The health and economic impact of switching vaccines in universal varicella vaccination programs using a dynamic transmission model: An Israel case study.

Currently available health economic models for varicella infection are designed to inform the cost-effectiveness of universal varicella vaccination (UVV) compared with no vaccination. However, in countries with an existing UVV program, these models cannot be used to evaluate whether to continue with the current varicella vaccine or to switch to an alternative vaccine. We developed a dynamic transmission model that incorporates the historical vaccination program to project the health and economic impact of changing vaccination strategies. We applied the model to Israel, which initiated UVV in 2008 with a quadrivalent vaccine, MMRV-GSK, and switched to MMRV-MSD in 2016. The model was calibrated to pre-vaccination incidence data before projecting the impact of the historical and future alternative vaccination strategies on the clinical burden of varicella. Total costs and QALYs lost due to varicella infections were projected to compare continuing with MMRV-MSD versus switching to MMRV-GSK in 2022. Over a 50-year time horizon, continuing with MMRV-MSD reduced varicella incidence further by 64%, reaching 35 cases per 100,000 population by 2072, versus a 136% increase in incidence with MMRV-GSK. Continuing with MMRV-MSD reduced cumulative hospitalization and outpatient cases by 48% and 58% (vs. increase of 137% and 91% with MMRV-GSK), respectively. Continuing with MMRV-MSD resulted in 139 fewer QALYs lost with total cost savings of 3% compared with switching to MMRV-GSK, from the societal perspective. In Israel, maintaining the UVV strategy with MMRV-MSD versus switching to MMRV-GSK is projected to further reduce the burden of varicella and cost less from the societal perspective.

Modeling the Impact of Exogenous Boosting and Universal Varicella Vaccination on the Clinical and Economic Burden of Varicella and Herpes Zoster in a Dynamic Population for England and Wales.

Universal varicella vaccination (UVV) in England and Wales has been hindered by its potential impact on exogenous boosting and increase in herpes zoster (HZ) incidence. We projected the impact of ten UVV strategies in England and Wales on the incidence of varicella and HZ and evaluated their cost-effectiveness over 50 years. The Maternal-Susceptible-Exposed-Infected-Recovered-Vaccinated transmission model was extended in a dynamically changing, age-structured population. Our model estimated that one- or two-dose UVV strategies significantly reduced varicella incidence (70-92%), hospitalizations (70-90%), and mortality (16-41%) over 50 years. A small rise in HZ cases was projected with UVV, peaking 22 years after introduction at 5.3-7.1% above pre-UVV rates. Subsequently, HZ incidence steadily decreased, falling 12.2-14.1% below pre-UVV rates after 50 years. At a willingness-to-pay threshold of 20,000 GBP/QALY, each UVV strategy was cost-effective versus no UVV. Frontier analysis showed that one-dose UVV with MMRV-MSD administered at 18 months is the only cost-effective strategy compared to other strategies. HZ incidence varied under alternative exogenous boosting assumptions, but most UVV strategies remained cost-effective. HZ vaccination decreased HZ incidence with minimal impact on the cost-effectiveness. Introducing a UVV program would significantly reduce the clinical burden of varicella and be cost-effective versus no UVV after accounting for the impact on HZ incidence.

Comparison of performance of varicella vaccines via infectious disease modeling.

