The Burden of Respiratory Syncytial Virus (RSV) in Germany: A Comprehensive Data Analysis Suggests Underdetection of Hospitalisations and Deaths in Adults 60 Years and Older.

INTRODUCTION: In Germany, the estimation of the disease burden of respiratory syncytial virus (RSV) in older adults is limited. This makes it challenging for public health decision-makers to develop evidence-based recommendations for newly available vaccines against RSV for individuals aged 60 years and older (60+). This study investigates publicly available data sources in Germany to address the current gaps in evidence regarding the burden of RSV. METHODS: Hospitalisation databases from the German Federal Statistical Office and national mortality statistic between 2000 and 2023, as well as regular surveillance reports from the national public health institute since 2014, were utilised to extract, combine and analyse data on RSV-related morbidity and mortality. These data were used to triangulate the age-specific burden of RSV. RESULTS: The data indicate that the number of RSV-related outpatient consultations ranges between 1,313,100 and 3,911,800 cases per season from 2014/2015 to 2022/2023 for all age groups, with approximately 13.0% of outpatient consultations occurring in adults 60+. The significant increase in hospitalisations over time suggests that heightened testing due to the coronavirus disease 2019 (COVID-19) pandemic revealed the underdetection of inpatient RSV cases in pre-pandemic seasons. In the most recent season recorded, 2022/2023, the data show 12,800 RSV-related hospitalisations in adults 60+ (24% of all RSV-related hospitalisations) and 1340 in-hospital deaths in adults 60+ (93% of all RSV-related deaths). CONCLUSION: The comparison of pre- to post-pandemic seasons strongly suggest up to a sevenfold underdetection of RSV in individuals 60+, and the analysis of in-hospital mortality reveals higher mortality rates compared with the general German mortality statistics. These findings highlight the urgent need to improve surveillance and implement targeted prevention strategies to mitigate the impact of RSV in older adults.

New Vaccine Platforms-Novel Dimensions of Economic and Societal Value and Their Measurement.

The COVID-19 pandemic's dramatic impact has been a vivid reminder that vaccines-especially in the context of infectious respiratory viruses-provide enormous societal value, well beyond the healthcare system perspective which anchors most Health Technology Assessment (HTA) and National Immunization Technical Advisory Group (NITAG) evaluation frameworks. Furthermore, the development of modified ribonucleic acid-based (mRNA-based) and nanoparticle vaccine technologies has brought into focus several new value drivers previously absent from the discourse on vaccines as public health interventions such as increased vaccine adaptation capabilities, the improved ability to develop combination vaccines, and more efficient vaccine manufacturing and production processes. We review these novel value dimensions and discuss how they might be measured and incorporated within existing value frameworks using existing methods. To realize the full potential of next-generation vaccine platforms and ensure their widespread availability across populations and health systems, it is important that value frameworks utilized by HTAs and NITAGs properly reflect the full range of benefits for population health and well-being and cost efficiencies that these new vaccines platforms provide.

Clinical impact and cost-effectiveness of the updated COVID-19 mRNA Autumn 2023 vaccines in Germany.

OBJECTIVES: To assess the potential clinical impact and cost-effectiveness of coronavirus disease 2019 (COVID-19) mRNA vaccines updated for Autumn 2023 in adults aged ≥60 years and high-risk persons aged 30-59 years in Germany over a 1-year analytic time horizon (September 2023-August 2024). METHODS: A compartmental Susceptible-Exposed-Infected-Recovered model was updated and adapted to the German market. Numbers of symptomatic infections, a number of COVID-19 related hospitalizations and deaths, costs, and quality-adjusted life-years (QALYs) gained were calculated using a decision tree model. The incremental cost-effectiveness ratio of an Autumn 2023 Moderna updated COVID-19 (mRNA-1273.815) vaccine was compared to no additional vaccination. Potential differences between the mRNA-1273.815 and the Autumn Pfizer-BioNTech updated COVID-19 (XBB.1.5 BNT162b2) vaccines, as well as societal return on investment for the mRNA-1273.815 vaccine relative to no vaccination, were also examined. RESULTS: Compared to no autumn vaccination, the mRNA-1273.815 campaign is predicted to prevent approximately 1,697,900 symptomatic infections, 85,400 hospitalizations, and 4,100 deaths. Compared to an XBB.1.5 BNT162b2 campaign, the mRNA-1273.815 campaign is also predicted to prevent approximately 90,100 symptomatic infections, 3,500 hospitalizations, and 160 deaths. Across both analyses we found the mRNA-1273.815 campaign to be dominant. CONCLUSIONS: The mRNA-1273.815 vaccine can be considered cost-effective relative to the XBB.1.5 BNT162b2 vaccine and highly likely to provide more benefits and save costs compared to no vaccine in Germany, and to offer high societal return on investment.

