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Cost-effectiveness analysis of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil
Vaccine xxx (xxxx) xxx
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Cost-effectiveness analysis of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil Eder Gatti Fernandes a,b,⇑, Ana Marli Christovam Sartori c,d, Patrícia Coelho de Soárez e,d, Marcos Amaku f, Raymundo Soares de Azevedo Neto f, Hillegonda Maria Dutilh Novaes e,d a
Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 2° andar, sala 2228, CEP: 01246-903 São Paulo, SP, Brazil Divisão de Imunização, Centro de Vigilância Epidemiológica ‘‘Prof. Alexandre Vranjac”, Coordenadoria de Controle de Doenças da Secretaria de Estado da Saúde de São Paulo, Av. Dr Arnaldo, 351, 6° andar, Pacaembu, CEP: 01246-000 São Paulo, SP, Brazil c Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, ICHC, 4° andar, sala 4028 Cerqueira César, CEP: 05403-000 São Paulo, SP, Brazil d Health Technology Assessment Institute (IATS), Brazil e Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, CEP: 01246-903 São Paulo, SP, Brazil f Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, CEP: 01246-903 São Paulo, SP, Brazil b
a r t i c l e
i n f o
Article history: Received 6 March 2019 Received in revised form 30 September 2019 Accepted 30 September 2019 Available online xxxx Keywords: Cost-benefit analysis Cost-effectiveness analysis Diphtheria-tetanus-acellular pertussis vaccines Pertussis vaccine Whooping cough Adult
a b s t r a c t Background: A pertussis outbreak occurred in Brazil from 2011 to 2014, despite high coverage of wholecell pertussis containing vaccines in early childhood. Infants were the most affected. This study aimed to evaluate the cost-effectiveness of introducing universal adult vaccination with Tdap into the National Immunization Program in Brazil. Methods: Economic evaluation using a dynamic model to compare two strategies: (1) universal vaccination with single dose of Tdap at 20 years of age and (2) current practice (only pregnant women pertussis vaccination). The health system perspective was adopted. Temporal horizon was 10 years. Discount rate of 5% was applied to costs and benefits. Vaccine effectiveness (VE) was obtained from a population-based observational study. Epidemiological, resource utilization and cost estimates were obtained from the Brazilian Health Information Systems. The primary outcome was cost per life year saved (LYS), based on life expectancy at birth in Brazil in 2015. Univariate and multivariate sensitivity analysis were performed. Results: Adult vaccination with VE of 82.6% and coverage of 40%, at price of US$7.01 per dose, and assuming herd protection would avoid 167 infant deaths by pertussis, saving 12,325 years of life and costing a total of US$105495891.61, from the health system perspective. The universal immunization would result in ICER of US$8459.13. The results were highly sensitive to disease incidence. Conclusions: The results suggest that universal adult vaccination with Tdap would not be a cost-effective intervention for preventing pertussis cases and deaths in infants in Brazil. Ó 2019 Elsevier Ltd. All rights reserved.
Abbreviations: AE, adverse events; ICER, incremental cost-effectiveness ratio; IBGE, Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Estatística e Geografia); IIER, Instituto de Infectologia Emílio Ribas; LYS, life year saved; MoH, Ministry of Health; NIP, National Immunization Program; R$, Brazilian Reais; SIH-SUS, Hospital Information System database; SINAN, Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação); SINASC, Live Birth Information System (Sistema de Informações sobre Nascidos Vivos); SP, São Paulo State; SUS, Sistema Único de Saúde; Td, tetanus – diphtheria vaccine; Tdap, reduced diphtheria toxoid, acellular pertussis vaccine; US$, United States Dollar; VE, Vaccine effectiveness. ⇑ Corresponding author at: Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 2◦andar, sala 2228, CEP: 01246-903 São Paulo, SP, Brazil. E-mail addresses: [email protected] (E.G. Fernandes), [email protected] (A.M.C. Sartori), [email protected] (P.C. de Soárez), [email protected] (M. Amaku), [email protected] (R.S. de Azevedo Neto), [email protected] (H.M.D. Novaes). https://doi.org/10.1016/j.vaccine.2019.09.100 0264-410X/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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1. Introduction Pertussis is a highly contagious respiratory disease mainly caused by Bordetella pertussis [1,2]. It causes uncontrollable violent coughing for long periods, most commonly affects infants and young children and can be fatal, especially in infants under 6 months of age [1]. The introduction of childhood immunization with pertussis containing vaccines led to important reduction in pertussis incidence in countries that achieved high vaccine coverage, even though the disease has never disappeared [2,3]. In the last 20 years, reemergence of pertussis has been reported in several high-income countries, despite high coverage of acellular pertussis vaccination in childhood [1,2,4–6]. Because of this, in recent years, several countries worldwide have adopted maternal immunization with tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) to protect the young infants, until they can receive their own routine primary vaccination [7]. This measure provides protection to newborns via passive transplacental transferring antibodies [8–10]. In places where most children are immunized for pertussis, the bacterium circulates mainly among unprotected adolescents and adults, due to waning immunity following vaccination or infection [11,12]. Household adults are the main source of infection for infants [13–16]. Adults’ immunization with a vaccine that provides herd protection could be an additional strategy to reduce pertussis among infants [17–22]. A significant increase in pertussis incidence rates was observed in Brazil from 2011 to 2014, in spite of high coverage of childhood immunization with whole-cell pertussis containing vaccines (from 93.8 to 99.6% in these years). Pertussis incidence among infants aged <1 year was 13.8 per 100,000 in 2010, jumped to 57.67 per 100,000 in 2011, reaching 171.9 per 100,000 in 2014. From 2011 to 2014, 470 pertussis-related deaths were reported in Brazil [23]. The highest pertussis rates occurred in infants younger than 3 months, with concomitant increase in pertussis-related infant deaths, which led to a review of control strategies [24,25]. In 2014, the Brazilian Ministry of Health (MoH) recommended Tdap to women between 27th to 36th of pregnancy, in every pregnancy [24,25]. In 2017, the MoH extended the recommendation from the 20th week of pregnancy [24].
In Brazil, health technology assessments and economic evaluations have been requested by the MoH as part of the decision processes for new vaccines introduction into the National Immunization Program (NIP) since 2005. This study aimed to evaluate the cost-effectiveness of introducing universal 20-years-old adult vaccination with Tdap into the NIP in comparison to the current practice (no adult pertussis vaccination). 2. Methods This cost-effectiveness analysis adopted the health system perspective. This included direct medical costs associated with the universal vaccination program, outpatient and hospital care in both public (Sistema Único de Saúde, SUS) and private health systems, and epidemiological investigation of contacts. A single dose of Tdap administered to 20-year-old adults was compared to the current tetanus - diphtheria (Td) vaccination schedule without the pertussis component. The time horizon used in the analysis was 10 years. The costs were estimated in 2015 Brazilian Reais (R$) and are presented in June 2015 United States Dollars (US$), at the exchange rate of US $1 = R$3.10. All costs and effects are presented in disaggregated and aggregated form, and incremental cost-effectiveness ratios (ICERs) are presented for the outcomes: pertussis cases, deaths and life year saved (LYS) of children under one year of age and adults between 20 and 40 years of age. Discount rate of 5% was applied to both future costs and health benefits, as recommended by the Brazilian guidelines [26]. We conducted a literature review and used National Health Information System databases to inform model parameters. The model parameters for vaccine effectiveness, epidemiological and cost are summarized in Tables 1 and 2. 2.1. Dynamic model A dynamic model was developed using the software R (R Core Team 2019. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at
Table 1 Vaccine parameters and epidemiological data used in the base case and sensitivity analysis in the cost-effectiveness analyses of adult immunization with tetanus-diphtheriaacellular pertussis (Tdap) in Brazil. Parameter Vaccination program Vaccine coverage (%) Vaccine effectiveness (%) Wastage rate (%) Cohort <1 year 20 - <40 years Life expectancy at birth (years) Transition probabilities Pertussis incidence in infants < 1 year (/100,000) Symptomatic cases among infected people <1 year - % 20 – <40 years - % Symptomatic cases that seek health assistance <1 year - % 20 – <40 years - % Hospitalization rate <1 year 20 - <40 years Case-fatality rate <1 year - % 20 – <40 years - %
Base case
Sensitivity analysis
Source
40.0 82.6 5.0
20 – 80 65.6 – 92.0
Authors’ assumption [31,66,67] Authors’ assumption
3,017,668 67,726,893 75.5
– –
SINASC IBGE IBGE
53.85
7.38 –217.20
SINAN-SP
100 10
– 4.5 – 20.0
[11]
100 8.89 76.99 8.33 4.98 –
SINAN, IIER, authors’ assumption
100
SINAN - SP IIER SINAN - SP SINAN - SP
SINASC: Live Birth Information System (Sistema de Informações sobre Nascidos Vivos), IBGE: Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Estatística e Geografia); SINAN: Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação); IIER: Instituto de Infectologia Emílio Ribas.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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Table 2 Costs data for base case model and sensitivity analysis ranges used in cost-effectiveness analyses of adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) in Brazil. In 2015 US$. Parameter Direct medical costs Vaccine dose Administration costs Outpatient care <1 year 20 - <40 years Hospital care <1 year 20 - <40 years Pertussis laboratory diagnoses <1 year 20 - <40 year Epidemiological investigation of contacts cost1 <1 year 20 - <40 years
Base case
Sourceb
Sensitivity analysis
7.01 1.50
Brazilian NIP [58] SIGTAP, BPS
12.27 12.09 SIGTAP, BPS, SIH-SUS 311.56 299.22
291.60– 476.16 81.35– 359.59
10.56 9.23
26.55 20.27
17.07 20.99