BACKGROUND: Population-level infectious disease models for varicella require vaccine parameters, namely 'take' and 'duration of protection' (defined here as vaccine performance), to quantify the impact of vaccination. Current published models for varicella use vaccine parameters derived from various methodologies which does not allow for the direct comparison of different vaccines. METHODS: We estimated take and duration of protection using deterministic compartmental models to simulate clinical trials of one- or two-dose varicella vaccination using Varivax® (V-MSD) and Varilrix® (V-GSK). We fit different models to clinical trial data on breakthrough infections and evaluated their respective goodness-of-fit using the Akaike Information Criterion (AIC). RESULTS: Based upon the clinical trial data, we estimated that 90.3% (95% CI: 87.8-92.9%) of the cohort gained permanent protection from breakthrough varicella after the first dose of V-MSD compared to 61.7% (95% CI: 58.2-65.3%) with the first dose of V-GSK. We further estimated that a total of 97.0% (95% CI: 95.2-98.8%) and 93.8% (95% CI: 92.2-95.4%) of the cohort were permanently protected after two-doses of V-MSD and V-GSK, respectively. According to the AIC, our new model (V-MSD AIC = 92.7; V-GSK AIC = 170.3) provided a better fit than an existing model (V-MSD AIC = 108.9; V-GSK AIC = 216.1). CONCLUSIONS: The model developed fits the long-term clinical trial data on breakthrough infections for both V-MSD and V-GSK, thus, allowing for the direct comparison of vaccine performance. We estimated that a single dose of V-MSD was more likely to provide permanent protection than a single dose of V-GSK, while the protection offered by two doses was similar for both vaccines.

Health Impact and Cost-effectiveness Assessment for the Introduction of Universal Varicella Vaccination in Switzerland.

BACKGROUND: Varicella, caused by the varicella-zoster virus, is a highly contagious infectious disease with substantial health and economic burden to society. Universal varicella vaccination (UVV) is not yet recommended by the Swiss National Immunization Program, which instead recommends catch-up immunization for children, adolescents and adults 11-40 years of age who have no reliable history of varicella or are varicella-zoster virus-IgG seronegative. The objective of this study was to perform an assessment of health impact and cost-effectiveness comparing UVV with current practice and recommendations in Switzerland. METHODS: A dynamic transmission model for varicella was adapted to Switzerland comparing 2 base-case schedules (no infant vaccination and 10% coverage with infant vaccination) to 3 different UVV schedules using quadrivalent (varicella vaccine combined with measles-mumps-rubella) and standalone varicella vaccines administered at different ages. Modeled UVV coverage rates were based on current measles-mumps-rubella coverage of approximately 95% (first dose) and 90% (second dose). Direct medical costs and societal perspectives were considered, with cost and outcomes discounted and calculated over a 50-year time horizon. RESULTS: UVV would reduce the number of varicella cases by 88%-90%, hospitalizations by 62%-69% and deaths by 75%-77%. UVV would increase direct medical costs by Swiss Franc (CHF) 39-49 (US $43-54) per capita and costs from a societal perspective by CHF 32-40 (US $35-44). Incremental quality-adjusted life-years per capita increased by 0.0012-0.0014. Incremental cost-effectiveness ratios for the UVV schedules versus the base-case were CHF 31,194-35,403 (US $34,452-39,100) per quality-adjusted life-year from the direct medical cost perspective and CHF 25,245-29,552 (US $27,881-32,638) from the societal perspective. CONCLUSIONS: UVV appears highly effective and cost-effective when compared with current clinical practice and recommendations in Switzerland from both a direct medical costs perspective and societal perspective.

Budget impact analysis of multiple varicella vaccination strategies: a Mexico perspective.

A number of live-attenuated varicella vaccines are produced globally that provide protection against the varicella zoster virus. In Mexico, varicella vaccination is not included in the national immunization program and is recommended for use only in high-risk subgroups. We developed a budget impact model to estimate the impact of universal childhood immunization against varicella on the national payer system in Mexico. A scenario of no varicella vaccination was compared to scenarios with vaccination with a single dose at 13 months of age, in alignment with the existing program of immunization with the measles-mumps-rubella vaccine. Nine different vaccination scenarios were envisioned, differing by vaccine type and by coverage. Varicella cases and treatment costs of each scenario were computed in a dynamic transmission model of varicella epidemiology, calibrated to the population of Mexico. Unit costs were based on Mexico sources or were from the literature. The results indicated that each of the three vaccine types increased vaccine acquisition and administration expenditures but produced overall cost savings in each of the first 10 years of the program, due to fewer cases and reduced varicella treatment costs. A highly effective vaccine at 95% coverage produced the greatest cost savings.

Cost-effectiveness analysis of universal varicella vaccination in Turkey using a dynamic transmission model.