Epidemiology, treatment and health care resource use of patients with severe asthma in Germany - a retrospective claims data analysis.

BACKGROUND: Asthma causes various clinical symptoms, including unpredictable severe exacerbations, and even though most patients can achieve a reasonable disease control due to adequate treatment, some patients do not. This study seeks to describe healthcare resource utilization (HCRU) and treatment of asthma and severe asthma patients in Germany. METHOD: A retrospective claims data analysis has been conducted on adult asthma patients and a subset of patients with severe asthma, identified during July 2017 - June 2018. A proxy was used to identify severe asthma patients based on therapy options recommended within the German treatment guideline for treating these patients. These include (i) biologics, (ii) medium/high-dose inhaled corticosteroids (ICS) in conjunction with LABA/montelukast and antibiotics/oral corticosteroids (OCS), and (iii) long-term OCS therapy. HCRU and treatment of patients were observed during a 1-year follow-up period (July 2018 - June 2019). RESULTS: The study included 388 932 adult asthma patients (prevalence: 7.90%), with 2.51%-12.88% affected by severe asthma (depending on the definition). 22.60% of all asthma patients experienced hospitalizations (severe asthma: 36.11%). Furthermore, 13.59% received OCS (severe asthma: 39.91%), but only 0.18% (severe asthma: 1.25%) received biologics. Only 23.95% (severe asthma: 41.17%) visited a pulmonologist. CONCLUSIONS: A considerable proportion of severe asthma patients receive long-term OCS therapy. However, less than 50% have seen a pulmonologist who would typically seek a change in treatment to avoid the long-term consequences of OCS. To optimize the treatment of severe asthma in Germany, better referral of these patients to specialists is needed and considering potential treatment alternatives.

Cost-utility analysis of increasing uptake of universal seasonal quadrivalent influenza vaccine (QIV) in children aged 6 months and older in Germany.

Seasonal influenza causes many cases and related deaths in Europe annually, despite ongoing vaccination programs for older adults and people at high-risk of complications. Children have the highest risk of infection and play a key role in disease transmission. Our cost-utility analysis, based on a dynamic transmission model, estimated the impact of increasing the current vaccination coverage with inactivated quadrivalent influenza vaccine in Germany to all (healthy and high-risk) children under 5 years of age (40% uptake), or under 18 years (40% uptake), or only high-risk children under 18 years (90% uptake). Eight influenza complications were modeled, hospitalization and death rates were based on age and risk status. All three vaccination strategies provided more health benefits than the existing vaccination situation, reducing influenza cases, complications, hospitalizations and deaths across the entire population. The strategy targeting all children under 5 years was highly cost-effective (€6/quality-adjusted life-year gained, payer perspective). The other strategies were cost saving from the payer and societal perspectives. The vaccination strategy targeting all children under 18 years was estimated to provide the most health benefits (preventing on average 1.66 million cases, 179,000 complications, 14,000 hospitalizations and 3,600 deaths due to influenza annually) and the most cost savings (annually €20.5 million and €731.3 million from payer and societal perspectives, respectively). Our analysis provides policy decision-makers with evidence supporting strategies to expand childhood influenza vaccination, to directly protect children, and indirectly all other unvaccinated age groups, in order to reduce the humanistic and economic burden on healthcare systems and society.

What is the context? Every winter, millions of people in Europe become ill due to influenza (flu), and some need to be hospitalized for complications that can sometimes lead to death.While mainly older adults and people with chronic illness are at higher risk of complications from influenza, children have the highest risk of infection and of transmitting the disease.Current vaccination policies in Europe, including Germany, target older adults and high-risk populations (pregnant women, children and other age groups with chronic diseases).What is new? This analysis simulates the effects of expanding current German vaccination programs in high-risk children to include healthy children, and of increasing vaccination coverage rates, for direct protection against infection, and to reduce the disease transmission in the rest of the population.We modeled three vaccination strategies: vaccinating 40% of all (healthy and high- risk) children under 5 years old;vaccinating 40% of all (healthy and high-risk) children under 18 years old;vaccinating 90% of high-risk children under 18 years old.What is the impact? All three strategies resulted in health gains, as more influenza cases, complications and deaths were prevented in all age groups of the population compared to the current situation.The strategies targeting both healthy and high-risk children provided the greatest health benefits. In particular, a vaccination policy targeting all children under 18 years old was predicted to provide the most health benefits as well as the highest cost savings: the increased costs of vaccination were more than offset by the savings in disease management costs as a result of having fewer influenza patients.Vaccinating healthy children against influenza is expected to significantly reduce the disease burden in the total population while saving costs, due to reduced transmission of the disease.