41.04 44.69
SINAN, IAL
SINAN, IAL, author’s assumption
1
Epidemiological investigation of contacts cost includes public health professional visit, laboratory testing, and antibiotic treatment of symptomatic contacts. NIP: National Immunization Program, SIGTAP: Sistema de Gerenciamento da Tabela de Procedimentos, medicamentos e OPM do SUS, BPS: Banco de Preços em Saúde, SIH: Hospital Information System (Sistema de Informações Hospitalares do SUS), SINAN: Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação), IAL: Adolfo Lutz Institute. b
dose, and (2) current practice (no adults pertussis vaccination). The structure of the model is presented in Fig. 1 and Supplementary Material 1. 2.2. Model assumptions Considering adults as the source of infection for infants <1 year of age, an infected adult would be necessary for each infected infant. Then, the number of infected adults was estimated based on the incidence of the disease in infants <1 year of age. Vaccinating adults would reduce adults cases and, consequently, reduce pertussis transmission in the community, reducing infant cases (herd protection). We also assumed that the force of infection
Adults
among adults (ka) and among infants <1 year of age (kc) were the same. We considered the period of transmissibility of 21 days (1) and waning immunity after adult vaccination of 0.4055/year, similar to waning immunity after Tdpa vaccination of adolescents [27]. Immunity after disease would wane over 20 years [28,29]. The overall mortality rate in one year was 1/75.5, considering the life expectancy of 75.5 years in Brazil in 2015 [30]. Infants (<1 year of age) pertussis mortality (a) was 4.98% (Table 1). 2.3. Vaccine effectiveness (VE) The effective vaccine coverage (pv ) would be the assumed effectiveness of the vaccine multiplied by the vaccine coverage. VE was
Infants
Fig. 1. Dynamic model for cost-effectiveness analysis of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil. Sa – susceptible adults; Ia – infected adults; Ra – recovered adults; V a – vaccinated adults (immunized); Sc – susceptible infants; Ic – infected infants; Rc – recovered infants; ka – force of infection in adults; c – recovery rate (inverse of infectious period); xR – rate of recovered adults that become susceptible; xV – rate of vaccinated adults that become susceptible; l – rate of natural mortality in population (inverse of life expectancy)); Ka – replacement rate of the adult population; Kc – replacement rate of the infant population; a – differential mortality of pertussis in children.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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assumed as 82.6%, obtained from a population-based observational study that evaluated Tdap effectiveness after pregnant women vaccination mass immunization in São Paulo State, Brazil [31]. Vaccine coverage was assumed at 40%, considering that Td coverage among adults is lower than 50% in Brazil (not published data from Brazilian MoH). Demographic, epidemiological and disease burden estimates Data from the São Paulo State (SP) was extrapolated to the whole country. SP is the wealthiest of 27 Brazilian states and Federal District, and has a population of 43.6 million (one-fifth of Brazilian population). In 2015, SP Surveillance service reported 18% of all confirmed pertussis cases in Brazil. São Paulo State is one of the three states with PCR available for pertussis diagnosis. Considering the greater availability of health services and diagnostic tools, pertussis surveillance in the State of São Paulo may be more sensitive than the rest of the country. In the last years, pertussis incidence in the São Paulo State had the same trend as in the rest of country [24]. The population of infants aged <1 year and adults from 20 to 40 years was retrieved from the Live Birth Information System (Sistema de Informações sobre Nascidos Vivos, SINASC) and Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Estatística e Geografia, IBGE), respectively. Pertussis incidence, hospitalization and case fatality rates in infants <1 year of age was estimated based on the number of confirmed cases reported, in 2015, to the Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação, SINAN), which records data from both public and private health services. In the sensitivity analysis, we considered the lowest and the highest incidence rates reported from 2001 to 2015 in São Paulo State (2002 and 2014, respectively). Pertussis incidence among adults aged 20 to <40 years was derived from the model, while hospitalization rates for this age group was based on primary data collected on pertussis cases who sought assistance at the Emergence Room of Instituto de Infectologia Emílio Ribas (IIER), a public hospital specialized in infectious diseases (Supplementary Material 2). Most pertussis cases in adults are asymptomatic or oligosymptomatic [11]. Although these cases contribute to pertussis transmission [32], they do not lead to health care utilization or costs for the health system. We assumed that 10% of infected adults would be symptomatic [11], 8.9% of symptomatic cases would seek health care and 8.33% of symptomatic cases seeking health assistance would be hospitalized (Supplementary Material 2). 2.4. Health services utilization and costs of pertussis treatment In line with the perspective adopted, the model included the following cost components: universal vaccination program, outpatient and hospital care in both public and private health systems, and epidemiological investigation of contacts. These components capture the main costs associated with pertussis treatment. The Brazilian public health system (SUS) is responsible for 78.6% of all hospitalizations of children aged less than one year and about 75% of hospitalizations of adults aged 20–40 years for clinical reasons [33]. Due to lack of data on costs in the Brazilian private health system, we applied the same values as in the public health system for both outpatient and hospital care. Cost data are shown in Table 2 and are described in more details below. 2.5. Universal vaccination program Tdap vaccine dose price was informed by the Brazilian NIP (US $7.01). A 5% wastage rate (US$0.35) and administration cost (US
$1.50) was added to this figure, totalizing US$8.86 per vaccine dose. The base case analysis considered a single vaccine dose given at 20th year of age. Costs of adverse events (AE) following Tdap immunization have not been considered, since AE are rare and mild [34–37]. 2.6. Outpatient care The outpatient care costs, estimated by age group (<1 year-old and 20 - <40 years-old), included the cost of two medical visits, diagnostic tests (blood cell count, chest X-ray, pertussis PCR and culture), and antibiotic treatment (azithromycin). The costs of medical visits, blood cell count and chest X-ray in June 2015, were retrieved from the Sistema de Gerenciamento da Tabela de Procedimentos, medicamentos e OPM do SUS [38]. The costs of pertussis specific diagnostic tests (PCR and culture) were informed by technicians of the Adolfo Lutz Institute (São Paulo State, Brazil). 2.7. Hospital care Hospitalizations costs in SUS were obtained from Hospital Information System (SIH-SUS) database [23]. To account for the skewed distribution of hospitalization costs we used the median annual cost. In the sensitivity analysis, the costs were varied from its 10th to 90th percentiles values. It was assumed that every hospitalized case would go through an emergency room visit and perform a chest X-ray and a blood cell count before hospitalization, and have a medical outpatient visit after discharge. The value of two medical visits (pre- and post-hospitalization), a chest X-ray, blood cell count, and pertussis diagnostic tests was added to the hospitalization costs. 2.8. Pertussis laboratory diagnosis In Brazil, nasopharyngeal swabs of suspected cases are sent to public health reference laboratories for pertussis diagnostic tests. In 2015, PCR and culture were performed in three states (São Paulo, Paraná and Espírito Santo), whereas only culture was performed in the rest of the country. The mean cost of pertussis considered the proportion of cases reported in the three states with both PCR and culture available and in the rest of the country, and the cost of each test [24,39,40]. 2.9. Public health response to pertussis In Brazil, reported pertussis cases should trigger an epidemiological investigation aiming to identify the source of infection or secondary cases among household contacts. A trained public health professional visit the household, identify exposed persons with respiratory symptoms, collect nasopharyngeal swabs from symptomatic contacts, and send this material to public health reference laboratories for diagnostic. Antibiotic treatment is offered to symptomatic contacts. Data on household contacts investigation were retrieved from SINAN of São Paulo State and extrapolated to the whole country. In 2015, 70.92% of pertussis cases in infants aged <1-year-old and 77.14% of cases in adults aged 20 to <40 years reported to SINAN triggered epidemiological investigation of household contacts. An average of 1.58 and 1.59 symptomatic household contacts per case were detected among infants <1 year of age and adults, respectively. The costs of epidemiological investigation, including laboratory testing and antibiotic treatment of symptomatic contacts were estimated in US $17.07 and US$20.99 per case in infants <1 year of age and adults, respectively.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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2.10. Sensitivity analysis We performed multiple sensitivity analyses to test the influence of parameters uncertainty on the economic outcomes of this model. First, we performed univariate sensitivity analyses evaluating changes in pertussis incidence, proportion of symptomatic cases among infected adults, hospitalization rate among infants <1 year of age, treatment cost, vaccination costs, and herd protection. Secondly, multivariate sensitivity analyses (best and worst case scenarios) were performed.
hospitalizations (3,344 infants and 76 adults) and 167 infant deaths, saving 12,325 years of life. The cumulative cost of the national Tdap adult vaccination program would be US$105,495,891.61. The health system costs related to direct medical costs (outpatient and hospital care, specific laboratory diagnosis and epidemiological surveillance) would be reduced by 30.67% (from US$4,024,927.05 to US$2,790,489.02). The universal adult immunization would result in an ICER of US $8,459.13 per life year saved (LYS), from the health system perspective (Table 3).
