Cost of Illness Analysis of Invasive Meningococcal Disease Caused by Neisseria Meningitidis Serogroup B in the Netherlands-a Holistic Approach.

INTRODUCTION: Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is a rapidly progressing, rare disease that often presents as meningitis or sepsis. It mostly affects infants and adolescents, with high fatality rates or long-term sequelae. In the Netherlands, serogroup B (MenB) is most prevalent. We aimed to estimate the economic burden of MenB-related IMD between 2015 and 2019, including direct and indirect medical costs from short- and long-term sequelae, from a societal perspective. METHODS: IMD incidence was based on laboratory-based case numbers from the Netherlands Reference Laboratory for Bacterial Meningitis (Amsterdam UMC, Amsterdam, the Netherlands); there were 74 MenB cases on average per year in the study period 2015-2019. Case-fatality rate (3.8%) and percentage of patients discharged with sequelae (46%) were derived from literature. Direct costs included treatment costs of the acute phase, long-term sequelae, and public health response. Indirect costs were calculated using the human capital (HCA) and friction costs (FCA) approaches, in which productivity losses were estimated for patients and parents during the acute and sequelae phases. Costs were discounted by 4% yearly. RESULTS: Estimated costs due to MenB IMD in an annual cohort were €3,094,199 with FCA and €9,480,764 with HCA. Direct costs amounted to €2,974,996, of which 75.2% were related to sequelae. Indirect costs related to sequelae were €52,532 with FCA and €5,220,398 with HCA. CONCLUSION: Our analysis reflects the high economic burden of MenB-related IMD in the Netherlands. Sequelae costs represent a high proportion of the total costs. Societal costs were dependent on the applied approach (FCA or HCA).

An Updated Analysis of the Impact of HPV Vaccination Based on Long-term Effectiveness in the Netherlands.

INTRODUCTION: Vaccination against human papillomavirus (HPV) is considered the most effective strategy to protect women from cervical cancer. Three HPV vaccines are currently licensed in Europe and, although they are generally supported by favorable health economic outcomes, current models fall short in predicting vaccination benefits. Here, we aim to re-evaluate the health benefits of HPV vaccination, using updated long-term effectiveness data and emphasizing quality of life losses related to pre-cancer disease and treatment. METHODS: We used a static Markov model that compared "only screening" (includes unvaccinated girls) and "vaccination" (assumes 100% vaccination coverage with the bivalent HPV vaccine). A lifetime cohort of 100,000 uninfected 12-year-old girls was included, in which the number of cases with cervical intraepithelial neoplasia grade 2 or higher/3 (CIN2+, CIN3), cervical cancer, and cervical cancer deaths per scenario were determined. Furthermore, the reduction in major excisional procedures, the preterm deliveries averted, and the related gain in quality-adjusted life years (QALYs) due to vaccination were estimated. RESULTS: The bivalent vaccine showed larger reductions in CIN2+, CIN3, cervical cancer cases, cervical cancer deaths, and major excisional treatments, after including long-term efficacy and effectiveness data, compared to previous data. Moreover, we observed an increased amount of QALYs gained due to prevention of major excisional treatment and the negative side effects related to it. CONCLUSIONS: Updated health economic models for HPV vaccination, using updated and long-term effectiveness data and including prevention of treatment-related side effects, demonstrate a substantial additional positive effect on vaccination outcomes. Indeed, extrapolation of the bivalent HPV vaccine's updated long-term effectiveness data against HPV-related cervical diseases shows that the positive effects of vaccination may be more substantial than previously estimated. There is a graphical abstract available for this article.