Use of Biologic Therapies in the Treatment of Asthma - A Comparative Real World Data Analysis on Healthcare Resource Utilization and Costs Before and After Therapy Initiation.

Background: Asthma is one of the most common chronic diseases in Germany. While many patients achieve asthma control under standard therapies, some patients still experience exacerbations and persistent airway obstructions. Thus, further pharmacological treatment is needed, and biologics could fill this gap, as they have shown clinical benefit in patients with severe asthma. Therefore, this real-world study aimed to compare healthcare resource utilization (HCRU) and associated costs before and after biologic therapy initiation. Methods: A retrospective claims data analysis has been conducted on adult asthma patients who initiated a long-term biologic therapy between January 2015 and June 2018. Patients were therapy-naïve to biologics for at least 12 months. HCRU and cost incurred by patients during 12 months before and after therapy initiation were compared. Results: Overall, 571 asthma patients initiated a biologic therapy during the observational period (316 omalizumab, 232 mepolizumab, 16 benralizumab, and 7 reslizumab). Patients had a mean age of 54.86 (62.70% female), and the majority (93.70%) received at least one follow-up prescription of their index-biologic agent within one year. During baseline, patients received on average 2.75 OCS prescriptions compared to 2.17 during follow-up. Most patients received less or the same amount of OCS after therapy initiation. Moreover, hospitalizations and asthma-related sick leave days decreased significantly. The average total costs per patient were €6618.90 during baseline and €22,832.33 during follow-up. Biologics mainly drove the increase; however, hospitalization costs were reduced significantly (€2443.37 vs €1941.93; p<0.001). Conclusion: Our study demonstrates an improved asthma control due to the initiation of a biologic therapy in terms of decreased hospitalization frequency, OCS consumption, and sick leave days. However, biologics are associated with high costs for healthcare providers during the first year after initiation. Therefore, short- and long-term clinical benefits and financial burden must be considered in the overall context of healthcare.

Epidemiology and treatment of patients with Chronic rhinosinusitis with nasal polyps in Germany-A claims data study.

BACKGROUND: There are different levels of severity among patients who suffer from chronic rhinosinusitis with nasal polyps (CRSwNP). In this study, the epidemiology of CRSwNP and severe CRswNP was estimated. METHODS: A retrospective claim data analysis was conducted on adult CRSwNP patients (ICD-10: J33), and those classified as severe CRSwNP patients with inadequate disease control (based upon combinations of previous and current treatments) between 2015 and 2019. Prevalence and incidence figures were calculated and extrapolated to the German population. In addition, baseline characteristics and treatment outcomes were analysed. RESULTS: Overall, the 5-year prevalence of adult CRSwNP cases from 2015 to 2019 in Germany was 374,115 cases (about 5500 per million), with 12,989 (about 200 per million) patients being classified as severe CRSwNP with inadequate disease control, whereas 267,880 (about 3900 per million) patients were identified as having an incident CRSwNP diagnosis between 2016 and 2019. From the incident CRSwNP cohort, 80.55% had received at least one intranasal corticosteroid (INCS), 24.27% received at least 1 systemic corticosteroid (SCS), and 17.33% received at least one functional endoscopic sinus surgery (FESS) within 12 months after their incident diagnosis. CONCLUSION: Severe CRSwNP with inadequate disease control affects about 200 per million people in Germany. INCS is the first-choice treatment for most CRSwNP patients; however, for patients with severe CRSwNP, SCS are prescribed more frequently and long-term effects of these should be further investigated, especially if despite treatment, adequate disease control cannot be achieved.

Public Health Impact and Cost-Effectiveness Analysis of Routine Infant 4CMenB Vaccination in Germany to Prevent Serogroup B Invasive Meningococcal Disease.