3. Ethics 4.2. Sensitivity analysis The study was approved by the Research Ethics Committee of Medical Scholl of São Paulo University, license number 1.073.607. 4. Results 4.1. Base case analysis The base case analysis followed a hypothetic cohort of infants (<1 year) and adults aged from 20 to <40 years old for 10 years. Without 20-year-old adult’s vaccination, 414,504 pertussis infections in adults would happen, among which 41,450 would be symptomatic and 3,687 would seek health care in 10 years; 17,875 pertussis cases in infants <1 year of age and 685 deaths would occur. Assuming vaccine effectiveness of 82.6%, vaccine coverage of 40% and herd protection, the model estimated that the universal Tdap vaccination at 20th year of age would avoid 14,547 symptomatic pertussis cases (4,344 infants and 10,203 adults), 5,252 cases requiring health care (4,344 infants and 908 adults), 3,420
Table 3 Expected cumulative effects and costs (2015 US$) of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap), in the health system perspective, 10 years after the program implementation in Brazil. Parameter
Disease impact N° of symptomatic cases among infants and adults aged 20- <40 years N° of symptomatic cases avoided N° of cases requiring health care N° of cases requiring health care avoided N° of deaths N° of deaths avoided Reduction in n° of deaths, % N° of life years lost N° of life years saved Reduction in the n° of life years lost, % Costs2 Disease treatment costs Disease treatment cost avoided Reduction in disease costs, % Vaccination program costs3 Total Incremental Cost Incremental Cost-effectiveness ratio – ICER Cost per case requiring health care avoided Cost per death avoided Cost per life year saved
Sensitivity analyses are presented in Table 4. Among the seven different varied parameters, the ICER was most sensitive to variation in disease incidence. When the model considered higher disease incidence rate, the ICER decreased 74.1% (US$8,459.13 to US $2,187.93). On the other hand, the ICER was 625.3% higher in the lower incidence scenario. The ICER was not sensitive to variations in hospitalization costs, hospitalization rate among infants <1 year of age, availability of PCR for diagnosis, and proportion of symptomatic cases among adults. The reduction of vaccine coverage to 20% resulted in the ICER reduction of 15.70%. In the multivariate analysis, the best scenario resulted in ICER reduction of 76.74%. By the other hand, the worst case scenario resulted in 635.05% increase in ICER. In the absence of herd protection, only adult cases would be avoided. Considering that deaths occur only among infants aged <1-year-old, adult vaccination would not prevent deaths and there would be no life-years saved. Therefore, it was not possible to calculate ICER per death avoided or LYS. The costeffectiveness ratio would be USD116,169.96/prevented case.
Table 4 Sensitivity analysis of universal adult with tetanus-diphtheria-acellular pertussis vaccine (Tdap) in Brazil, in 2015 US$.
Current practice1
Adult vaccination at 20 years
47,038
32,491
Univariates Base case
14,547 11,844 5,252 377 167 31 27,887 12,325 30.65
Low disease incidence2 High disease incidence3 Low vaccine coverage (20%) High vaccine coverage (80%) Low vaccine effectiveness (65.6%) High vaccine effectiveness (92.0%) 100% of hospitalization rate among infants Hospitalization cost (percentile 10) Hospitalization cost (percentile 90) Availability of PCR for diagnosis all over the country Symptomatic cases among infected adults – 4.5% Symptomatic cases among infected adults – 20% Multivariates Best scenario4 Worst scenario5
17,096 543
40,212
4,024,927.05
Cost per life year saved1
2,790,489.02 1,234,438.03 30.67 105,495,891.58 104,261,453.55
19,852.79 625,975.76 8,459.13
1 Current practice: no adult vaccination with Tdap, except for of pregnant woman vaccination. 2 In United States Dollars (US$) as of 2015. 3 Intervention cost includes the vaccine dose price (US$7.01), administration costs (US$1.50 per dose) and 5% vaccine wastage.
8,459.13 61,354.39 2,187.93 7,131.29 11,342.89 9,974.82 7,867.03 6,491.51 8,465.88 8,414.09 8,442.45 8,461.81 8,454.25 1,967.31 6,2178.43
1
In United States Dollars (US$) as of 2015. 2002 pertussis incidence in São Paulo State, Brazil (7.38 per 100,000). 2014 pertussis incidence in São Paulo State, Brazil (217.2 per 100,000). 4 Best scenario – High incidence, 20% of symptomatic cases among infected adults, 80% of vaccine coverage, 92.0% of vaccine effectiveness, 100% of hospitalization rate among infants, high hospitalization cost (percentile 90), and PCR available all over the country. 5 Worst scenario – Low incidence, 4.5% of symptomatic cases among infected adults, 20% of vaccine coverage, 65.6% of vaccine effectiveness, and low hospitalization cost (percentile 10). 2 3
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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5. Discussion This study evaluated the cost-effectiveness of introducing universal adult immunization with Tdap in Brazil, considering the prevention of disease among vaccinated and herd protection for other groups, particularly infants. In the base-case scenario of pertussis incidence of 53.85/100,000 among infants <1 year of age, vaccine coverage of 40% among adults aged 20 years and vaccine effectiveness 82.6%, the ICER was US$8,459.13 from the health system perspective. Brazil does not have established cost-effectiveness thresholds. According to the Center for Health Economics of York University, England, the Brazilian cost effectiveness threshold in 2015 would be US$6,233.98 [41–43]. Therefore, universal vaccination of adults with dTpa would not be a cost-effective intervention from the perspective of the health system. In the sensitivity analysis, considering the higher incidence of 2014 (peak of the 2011–2014 outbreak) and assuming the existence of herd protection, the ICER was US$2,187.93/LYS from the perspective of the health system. In this setting, Tdap adult vaccination could be considered cost-effective. Tdap pregnant women vaccination has been introduced in Brazil in November 2014, and achieved coverage of 61% in São Paulo State in 2015, reference year of this study [24]. This is the only study that evaluated the vaccination of adults in a population in which a pregnant women vaccination program has already been introduced. Most previous studies that evaluated vaccination of adolescents or adults used dynamic model and included herd protection [17,18,20–22,44–49]. Considering that severe cases and deaths happen mostly among infants and adults are the main source of infection for infants [3,13–16,50,51], vaccinating adults would have better performance if this strategy results in herd protection and prevent cases in infants under one year of age [52]. In 2015, 339 pertussis cases in infants < 1 year of age and 56 cases in adults from 20 to < 40 years were reported in São Paulo State, corresponding to incidence of 53.85 and 0.18/100,000, respectively. The reported adults pertussis cases do not represent the total number of infected or symptomatic cases in this age group. Adult cases are mostly asymptomatic [11] or the disease is mild with nonspecific symptoms [28,53]. Few symptomatic adults seek health services and, frequently, the diagnosis is not made. Underreporting among infants is supposed to be smaller and pertussis incidence reported by surveillance system is assumed to be closer to the real incidence in this age group, since the disease is more typical and severe in this age group. To overcome pertussis underreporting among adults we used the number of infant cases to estimate the force of infection in adults, assuming that each infant case results from the transmission of an infected adult. Our model resulted in a number of infected adults by B. pertussis 178 times higher than reported by the surveillance system [23]. Underreporting is a challenge for all economic study of Tdap for adolescents and adults [52]. Previous economic evaluations of adolescents and adults Tdap vaccination used different approaches to account for pertussis underreporting in these age groups [17,21,45–47]. Some cost-effectiveness studies have multiplied the official incidence among adolescents or adults recorded by surveillance by a correction factor that ranged from 2.5 to 600 [52]. Serological survey, capture and recapture studies, enhanced surveillance data and assumptions by the authors were sources for the correction factors [52]. The largest corrections (from 200 to 660 times) were based on a serological survey in the general (non-symptomatic) population aged from 3 to 70 years in the Netherlands [54]. Minor correction factors (up to 9 times) resulted from serological investigations among symptomatic patients,
