistic	[14]
Hay et al. (2005)	The Pediatric Infectious Disease Journal	Independent	USA	Economic impact analysis	(0) no booster vaccination (1) adults >10 years of age (2) adults >20 years of age (3) adults >50 years of age (4) adolescents 10–19 years of age (5) persons >18 years of age with COPD (6) adults >15 years of age who are the primary caretakers of infants <1 year of age (7) healthcare workers >20 years of age	Immunizing adolescents with a pertussis booster in the form of Tdap is the most economical and easiest-to-implement strategy and should provide significant health and economic benefits	[24]
Lee et al. (2005)	Pediatrics	Independent	USA	CEA + CUA + economic impact analysis	(0) no vaccination (or status quo, with children being vaccinated at 2, 4, 6 and 12–15 months and 4–6 years of age) (1) one-time adolescent vaccination at 11 years of age (2) one-time adult vaccination at 20 years of age (3) adult vaccination with 10-year boosters (4) adolescent and adult vaccination with 10-year boosters (5) postpartum vaccination (vaccinating mothers after birth plus another adult caregiver after the firstborn child)	Routine pertussis vaccination of adolescents results in net health benefits and may be relatively cost effective	[15]
Lee et al. (2007)	American Journal of Preventive Medicine	Independent	USA	CEA + CUA + economic impact analysis	(0) no adult pertussis vaccination (1) one-time adult pertussis vaccination at 20–64 years, where Tdap is administered instead of Td (2) adult pertussis vaccination with decennial boosters	Routine vaccination of adults aged 20–64 years with combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis is cost effective if pertussis incidence in this age group is greater than 120 per 100,000 population	[25]
Coudeville et al. (2010)	PLoS ONE	Sanofi-Pasteur	USA	CEA + economic impact analysis	(0) childhood vaccination (1) childhood + adolescent (2) childhood + adolescent + cocoon (3) childhood + adolescent + cocoon + one dose at 40 years of age (4) childhood + adolescent + routine adult	By providing a high level of disease control, the implementation of an adult vaccination program against pertussis appears to be highly cost effective and often cost saving	[16]
*Oceanic studies*
Scuffham et al. (2004)	Vaccine	Independent	Australia	CEA + economic impact analysis	(0) childhood vaccination (1) at-birth immunization (2) 1-month vaccination (3) parental vaccination at birth	The birth vaccination strategy appears to offer the greatest potential for one-child families, but the efficacy at birth needs to be established	[22]

^†Strategy '(0)' is the current situation of the country, as stated in the publication.
^‡Purdy et al. presents its analysis as a cost–benefit analysis; nevertheless, there is no monetary valuation of health benefits. It is counted as an economic impact analysis in this review, as is Hay et al., as it is based on Purdy et al.
CE: Cost–effectiveness; CEA: Cost–effectiveness analysis; COPD: Chronic obstructive pulmonary disease; CUA: Cost–utility analysis; dTacp: Diphtheria and acellular pertussis; ICER: Incremental cost–effectiveness ratio; MOH: Ministry of health; QALY: Quality-adjusted life-year; Td: Tetanus–diphtheria; Tdap: Tetanus–diphtheria–acellular pertussis

Table 2. Summary of cost–effectiveness results.
Study (year)	Country	Comparator	Vaccination strategy									Ref.
Study (year)	Country	Comparator	Adolescent	One-time adult	Cocooning	Decennial adult	Immunization at birth	Immunization at 1 month	Maternal immunization	COPD^†	HCW^‡	Ref.