INTRODUCTION: Invasive meningococcal disease (IMD) is an uncommon, severe, life-threatening disease primarily affecting infants, with potential lifelong sequelae. Neisseria meningitidis (Nm) serogroup B (MenB) causes most IMD cases in Germany, many of which can be prevented with four-component MenB (4CMenB) vaccination. The potential public health and economic impact of introducing routine 4CMenB infant vaccination in Germany was assessed. METHODS: A dynamic transmission-based cost-effectiveness model adapted for Germany assessed the impact of infant 4CMenB universal mass vaccination (UMV) versus no vaccination. The model included the latest real-world evidence on vaccine effectiveness, the comprehensive burden of disease on patients (sequelae) and their family (quality of life impact), comprehensive German IMD costs, and vaccination uptake assumptions. RESULTS: The largest public health impact was predicted in children: a rapid decline, 5 years after UMV implementation, of 39.9% (34.7%) for MenB (all IMD) cases aged 0-4 years and 42.4% (36.8%) in infants. Over lifetime (100-year time horizon), 4CMenB could prevent 3154 MenB (3303 all IMD) cases, 291 MenB (304 all IMD) deaths and 1370 MenB (1435 all IMD) long-term sequelae. 4CMenB saved 25,878 quality-adjusted life-years (QALYs), at a cost of €188,762 per QALY gained in the base case (societal perspective including lost productivity). Scenarios including potential Nm carriage protection (enabling herd protection) or societal preferences for the prevention of severe diseases led to more cost-effective results, while a scenario excluding IMD impact beyond the patient with increased discounting of vaccination health benefits produced less cost-effective results. CONCLUSIONS: MenB IMD is a vaccine-preventable disease. This analysis for Germany can inform decision-makers on the potential impact of introducing infant 4CMenB UMV. The program is predicted to rapidly produce health benefits (reduction in child cases, deaths and sequelae) at a cost per QALY to society of around €190,000 (base case), decreasing to around €78,000 when considering societal preferences and IMD underreporting.

Invasive meningococcal disease (IMD) is an uncommon but severe infection, usually presenting as meningitis and/or sepsis, caused by the bacteria Neisseria meningitidis. Most cases occur in infants, young children and adolescents. Patients who survive the disease can develop lifelong sequelae, such as physical, neurological and psychological/behavioural problems that impact their quality of life and that of their family/caregivers. This disease can be prevented by vaccination. The use of the four-component meningococcal serogroup B vaccine (4CMenB) in countries like Germany can prevent the most common form of this disease, IMD caused by serogroup B. This study assessed the public health and economic impact of infant vaccination in Germany with 4CMenB. For this, the authors used an economic model that measured the lifetime impact of the disease on patients but also on their families. The model predicted that after 5 years of vaccination, the number of cases and deaths in infants and young children aged 0­4 years would rapidly decrease by almost 40%. Over a long-term horizon of 100 years, this number was predicted to remain stable. Due to the reduced number of cases, vaccination would also result in fewer deaths and patients with sequelae, as well as cost savings for the healthcare system and society due to the reduced loss of productivity. In conclusion, in Germany, IMD caused by serogroup B is preventable through vaccination, and the 4CMenB vaccine in German infants is predicted to rapidly reduce the disease burden, save lives and prevent healthcare costs.

Burden of Herpes Zoster in Adult Patients with Underlying Conditions: Analysis of German Claims Data, 2007-2018.

INTRODUCTION: Several chronic underlying conditions (UCs) are known to be risk factors for developing herpes zoster (HZ) and to increase the severity of HZ and its risk of recurrence. The aim of this study was to investigate the incidence and recurrence of HZ in adult patients with one or multiple UCs. METHODS: A retrospective cohort study based on claims data representing 13% of the statutory health insurance population from 2007 to 2018 in Germany was performed. Patients aged ≥ 18 years were included when at least one of the following UCs was diagnosed: asthma, chronic heart failure, chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), depression, diabetes mellitus type 1 or 2, and rheumatoid arthritis (RA). Exact matching was used to account for differences in the distribution of age and sex between the case and matched control cohorts. Multi-morbidity was considered in sensitivity analyses by analyzing patients with only one UC. RESULTS: Patients with asthma, CHD, COPD, depression, and RA had, on average, a 30% increased risk of developing acute HZ compared to patients without any UC. RA was found to have the highest odds ratio among these conditions, varying from 1.37 to 1.57 for all age groups. Patients with depression also showed a high risk of developing HZ. Analysis of recurrence indicated that patients with at least one UC in the age groups 18-49 years and 50-59 years had the highest risk for a recurrent HZ. After experiencing a first recurrence, patients, regardless of age group, had a two- to threefold higher risk for a second recurrence. CONCLUSION: This study of representative claims data shows a higher HZ incidence and recurrence frequency in patients with UCs. These results provide relevant information for national health care guidelines and disease management programs.