intensified surveillance using serology and corrections assumed by the authors. Correcting underreporting impacted the results of economic studies, favoring vaccination strategies [17,21,45–47,52]. Despite the correction, the number of infected adults resulted from our model may be underestimated. First, infant pertussis incidence used in the model may be underestimated. SINAN-SP database recorded 339 confirmed cases in infants < 1 year of age, in 2015, but 2,852 suspected cases was recorded in the same year. Pertussis diagnosis is often not made because of the long time of symptoms, errors in the collection of oropharynx swab for tests and previous antibiotics use [53]. In our model, underestimating pertussis incidence in infants would lead to underestimation of the force of infection in adults. Second, the force of pertussis infection among adults may be higher than the force of infection in transmission among adults and infants. Finally, other age groups participated in the dynamics of the disease, but were not included in the model, which favored the economic performance of vaccination strategy. In Brazil, whooping cough surveillance is not homogeneous, since the diagnostic tests are not standardized throughout the country. While PCR and culture are used in three states for diagnosis only culture is used in the rest of the country. We chose São Paulo state data due to easier access and greater homogeneity of information. However, it may have overestimated disease incidence and positively impacted the economic performance of vaccination. We assumed that 10% of infected adults manifest symptoms, and 8.89% of these would seek health care. In our dynamic model, even asymptomatic or mild cases contribute to disease transmission. Other Tdap economic evaluations using dynamic models also considered the contribution of asymptomatic cases in disease transmission [20–22,45,55]. However, most of previous studies considered costs with health services or products for all infected adolescents and adults [17–19,46,47,56]. This assumption may have overestimated the total disease cost, favoring the economic performance of vaccination strategies, which partly justifies the favorable results found in most economic evaluations of adult and adolescents Tdap vaccination. Based on the estimated number of cases in adults aged 20 to < 40 years who would seek health care in our model (368 cases) and the number of cases reported by surveillance (212 cases), underreporting of adults cases was 57.6% in our model [23]. The number derived from the model may be underestimated, considering the difficulty in pertussis diagnosis. In sensitivity analysis, increasing the proportion of symptomatic among infected adults from 10% to 20% did not have a significant impact on ICER. This is due to the low importance of the adult cases on the total cost of the disease. In our base case analysis, we assumed adults Tdap vaccination coverage of 40%. According to MoH, in Brazil, Td coverage among adults is about 30%. Vaccination coverage among adolescents and adults is low for most vaccines in most countries. In the United States, Tdap vaccine coverage among adults aged 19–64 years was 24.7%, in 2014–2015 [57]. In Europe, adults dT vaccine coverage ranged from 61% to 74%, in 2010–2011 [7]. Some economic evaluations of adolescents and adults overestimated vaccine coverage, reaching 96%, which contributed to the good performance of the strategies [52]. The cost of pertussis cases in infants were based on another cost-effectiveness study of pregnant women vaccination with Tdap performed in Brazil [58]. There is no information system that organizes data on the use of outpatient or emergency health care services in Brazil. Therefore, the use of health services by mild cases (outpatient) was assumed by the authors, based on experts opinion. The choices made for the adult cases were supported by data
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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collection on adult pertussis cases cared in a specialized Public Hospital (IIER) in São Paulo city. Due to the lack of data on hospitalization costs in the private health system (accounting for approximately 21.4% of all hospital admissions of infants), the average reimbursement value paid by the public health system (SUS) was assumed for hospitalizations in the private system. In the same way, outpatient care costs estimates for SUS were used for the private system. Since the costs tend to be lower in the public system, direct costs of disease might have been underestimated. This is also a conservative approach, against vaccine incorporation. The hospitalization costs in the private health system was not included in the sensitivity analysis. However, variation of hospitalization costs in the sensitivity analysis did not result in significant increase in the ICERs. Surveillance costs are not often considered in economic evaluations of Tdap. We identified eight studies that included the public health response costs [46,47,58–63]. Epidemiological investigation of household contacts, laboratory testing and prophylactic treatment of symptomatic contacts is an important component of costs. Adult Tdap vaccination has been shown to be effective in reducing the incidence of the disease in vaccinated populations [64]. However, protection conferred by acellular vaccines is short and does not prevent colonization by Bordetella pertussis and its transmission. While natural infection and immunization with whole cell pertussis vaccines result in Th1 and Th17 responses, immunization with acellular vaccines results in a Th2 response [65]. Th17 response plays a critical role in mucosal immunity and host defense against various pathogens [65]. An animal model study showed that although acellular vaccines block the occurrence of symptoms, they do not block nasopharynx Bordetella pertussis colonization, allowing bacteria transmission from vaccinated, infected and asymptomatic individuals to non-immunized persons [65]. Therefore, acellular vaccines do not result in herd protection. In the sensitivity analysis, in the absence of herd protection, no infant case would be avoided and, consequently, no death would be avoided and no life year would be saved. In this scenario, one case of adult pertussis prevented would cost US$116,169.96. New and safe vaccines for adults that stimulate Th1/Th17 response and induce herd protection are necessary for better performance of adults vaccination.
6. Conclusion We concluded that universal Tdap vaccination of adults aged 20 years, considering medium disease incidence scenario, vaccine coverage of 40% and effectiveness of 82.6%, and including herd protection would not be cost-effective in Brazil.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements Patrícia C. de Soárez, Ana M.C. Sartori and Hillegonda M.D. Novaes are researchers of the National Institute of Health Technology Assessment of the National Council of Technological and Scientific Development (Instituto de Avaliação de Tecnologia em Saúde – IATS/CNPq). The study was approved by the Research Ethics Committee of Medical Scholl of São Paulo University, license number 1.073.607.
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Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions EGF, AMCS, PCS, contributed to the design of the study. EGF and PCS collected or generated the data. MA and RSAN developed the model. MA, RSAN and PCS analyzed study data. EGF, AMCS and PCS interpreted study data. All authors participated in the development of this manuscript and in its critical review with important intellectual contributions. All authors had full access to the data and gave final approval before submission. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2019.09.100. References [1] Kilgore PE, Salim AM, Zervos MJ, Schmitt HJ. Pertussis: microbiology, disease, treatment, and prevention. Clin Microbiol Rev 2016;29(3):449–86. [2] Guiso N. Bordetella pertussis and pertussis vaccines. Clin Infect Dis. 2009;49 (10):1565–9. [3] Pertussis vaccines: WHO position paper - September 2015. Wkly Epidemiol Rec 2015;90(35):433–58. [4] Falleiros Arlant LH, de Colsa A, Flores D, Brea J, Avila Aguero ML, Hozbor DF. Pertussis in Latin America: epidemiology and control strategies. Exp Rev Antiinfective Therapy 2014;12(10):1265–75. [5] Tan T, Trindade E, Skowronski D. Epidemiology of pertussis. Pediatr Infect Dis J 2005;24(5 Suppl):S10–8. [6] Winter K, Glaser C, Watt J, Harriman K, Centers for Disease C, Prevention. Pertussis epidemic–California, 2014. MMWR Morb Mortal Wkly Rep. 2014;63 (48):1129–32. [7] Lee HJ, Choi JH. Tetanus-diphtheria-acellular pertussis vaccination for adults: an update. Clin Exp Vacc Res 2017;6(1):22–30. [8] Leuridan E, Hens N, Peeters N, de Witte L, Van der Meeren O, Van Damme P. Effect of a prepregnancy pertussis booster dose on maternal antibody titers in young infants. Pediatr Infect Dis J. 2011;30(7):608–10. [9] Hardy-Fairbanks AJ, Pan SJ, Decker MD, Johnson DR, Greenberg DP, Kirkland KB, et al. Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J. 2013;32(11):1257–60. [10] Munoz FM, Bond NH, Maccato M, Pinell P, Hammill HA, Swamy GK, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA 2014;311(17):1760–9. [11] Cherry JD. Adult pertussis in the pre- and post-vaccine eras: lifelong vaccineinduced immunity?. Exp Rev Vacc 2014;13(9):1073–80. [12] Pichichero ME, Casey JR. Acellular pertussis vaccines for adolescents. Pediatr Infect Dis J. 2005;24(6 Suppl):S117–26. [13] Bisgard KM, Pascual FB, Ehresmann KR, Miller CA, Cianfrini C, Jennings CE, et al. Infant pertussis: who was the source?. Pediatr Infect Dis J 2004;23 (11):985–9. [14] Wendelboe AM, Njamkepo E, Bourillon A, Floret DD, Gaudelus J, Gerber M, et al. Transmission of Bordetella pertussis to young infants. Pediatr Infect Dis J 2007;26(4):293–9. [15] Baptista PN, Magalhaes V, Rodrigues LC, Rocha MA, Pimentel AM. Source of infection in household transmission of culture-confirmed pertussis in Brazil. Pediatr Infect Dis J 2005;24(11):1027–8. [16] Berezin EN, de Moraes JC, Leite D, Carvalhanas TR, Yu AL, Blanco RM, et al. Sources of pertussis infection in young babies from Sao Paulo State, Brazil. Pediatr Infect Dis J 2014;33(12):1289–91. [17] Lee GM, Lebaron C, Murphy TV, Lett S, Schauer S, Lieu TA. Pertussis in adolescents and adults: should we vaccinate?. Pediatrics 2005;115 (6):1675–84. [18] Lee GM, Murphy TV, Lett S, Cortese MM, Kretsinger K, Schauer S, et al. Cost effectiveness of pertussis vaccination in adults. Am J Prev Med 2007;32 (3):186–93. [19] Lee GM, Riffelmann M, Wirsing von Konig CH. Cost-effectiveness of adult pertussis vaccination in Germany. Vaccine 2008;26(29–30):3673–9.