*European studies*
Edmunds et al. (2002)	England and Wales	No booster vaccination	✓ At ages 4 and 15 years	–	–	–	–	–	–	–	–	[19]
Lee et al. (2008)	Germany	No adult booster vaccination	–	✓	–	✓	–	–	–	–	–	[20]
De Vries et al. (2010)	The Netherlands	No booster vaccination	✓ At age 12 years	–	–	–	–	–	–	–	–	[13]
Westra et al. (2010)	The Netherlands	Current Dutch vaccination schedule	–	–	✓	–	×	–	✓	–	–	[21]
*North American studies*
Purdy et al. (2004)	USA	No booster vaccination	?	?	?	–	–	–	–	?	?	[23]
Iskedjian et al. (2004)	Ontario, Canada	Current practice: no booster	? At age 14 years	–	–	–	–	–	–	–	–	[17]
Iskedjian et al. (2005)	Quebec, Canada	Current practice: no booster	? At age 12 years	–	–	–	–	–	–	–	–	[18]
Caro et al. (2005)	USA	No booster vaccination	✓ At age 11–18 years^§	–	–	–	–	–	–	–	–	[14]
Hay et al. (2005)	USA	No booster vaccination	?	?	?	–	–	–	–	?	?	[24]
Lee et al. (2005)	USA	No booster vaccination	✓ At age 11 years	×	×	× Alone ✓! + adolescent	–	–	–	–	–	[15]
Lee et al. (2007)	USA	No adult pertussis vaccination	–	✓ If incidence >120 per 100,000	–	✓ If incidence >120 per 100,000	–	–	–	–	–	[25]
Coudeville et al. (2009)	USA	Childhood vaccination	✓!	+ cocoon + adolescent ✓ at age 40 years	+ adolescent ✓!	+ adolescent ✓!	–	–	–	–	–	[16]
*Oceanic studies*
Schuffham et al. (2004)	Australia	Childhood vaccination	–	–	–	–	×	×	×	–	–	[22]

^†Persons ≥18 years of age with COPD (i.e., asthma, chronic bronchitis, emphysema and so on). ^‡Healthcare workers ≥20 years of age.
^§Cost per life-year gained below US$23,000.
✓Cost-effective strategy vs comparator.
! Strategy not cost effective vs an alternative booster strategy.
× Strategy not cost effective.
? No base-case incremental cost–effectiveness ratio or uncertain cost–effectiveness results.
COPD: Chronic obstructive pulmonary disease; HCW: Healthcare worker.

Table 3. Epidemiology input parameters used in economic evaluations.
Study (year)	Incidence rate^†	Under-reporting correction factor	Other epidemiological inputs	Epidemiological source	Ref.
*European studies*
Edmunds et al. (2002)	Not reported	Adolescents: 2.5 for GP consultation	0–0.25 years/0.25–4 years/5–14 years/15–44 years/>45 years, per 100,000 population per year Consultation rate: 38.58/107.88/49.27/5.33/2.21 Consultations per episode: 1.70 Admission rate: 89.58/15.17/2.11/0.02/0.02 LOS per admission: 7.27/2.33/2.36/8.33/9.31 Percentage time in intensive care (%): 1.1/0.00/0.00/0.00/0.00 Death rate: 1.29/0.04/0.00/0.00/0.00	Royal College of General Practitioners Weekly Returns Service Hospital Episode Statistics Office of National Statistics population projections	[19]
Lee et al. (2008)	Adults: 165 per 100,000 Adolescents: 95 per 100,000 Infants: 22 per 100,000	Not reported	Adult and adolescent disease outcomes Mild cough illness: 1% Moderate cough illness: 72% Severe cough illness: 26% Pneumonia (hospitalized): 1% Infant disease outcomes Respiratory (outpatient): 38.8% Respiratory (inpatient): 59% Neurologic: 1.2% Death: 0.7%	Not reported	[20]
De Vries et al. (2010)	Age specific	Age specific (up to 660)	Not reported	Not reported	[13]