Cervical cancer is one of the most common cancers among women, and the most effective strategy for its prevention is vaccination against HPV infection. Several studies have predicted the benefits of vaccination; however, most of them fall short due to a lack of long-term data and treatment impact. The aim of this study is to re-evaluate the benefits of vaccination with the bivalent vaccine in the Netherlands using updated longer-term data and benefits from preventing treatment.We used a cost-effectiveness model to compare two scenarios: only screening and vaccination plus screening. We included 100,000 12-year-old girls in the model and compared the following outcomes: number of individuals with benign cervical lesions, number of individuals with cervical cancer, number of deaths, reduction in treatment after vaccination, premature births avoided after vaccination, and quality of life gains.We found that the bivalent vaccine showed larger reductions in pre-cancerous lesions (CIN2+, CIN3), cervical cancer cases, cervical cancer deaths, and major excisional treatments, compared to the results of previously published cost-effectiveness analyses when new longer-term data were included. The prevention of treatment for the lesions represents a significant added value for vaccination.Our modeling study confirms the protective effect of the bivalent vaccine on cervical cancer. Moreover, it reflects a substantial additional value of vaccination compared to the benefits of vaccination that have been shown before.

Reducing Hospital Capacity Needs for Seasonal Respiratory Infections: The Case of Switching to High-Dose Influenza Vaccine for Dutch Older Adults.

OBJECTIVES: Influenza is responsible for considerable health and economic burden every year. Especially older adults are vulnerable for influenza infection and its complications due to immunosenescence and often-underlying medical conditions. Recently, the innovative quadrivalent high-dose influenza vaccine (QIV-HD) has become available in Europe. Through its enhanced immunogenicity, QIV-HD offers improved protection for older adults against respiratory as well as cardiovascular complications. We estimated the potential impact-specifically in terms of hospital admissions and related costs-of a hypothetical past switch from QIV-Standard dose (SD) to QIV-HD in The Netherlands. METHODS: Estimates of hospitalizations for the older adults vaccinated with QIV-SD were derived from the seasons 2010/2011-2017/2018. Subsequently, the number of respiratory infections and cardiovascular complications of influenza were estimated for the year 2019/2020 for both QIV-SD and QIV-HD. To calculate the overall corresponding savings, costs for hospital complications, derived from literature, were used. RESULTS: When QIV-HD would have been used instead of QIV-SD during the season 2019/2020, an additional 220 hospitalizations would have been averted among older adults of 60 years and older in the Netherlands. This corresponds to savings of €1 219 779 (uncertainty interval: 1 089 813-1 348 549), of which 69% is attributable to cardiovascular-related hospitalizations. CONCLUSIONS: We demonstrate that a relevant improvement in influenza vaccination among older adults in The Netherlands can be achieved by switching from the current QIV-SD to QIV-HD. Not only comes a switch from QIV-SD to QIV-HD with a significant reduction in pressure on hospital capacity but also with notable cost savings.

[Rotavirus vaccination for all Dutch infants]. / Rotavirusvaccinatie voor alle jonge kinderen.

Recently, the Netherlands Health Council (HC) issued an updated advice on rotavirus vaccination. Rotavirus gastro-enteritis primarily affects young children, of whom, in the Netherlands, annually ~2700 end up in the hospital and 5-7 die. In 2017, the HC judged positively on rotavirus vaccination of young children, but also concluded that the cost-effectiveness of general vaccination was unfavorable. Yet, the HC recommended to at least vaccinate vulnerable children in specific risk-groups. Because of the corona crisis, this, however, has not materialized. Meanwhile, the Dutch Risk-group Infant Vaccination Against Rotavirus study has demonstrated that rotavirus vaccination of children in risk-groups is less effective than previously thought. Therefore, the HC now recommends rotavirus vaccination of all children. General vaccination within the Dutch NIP is expected to result in herd-immunity, such that all children, including those in risk-groups, are protected. Nonetheless, the Dutch Ministry of Health has decided to postpone implementation of rotavirus vaccination.

[Influenza vaccination: the Netherlands Health Council missed opportunities]. / De griepprik.

Older adults may suffer from severe sequelae of influenza, including not only respiratory but also cardiovascular complications. Innovative influenza vaccines, such as a high-dose vaccine, offer improved protection for the elderly population. Evidence for the enhanced effectiveness and potential cost savings of these vaccines stems from clinical trials and large observational studies, and several countries already recommend their use. Nonetheless, the Netherlands Health Council, in its recent recommendation, judges that the scientific evidence for added value of these improved vaccines is insufficient. Following the recommendation of the WHO of 2012, the council now does include pregnant women in the target groups for influenza vaccination, primarily to improve indirect protection of newborn children. However, judging that the burden of influenza disease among children is relatively modest, the council does not recommend to include healthy children, despite available evidence for favourable effectiveness and cost-effectiveness of paediatric flu vaccination with a live-attenuated vaccine.