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Cost-effectiveness analysis of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil Eder Gatti Fernandes a,b,⇑, Ana Marli Christovam Sartori c,d, Patrícia Coelho de Soárez e,d, Marcos Amaku f, Raymundo Soares de Azevedo Neto f, Hillegonda Maria Dutilh Novaes e,d a
Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 2° andar, sala 2228, CEP: 01246-903 São Paulo, SP, Brazil Divisão de Imunização, Centro de Vigilância Epidemiológica ‘‘Prof. Alexandre Vranjac”, Coordenadoria de Controle de Doenças da Secretaria de Estado da Saúde de São Paulo, Av. Dr Arnaldo, 351, 6° andar, Pacaembu, CEP: 01246-000 São Paulo, SP, Brazil c Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, ICHC, 4° andar, sala 4028 Cerqueira César, CEP: 05403-000 São Paulo, SP, Brazil d Health Technology Assessment Institute (IATS), Brazil e Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, CEP: 01246-903 São Paulo, SP, Brazil f Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, CEP: 01246-903 São Paulo, SP, Brazil b
a r t i c l e
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Article history: Received 6 March 2019 Received in revised form 30 September 2019 Accepted 30 September 2019 Available online xxxx Keywords: Cost-benefit analysis Cost-effectiveness analysis Diphtheria-tetanus-acellular pertussis vaccines Pertussis vaccine Whooping cough Adult
a b s t r a c t Background: A pertussis outbreak occurred in Brazil from 2011 to 2014, despite high coverage of wholecell pertussis containing vaccines in early childhood. Infants were the most affected. This study aimed to evaluate the cost-effectiveness of introducing universal adult vaccination with Tdap into the National Immunization Program in Brazil. Methods: Economic evaluation using a dynamic model to compare two strategies: (1) universal vaccination with single dose of Tdap at 20 years of age and (2) current practice (only pregnant women pertussis vaccination). The health system perspective was adopted. Temporal horizon was 10 years. Discount rate of 5% was applied to costs and benefits. Vaccine effectiveness (VE) was obtained from a population-based observational study. Epidemiological, resource utilization and cost estimates were obtained from the Brazilian Health Information Systems. The primary outcome was cost per life year saved (LYS), based on life expectancy at birth in Brazil in 2015. Univariate and multivariate sensitivity analysis were performed. Results: Adult vaccination with VE of 82.6% and coverage of 40%, at price of US$7.01 per dose, and assuming herd protection would avoid 167 infant deaths by pertussis, saving 12,325 years of life and costing a total of US$105495891.61, from the health system perspective. The universal immunization would result in ICER of US$8459.13. The results were highly sensitive to disease incidence. Conclusions: The results suggest that universal adult vaccination with Tdap would not be a cost-effective intervention for preventing pertussis cases and deaths in infants in Brazil. Ó 2019 Elsevier Ltd. All rights reserved.
Abbreviations: AE, adverse events; ICER, incremental cost-effectiveness ratio; IBGE, Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Estatística e Geografia); IIER, Instituto de Infectologia Emílio Ribas; LYS, life year saved; MoH, Ministry of Health; NIP, National Immunization Program; R$, Brazilian Reais; SIH-SUS, Hospital Information System database; SINAN, Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação); SINASC, Live Birth Information System (Sistema de Informações sobre Nascidos Vivos); SP, São Paulo State; SUS, Sistema Único de Saúde; Td, tetanus – diphtheria vaccine; Tdap, reduced diphtheria toxoid, acellular pertussis vaccine; US$, United States Dollar; VE, Vaccine effectiveness. ⇑ Corresponding author at: Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 2◦andar, sala 2228, CEP: 01246-903 São Paulo, SP, Brazil. E-mail addresses: [email protected] (E.G. Fernandes), [email protected] (A.M.C. Sartori), [email protected] (P.C. de Soárez), [email protected] (M. Amaku), [email protected] (R.S. de Azevedo Neto), [email protected] (H.M.D. Novaes). https://doi.org/10.1016/j.vaccine.2019.09.100 0264-410X/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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1. Introduction Pertussis is a highly contagious respiratory disease mainly caused by Bordetella pertussis [1,2]. It causes uncontrollable violent coughing for long periods, most commonly affects infants and young children and can be fatal, especially in infants under 6 months of age [1]. The introduction of childhood immunization with pertussis containing vaccines led to important reduction in pertussis incidence in countries that achieved high vaccine coverage, even though the disease has never disappeared [2,3]. In the last 20 years, reemergence of pertussis has been reported in several high-income countries, despite high coverage of acellular pertussis vaccination in childhood [1,2,4–6]. Because of this, in recent years, several countries worldwide have adopted maternal immunization with tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) to protect the young infants, until they can receive their own routine primary vaccination [7]. This measure provides protection to newborns via passive transplacental transferring antibodies [8–10]. In places where most children are immunized for pertussis, the bacterium circulates mainly among unprotected adolescents and adults, due to waning immunity following vaccination or infection [11,12]. Household adults are the main source of infection for infants [13–16]. Adults’ immunization with a vaccine that provides herd protection could be an additional strategy to reduce pertussis among infants [17–22]. A significant increase in pertussis incidence rates was observed in Brazil from 2011 to 2014, in spite of high coverage of childhood immunization with whole-cell pertussis containing vaccines (from 93.8 to 99.6% in these years). Pertussis incidence among infants aged <1 year was 13.8 per 100,000 in 2010, jumped to 57.67 per 100,000 in 2011, reaching 171.9 per 100,000 in 2014. From 2011 to 2014, 470 pertussis-related deaths were reported in Brazil [23]. The highest pertussis rates occurred in infants younger than 3 months, with concomitant increase in pertussis-related infant deaths, which led to a review of control strategies [24,25]. In 2014, the Brazilian Ministry of Health (MoH) recommended Tdap to women between 27th to 36th of pregnancy, in every pregnancy [24,25]. In 2017, the MoH extended the recommendation from the 20th week of pregnancy [24].
In Brazil, health technology assessments and economic evaluations have been requested by the MoH as part of the decision processes for new vaccines introduction into the National Immunization Program (NIP) since 2005. This study aimed to evaluate the cost-effectiveness of introducing universal 20-years-old adult vaccination with Tdap into the NIP in comparison to the current practice (no adult pertussis vaccination). 2. Methods This cost-effectiveness analysis adopted the health system perspective. This included direct medical costs associated with the universal vaccination program, outpatient and hospital care in both public (Sistema Único de Saúde, SUS) and private health systems, and epidemiological investigation of contacts. A single dose of Tdap administered to 20-year-old adults was compared to the current tetanus - diphtheria (Td) vaccination schedule without the pertussis component. The time horizon used in the analysis was 10 years. The costs were estimated in 2015 Brazilian Reais (R$) and are presented in June 2015 United States Dollars (US$), at the exchange rate of US $1 = R$3.10. All costs and effects are presented in disaggregated and aggregated form, and incremental cost-effectiveness ratios (ICERs) are presented for the outcomes: pertussis cases, deaths and life year saved (LYS) of children under one year of age and adults between 20 and 40 years of age. Discount rate of 5% was applied to both future costs and health benefits, as recommended by the Brazilian guidelines [26]. We conducted a literature review and used National Health Information System databases to inform model parameters. The model parameters for vaccine effectiveness, epidemiological and cost are summarized in Tables 1 and 2. 2.1. Dynamic model A dynamic model was developed using the software R (R Core Team 2019. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at
Table 1 Vaccine parameters and epidemiological data used in the base case and sensitivity analysis in the cost-effectiveness analyses of adult immunization with tetanus-diphtheriaacellular pertussis (Tdap) in Brazil. Parameter Vaccination program Vaccine coverage (%) Vaccine effectiveness (%) Wastage rate (%) Cohort <1 year 20 - <40 years Life expectancy at birth (years) Transition probabilities Pertussis incidence in infants < 1 year (/100,000) Symptomatic cases among infected people <1 year - % 20 – <40 years - % Symptomatic cases that seek health assistance <1 year - % 20 – <40 years - % Hospitalization rate <1 year 20 - <40 years Case-fatality rate <1 year - % 20 – <40 years - %
Base case
Sensitivity analysis
Source
40.0 82.6 5.0
20 – 80 65.6 – 92.0
Authors’ assumption [31,66,67] Authors’ assumption
3,017,668 67,726,893 75.5
– –
SINASC IBGE IBGE
53.85
7.38 –217.20
SINAN-SP
100 10
– 4.5 – 20.0
[11]
100 8.89 76.99 8.33 4.98 –
SINAN, IIER, authors’ assumption
100
SINAN - SP IIER SINAN - SP SINAN - SP
SINASC: Live Birth Information System (Sistema de Informações sobre Nascidos Vivos), IBGE: Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Estatística e Geografia); SINAN: Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação); IIER: Instituto de Infectologia Emílio Ribas.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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Table 2 Costs data for base case model and sensitivity analysis ranges used in cost-effectiveness analyses of adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) in Brazil. In 2015 US$. Parameter Direct medical costs Vaccine dose Administration costs Outpatient care <1 year 20 - <40 years Hospital care <1 year 20 - <40 years Pertussis laboratory diagnoses <1 year 20 - <40 year Epidemiological investigation of contacts cost1 <1 year 20 - <40 years
Base case
Sourceb
Sensitivity analysis
7.01 1.50
Brazilian NIP [58] SIGTAP, BPS
12.27 12.09 SIGTAP, BPS, SIH-SUS 311.56 299.22
291.60– 476.16 81.35– 359.59
10.56 9.23
26.55 20.27
17.07 20.99
41.04 44.69
SINAN, IAL
SINAN, IAL, author’s assumption
1