Westra et al. (2010)	Infants <1 year of age 0 months: 9.0 per 100,000 1 month: 27.7 per 100,000 2 months: 23.4 per 100,000 3 months: 14.4 per 100,000 4 months: 6.9 per 100,000 5 months: 3.5 per 100,000 6 months: 10.1 per 100,000 7 months: 5.5 per 100,000 8 months: 10.3 per 100,000 9 months: 7.1 per 100,000 10 months: 6.4 per 100,000 11 months: 4.9 per 100,000 Adults 25–34 years of age 17.9 per 100,000	Adults: 200 Children: 1	Number of hospital admissions in infants <1 year of age 0 months: 9.0 per 100,000 1 month: 27.7 per 100,000 2 months: 23.4 per 100,000 3 months: 14.4 per 100,000 4 months: 6.9 per 100,000 5 months: 3.5 per 100,000 6 months: 4.2 per 100,000 7 months: 2.3 per 100,000 8 months: 4.3 per 100,000 9 months: 2.9 per 100,000 10 months: 2.4 per 100,000 11 months: 2.0 per 100,000 Adults 25–34 years of age 0.035 per 100,000	Literature, national databases and expert opinions	[21]
*North American studies*
Purdy et al. (2004)	Adolescents: 450 per 100,000 person-years Adults: 507 per 100,000 person-years (ages 10–19 years: 41%; 20–29 years: 7%; 30–39 years: 17%; 40–49 years: 28%)	Children aged 0–9 years: 2 (50% of cases among the US children aged 0–9 years not reported)	–	US Census Bureau population projections for 2001–2010	[23]
Iskedjian et al. (2004)	Adolescents (aged 12–17 years): 511 per 100,000 Young adults (aged 18–21 years): 65 per 100,000	Adolescents: 9	Adolescents (aged 12–17 years)/young adults (aged 18–21 years) Overall pertussis-related hospitalization rate: 1.07%/1.8% Overall rate of pertussis cases managed at clinic: 89%/89% Overall rate of pertussis cases managed at emergency room: 11%/11% Duration of hospital stay (days): 4.3/8.5 Physician office visits per pertussis case: 2.3/2.5 Sinusitis: 11%/15% Pneumonia: 2%/5%	Not reported	[17]
Iskedjian et al. (2005)	Adolescents: (14–17 years) 511 per 100,000 Young adults: (18–24 years) 65 per 100,000	Adolescents: 9	Adolescents (14–17 years)/young adults (18–24 years) Overall pertussis-related hospitalization rate: 1.07%/1.8% Overall rate of pertussis cases managed at clinic: 89%/89% Overall rate of pertussis cases managed at emergency room: 11%/15% Physician office visit per case: 2.3/2.5	Not reported	[18]
Caro et al. (2005)	(per 100,000 person-years) 0.2–57 (age-specific rates used)	All: 8.6 (Unreported cases/reported case: 7.6 [estimated by GPI], unreported cases [mild] 68%)	Case fatality: infants 0.69%, children 0.05%, adolescents 0.00%, adults 0.03% Hospitalizations per case: infants 58.5%, children 7.0%, adolescents 2.1%, adults 3.5%	Average of estimates from the CDC from 1996 to 1999	[14]
Hay et al. (2005)	Not clear	Not reported	Not clear	US Census Bureau population projections for 2001–2010	[24]
Lee et al. (2005)	Adolescents: 155 per 100,000 Adults: 11 per 100,000 Infants: 58.5 per 100,000	Not reported	Disease outcomes Severe cough: adolescents 58%, adults 67% Pneumonia: adolescents 1%, adults 3% Respiratory disease (hospitalized), infants: 58.5% Neurologic disease, infants : 2% Death, infants : 0.7%	Review of the literature, recent vaccine clinical trial data and unpublished data provided by the CDC and the Massachusetts Department of Public Health	[15]
Lee et al. (2007)	Not reported	Not reported	Adult with symptomatic pertussis Mild cough illness: 38% Moderate cough illness: 21% Severe cough illness: 40% Pneumonia (hospitalized): 1% Infant disease outcomes Respiratory (outpatient): 38.8% Respiratory (inpatient): 58.5% Neurologic: 2%^[1] Death: 0.7%	Not reported	[25]