Economic Assessment of High-Dose Versus Adjuvanted Influenza Vaccine: An Evaluation of Hospitalization Costs Based on a Cohort Study.

Two influenza vaccines are licensed in the U.S. exclusively for the 65 years and older population: a trivalent inactivated high-dose influenza vaccine (HD-IIV3) and a trivalent inactivated adjuvanted influenza vaccine (aIIV3). In a recent publication, we estimated a relative vaccine effectiveness (rVE) of HD-IIV3 vs. aIIV3 of 12% (95% CI: 3.3-20%) for influenza-related hospitalizations using a retrospective study design, but did not report the number of prevented hospitalizations nor the associated avoided cost. In this paper we report estimations for both. METHODS: Leveraging the rVE of a cohort study over two influenza seasons (2016/17 and 2017/18), we collected cost data for healthcare provided to the same study population. Vaccine costs were obtained from the Medicare pricing schedule. Our economic assessment compared cost of vaccination and hospital care for patients experiencing acute respiratory or cardiovascular illness. RESULTS: We analyzed 1.9 million HD-IIV3 and 223,793 aIIV3 recipients. Average vaccine list prices were $46.23 for HD-IIV3 and $48.26 for aIIV3. The hospitalization rates for respiratory disease in HD-IIV3 and aIIV3 recipients were 187 (95% CI: 185-189) and 212 (195-231) per 10,000 persons-years, respectively. Attributing the average cost per hospitalization of $12,652 ($12,214-$13,090) to the difference in hospitalization rates, we estimate net savings of HD-IIV3 to be $34 ($10-$62) per recipient. CONCLUSION: Pooled over two predominantly A/H3N2 respiratory seasons, vaccination with HD-IIV3 was associated with lower hospitalization rates and associated costs compared to aIIV3 in senior members of a large national managed health care company in the U.S. Reduced hospitalizations affect healthcare utilization overall, and therefore other costly health outcomes.

Requirement of respiratory support in acute bronchiolitis in infants is linked to endothelial and neutrophil activation.

BACKGROUND: Evidence shows that activation of pulmonary vascular endothelium and neutrophils are involved in the pathophysiology of acute bronchiolitis. We hypothesized that levels of markers of endothelial activation and leukocyte counts are associated with requirement and duration of respiratory support. METHODS: Thirty-four infants with bronchiolitis and eight controls were included. Nasopharyngeal swabs and blood samples were taken at admission. Serum levels of Angiopoietin (Ang)-1, Ang-2, sP-selectin, sE-selectin, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and leukocyte counts were measured. For univariate analysis, bronchiolitis cases were grouped into two groups, namely those not requiring and those requiring any form of respiratory support. To control for known risk factors for poor outcome (i.e., age, prematurity, and congenital heart disease), and for days post symptom onset, linear regression analysis was performed with duration of any type of respiratory support in days. RESULTS: Ang-2 levels, Ang-2/Ang-1 ratios, sE-selectin levels, immature neutrophil count, and neutrophil/lymphocyte ratio (NLR) were higher in acute bronchiolitis versus controls. Ang-2, and NLR levels were significantly higher, and lymphocyte counts significantly lower, in infants that required respiratory support versus those that did not. Ang-2 levels (ß: .32, 95% confidence interval [CI]: 0.19-1.19) and NLR (ß: .68, 95% CI: 0.17-1.19) were positive predictors for the duration of respiratory support. CONCLUSIONS: Markers of endothelial and neutrophil activation are associated with respiratory support for acute bronchiolitis. Admission Ang-2 levels and NLR may be promising markers to determine requirement of respiratory support and deserve further study.

Viral causes of severe acute respiratory infection in hospitalized children and association with outcomes: A two-year prospective surveillance study in Suriname.