BACKGROUND: In 2013, Turkey introduced one-dose universal varicella vaccination (UVV) at 12 months of age. Inclusion of a second dose is being considered. METHODS: We developed a dynamic transmission model to evaluate three vaccination strategies: single dose at 12 months (1D) or second dose at either 18 months (2D-short) or 6 years of age (2D-long). Costs and utilization were age-stratified and separated into inpatient and outpatient costs for varicella and herpes zoster (HZ). We ran the model including and excluding HZ-related costs and impact of exogenous boosting. RESULTS: Five years post-introduction of UVV (1D), the projected varicella incidence rate decreases from 1,674 cases pre-vaccine to 80 cases/100,000 person-years. By 25 years, varicella incidence equilibrates at 39, 12, and 16 cases/100,000 person-years for 1D, 2D-short, and 2D-long strategies, respectively, using a highly effective vaccine. With or without including exogenous boosting impact and/or HZ-related costs and health benefits, the 1D strategy is least costly, but 2-dose strategies are cost-effective considering a willingness-to-pay threshold equivalent to the gross domestic product. The model predicted a modest increase in HZ burden during the first 20-30 years, after which time HZ incidence equilibrates at a lower rate than pre-vaccine. CONCLUSIONS: Our findings support adding a second varicella vaccine dose in Turkey, as doing so is highly cost-effective across a wide range of assumptions regarding the burden associated with varicella and HZ disease.

Correction: Modelling the effects of quadrivalent Human Papillomavirus (HPV) vaccination in Puerto Rico.

[This corrects the article DOI: 10.1371/journal.pone.0184540.].

Modelling the effects of quadrivalent Human Papillomavirus (HPV) vaccination in Puerto Rico.

BACKGROUND: No study has estimated the potential impact of Human Papillomavirus (HPV) vaccination in Puerto Rico, a population with considerable burden of HPV-related morbidities. We evaluated the health and economic impacts of implementing a vaccination strategy for females and males in Puerto Rico, with the quadrivalent HPV (HPV4) vaccine, under different vaccination scenarios. METHODS: We adapted a mathematical model which estimates the direct and indirect health benefits and costs of HPV4 vaccination in a dynamic population. The model compared three vaccination scenarios against screening only (no-vaccination) for three doses of HPV4 vaccine among individuals aged 11-15 years in Puerto Rico: 1) 34% for females and 13% for males (34%F/13%M), 2) 50% for females and 40% for males (50%F/40%M), and 3) 80% for female and 64% for male (80%F/64%M). Data specific to Puerto Rico was used. When not available, values from the United States were used. Input data consisted of demographic, behavioral, epidemiological, screening, and economic parameters. RESULTS: The model predicted decreases in: 1) HPV infection prevalence for females and males, 2) cervical intraepithelial neoplasia and cervical cancer incidence for females, 3) genital warts incidence for females and males, and 4) cervical cancer deaths among females, when various vaccination program scenarios were considered. In addition, when the vaccination percentage was increased in every scenario, the reduction was greater and began earlier. The analysis also evidenced an incremental cost effectiveness ratio (ICER) of $1,964 per quality-adjusted life year gained for the 80%F/64%M uptake scenario. CONCLUSIONS: HPV vaccine can prove its cost effectiveness and substantially reduce the burden and costs associated to various HPV-related conditions when targeted to the adequate population together with an organized HPV vaccination program.

Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models.

BACKGROUND: Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination. METHODS: We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]). FINDINGS: 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0·53 (80% UI 0·46-0·68) and 0·36 (0·28-0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0·93 (0·90-1·00) and 0·83 (0·75-1·00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0·18 (0·13-0·32) and 0·35 (0·27-0·39) for 40% coverage, and 0·07 (0·00-0·10) and 0·16 (0·01-0·25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years). INTERPRETATION: Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time. FUNDING: Canadian Institutes of Health Research.

Public Health Impact and Cost-Effectiveness of Hepatitis A Vaccination in the United States: A Disease Transmission Dynamic Modeling Approach.