Shingles is caused by the reactivation of the chickenpox virus and is characterized by a painful skin rash with blisters, commonly occurring on the trunk. Underlying conditions (UCs) are conditions that persist for a long time, require ongoing medical attention, and are rarely completely cured (chronic conditions). UCs can increase the severity, the risk, and the frequency of shingles. Here, data from a large German health care insurance provider was used to investigate whether patients with one or more UCs have a higher risk for getting shingles compared to healthy people. In particular, patients with asthma, chronic heart failure, chronic obstructive pulmonary disease, coronary heart disease, depression, diabetes, and rheumatoid arthritis were investigated. The study shows that patients with asthma, coronary heart disease, chronic obstructive pulmonary disease, depression, and rheumatoid arthritis have, on average, a 30% higher risk of developing shingles, regardless of their age. The risk of developing shingles two or more times is also higher for patients with at least one UC, with those aged 18­59 experiencing an even greater risk. It was found that patients with an UC are more exposed to develop shingles and that younger patients have a higher risk of a recurrent episode. The findings provide important information for the development or adaption of national health care guidelines and shingles vaccination recommendations.

Cost-Effectiveness of Routine Childhood Vaccination Against Seasonal Influenza in Germany.

OBJECTIVES: In Germany, routine influenza vaccination with quadrivalent influenza vaccines (QIV) is recommended and reimbursed for individuals ≥60 years of age and individuals with underlying chronic conditions. The present study examines the cost-effectiveness of a possible extension of the recommendation to include strategies of childhood vaccination against seasonal influenza using QIV. METHODS: A dynamic transmission model was used to examine the epidemiological impact of different childhood vaccination strategies. The outputs were used in a health economic decision tree to calculate the costs per quality-adjusted life year (QALY) gained from a societal and a third-party payer (TPP) perspective. Strain-specific epidemiology, vaccine uptake, and vaccine efficacy data from the 10 non-pandemic seasons from 2003/2004 to 2013/2014 were used, and cost data were drawn mainly from a health insurance claims data analysis and supplemented by estimates from literature. Uncertainty is explored via scenario, deterministic, and probabilistic sensitivity analyses. RESULTS: Vaccinating 2- to 9-year-olds with QIV assuming a vaccine uptake of 40% is cost-saving with a benefit-cost ratio of 1.66 from a societal perspective and an incremental cost-effectiveness ratio of €998/QALY from a TPP perspective. Lower and higher vaccine uptakes show marginal effects, while extending the target group to 2- to 17-year-olds further increases the health benefits while still being below the willingness-to-pay (WTP) threshold. Assuming no vaccine-induced herd protection has a negative effect on the cost-effectiveness ratio, but childhood vaccination remains cost-effective. CONCLUSION: Routine childhood vaccination against seasonal influenza in Germany is most likely to be cost-saving from a societal perspective and highly cost-effective from a TPP perspective.

Epidemiology and cost of seasonal influenza in Germany - a claims data analysis.

BACKGROUND: Seasonal influenza contributes substantially to the burden of communicable diseases in Europe, especially among paediatric populations and the elderly. The aim of the present study was to estimate the incidence of seasonal influenza in Germany, the probabilities of related complications and the economic burden of influenza per case and on a population level for different age groups. METHODS: Claims data from 2012 to 2014 from > 8 million insured of a large German sick-ness fund were analysed. A matched case control study was used on a sub-sample of 100,000 influenza cases to calculate complication rates for ear infections/acute otitis media (AOM) and community-acquired pneumonia (CAP) as well as resource use and costs for seven age groups. RESULTS: Incidence of seasonal influenza varies between the years and is highest among infants and children 2 to 5 years of age. AOM is more likely in the younger age groups with up to 14% more patients in the influenza group than in the control group. CAP is more frequently observed in the younger age groups and in influenza patients 60 years and older. The manifestation of one influenza complication (AOM or CAP) significantly in-creases the occurrence of a second complication (AOM or CAP). The economic burden per case is highest in infants (€251.91) and persons over 60 years of age (€131.59). CONCLUSION: The burden of influenza is highest among infants and young children, which is also reflected in the economic burden. Influenza related costs per case are nearly double for infants compared to persons over 60 years of age.

The cost-of-illness for invasive meningococcal disease caused by serogroup B Neisseria meningitidis (MenB) in Germany.