Epidemiological investigation of contacts cost includes public health professional visit, laboratory testing, and antibiotic treatment of symptomatic contacts. NIP: National Immunization Program, SIGTAP: Sistema de Gerenciamento da Tabela de Procedimentos, medicamentos e OPM do SUS, BPS: Banco de Preços em Saúde, SIH: Hospital Information System (Sistema de Informações Hospitalares do SUS), SINAN: Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação), IAL: Adolfo Lutz Institute. b
dose, and (2) current practice (no adults pertussis vaccination). The structure of the model is presented in Fig. 1 and Supplementary Material 1. 2.2. Model assumptions Considering adults as the source of infection for infants <1 year of age, an infected adult would be necessary for each infected infant. Then, the number of infected adults was estimated based on the incidence of the disease in infants <1 year of age. Vaccinating adults would reduce adults cases and, consequently, reduce pertussis transmission in the community, reducing infant cases (herd protection). We also assumed that the force of infection
Adults
among adults (ka) and among infants <1 year of age (kc) were the same. We considered the period of transmissibility of 21 days (1) and waning immunity after adult vaccination of 0.4055/year, similar to waning immunity after Tdpa vaccination of adolescents [27]. Immunity after disease would wane over 20 years [28,29]. The overall mortality rate in one year was 1/75.5, considering the life expectancy of 75.5 years in Brazil in 2015 [30]. Infants (<1 year of age) pertussis mortality (a) was 4.98% (Table 1). 2.3. Vaccine effectiveness (VE) The effective vaccine coverage (pv ) would be the assumed effectiveness of the vaccine multiplied by the vaccine coverage. VE was
Infants
Fig. 1. Dynamic model for cost-effectiveness analysis of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil. Sa – susceptible adults; Ia – infected adults; Ra – recovered adults; V a – vaccinated adults (immunized); Sc – susceptible infants; Ic – infected infants; Rc – recovered infants; ka – force of infection in adults; c – recovery rate (inverse of infectious period); xR – rate of recovered adults that become susceptible; xV – rate of vaccinated adults that become susceptible; l – rate of natural mortality in population (inverse of life expectancy)); Ka – replacement rate of the adult population; Kc – replacement rate of the infant population; a – differential mortality of pertussis in children.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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assumed as 82.6%, obtained from a population-based observational study that evaluated Tdap effectiveness after pregnant women vaccination mass immunization in São Paulo State, Brazil [31]. Vaccine coverage was assumed at 40%, considering that Td coverage among adults is lower than 50% in Brazil (not published data from Brazilian MoH). Demographic, epidemiological and disease burden estimates Data from the São Paulo State (SP) was extrapolated to the whole country. SP is the wealthiest of 27 Brazilian states and Federal District, and has a population of 43.6 million (one-fifth of Brazilian population). In 2015, SP Surveillance service reported 18% of all confirmed pertussis cases in Brazil. São Paulo State is one of the three states with PCR available for pertussis diagnosis. Considering the greater availability of health services and diagnostic tools, pertussis surveillance in the State of São Paulo may be more sensitive than the rest of the country. In the last years, pertussis incidence in the São Paulo State had the same trend as in the rest of country [24]. The population of infants aged <1 year and adults from 20 to 40 years was retrieved from the Live Birth Information System (Sistema de Informações sobre Nascidos Vivos, SINASC) and Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Estatística e Geografia, IBGE), respectively. Pertussis incidence, hospitalization and case fatality rates in infants <1 year of age was estimated based on the number of confirmed cases reported, in 2015, to the Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação, SINAN), which records data from both public and private health services. In the sensitivity analysis, we considered the lowest and the highest incidence rates reported from 2001 to 2015 in São Paulo State (2002 and 2014, respectively). Pertussis incidence among adults aged 20 to <40 years was derived from the model, while hospitalization rates for this age group was based on primary data collected on pertussis cases who sought assistance at the Emergence Room of Instituto de Infectologia Emílio Ribas (IIER), a public hospital specialized in infectious diseases (Supplementary Material 2). Most pertussis cases in adults are asymptomatic or oligosymptomatic [11]. Although these cases contribute to pertussis transmission [32], they do not lead to health care utilization or costs for the health system. We assumed that 10% of infected adults would be symptomatic [11], 8.9% of symptomatic cases would seek health care and 8.33% of symptomatic cases seeking health assistance would be hospitalized (Supplementary Material 2). 2.4. Health services utilization and costs of pertussis treatment In line with the perspective adopted, the model included the following cost components: universal vaccination program, outpatient and hospital care in both public and private health systems, and epidemiological investigation of contacts. These components capture the main costs associated with pertussis treatment. The Brazilian public health system (SUS) is responsible for 78.6% of all hospitalizations of children aged less than one year and about 75% of hospitalizations of adults aged 20–40 years for clinical reasons [33]. Due to lack of data on costs in the Brazilian private health system, we applied the same values as in the public health system for both outpatient and hospital care. Cost data are shown in Table 2 and are described in more details below. 2.5. Universal vaccination program Tdap vaccine dose price was informed by the Brazilian NIP (US $7.01). A 5% wastage rate (US$0.35) and administration cost (US
$1.50) was added to this figure, totalizing US$8.86 per vaccine dose. The base case analysis considered a single vaccine dose given at 20th year of age. Costs of adverse events (AE) following Tdap immunization have not been considered, since AE are rare and mild [34–37]. 2.6. Outpatient care The outpatient care costs, estimated by age group (<1 year-old and 20 - <40 years-old), included the cost of two medical visits, diagnostic tests (blood cell count, chest X-ray, pertussis PCR and culture), and antibiotic treatment (azithromycin). The costs of medical visits, blood cell count and chest X-ray in June 2015, were retrieved from the Sistema de Gerenciamento da Tabela de Procedimentos, medicamentos e OPM do SUS [38]. The costs of pertussis specific diagnostic tests (PCR and culture) were informed by technicians of the Adolfo Lutz Institute (São Paulo State, Brazil). 2.7. Hospital care Hospitalizations costs in SUS were obtained from Hospital Information System (SIH-SUS) database [23]. To account for the skewed distribution of hospitalization costs we used the median annual cost. In the sensitivity analysis, the costs were varied from its 10th to 90th percentiles values. It was assumed that every hospitalized case would go through an emergency room visit and perform a chest X-ray and a blood cell count before hospitalization, and have a medical outpatient visit after discharge. The value of two medical visits (pre- and post-hospitalization), a chest X-ray, blood cell count, and pertussis diagnostic tests was added to the hospitalization costs. 2.8. Pertussis laboratory diagnosis In Brazil, nasopharyngeal swabs of suspected cases are sent to public health reference laboratories for pertussis diagnostic tests. In 2015, PCR and culture were performed in three states (São Paulo, Paraná and Espírito Santo), whereas only culture was performed in the rest of the country. The mean cost of pertussis considered the proportion of cases reported in the three states with both PCR and culture available and in the rest of the country, and the cost of each test [24,39,40]. 2.9. Public health response to pertussis In Brazil, reported pertussis cases should trigger an epidemiological investigation aiming to identify the source of infection or secondary cases among household contacts. A trained public health professional visit the household, identify exposed persons with respiratory symptoms, collect nasopharyngeal swabs from symptomatic contacts, and send this material to public health reference laboratories for diagnostic. Antibiotic treatment is offered to symptomatic contacts. Data on household contacts investigation were retrieved from SINAN of São Paulo State and extrapolated to the whole country. In 2015, 70.92% of pertussis cases in infants aged <1-year-old and 77.14% of cases in adults aged 20 to <40 years reported to SINAN triggered epidemiological investigation of household contacts. An average of 1.58 and 1.59 symptomatic household contacts per case were detected among infants <1 year of age and adults, respectively. The costs of epidemiological investigation, including laboratory testing and antibiotic treatment of symptomatic contacts were estimated in US $17.07 and US$20.99 per case in infants <1 year of age and adults, respectively.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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2.10. Sensitivity analysis We performed multiple sensitivity analyses to test the influence of parameters uncertainty on the economic outcomes of this model. First, we performed univariate sensitivity analyses evaluating changes in pertussis incidence, proportion of symptomatic cases among infected adults, hospitalization rate among infants <1 year of age, treatment cost, vaccination costs, and herd protection. Secondly, multivariate sensitivity analyses (best and worst case scenarios) were performed.
hospitalizations (3,344 infants and 76 adults) and 167 infant deaths, saving 12,325 years of life. The cumulative cost of the national Tdap adult vaccination program would be US$105,495,891.61. The health system costs related to direct medical costs (outpatient and hospital care, specific laboratory diagnosis and epidemiological surveillance) would be reduced by 30.67% (from US$4,024,927.05 to US$2,790,489.02). The universal adult immunization would result in an ICER of US $8,459.13 per life year saved (LYS), from the health system perspective (Table 3).
