Correction: Universal varicella vaccination in Denmark: Modeling public health impact, age-shift, and cost-effectiveness.

[This corrects the article DOI: 10.1371/journal.pgph.0001743.].

Cost-effectiveness of measles and rubella elimination in low-income and middle-income countries.

BACKGROUND: Since 2000, the incidence of measles and rubella has declined as measles-rubella (MR) vaccine coverage increased due to intensified routine immunisation (RI) and supplementary immunisation activities (SIAs). The World Health Assembly commissioned a feasibility assessment of eliminating measles and rubella. The objective of this paper is to present the findings of cost-effectiveness analysis (CEA) of ramping up MR vaccination with a goal of eliminating transmission in every country. METHODS: We used projections of impact of routine and SIAs during 2018-2047 for four scenarios of ramping up MR vaccination. These were combined with economic parameters to estimate costs and disability-adjusted life years averted under each scenario. Data from the literature were used for estimating the cost of increasing routine coverage, timing of SIAs and introduction of rubella vaccine in countries. RESULTS: The CEA showed that all three scenarios with ramping up coverage above the current trend were more cost-effective in most countries than the 2018 trend for both measles and rubella. When the measles and rubella scenarios were compared with each other, the most cost-effective scenario was likely to be the most accelerated one. Even though this scenario is costlier, it averts more cases and deaths and substantially reduces the cost of treatment. CONCLUSIONS: The Intensified Investment scenario is likely the most cost-effective of the vaccination scenarios evaluated for reaching both measles and rubella disease elimination. Some data gaps on costs of increasing coverage were identified and future efforts should focus on filling these gaps.

Universal varicella vaccination in Denmark: Modeling public health impact, age-shift, and cost-effectiveness.

We modeled the long-term clinical and economic impact of two-dose universal varicella vaccination (UVV) strategies in Denmark using a dynamic transmission model. The cost-effectiveness of UVV was evaluated along with the impact on varicella (including age-shift) and herpes zoster burden. Six two-dose UVV strategies were compared to no vaccination, at either short (12/15 months) or medium (15/48 months) intervals. Monovalent vaccines (V-MSD or V-GSK) for the 1st dose, and either monovalent or quadrivalent vaccines (MMRV-MSD or MMRV-GSK) for the 2nd dose were considered. Compared to no vaccination, all two-dose UVV strategies reduced varicella cases by 94%-96%, hospitalizations by 93%-94%, and deaths by 91%-92% over 50 years; herpes zoster cases were also reduced by 9%. There was a decline in the total number of annual varicella cases in all age groups including adolescents and adults. All UVV strategies were cost-effective compared to no vaccination, with ICER values ranging from €18,228-€20,263/QALY (payer perspective) and €3,746-€5,937/QALY (societal perspective). The frontier analysis showed that a two-dose strategy with V-MSD (15 months) and MMRV-MSD (48 months) dominated all other strategies and was the most cost-effective. In conclusion, all modeled two-dose UVV strategies were projected to substantially reduce the clinical and economic burden of varicella disease in Denmark compared to the current no vaccination strategy, with declines in both varicella and zoster incidence for all age groups over a 50-year time horizon.

The Long-Term Clinical and Economic Impact of Universal Varicella Vaccination in Slovenia.

Background: Despite the substantial burden of varicella infection, Slovenia does not currently have a universal varicella vaccination (UVV) program. We modeled the long-term clinical and economic impact of implementing 2-dose UVV strategies compared with no vaccination in Slovenia. Methods: A previously published dynamic transmission model was adapted to the demographics, varicella seroprevalence, herpes zoster incidence, and contact patterns in Slovenia. Six 2-dose UVV strategies, vs no vaccination, were considered over a 50-year period, including monovalent vaccination (Varivax® [V-MSD] or Varilrix® [V-GSK]) at ages 12 and 24 months, or monovalent vaccination at 15 months followed by monovalent or quadrivalent vaccination (ProQuad® [MMRV-MSD] or Priorix- Tetra® [MMRV-GSK]) at 5.5 years. Costs, quality-adjusted life-years, and incremental cost-effectiveness ratios vs no vaccination were calculated to assess the economic impact of each strategy from payer and societal perspectives. Results: The incidence of varicella infection was estimated as 1228 per 100 000 population in the absence of UVV. Over 50 years, depending on vaccination strategy, UVV reduced varicella cases by 77% to 85% and was associated with substantial reductions in varicella deaths (39%-44%), outpatient cases (74%-82%), and hospitalizations (74%-82%). The greatest reductions were predicted with V-MSD (15 months/5.5 years) and V MSD/MMRV-MSD (15 months/5.5 years). Discussion: All 2-dose UVV strategies were cost-effective compared with no vaccination from payer and societal perspectives, with V-MSD (15 months/5.5 years) being the most favorable from both perspectives. Conclusion: Policymakers should consider implementing UVV to reduce the burden of varicella disease in Slovenia.