INTRODUCTION: Invasive meningococcal disease (IMD) is a severe disease mainly affecting infants and young children. The most common serogroup causing IMD in Germany is the serogroup type B Neisseria meningitidis (MenB). The aim of the present study is to estimate the economic burden of MenB-related IMD in Germany. METHOD: A bottom-up, model-based costing approach has been used to calculate the diagnose- and age-specific yearly lifetime costs of a hypothetical cohort of MenB-related IMD cases. Direct costs contain the treatment cost for the acute phase of the disease, long-term sequelae, costs for rehabilitation, and public health response. Indirect costs are calculated for the human-capital approach and the friction-cost approach considering productivity losses of patients or parents for the acute phase and long-term sequelae. Publicly available databases from the Federal Statistical Office, the SOEP panel data set, literature, and expert opinion were used as data sources. All future costs beyond the reference year of 2015 were discounted at 3%. RESULTS: The total costs for the hypothetical cohort (343 patients) from a societal perspective are €19.6 million (€57,100/IMD case) using the friction-cost approach and €58.8 million (€171,000/IMD case) using the human-capital approach. Direct costs amount to €18.6 million or €54,300 €/case. Sequelae are responsible for 81% of the direct costs/case. DISCUSSION: The elevated costs/MenB-related IMD case reflect the severity of the disease. The total costs are sensitive to the productivity-loss estimation approach applied. MenB is an uncommon but severe disease; The costs/case reflect the severity of the disease and is within the same magnitude as for human papilloma virus infections. The available literature on sequelae is due to the uncommonness limited and heterogeneous.

Influence of demographic changes on the impact of vaccination against varicella and herpes zoster in Germany - a mathematical modelling study.

BACKGROUND: Epidemiological studies suggest that reduced exposure to varicella might lead to an increased risk for herpes zoster (HZ). Reduction of exposure to varicella is a consequence of varicella vaccination but also of demographic changes. We analyzed how the combination of vaccination programs and demographic dynamics will affect the epidemiology of varicella and HZ in Germany over the next 50 years. METHODS: We used a deterministic dynamic compartmental model to assess the impact of different varicella and HZ vaccination strategies on varicella and HZ epidemiology in three demographic scenarios, namely the projected population for Germany, the projected population additionally accounting for increased immigration as observed in 2015/2016, and a stationary population. RESULTS: Projected demographic changes alone result in an increase of annual HZ cases by 18.3% and a decrease of varicella cases by 45.7% between 1990 and 2060. Independently of the demographic scenario, varicella vaccination reduces the cumulative number of varicella cases until 2060 by approximately 70%, but also increases HZ cases by 10%. Unlike the currently licensed live attenuated HZ vaccine, the new subunit vaccine candidate might completely counteract this effect. Relative vaccine effects were consistent across all demographic scenarios. CONCLUSION: Demographic dynamics will be a major determinant of HZ epidemiology in the next 50 years. While stationary population models are appropriate for assessing vaccination impact, models incorporating realistic population structures allow a direct comparison to surveillance data and can thus provide additional input for immunization decision-making and resource planning.

Cost-effectiveness of human papillomavirus vaccination in Germany.

BACKGROUND: The aim of this study was to assess the cost-effectiveness of human papillomavirus (HPV) vaccination in addition to the current cervical cancer screening programme in Germany using a dynamic transmission model. METHODS: Based on a mathematical model simulating the transmission dynamics and the natural history of HPV infection and associated diseases (cervical intraepithelial neoplasia, cervical cancer, and genital warts), we estimated the epidemiological and economic consequences of HPV vaccination with both the quadrivalent and bivalent vaccines. In our base case analysis, we assessed the cost-effectiveness of vaccinating 12-year-old girls with a 3-dose schedule. In sensitivity analysis, we also evaluated the use of a 2-dose schedule and assessed the impact of vaccinating boys. RESULTS: From a health care payer perspective, incremental cost-effectiveness ratios (ICERs) of a 3-dose schedule were €34,249 per quality-adjusted life year (QALY) for the bivalent and €14,711 per QALY for the quadrivalent vaccine. Inclusion of indirect costs decreased ICERs by up to 40%. When adopting a health care payer perspective, ICERs of a 2-dose approach decreased to €19,450 per QALY for the bivalent and to €3645 per QALY for the quadrivalent vaccine. From a societal perspective, a 2-dose approach using the quadrivalent vaccine was a cost-saving strategy while using the bivalent vaccine resulted in an ICER of €13,248 per QALY. Irrespective of the perspective adopted, additional vaccination of boys resulted in ICERs exceeding €50,000 per QALY, except for scenarios with low coverage (20%) in girls. CONCLUSIONS: Our model results suggest that routine HPV vaccination of 12-year-old girls with three doses is likely to be cost-effective in Germany. Due to the additional impact on genital warts, the quadrivalent vaccine appeared to be more cost-effective than the bivalent vaccine. A 2-dose schedule of the quadrivalent vaccine might even lead to cost savings when adopting a societal perspective. The cost-effectiveness of additional vaccination of boys was highly dependent on the coverage in girls.