Coudeville et al. (2009)	90 per 100,000 for adult cases requiring medical attention	All: age specific	% of cases resulting from exposure to household contacts 0–1 months 48.1%, 2–3 months 48.1%, 4–5 months 48.1%, 6–12 months 33.6% 13–18 months 39.2%, 19–24 months 41.7%, 2 years 38.2%, 3 years 41.5%, 4 years 40.5%, 5 years 23.6% Case fatality rates Typical cases: <1 year 0.69%, 1–9 years 0.05%, 10–17 years 0%, 18+ years 0.03% Mild cases: <1 year 0.0%, 1–9 years 0.0%, 10–17 years 0.0%, 18+ years 0.0% Rates of long-term sequelae Typical cases: <1 year 0.06%, 1–9 years 0.02%, 10–17 years 0.02%, 18+ years 0.02% Mild cases: <1 year 0.0%, 1–9 years 0.0%, 10–17 years 0.0%, 18+ years 0.0%	Based on incidence data reported in APERT for adolescents and adults For children, CDC surveillance data were adjusted for under-reporting using age-specific under-reporting estimates	[16]
*Oceanic studies*
Schuffham et al. (2004)	Notified cases per 100,000 infants per week: 5.171	–	No. of GP consultations per case: 2.0 Probability of infections from parents: 0.51 Case duration: 2.0 weeks Hospitalization rate for notified cases (age ≤9 weeks): 0.529 Hospitalization rate for notified cases (age >10 weeks): 0.386 Probability of complication in hospitalized cases: 0.17 Probability of death from complications: 0.125 All-cause mortality rate per 1000 infants ≤4 weeks: 3.91 All-cause mortality rate per 1000 infants aged 5–52 weeks: 1.95	Health Outcomes Information Statistical Toolkit of the New South Wales Department Australian Childhood Immunization register	[22]

^†In most cases, it seems that the numbers provided are the numbers after correction for under-reporting.
GP: General practitioner; GPI: Global Pertussis Initiative; LOS: Length of stay.

Table 4. Herd immunity consideration in economic evaluations.
Study (year)	Herd immunity consideration	Comments	Ref.
*European studies*
Edmunds et al. (2002)	Yes	Results are presented according to herd immunity percentage, from 20 to 100% Herd immunity was estimated from transmission dynamic model solved at equilibrium. It is only considered in younger children, and impact on other populations is not considered at all	[19]
Lee et al. (2008)	Yes	10% among adults from 20 to 29 years of age, 12% from 30 to 39 years of age and 14% from 40 to 64 years of age	[20]
De Vries et al. (2010)	Yes	Transmission dynamic discrete event simulation model. Authors do not report direct and indirect effects of vaccination separately	[13]
Westra et al. (2010)	No	NA	[21]
*North American studies*
Purdy et al. (2004)	No	NA	[23]
Iskedjian et al. (2004)	No	NA	[17]
Iskedjian et al. (2005)	No	NA	[18]
Caro et al. (2005)	Yes	Reduction in nontarget cases (herd immunity): 20% Duration of herd immunity: 10 years Distribution of herd immunity: infants 20%, children 30%, adolescents 25%, adults 25%	[14]
Hay et al. (2005)	No	NA	[24]
Lee et al. (2005)	Yes	(Sensitivity analysis) Potential to reduce infant transmission for each strategy: 17% for the one-time adolescent vaccination strategy 10% for the one-time adult vaccination strategy 17% for the adult vaccination with 10-year boosters 35% for adolescent and adult vaccination with 10-year boosters 40% for the postpartum vaccination strategy (in both baseline and alternative analyses)	[15]
Lee et al. (2007)	Yes	(Sensitivity analysis) Potential to reduce infant transmission for each strategy: 15% for the one-time adult vaccination strategy 0, 15, 30 and 45% for the adult vaccination with decennial boosters	[25]
Coudeville et al. (2009)	Yes	Transmission dynamic compartmental model	[16]
*Oceanic studies*
Schuffham et al. (2004)	No	NA	[22]

NA: Not applicable.