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.

Feasibility of measles and rubella vaccination programmes for disease elimination: a modelling study.

BACKGROUND: Marked reductions in the incidence of measles and rubella have been observed since the widespread use of the measles and rubella vaccines. Although no global goal for measles eradication has been established, all six WHO regions have set measles elimination targets. However, a gap remains between current control levels and elimination targets, as shown by large measles outbreaks between 2017 and 2019. We aimed to model the potential for measles and rubella elimination globally to inform a WHO report to the 73rd World Health Assembly on the feasibility of measles and rubella eradication. METHODS: In this study, we modelled the probability of measles and rubella elimination between 2020 and 2100 under different vaccination scenarios in 93 countries of interest. We evaluated measles and rubella burden and elimination across two national transmission models each (Dynamic Measles Immunisation Calculation Engine [DynaMICE], Pennsylvania State University [PSU], Johns Hopkins University, and Public Health England models), and one subnational measles transmission model (Institute for Disease Modeling model). The vaccination scenarios included a so-called business as usual approach, which continues present vaccination coverage, and an intensified investment approach, which increases coverage into the future. The annual numbers of infections projected by each model, country, and vaccination scenario were used to explore if, when, and for how long the infections would be below a threshold for elimination. FINDINGS: The intensified investment scenario led to large reductions in measles and rubella incidence and burden. Rubella elimination is likely to be achievable in all countries and measles elimination is likely in some countries, but not all. The PSU and DynaMICE national measles models estimated that by 2050, the probability of elimination would exceed 75% in 14 (16%) and 36 (39%) of 93 modelled countries, respectively. The subnational model of measles transmission highlighted inequity in routine coverage as a likely driver of the continuance of endemic measles transmission in a subset of countries. INTERPRETATION: To reach regional elimination goals, it will be necessary to innovate vaccination strategies and technologies that increase spatial equity of routine vaccination, in addition to investing in existing surveillance and outbreak response programmes. FUNDING: WHO, Gavi, the Vaccine Alliance, US Centers for Disease Control and Prevention, and the Bill & Melinda Gates Foundation.

Clinical and economic impact of universal varicella vaccination in Norway: A modeling study.

BACKGROUND: Norway has not implemented universal varicella vaccination, despite the considerable clinical and economic burden of varicella disease. METHODS: An existing dynamic transmission model of varicella infection was calibrated to age-specific seroprevalence rates in Norway. Six two-dose vaccination strategies were considered, consisting of combinations of two formulations each of a monovalent varicella vaccine (Varivax® or Varilrix®) and a quadrivalent vaccine against measles-mumps-rubella-varicella (ProQuad® or PriorixTetra®), with the first dose given with a monovalent vaccine at age 15 months, and the second dose with either a monovalent or quadrivalent vaccine at either 18 months, 7 or 11 years. Costs were considered from the perspectives of both the health care system and society. Quality-adjusted life-years saved and incremental cost-effectiveness ratios relative to no vaccination were calculated. A one-way sensitivity analysis was conducted to assess the impact of vaccine efficacy, price, the costs of a lost workday and of inpatient and outpatient care, vaccination coverage, and discount rate. RESULTS: In the absence of varicella vaccination, the annual incidence of natural varicella is estimated to be 1,359 per 100,000 population, and the cumulative numbers of varicella outpatient cases, hospitalizations, and deaths over 50 years are projected to be 1.81 million, 10,161, and 61, respectively. Universal varicella vaccination is projected to reduce the natural varicella incidence rate to 48-59 per 100,000 population, depending on the vaccination strategy, and to reduce varicella outpatient cases, hospitalizations, and deaths by 75-85%, 67-79%, and 75-79%, respectively. All strategies were cost-saving, with the most cost-saving as two doses of Varivax® at 15 months and 7 years (payer perspective) and two doses of Varivax® at 15 months and 18 months (societal perspective). CONCLUSIONS: All modeled two-dose varicella vaccination strategies are projected to lead to substantial reductions in varicella disease and to be cost saving compared to no vaccination in Norway.