A systematic review of the health economic consequences of quadrivalent influenza vaccination.

BACKGROUND: Quadrivalent influenza vaccines (QIVs) contain antigens derived from an additional influenza type B virus as compared with currently used trivalent influenza vaccines (TIVs). This should overcome a potential reduced vaccine protection due to mismatches between TIV and circulating B viruses. In this study, we systematically reviewed the available literature on health economic evaluations of switching from TIV to QIV. Areas covered: The databases of Medline and Embase were searched systematically to identify health economic evaluations of QIV versus TIV published before September 2016.A total of sixteen studies were included, thirteen cost-effectiveness analyses and three cost-comparisons. Expert commentary: Published evidence on the cost-effectiveness of QIV suggests that switching from TIV to QIV would be a valuable intervention from both the public health and economic viewpoint. However, more research seems mandatory. Our main recommendations for future research include: 1) more extensive use of dynamic models in order to estimate the full impact of QIV on influenza transmission including indirect effects, 2) improved availability of data on disease outcomes and costs related to influenza type B viruses, and 3) more research on immunogenicity of natural influenza infection and vaccination, with emphasis on cross-reactivity between different influenza B viruses and duration of protection.

Is the impact of childhood influenza vaccination less than expected: a transmission modelling study.

BACKGROUND: To reduce the burden of severe influenza, most industrialized countries target specific risk-groups with influenza vaccines, e.g. the elderly or individuals with comorbidities. Since children are the main spreaders, some countries have recently implemented childhood vaccination programs to reduce overall virus transmission and thereby influenza disease in the whole population. The introduction of childhood vaccination programs was often supported by modelling studies that predicted substantial incidence reductions. We developed a mathematical transmission model to examine the potential impact of childhood influenza vaccination in Germany, while also challenging established modelling assumptions. METHODS: We developed an age-stratified SEIR-type transmission model to reproduce the epidemic influenza seasons between 2003/04 and 2013/14. The model was built upon German population counts, contact patterns, and vaccination history and was fitted to seasonal data on influenza-attributable medically attended acute respiratory infections (I-MAARI) and strain distribution using Bayesian methods. As novelties we (i) implemented a stratified model structure enabling seasonal variability and (ii) deviated from the commonly assumed mass-action-principle by employing a phenomenological transmission rate. RESULTS: According to the model, by vaccinating primarily the elderly over ten seasons 4 million (95% prediction interval: 3.84 - 4.19) I-MAARI were prevented which corresponds to an 8.6% (8.3% - 8.9%) reduction compared to a no-vaccination scenario and a number-needed-to-vaccinate (NNV) to prevent one I-MAARI of 37.1 (35.5 - 38.7). Additional vaccination of 2-10 year-old children at 40% coverage would have led to an overall I-MAARI reduction of 17.8% (17.1 - 18.7%) mostly due to indirect effects with a NNV of 20.7 (19.6 - 21.6). When employing the traditional mass-action-principle, the model predicted a more than 3-fold higher I-MAARI reduction (55.6%) due to childhood vaccination. CONCLUSION: In Germany, the introduction of routine childhood influenza vaccination could considerably reduce I-MAARI among all age-groups and improve the NNV. However, the predicted impact is much lower compared to previous studies, which is primarily caused by our phenomenological approach to modelling influenza virus transmission.

Epidemiological impact and cost-effectiveness of universal vaccination with Bexsero(®) to reduce meningococcal group B disease in Germany.