BACKGROUND: Viruses are the most frequent cause of severe acute respiratory infection (SARI) in children. It is currently unknown whether presence of a virus, the number of viruses, or type of virus, are associated with clinical outcomes of pediatric SARI in developing countries. METHODS: Between 2012 and 2014 nasopharyngeal swabs and demographic and clinical variables were prospectively collected for surveillance of viral causes of SARI in Surinamese children within 48 hours after hospitalization. These swabs were tested for 18 respiratory viruses using a multiplex polymerase chain reaction (PCR) panel to identify the specific viral causes of SARI, unknown to the treating physicians. In post hoc analyses we evaluated if the PCR results, and demographic and clinical characteristics, were associated with course of disease, duration of respiratory support, and length of stay (LOS). RESULTS: Of a total of 316 analyzed children, 290 (92%) had one or more viruses. Rhinovirus/enterovirus (43%) and respiratory syncytial virus (34%) were most prevalent. Course of disease was mild in 234 (74%), moderate in 68 (22%), and severe in 14 (4%) children. Neither presence of a single virus, multiple viruses, or the type of virus, were different between groups. Prematurity and lower weight-for-age-z-score were independent predictors of a severe course of disease, longer duration of respiratory support, and longer LOS. CONCLUSIONS: Viruses are common causes of pediatric SARI in Suriname, yet not necessarily associated with clinical outcomes. In developing countries, demographic and clinical variables can help to identify children at-risk for worse outcome, while PCR testing may be reserved to identify specific viruses, such as influenza, in specific patient groups or during outbreaks.

Rotavirus Vaccination of Infants Delayed and Limited within the National Immunization Programme in the Netherlands: An Opportunity Lost.

In this study, we estimated the benefits of rotavirus vaccination for infants had the rotavirus vaccine been introduced in the Netherlands as of its market authorization in 2006. An age-structured, deterministic cohort model was developed to simulate different birth cohorts over a period of 15 years from 2006 until 2021, comparing both universal and targeted high-risk group vaccination to no vaccination. Different scenarios for the duration of protection (5 or 7 years) and herd immunity (only for universal vaccination) were analyzed. All birth cohorts together included 2.6 million infants, of which 7.9% were high-risk individuals, and an additional 13.2 million children between 1-15 years born prior to the first cohort in 2006. The costs and health outcomes associated with rotavirus vaccination were calculated per model scenario and discounted at 4% and 1.5%, respectively. Our analysis reveals that, had rotavirus vaccination been implemented in 2006, it would have prevented 356,800 (51% decrease) and 32,200 (5% decrease) cases of rotavirus gastroenteritis after universal and targeted vaccination, respectively. Over the last 15 years, this would have led to significant avoided costs and quality-adjusted life year losses for either vaccination strategy with the most favorable outcomes for universal vaccination. Clearly, an opportunity has been lost.

Cost-Effectiveness of Pediatric Influenza Vaccination in The Netherlands.

OBJECTIVE: This study evaluates the cost-effectiveness of extending the Dutch influenza vaccination program for elderly and medical high-risk groups to include pediatric influenza vaccination, taking indirect protection into account. METHODS: An age-structured dynamic transmission model was used that was calibrated to influenza-associated GP visits over 4 seasons (2010-2011 to 2013-2014). The clinical and economic impact of different pediatric vaccination strategies were compared over 20 years, varying the targeted age range, the vaccine type for children or elderly and high-risk groups. Outcome measures include averted symptomatic infections and deaths, societal costs and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Costs and QALYs were discounted at 4% and 1.5% annually. RESULTS: At an assumed coverage of 50%, adding pediatric vaccination for 2- to 17-year-olds with quadrivalent live-attenuated vaccine to the current vaccination program for elderly and medical high-groups with quadrivalent inactivated vaccine was estimated to avert, on average, 401 820 symptomatic cases and 72 deaths per year. Approximately half of averted symptomatic cases and 99% of averted deaths were prevented in other age groups than 2- to 17-year-olds due to herd immunity. The cumulative discounted 20-year economic impact was 35 068 QALYs gained and €1687 million saved, that is, the intervention was cost-saving. This vaccination strategy had the highest probability of being the most cost-effective strategy considered, dominating pediatric strategies targeting 2- to 6-year-olds or 2- to 12-year-olds or strategies with trivalent inactivated vaccine. CONCLUSION: Modeling indicates that introducing pediatric influenza vaccination in The Netherlands is cost-saving, reducing the influenza-related disease burden substantially.