Modeling Zika Vaccination Combined With Vector Interventions in DoD Populations.

INTRODUCTION: Zika virus (ZIKV) is a mild febrile illness generally transmitted via the bite of infected Aedes species mosquitoes, including Aedes aegypti, with the potential to cause neurological complications. Nearly 200 U.S. military installations are located within areas where Aedes mosquitos are found, putting thousands of personnel at risk for infection with ZIKV. This analysis aims to quantify the benefits of interventions, including vaccination, to decrease the risk of ZIKV on U.S. military installations. METHODS: The authors developed a dynamic transmission model to test the "effectiveness" of vaccination, personal protective measures (PPM), and mosquito control at reducing morbidity within U.S. military populations. ZIKV transmission was modeled as a compartmental susceptible-exposed-infected-recovered model tracking interactions between humans and mosquitos and incorporating seasonality of mosquito populations and the potential for herd immunity. The model included two-dose vaccination as well as symptomatic and asymptomatic infection. The model was calibrated against 2016 public health data in Puerto Rico; sensitivity analyses were performed on model parameters and interventions. RESULTS: The greatest reduction in total modeled ZIKV cases resulted from vaccination combined with mosquito control and PPM. All three interventions at their highest estimated level of efficiency reduced ZIKV cases by 99.9% over the baseline case of low-level adherence to PPM. The addition of vaccination had limited additional benefit over effective vector control and PPM since the significant lag to vaccine-induced protection limited effectiveness of vaccination. CONCLUSIONS: Given the current vaccine, the model predicted that up to 92.8% of Zika cases occurring in deployment settings over a 10-year period could be prevented by adding vaccination to current low-level PPM. Combining vaccination with other interventions can reduce cases further. A location-specific cost-benefit analysis would be a valuable contribution to outbreak control policy as it could evaluate the economic impact of the interventions versus the reduced level of illness and downtime in this setting.

Modeling the Potential Impact of Norovirus Vaccination Among DoD Forces.

INTRODUCTION: Norovirus, a contagious disease that spreads rapidly in close-quartered communities, has a debilitating effect in military settings, affecting troops' health, productivity, and mission-readiness. This research presents a model of norovirus transmission, testing the vaccination's effectiveness in military training centers. METHODS: Transmission was modeled using structured ordinary differential equations, including symptomatic and asymptomatic infection, genetic resistance, vaccination, and herd-immunity effects, within a hypothetical cohort of trainees and support staff. The modeled vaccine had an efficacy of 72%, 4 weeks after a single dose in phase 2 clinical trials. The transmission model was calibrated against data from a norovirus outbreak in a university setting. Sensitivity and uncertainty analyses were performed on 22 parameters. RESULTS: The greatest reduction in norovirus cases resulted from prophylactic environmental decontamination and vaccination of trainee and staff populations. These combined interventions prevented more than 6,800 cases of norovirus over the 10-year simulated period-a 15% reduction over the baseline scenario of no interventions. Implementing vaccination and environmental decontamination with an outbreak response threshold of 0.1%, prevented more than 5,300 infections; raising the threshold to 0.2% to 0.5% significantly reduced effectiveness. Environmental decontamination and contact reduction alone had little impact on overall norovirus cases. CONCLUSIONS: Given vaccine characteristics, the model predicted that up to 15% of norovirus cases occurring in training settings over a 10-year period could be prevented by vaccinating all trainees and staff members immediately upon arrival on-base combined with continuous environmental decontamination. There was an impact on morbidity from implementing vaccination of trainees, alone and in combination with staff members. However, vaccinating staff alone prevented few cases over the simulation period, indicating the importance of trainees in norovirus transmission. Likewise, the negligible impact of environmental decontamination or contact reduction alone highlights the importance of addressing both person-to-person and environmental transmission together to minimize illnesses and training downtime.

Modelling Risk to US Military Populations from Stopping Blanket Mandatory Polio Vaccination.