Bexsero, a new vaccine against serogroup B meningococcal disease (MenB), was licensed in Europe in January 2013. In Germany, Bexsero is recommended for persons at increased risk of invasive meningococcal disease, but not for universal childhood vaccination. To support decision making we adapted the independently developed model for England to the German setting to predict the potential health impact and cost-effectiveness of universal vaccination with Bexsero(®) against MenB disease. We used both cohort and transmission dynamic mathematical models, the latter allowing for herd effects, to consider the impact of vaccination on individuals aged 0-99 years. Vaccination strategies included infant and adolescent vaccination, alone or in combination, and with one-off catch-up programmes. German specific data were used where possible from routine surveillance data and the literature. We assessed the impact of vaccination through cases averted and quality adjusted life years (QALY) gained and calculated costs per QALY gained. Assuming 65% vaccine uptake and 82% strain coverage, infant vaccination was estimated to prevent 15% (34) of MenB cases over the lifetime of one birth cohort. Including herd effects from vaccination increased the cases averted by infant vaccination to 22%, with an estimated 8461 infants requiring vaccination to prevent one case. In the short term the greatest health benefit is achieved through routine infant vaccination with large-scale catch-up, which could reduce cases by 24.9% after 5 years and 27.9% after 10 years. In the long term (20+ years) policies including routine adolescent vaccination are most favourable if herd effects are assumed. Under base case assumptions with a vaccine list price of €96.96 the incremental cost-effectiveness ratio (ICER) was >€500,000 per QALY for all considered strategies. Given the current very low incidence of MenB disease in Germany, universal vaccination with Bexsero(®) would prevent only a small absolute number of cases, at a high overall cost.

Current and future effects of varicella and herpes zoster vaccination in Germany - Insights from a mathematical model in a country with universal varicella vaccination.

Varicella zoster virus (VZV) is primarily known for causing varicella in childhood, but can reactivate again as herpes zoster (HZ) after a period of latency, mainly in persons older than 50 years. Universal varicella vaccination was introduced in Germany in 2004, while HZ vaccination has not been recommended yet. We aimed to quantify the potential long-term effects of universal childhood varicella vaccination and HZ vaccination of the elderly on varicella and HZ incidence in Germany over a time horizon of 100 years, using a transmission model calibrated to pre-vaccination data and validated against early post-vaccination data. Using current vaccination coverage rates of 87% (64%) with one (two) varicella vaccine dose(s), the model predicts a decrease in varicella cases by 89% for the year 2015. In the long run, the incidence reduction will stabilize at about 70%. Under the assumption of the boosting hypothesis of improved HZ protection caused by exposure to VZV, the model predicts a temporary increase in HZ incidence of up to 20% for around 50 years. HZ vaccination of the elderly with an assumed coverage of 20% has only limited effects in counteracting this temporary increase in HZ incidence. However, HZ incidence is shown to decrease in the long-term by 58% as vaccinated individuals get older and finally reach age-classes with originally high HZ incidence. Despite substantial uncertainties around several key variables, the model's results provide valuable insights that support decision-making regarding national VZV vaccination strategies.

Methods for Health Economic Evaluation of Vaccines and Immunization Decision Frameworks: A Consensus Framework from a European Vaccine Economics Community.

BACKGROUND: Incremental cost-effectiveness and cost-utility analyses [health economic evaluations (HEEs)] of vaccines are routinely considered in decision making on immunization in various industrialized countries. While guidelines advocating more standardization of such HEEs (mainly for curative drugs) exist, several immunization-specific aspects (e.g. indirect effects or discounting approach) are still a subject of debate within the scientific community. OBJECTIVE: The objective of this study was to develop a consensus framework for HEEs of vaccines to support the development of national guidelines in Europe. METHODS: A systematic literature review was conducted to identify prevailing issues related to HEEs of vaccines. Furthermore, European experts in the field of health economics and immunization decision making were nominated and asked to select relevant aspects for discussion. Based on this, a workshop was held with these experts. Aspects on 'mathematical modelling', 'health economics' and 'decision making' were debated in group-work sessions (GWS) to formulate recommendations and/or--if applicable--to state 'pros' and 'contras'. RESULTS: A total of 13 different aspects were identified for modelling and HEE: model selection, time horizon of models, natural disease history, measures of vaccine-induced protection, duration of vaccine-induced protection, indirect effects apart from herd protection, target population, model calibration and validation, handling uncertainty, discounting, health-related quality of life, cost components, and perspectives. For decision making, there were four aspects regarding the purpose and the integration of HEEs of vaccines in decision making as well as the variation of parameters within uncertainty analyses and the reporting of results from HEEs. For each aspect, background information and an expert consensus were formulated. CONCLUSIONS: There was consensus that when HEEs are used to prioritize healthcare funding, this should be done in a consistent way across all interventions, including vaccines. However, proper evaluation of vaccines implies using tools that are not commonly used for therapeutic drugs. Due to the complexity of and uncertainties around vaccination, transparency in the documentation of HEEs and during subsequent decision making is essential.