OBJECTIVE: To assess the population-level impact and cost-effectiveness of hepatitis A vaccination programs in the United States. METHODS: We developed an age-structured population model of hepatitis A transmission dynamics to evaluate two policies of administering a two-dose hepatitis A vaccine to children aged 12 to 18 months: 1) universal routine vaccination as recommended by the Advisory Committee on Immunization Practices in 2006 and 2) Advisory Committee on Immunization Practices's previous regional policy of routine vaccination of children living in states with high hepatitis A incidence. Inputs were obtained from the published literature, public sources, and clinical trial data. The model was fitted to hepatitis A seroprevalence (National Health and Nutrition Examination Survey II and III) and reported incidence from the National Notifiable Diseases Surveillance System (1980-1995). We used a societal perspective and projected costs (in 2013 US $), quality-adjusted life-years, incremental cost-effectiveness ratio, and other outcomes over the period 2006 to 2106. RESULTS: On average, universal routine hepatitis A vaccination prevented 259,776 additional infections, 167,094 outpatient visits, 4781 hospitalizations, and 228 deaths annually. Compared with the regional vaccination policy, universal routine hepatitis A vaccination was cost saving. In scenario analysis, universal vaccination prevented 94,957 infections, 46,179 outpatient visits, 1286 hospitalizations, and 15 deaths annually and had an incremental cost-effectiveness ratio of $21,223/quality-adjusted life-year when herd protection was ignored. CONCLUSIONS: Our model predicted that universal childhood hepatitis A vaccination led to significant reductions in hepatitis A mortality and morbidity. Consequently, universal vaccination was cost saving compared with a regional vaccination policy. Herd protection effects of hepatitis A vaccination programs had a significant impact on hepatitis A mortality, morbidity, and cost-effectiveness ratios.

The epidemiological and economic impact of a quadrivalent human papillomavirus (hpv) vaccine in Estonia.

BACKGROUND: This analysis assessed the epidemiological and economic impact of quadrivalent human papillomavirus (HPV4: 6/11/16/18) vaccination in Estonia. METHODS: A dynamic transmission model was used to assess the epidemiological and economic impact of the routine vaccination of 12-year-old girls with a HPV4 vaccine in preventing cervical cancer, cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 and genital warts. RESULTS: The model projected that at year 100, HPV4 vaccination would lead to a reduction of HPV 16/18 related cervical cancer incidence and deaths by over 97% and the incidence of HPV 6/11 related genital warts among Estonian women and men by over 94% and 81%, respectively. The incremental cost-effectiveness ratio of the HPV4 vaccination strategy was € 4,889 per QALY gained over a time horizon of 100 years. CONCLUSIONS: Routine vaccination of 12-year-old girls with HPV4 vaccine appears to be cost-effective in Estonia, in addition to providing both short term and long term health gains.

Estimated health and economic impact of quadrivalent HPV (types 6/11/16/18) vaccination in Brazil using a transmission dynamic model.

BACKGROUND: Cervical cancer is the second most common cancer among women in Brazil. We examined the health and economic impacts of quadrivalent HPV vaccination in Brazil. METHODS: We adapted a previously developed transmission dynamic model to estimate the effectiveness of HPV vaccination on cervical cancer, cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3), CIN1, and genital warts. We evaluated following vaccination strategies: routine vaccination of 12-year-old girls and routine vaccination in combination with a catch-up vaccination of 12 to 26-year-old women. RESULTS: The model projected that the vaccination would reduce the incidence rates of HPV 6/11/16/18-related cervical cancer, CIN2/3, CIN1, and female genital warts by 94% to 98% at year 100. Routine vaccination in combination with a catch-up vaccination could prevent approximately 163,000 cases of cervical cancer, 48,000 deaths from cervical cancer, 2.3 million cases of CIN2/3, and 11.4 million genital warts in the next 50 years. The incremental cost-effectiveness ratios for female vaccination strategies ranged from R$350 to R$720 (US$219 to US$450) per quality-adjusted life year (QALY) gained. CONCLUSIONS: Our study demonstrates that quadrivalent HPV female vaccination can be a cost-effective public health intervention that can substantially reduce the burden of cervical diseases and genital warts in Brazil.