3. Ethics 4.2. Sensitivity analysis The study was approved by the Research Ethics Committee of Medical Scholl of São Paulo University, license number 1.073.607. 4. Results 4.1. Base case analysis The base case analysis followed a hypothetic cohort of infants (<1 year) and adults aged from 20 to <40 years old for 10 years. Without 20-year-old adult’s vaccination, 414,504 pertussis infections in adults would happen, among which 41,450 would be symptomatic and 3,687 would seek health care in 10 years; 17,875 pertussis cases in infants <1 year of age and 685 deaths would occur. Assuming vaccine effectiveness of 82.6%, vaccine coverage of 40% and herd protection, the model estimated that the universal Tdap vaccination at 20th year of age would avoid 14,547 symptomatic pertussis cases (4,344 infants and 10,203 adults), 5,252 cases requiring health care (4,344 infants and 908 adults), 3,420
Table 3 Expected cumulative effects and costs (2015 US$) of universal adult immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap), in the health system perspective, 10 years after the program implementation in Brazil. Parameter
Disease impact N° of symptomatic cases among infants and adults aged 20- <40 years N° of symptomatic cases avoided N° of cases requiring health care N° of cases requiring health care avoided N° of deaths N° of deaths avoided Reduction in n° of deaths, % N° of life years lost N° of life years saved Reduction in the n° of life years lost, % Costs2 Disease treatment costs Disease treatment cost avoided Reduction in disease costs, % Vaccination program costs3 Total Incremental Cost Incremental Cost-effectiveness ratio – ICER Cost per case requiring health care avoided Cost per death avoided Cost per life year saved
Sensitivity analyses are presented in Table 4. Among the seven different varied parameters, the ICER was most sensitive to variation in disease incidence. When the model considered higher disease incidence rate, the ICER decreased 74.1% (US$8,459.13 to US $2,187.93). On the other hand, the ICER was 625.3% higher in the lower incidence scenario. The ICER was not sensitive to variations in hospitalization costs, hospitalization rate among infants <1 year of age, availability of PCR for diagnosis, and proportion of symptomatic cases among adults. The reduction of vaccine coverage to 20% resulted in the ICER reduction of 15.70%. In the multivariate analysis, the best scenario resulted in ICER reduction of 76.74%. By the other hand, the worst case scenario resulted in 635.05% increase in ICER. In the absence of herd protection, only adult cases would be avoided. Considering that deaths occur only among infants aged <1-year-old, adult vaccination would not prevent deaths and there would be no life-years saved. Therefore, it was not possible to calculate ICER per death avoided or LYS. The costeffectiveness ratio would be USD116,169.96/prevented case.
Table 4 Sensitivity analysis of universal adult with tetanus-diphtheria-acellular pertussis vaccine (Tdap) in Brazil, in 2015 US$.
Current practice1
Adult vaccination at 20 years
47,038
32,491
Univariates Base case
14,547 11,844 5,252 377 167 31 27,887 12,325 30.65
Low disease incidence2 High disease incidence3 Low vaccine coverage (20%) High vaccine coverage (80%) Low vaccine effectiveness (65.6%) High vaccine effectiveness (92.0%) 100% of hospitalization rate among infants Hospitalization cost (percentile 10) Hospitalization cost (percentile 90) Availability of PCR for diagnosis all over the country Symptomatic cases among infected adults – 4.5% Symptomatic cases among infected adults – 20% Multivariates Best scenario4 Worst scenario5
17,096 543
40,212
4,024,927.05
Cost per life year saved1
2,790,489.02 1,234,438.03 30.67 105,495,891.58 104,261,453.55
19,852.79 625,975.76 8,459.13
1 Current practice: no adult vaccination with Tdap, except for of pregnant woman vaccination. 2 In United States Dollars (US$) as of 2015. 3 Intervention cost includes the vaccine dose price (US$7.01), administration costs (US$1.50 per dose) and 5% vaccine wastage.
8,459.13 61,354.39 2,187.93 7,131.29 11,342.89 9,974.82 7,867.03 6,491.51 8,465.88 8,414.09 8,442.45 8,461.81 8,454.25 1,967.31 6,2178.43
1
In United States Dollars (US$) as of 2015. 2002 pertussis incidence in São Paulo State, Brazil (7.38 per 100,000). 2014 pertussis incidence in São Paulo State, Brazil (217.2 per 100,000). 4 Best scenario – High incidence, 20% of symptomatic cases among infected adults, 80% of vaccine coverage, 92.0% of vaccine effectiveness, 100% of hospitalization rate among infants, high hospitalization cost (percentile 90), and PCR available all over the country. 5 Worst scenario – Low incidence, 4.5% of symptomatic cases among infected adults, 20% of vaccine coverage, 65.6% of vaccine effectiveness, and low hospitalization cost (percentile 10). 2 3
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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5. Discussion This study evaluated the cost-effectiveness of introducing universal adult immunization with Tdap in Brazil, considering the prevention of disease among vaccinated and herd protection for other groups, particularly infants. In the base-case scenario of pertussis incidence of 53.85/100,000 among infants <1 year of age, vaccine coverage of 40% among adults aged 20 years and vaccine effectiveness 82.6%, the ICER was US$8,459.13 from the health system perspective. Brazil does not have established cost-effectiveness thresholds. According to the Center for Health Economics of York University, England, the Brazilian cost effectiveness threshold in 2015 would be US$6,233.98 [41–43]. Therefore, universal vaccination of adults with dTpa would not be a cost-effective intervention from the perspective of the health system. In the sensitivity analysis, considering the higher incidence of 2014 (peak of the 2011–2014 outbreak) and assuming the existence of herd protection, the ICER was US$2,187.93/LYS from the perspective of the health system. In this setting, Tdap adult vaccination could be considered cost-effective. Tdap pregnant women vaccination has been introduced in Brazil in November 2014, and achieved coverage of 61% in São Paulo State in 2015, reference year of this study [24]. This is the only study that evaluated the vaccination of adults in a population in which a pregnant women vaccination program has already been introduced. Most previous studies that evaluated vaccination of adolescents or adults used dynamic model and included herd protection [17,18,20–22,44–49]. Considering that severe cases and deaths happen mostly among infants and adults are the main source of infection for infants [3,13–16,50,51], vaccinating adults would have better performance if this strategy results in herd protection and prevent cases in infants under one year of age [52]. In 2015, 339 pertussis cases in infants < 1 year of age and 56 cases in adults from 20 to < 40 years were reported in São Paulo State, corresponding to incidence of 53.85 and 0.18/100,000, respectively. The reported adults pertussis cases do not represent the total number of infected or symptomatic cases in this age group. Adult cases are mostly asymptomatic [11] or the disease is mild with nonspecific symptoms [28,53]. Few symptomatic adults seek health services and, frequently, the diagnosis is not made. Underreporting among infants is supposed to be smaller and pertussis incidence reported by surveillance system is assumed to be closer to the real incidence in this age group, since the disease is more typical and severe in this age group. To overcome pertussis underreporting among adults we used the number of infant cases to estimate the force of infection in adults, assuming that each infant case results from the transmission of an infected adult. Our model resulted in a number of infected adults by B. pertussis 178 times higher than reported by the surveillance system [23]. Underreporting is a challenge for all economic study of Tdap for adolescents and adults [52]. Previous economic evaluations of adolescents and adults Tdap vaccination used different approaches to account for pertussis underreporting in these age groups [17,21,45–47]. Some cost-effectiveness studies have multiplied the official incidence among adolescents or adults recorded by surveillance by a correction factor that ranged from 2.5 to 600 [52]. Serological survey, capture and recapture studies, enhanced surveillance data and assumptions by the authors were sources for the correction factors [52]. The largest corrections (from 200 to 660 times) were based on a serological survey in the general (non-symptomatic) population aged from 3 to 70 years in the Netherlands [54]. Minor correction factors (up to 9 times) resulted from serological investigations among symptomatic patients,