Table 5. Cost parameters in economic evaluations.
Study (year)	Perspective	Monetary unit	Direct costs	Indirect costs	Vaccination costs	Ref.
*European studies*
Edmunds et al. (2002)	TPP and societal	1999/2000 GBP£	(≤0.25 years/0.25–4 years/5–14 years/15–44 years/>45 years) GP consultation: 24/24/24/24/24 Cost per inpatient day: 297/297/297/222/222 Cost per intensive care day: 1065/0/0/0/0	(≤0.25 years/0.25–4 years/5–14 years/15–44 years/>45 years) Work days lost: 0/7/7/7/7 Average daily wage: 50/50/50/52/67	Vaccine price Incremental cost of booster (vs Td): 5 (Assuming 15% wastage, then the cost per course of vaccine becomes 5.75 in the base case)	[19]
Lee et al. (2008)	TPP and societal	2006 €	Medical costs for adults Mild cough illness: 10; moderate cough illness: 97; severe cough illness: 165; pneumonia: 2435 Nonmedical costs for adults Mild cough illness: 58; moderate cough illness: 442; severe cough illness: 442; pneumonia: 789 Medical costs for adolescents Mild cough illness: 7; moderate cough illness: 72; severe cough illness: 122; pneumonia: 1802 Nonmedical costs for adolescents Mild cough illness: 20; moderate cough illness: 155; severe cough illness: 155; pneumonia: 276 Medical costs for infants Respiratory (outpatient): 43; respiratory (inpatient): 4771; neurologic: 2539 (not specified if inpatient or not); death: 4771 Nonmedical costs for infants Respiratory (outpatient): 119; respiratory (inpatient): 1132; neurologic: 1115; death: 1132		Vaccine price Incremental Tdap vs Td: 12 Administration costs Vaccine visit: 0 Vaccine administration: 0 Vaccine AEs Local reaction: 1 Systemic reaction: 1 Anaphylaxis: 1162	[20]
De Vries et al. (2010)	Societal	2008 €	Diagnostic procedures Chest radiography: 48.49; C-reactive protein: 6.09 Blood concentration determination: 9.74; PCR: 99.13 Serology: 43.38; culture: 15.00 Treatment Azithromycine for adolescents and adults: 8.20 Azithromycine for infants <12 years of age: 2.44/kg Prescription fee (pharmacist): 6.10 Consultations Consult GP: 21.75 Consult medical specialist: 52.89	Standard day care: 387.75 Pediatric intensive day care: 1500 Pediatric intensive care admission costs (one-off): 5000	Vaccine price: 18.30 Administration costs: 6	[13]
Westra et al. (2010)	TPP and societal	2008 €	(Ambulatory cases treated in hospital/GP) Diagnostics: 221.83/52.48 Visits to general practitioner: 22.59/45.18 Visits to specialist: 158.67/0 Treatment: 9.40 infant; 17.24 adult/9.40 infant; 17.24 adult	(Ambulatory cases treated in hospital/GP) Infants: 508.00/508.00 Adult female, reported: 254.00/254.00 Adult male, reported: 403.00/403.00 Adult female, unreported: 127.00/127.00 Adult male, unreported: 202.00/202.00	Vaccine price: 18.30 Administration costs: 6	[21]
*North American studies*
Purdy et al. (2004)	Societal	2002 US$	(Children/adolescents/adults) Outpatient costs Office/emergency department visit: 127.76/105.52/67.50 Medication: 22.98/22.45/16.50 Procedure/test: 73.93/46.66/57.03 Inpatient costs Number of inpatient days: 7/3/1 Total per inpatient day: 1100/1100/1100 Base-case hospitalization: 7700/3300/1100 Additional, by illness Seizures: 4000/3000/2000 Pneumonia: 2000/1300/1000 Encephalopathy: 6000/5000/4000 Terminal: 20,000/17,000/12,000	(Children/adolescents/adults) Work, hours: 48/16/28 Other activities, hours: 96/16/28 Total, per hour of activity: 22/22/22 Overall (base-case estimate): 3168/704/1232 Societal costs Per case of encephalopathy: 20,000/20,000/20,000 Per case of PBD: 2400,000/2400,000/2400,000 Per death: 5,000,000/5,000,000/5,000,000	Not reported	[23]