Cost-effectiveness of hepatitis C virus screening, and subsequent monitoring or treatment among pregnant women in the Netherlands.

BACKGROUND: The prevalence of diagnosed chronic hepatitis C virus (HCV) infection among pregnant women in the Netherlands is 0.26%, yet many cases remain undiagnosed. HCV screening and treatment of pregnant HCV carriers could reduce the burden of disease and limit vertical transmission from mother to child. We assessed the impact of HCV screening and subsequent treatment with new direct-acting antivirals (DAAs) among pregnant women in the Netherlands. METHODS: An HCV natural history Markov transition state model was developed, to evaluate the public-health and economic impact of HCV screening and treatment. Besides all 179,000 pregnant women in the Netherlands (cohort 1), we modelled 3 further cohorts: all 79,000 first-time pregnant women (cohort 2), 33,000 pregnant migrant women (cohort 3) and 16,000 first-time pregnant migrant women (cohort 4). Each cohort was analyzed in various scenarios: i no intervention, i.e., the current practice, ii screen-and-treat, i.e., the most extensive approach involving treatment of all individuals found HCV-positive, and iii screen-and-treat/monitor, i.e., a strategy involving treatment of symptomatic (F1-F4) patients and follow-up of asymptomatic (F0) HCV carriers with subsequent treatment only at progression. RESULTS: For all cohorts, comparison between scenarios (ii) and (i) resulted in ICERs between €9,306 and €10,173 per QALY gained and 5 year budget impacts varying between €6,283,830 and €19,220,405. For all cohorts, comparison between scenarios (iii) and (i) resulted in ICERs between €1,739 and €2,749 per QALY gained and budget impacts varying between €1,468,670 and €5,607,556. For all cohorts, the ICERs (scenario iii versus ii) involved in delayed treatment of asymptomatic (F0) HCV carriers varied between €56,607 and €56,892, well above the willingness-to-pay (WTP) threshold of €20,000 per QALY gained and even above a threshold of €50,000 per QALY gained. CONCLUSION: Universal screening for HCV among all pregnant women in the Netherlands is cost-effective. However, it would be reasonable to consider smaller risk groups in view of the budget impact of the intervention.

Reconstructing the Effectiveness of Policy Measures to Avoid Next-Wave COVID-19 Infections and Deaths Using a Dynamic Simulation Model: Implications for Health Technology Assessment.

OBJECTIVE: The goal of this study was to dynamically model next-wave scenarios to observe the impact of different lockdown measures on the infection rates (IR) and mortality for two different prototype countries, mimicking the 1st year of the COVID-19 pandemic in Europe. METHODS: A dynamic simulation SIRD model was designed to assess the effectiveness of policy measures on four next-wave scenarios, each preceded by two different lockdowns. The four scenarios were (1) no-measures, (2) uniform measures, (3) differential measures based on isolating > 60 years of age group, and (4) differential measures with additional contact reduction measures for the 20-60 years of age group. The dynamic simulation model was prepared for two prototype European countries, Northwestern (NW) and Southern (S) country. Both prototype countries were characterized based on age composition and contact matrix. RESULTS: The results show that the outcomes of the next-wave scenarios depend on number of infections of previous lockdowns. All scenarios reduce the incremental deaths compared with a no-measures scenario. Differential measures show lower number of deaths despite an increase of infections. Additionally, prototype S shows overall more deaths compared with prototype NW due to a higher share of older citizens. CONCLUSION: This study shows that differential measures are a worthwhile option for controlling the COVID-19 epidemic. This may also be the case in situations where relevant parts of the population have taken up vaccination. Additionally, the effectiveness of interventions strongly depends on the number of previously infected individuals. The results of this study may be useful when planning and forecasting the impact of non-pharmacological interventions and vaccination campaigns.

First-in-Human Phase I Clinical Trial of an SFV-Based RNA Replicon Cancer Vaccine against HPV-Induced Cancers.