OBJECTIVES: Transmission of polio poses a threat to military forces when deploying to regions where such viruses are endemic. US-born soldiers generally enter service with immunity resulting from childhood immunization against polio; moreover, new recruits are routinely vaccinated with inactivated poliovirus vaccine (IPV), supplemented based upon deployment circumstances. Given residual protection from childhood vaccination, risk-based vaccination may sufficiently protect troops from polio transmission. METHODS: This analysis employed a mathematical system for polio transmission within military populations interacting with locals in a polio-endemic region to evaluate changes in vaccination policy. RESULTS: Removal of blanket immunization had no effect on simulated polio incidence among deployed military populations when risk-based immunization was employed; however, when these individuals reintegrated with their base populations, risk of transmission to nondeployed personnel increased by 19%. In the absence of both blanket- and risk-based immunization, transmission to nondeployed populations increased by 25%. The overall number of new infections among nondeployed populations was negligible for both scenarios due to high childhood immunization rates, partial protection against transmission conferred by IPV, and low global disease incidence levels. CONCLUSION: Risk-based immunization driven by deployment to polio-endemic regions is sufficient to prevent transmission among both deployed and nondeployed US military populations.

Impact of oral cholera vaccines in cholera-endemic countries: A mathematical modeling study.

BACKGROUND: Impact evaluation of vaccination programs is necessary for making decisions to introduce oral cholera vaccines (OCVs) in cholera-endemic countries. METHODS: We analyzed data to forecast the future global burden of cholera. We developed a mathematical model of cholera transmission in three countries as examples: Nigeria, Uganda, and Indonesia. After fitting the model, we evaluated the impact of OCVs delivered in four vaccination strategies varying by target age group and frequency of vaccination over the period of 2015-2030. RESULTS: Data suggest that the global annual incidence of cholera will increase from 3046238 in 2015 to 3787385 in 2030 with the highest burden in Asia and Africa where overall population size is large and the proportion of population with access to improved sanitation facilities is low. We estimate that OCV will reduce the cumulative incidence of cholera by half in Indonesia and >80% in Nigeria and Uganda when delivered to 1+ year olds every three years at a coverage rate of 50%, although cholera may persist through higher coverage rates (i.e., >90%). The proportion of person-to-person transmission compared to water-to-person transmission is positively correlated with higher vaccination impact in all three countries. CONCLUSIONS: Periodic OCV vaccination every three or five years can significantly reduce the global burden of cholera although cholera may persist even with high OCV coverage. Vaccination impact will likely vary depending on local epidemiological conditions including age distribution of cases and relative contribution of different transmission routes.

Computational modeling of interventions and protective thresholds to prevent disease transmission in deploying populations.

Military personnel are deployed abroad for missions ranging from humanitarian relief efforts to combat actions; delay or interruption in these activities due to disease transmission can cause operational disruptions, significant economic loss, and stressed or exceeded military medical resources. Deployed troops function in environments favorable to the rapid and efficient transmission of many viruses particularly when levels of protection are suboptimal. When immunity among deployed military populations is low, the risk of vaccine-preventable disease outbreaks increases, impacting troop readiness and achievement of mission objectives. However, targeted vaccination and the optimization of preexisting immunity among deployed populations can decrease the threat of outbreaks among deployed troops. Here we describe methods for the computational modeling of disease transmission to explore how preexisting immunity compares with vaccination at the time of deployment as a means of preventing outbreaks and protecting troops and mission objectives during extended military deployment actions. These methods are illustrated with five modeling case studies for separate diseases common in many parts of the world, to show different approaches required in varying epidemiological settings.

Global eradication of measles: an epidemiologic and economic evaluation.

BACKGROUND: Measles remains an important cause of morbidity and mortality in children in developing countries. Due to the success of the measles mortality reduction and elimination efforts thus far, the WHO has raised the question of whether global eradication of measles is economically feasible. METHODS: The cost-effectiveness of various measles mortality reduction and eradication scenarios was evaluated vis-à-vis the current mortality reduction goal in six countries and globally. Data collection on costs of measles vaccination were conducted in six countries in four regions: Bangladesh, Brazil, Colombia, Ethiopia, Tajikistan, and Uganda. The number of measles cases and deaths were projected from 2010 to 2050 using a dynamic, age-structured compartmental model. The incremental cost-effectiveness ratios were then calculated for each scenario vis a vis the baseline. RESULTS: Measles eradication by 2020 was the found to be the most cost-effective scenario, both in the six countries and globally. Eradicating measles by 2020 is projected to cost an additional discounted $7.8 billion and avert a discounted 346 million DALYs between 2010 and 2050. CONCLUSIONS: In conclusion, the study found that, compared to the baseline, reaching measles eradication by 2020 would be the most cost-effective measles mortality reduction scenario, both for the six countries and on a global basis.