Iskedjian et al. (2004)	MOH and societal	2001 CAD$	Cost of purchasing and administering the vaccine, physician fees, hospitalization, contact tracing and cost of medications	Productivity loss by parents of younger adolescents or by older adolescents Younger adolescent hospitalized (work time lost = 1 day): 139.52 Older adolescent hospitalized (work time lost = 5 days): 697.60 Younger adolescent hospitalized (leisure time lost = 1 day): 139.52 Older adolescent hospitalized (leisure time lost = 5 days): 697.60 Younger adolescent nonhospitalized (work time lost = 2 h): 34.88 Younger adolescent nonhospitalized (leisure time lost = 4 h): 69.76 Older adolescent nonhospitalized (work time lost = 1 day): 139.52 Older adolescent nonhospitalized (leisure time lost = 1 day): 139.52 dT administration (1 h for 50% of subjects): 8.72	Vaccine price DTacp vaccine 20.82 + dT vaccine 5.10 Administration costs Physician outpatient injection 8.40 + nurse outpatient injection 1.00 Immunization supplies: 1.17	[17]
Iskedjian et al. (2005)	MOH and societal	2003 CAD$	Treatment costs Consultation clinic: 31.40 + physician on duty Emergency room: 36.40 Investigations Nasopharyngeal aspirate: 40.05 Chest radiograph: 20.75 Sinus radiograph: 31.00 Contact tracing: 273.08 Comorbidities Pneumonia: 130.66 + sinusitis 64.46 Hospitalization: per day 402.95	Productivity loss by parents of younger adolescents or by older adolescents Younger adolescent hospitalized (work time lost = 1 day): 139.52 Older adolescent hospitalized (work time lost = 5 days): 697.60 Younger adolescent hospitalized (leisure time lost = 1 day): 139.52 Older adolescent hospitalized (leisure time lost = 5 days): 697.60 Younger adolescent nonhospitalized (work time lost = 2 h): 34.88 Younger adolescent nonhospitalized (leisure time lost = 4 h): 69.76 Older adolescent nonhospitalized (work time lost = 1 day): 139.52 Older adolescent nonhospitalized (leisure time lost = 1 day): 139.52 dT administration (1 h for 50% of subjects): 8.72	Vaccine price DTacp vaccine: 20.82 + dT vaccine: 5.10 Administration costs 2.17 (administration + supplies)	[18]
Caro et al. (2005)	TPP and societal	2002 US$	Costs per case Infants: 5925; children: 546; adolescents: 300; adults: 337 Cost of long-term disability Annual direct 43,680 if institutionalized	Costs per case Infants 330; children 330; adolescents 55; adults 632 Cost of long-term disability Annual indirect 23,064 (lost wages)	Not reported	[14]
Hay et al. (2005)	Societal	Not reported	(Adolescent/adult) Hospitalization: 18/70 Physician visits: 104/117 Chest radiography: 19/27 Laboratory test: 32/29 Prescription drugs Antibiotics: 57/58 Cough medicine: 3/15 Inhalers: 8/11 Total direct cost per case: 242/326	(Adolescent/adult) Childcare: 4/4 Transportation: 20/21 Informal caregiver time (unpaid): 14/41 Time costs (for adults) Work missed: 94/360 Hospitalization: 0/2 Emergency department visit: 1/2 Doctor visit: 12/4 Over-the-counter drugs Cough medicine: 5/7 Other (e.g., pain relievers, herbal agents): 4/5 Total indirect cost per case: 155/447 Societal total cost per case: 397/773	Not reported	[24]