A first-in-human phase I trial of Vvax001, an alphavirus-based therapeutic cancer vaccine against human papillomavirus (HPV)-induced cancers was performed assessing immunological activity, safety, and tolerability. Vvax001 consists of replication-incompetent Semliki Forest virus replicon particles encoding HPV16-derived antigens E6 and E7. Twelve participants with a history of cervical intraepithelial neoplasia were included. Four cohorts of three participants were treated per dose level, ranging from 5 × 105 to 2.5 × 108 infectious particles per immunization. The participants received three immunizations with a 3-week interval. For immune monitoring, blood was drawn before immunization and 1 week after the second and third immunization. Immunization with Vvax001 was safe and well tolerated, with only mild injection site reactions, and resulted in both CD4+ and CD8+ T cell responses against E6 and E7 antigens. Even the lowest dose of 5 × 105 infectious particles elicited E6/E7-specific interferon (IFN)-γ responses in all three participants in this cohort. Overall, immunization resulted in positive vaccine-induced immune responses in 12 of 12 participants in one or more assays performed. In conclusion, Vvax001 was safe and induced immune responses in all participants. These data strongly support further clinical evaluation of Vvax001 as a therapeutic vaccine in patients with HPV-related malignancies.

Comparing the impact of high-dose versus standard dose influenza vaccines on hospitalization cost for cardiovascular and respiratory diseases: Economic assessment in the US Veteran population during 5 respiratory seasons using an instrumental variable method.

OBJECTIVES: Cost savings associated with high-dose (HD) as compared to standard-dose (SD) influenza vaccination in the United States (US) Veteran's Health Administration (VHA) population have been attributed to better protection against hospitalization for cardiac and respiratory diseases. The relative contribution of each of these disease categories to the reported savings remains to be explored. METHODS: During a recently completed study of HD versus SD vaccine effectiveness (conducted in the VHA over five respiratory seasons from 2010/11 through 2014/15), we collected cost data for all healthcare services provided at both VHA and Medicare-funded facilities. In that analysis, we compared the costs of vaccination and hospital care for patients admitted with either cardiovascular or respiratory disease. Treatment selection bias and other confounding factors were adjusted using an instrumental variable (IV) method. In this brief report we use the same study cohort and methods to stratify the results by patients admitted for cardiovascular disease (CVD) and those admitted for respiratory disease. RESULTS: We analyzed 3.5 million SD and 0.16 million HD person-seasons. The IV-adjusted rVEs were 14% (7-20%) against hospitalizations for CVD and 15% (5-25%) against respiratory hospitalizations. Net cost savings per HD recipient were $138 ($66-$200) for CVD related hospitalizations and $62 ($10-$107) for respiratory disease related hospitalizations. CONCLUSIONS: In the US VHA population, the reduction in hospitalizations for CVD over five respiratory seasons contributed twice the cost savings (per HD recipient) of the reduction in hospitalizations for respiratory disease.

The Cost-Effectiveness of Hepatitis C Virus Screening Strategies among Recently Arrived Migrants in the Netherlands.

OBJECTIVE: We aimed to assess the cost-effectiveness of hepatitis C virus (HCV) screening strategies among recently arrived migrants in the Netherlands. METHODS: A Markov model was used to estimate the health effects and costs of HCV screening from the healthcare perspective. A cohort of 50,000 recently arrived migrants was used. In this cohort, three HCV screening strategies were evaluated: (i) no screening, (ii) screening of migrants from HCV-endemic countries and (iii) screening of all migrants. RESULTS: Strategy (ii) screening of migrants from HCV-endemic countries compared to strategy (i) no screening, yielded an incremental cost-effectiveness ratio (ICER) of €971 per quality-adjusted life-years (QALYs) gained. Strategy (iii) screening of all migrants compared with strategy (ii) screening of migrants from HCV-endemic countries yielded an ICER of €1005 per QALY gained. The budget impact of strategy (ii) screening of migrants from HCV-endemic countries and strategy (iii) screening of all migrants was €13,752,039 and €20,786,683, respectively. CONCLUSION: HCV screening is cost-effective. However, the budget impact may have a strong influence on decision making.