intensified surveillance using serology and corrections assumed by the authors. Correcting underreporting impacted the results of economic studies, favoring vaccination strategies [17,21,45–47,52]. Despite the correction, the number of infected adults resulted from our model may be underestimated. First, infant pertussis incidence used in the model may be underestimated. SINAN-SP database recorded 339 confirmed cases in infants < 1 year of age, in 2015, but 2,852 suspected cases was recorded in the same year. Pertussis diagnosis is often not made because of the long time of symptoms, errors in the collection of oropharynx swab for tests and previous antibiotics use [53]. In our model, underestimating pertussis incidence in infants would lead to underestimation of the force of infection in adults. Second, the force of pertussis infection among adults may be higher than the force of infection in transmission among adults and infants. Finally, other age groups participated in the dynamics of the disease, but were not included in the model, which favored the economic performance of vaccination strategy. In Brazil, whooping cough surveillance is not homogeneous, since the diagnostic tests are not standardized throughout the country. While PCR and culture are used in three states for diagnosis only culture is used in the rest of the country. We chose São Paulo state data due to easier access and greater homogeneity of information. However, it may have overestimated disease incidence and positively impacted the economic performance of vaccination. We assumed that 10% of infected adults manifest symptoms, and 8.89% of these would seek health care. In our dynamic model, even asymptomatic or mild cases contribute to disease transmission. Other Tdap economic evaluations using dynamic models also considered the contribution of asymptomatic cases in disease transmission [20–22,45,55]. However, most of previous studies considered costs with health services or products for all infected adolescents and adults [17–19,46,47,56]. This assumption may have overestimated the total disease cost, favoring the economic performance of vaccination strategies, which partly justifies the favorable results found in most economic evaluations of adult and adolescents Tdap vaccination. Based on the estimated number of cases in adults aged 20 to < 40 years who would seek health care in our model (368 cases) and the number of cases reported by surveillance (212 cases), underreporting of adults cases was 57.6% in our model [23]. The number derived from the model may be underestimated, considering the difficulty in pertussis diagnosis. In sensitivity analysis, increasing the proportion of symptomatic among infected adults from 10% to 20% did not have a significant impact on ICER. This is due to the low importance of the adult cases on the total cost of the disease. In our base case analysis, we assumed adults Tdap vaccination coverage of 40%. According to MoH, in Brazil, Td coverage among adults is about 30%. Vaccination coverage among adolescents and adults is low for most vaccines in most countries. In the United States, Tdap vaccine coverage among adults aged 19–64 years was 24.7%, in 2014–2015 [57]. In Europe, adults dT vaccine coverage ranged from 61% to 74%, in 2010–2011 [7]. Some economic evaluations of adolescents and adults overestimated vaccine coverage, reaching 96%, which contributed to the good performance of the strategies [52]. The cost of pertussis cases in infants were based on another cost-effectiveness study of pregnant women vaccination with Tdap performed in Brazil [58]. There is no information system that organizes data on the use of outpatient or emergency health care services in Brazil. Therefore, the use of health services by mild cases (outpatient) was assumed by the authors, based on experts opinion. The choices made for the adult cases were supported by data
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
E.G. Fernandes et al. / Vaccine xxx (xxxx) xxx
collection on adult pertussis cases cared in a specialized Public Hospital (IIER) in São Paulo city. Due to the lack of data on hospitalization costs in the private health system (accounting for approximately 21.4% of all hospital admissions of infants), the average reimbursement value paid by the public health system (SUS) was assumed for hospitalizations in the private system. In the same way, outpatient care costs estimates for SUS were used for the private system. Since the costs tend to be lower in the public system, direct costs of disease might have been underestimated. This is also a conservative approach, against vaccine incorporation. The hospitalization costs in the private health system was not included in the sensitivity analysis. However, variation of hospitalization costs in the sensitivity analysis did not result in significant increase in the ICERs. Surveillance costs are not often considered in economic evaluations of Tdap. We identified eight studies that included the public health response costs [46,47,58–63]. Epidemiological investigation of household contacts, laboratory testing and prophylactic treatment of symptomatic contacts is an important component of costs. Adult Tdap vaccination has been shown to be effective in reducing the incidence of the disease in vaccinated populations [64]. However, protection conferred by acellular vaccines is short and does not prevent colonization by Bordetella pertussis and its transmission. While natural infection and immunization with whole cell pertussis vaccines result in Th1 and Th17 responses, immunization with acellular vaccines results in a Th2 response [65]. Th17 response plays a critical role in mucosal immunity and host defense against various pathogens [65]. An animal model study showed that although acellular vaccines block the occurrence of symptoms, they do not block nasopharynx Bordetella pertussis colonization, allowing bacteria transmission from vaccinated, infected and asymptomatic individuals to non-immunized persons [65]. Therefore, acellular vaccines do not result in herd protection. In the sensitivity analysis, in the absence of herd protection, no infant case would be avoided and, consequently, no death would be avoided and no life year would be saved. In this scenario, one case of adult pertussis prevented would cost US$116,169.96. New and safe vaccines for adults that stimulate Th1/Th17 response and induce herd protection are necessary for better performance of adults vaccination.
6. Conclusion We concluded that universal Tdap vaccination of adults aged 20 years, considering medium disease incidence scenario, vaccine coverage of 40% and effectiveness of 82.6%, and including herd protection would not be cost-effective in Brazil.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements Patrícia C. de Soárez, Ana M.C. Sartori and Hillegonda M.D. Novaes are researchers of the National Institute of Health Technology Assessment of the National Council of Technological and Scientific Development (Instituto de Avaliação de Tecnologia em Saúde – IATS/CNPq). The study was approved by the Research Ethics Committee of Medical Scholl of São Paulo University, license number 1.073.607.
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Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions EGF, AMCS, PCS, contributed to the design of the study. EGF and PCS collected or generated the data. MA and RSAN developed the model. MA, RSAN and PCS analyzed study data. EGF, AMCS and PCS interpreted study data. All authors participated in the development of this manuscript and in its critical review with important intellectual contributions. All authors had full access to the data and gave final approval before submission. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2019.09.100. References [1] Kilgore PE, Salim AM, Zervos MJ, Schmitt HJ. Pertussis: microbiology, disease, treatment, and prevention. Clin Microbiol Rev 2016;29(3):449–86. [2] Guiso N. Bordetella pertussis and pertussis vaccines. Clin Infect Dis. 2009;49 (10):1565–9. [3] Pertussis vaccines: WHO position paper - September 2015. Wkly Epidemiol Rec 2015;90(35):433–58. [4] Falleiros Arlant LH, de Colsa A, Flores D, Brea J, Avila Aguero ML, Hozbor DF. Pertussis in Latin America: epidemiology and control strategies. Exp Rev Antiinfective Therapy 2014;12(10):1265–75. [5] Tan T, Trindade E, Skowronski D. Epidemiology of pertussis. Pediatr Infect Dis J 2005;24(5 Suppl):S10–8. [6] Winter K, Glaser C, Watt J, Harriman K, Centers for Disease C, Prevention. Pertussis epidemic–California, 2014. MMWR Morb Mortal Wkly Rep. 2014;63 (48):1129–32. [7] Lee HJ, Choi JH. Tetanus-diphtheria-acellular pertussis vaccination for adults: an update. Clin Exp Vacc Res 2017;6(1):22–30. [8] Leuridan E, Hens N, Peeters N, de Witte L, Van der Meeren O, Van Damme P. Effect of a prepregnancy pertussis booster dose on maternal antibody titers in young infants. Pediatr Infect Dis J. 2011;30(7):608–10. [9] Hardy-Fairbanks AJ, Pan SJ, Decker MD, Johnson DR, Greenberg DP, Kirkland KB, et al. Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J. 2013;32(11):1257–60. [10] Munoz FM, Bond NH, Maccato M, Pinell P, Hammill HA, Swamy GK, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA 2014;311(17):1760–9. [11] Cherry JD. Adult pertussis in the pre- and post-vaccine eras: lifelong vaccineinduced immunity?. Exp Rev Vacc 2014;13(9):1073–80. [12] Pichichero ME, Casey JR. Acellular pertussis vaccines for adolescents. Pediatr Infect Dis J. 2005;24(6 Suppl):S117–26. [13] Bisgard KM, Pascual FB, Ehresmann KR, Miller CA, Cianfrini C, Jennings CE, et al. Infant pertussis: who was the source?. Pediatr Infect Dis J 2004;23 (11):985–9. [14] Wendelboe AM, Njamkepo E, Bourillon A, Floret DD, Gaudelus J, Gerber M, et al. Transmission of Bordetella pertussis to young infants. Pediatr Infect Dis J 2007;26(4):293–9. [15] Baptista PN, Magalhaes V, Rodrigues LC, Rocha MA, Pimentel AM. Source of infection in household transmission of culture-confirmed pertussis in Brazil. Pediatr Infect Dis J 2005;24(11):1027–8. [16] Berezin EN, de Moraes JC, Leite D, Carvalhanas TR, Yu AL, Blanco RM, et al. Sources of pertussis infection in young babies from Sao Paulo State, Brazil. Pediatr Infect Dis J 2014;33(12):1289–91. [17] Lee GM, Lebaron C, Murphy TV, Lett S, Schauer S, Lieu TA. Pertussis in adolescents and adults: should we vaccinate?. Pediatrics 2005;115 (6):1675–84. [18] Lee GM, Murphy TV, Lett S, Cortese MM, Kretsinger K, Schauer S, et al. Cost effectiveness of pertussis vaccination in adults. Am J Prev Med 2007;32 (3):186–93. [19] Lee GM, Riffelmann M, Wirsing von Konig CH. Cost-effectiveness of adult pertussis vaccination in Germany. Vaccine 2008;26(29–30):3673–9.
Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100
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Please cite this article as: E. G. Fernandes, A. M. C. Sartori, P. C. de Soárez et al., Cost-effectiveness analysis of universal adult immunization with tetanusdiphtheria-acellular pertussis vaccine (Tdap) versus current practice in Brazil, Vaccine, https://doi.org/10.1016/j.vaccine.2019.09.100