Lee et al. (2005)	TPP and societal	2004 US$	Medical cost for mild cough Adolescent: 201; adult: 243 Medical cost for severe cough Adolescent: 256; adult: 338 Medical cost for pneumonia Adolescent: 402; adult: 373 Medical cost for infants Respiratory disease: 98 Respiratory disease with hospitalization: 6496 Neurologic disease: 6238 Death: 13,559 Nonmedical costs attributable to pertussis Adolescent: 160; adult: 460 Nonmedical costs for infants Respiratory disease: 43 Respiratory disease with hospitalization: 449 Neurologic disease: 688 Death: 652	–	Vaccine price Vaccine incremental price (vs Td): 15 Administration costs Adolescent or adult booster: 0 Significant other in postpartum strategy: 10 Cost of vaccine visit Adolescent or adult booster: 0 Significant other in postpartum strategy: 20 Vaccine AEs Cost of local reaction: 1 Cost of systemic reaction: 1 Cost of anaphylaxis: 2066	[28]
Lee et al. (2007)	TPP and societal	2005 US$	Medical costs for adults Mild cough illness: 50; moderate cough illness: 246; severe cough illness: 342; pneumonia: 377 Medical cost for infants Respiratory illness (outpatient): 99; respiratory illness (hospitalization): 6577; neurologic illness: 6315; death: 14,197 Nonmedical costs for adults: 466 Nonmedical costs for infants Respiratory disease (outpatient): 42; respiratory disease (hospitalization): 437; neurologic disease: 669; death: 660	–	Vaccine price Incremental Tdap vs Td: 20 Vaccine administration: 0 Vaccine adverse events Local reaction: 1 Systemic reaction: 1 Anaphylaxis: 2091	[25]
Coudeville et al. (2009)	Societal assumed	2006 US$	(<1 year/1–9 years/10–17 years/>18 years) Typical cases Short-term direct costs: 7006/646/256/338 Medical disability costs per year: 51,648/51,648/51,648/51,648 Mild cases Short-term direct costs: 377/256/219/265	(<1 year/1–9 years/10–17 years/>18 years) Typical cases Short-term indirect costs: 390/390/174/501 Indirect costs due to disability or death per year: 25,036/25,036/25,036/25,036 Mild cases Short-term indirect costs: 390/390/174/501	Vaccine price: 14.13^† Administration costs No additional administration costs Cocoon strategy (additional visit for father of newborns): 30 AE: 0.74/dose administered	[16]
*Oceanic studies*
Schuffham et al. (2004)	TPP	2000 AUS$	GP consultation: 23.45 Hospital admission with complications (age <1 year): 15.830 Hospital admission no complications (age <1 year): 2.815 Hospitalization for IHPS from erythromycin: 2.646 Treatment medications: 10.00		Vaccine per dose: 25.00 Administration costs Administration of vaccine as per schedule: 12.00 Administration of vaccine at birth: 9.00 Administration of parental vaccine: 12.00	[22]

^†For the cost of the vaccine itself, the authors applied the price difference between a combined Td vaccine and the price of a combined TdaP vaccine in the public sector, available at [102].
AE: Adverse event; dT: Diphtheria–tetanus; DTacp: Diphtheria–tetanus–acellular pertussis; GP: General practitioner; IHPS: Idiopathic hypertrophic pyloric stenosis; MOH: Ministry of health; PBD: Permanent brain damage; Td: Tetanus–diphtheria; Tdap: Tetanus–diphtheria–acellular pertussis; TPP: Third-party payer.

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