[Continue to use the bivalent HPV vaccine; bivalent vaccine more effective than expected]. / Blijf het bivalente HPV-vaccin gebruiken.

It is becoming clear that there are significant differences between the two principal human papillomavirus (HPV) vaccines, namely the bivalent vaccine and the quadrivalent vaccine. Both vaccines contain HPV16 and HPV18, together responsible for approximately 73% of cases of cervical cancer. The quadrivalent vaccine also contains HPV6 and HPV11, thus protecting against genital warts. Real-world data show 89% efficacy for the bivalent vaccine against cervical intraepithelial neoplasia stage 3, irrespective of the HPV type involved, versus 64% for the quadrivalent vaccine. This suggests superior cross-reactivity of the bivalent vaccine against oncogenic HPV types not contained in the vaccine, presumably thanks to the MPLA adjuvant in the vaccine. In the Netherlands, the cross-reactivity of the bivalent vaccine may ultimately lead to a significant additional reduction of cervical cancer deaths per year. Since protection against genital warts should not be pursued at the expense of protection against cervical cancer, we recommend that the Netherlands continue to use the bivalent vaccine in its national immunisation programme.

Neutrophil-endothelial interactions in respiratory syncytial virus bronchiolitis: An understudied aspect with a potential for prediction of severity of disease.

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) causes significant morbidity and mortality among young infants worldwide. It is currently widely accepted that neutrophil influx into the airways is a hallmark of the pathophysiology. However, the exact mechanism of neutrophil migration from the vasculature into the alveolar space in RSV LRTI has received little attention. Data shows that endothelial cells become activated upon RSV infection, driving a 'pro-adhesive state' for circulating neutrophils with upregulation of endothelial intercellular adhesion molecule-1 (ICAM-1). During RSV LRTI different subsets of immature and mature neutrophils are present in the bloodstream, that upregulate integrins lymphocyte-function associated antigen (LFA)-1 and macrophage (Mac)-1, serving as ICAM-1 ligands. An alveolar gradient of interleukin-8 may serve as a potent chemoattractant for circulating neutrophils. Neutrophils from lung aspirates of RSV-infected infants show further signs of inflammatory and migratory activation, while soluble endothelial cell adhesion molecules (sCAMs), such as sICAM-1, have become measurable in the systemic circulation. Whether these mechanisms are solely responsible for neutrophil migration into the alveolar space remains under debate. However, data indicate that the currently postulated neutrophil influx into the lungs should rather be regarded as a neutrophil efflux from the vasculature, involving substantial neutrophil-endothelial interactions. Molecular patterns of these interactions may be clinically useful to predict outcomes of RSV LRTI and deserve further study.

Comparative effectiveness of high dose versus adjuvanted influenza vaccine: A retrospective cohort study.

BACKGROUND: Adults 65 years and older (seniors) experience more complications following influenza infection than younger adults. We estimated the relative vaccine effectiveness (rVE) of a trivalent high dose (HD-IIV3) versus an adjuvanted trivalent influenza vaccine (aIIV3) in seniors for respiratory-related hospitalizations. METHODS: We conducted a retrospective cohort study using claims data from Optum's Clinformatics® Data Mart to compare outcome rates between seniors who received HD-IIV3 versus aIIV3 during the 2016/17 and 2017/18, predominantly A/H3N2 respiratory seasons. Rates were adjusted for demographic characteristics, comorbid conditions, previous influenza vaccination, and geography. We used the previous event rate ratio (PERR) approach to address bias by time-fixed unmeasured confounders. RESULTS: We identified 842,282 HD-IIV3 and 34,157 aIIV3 recipients for the 2016/17 season and 1,058,638 HD-IIV3 and 189,636 aIIV3 recipients for the 2017/18 season. The pooled rVE of HD-IIV3 versus aIIV3 for respiratory-related hospitalizations over both seasons was 12% (95% confidence interval: 3.3%-20%); 13% (-6.4% to 32%) for the 2016/17 season and 12% (2.1%-21%) for the 2017/18 season. CONCLUSIONS: Pooled over two predominantly A/H3N2 respiratory seasons, HD-IIV3 was associated with fewer respiratory hospital admissions than aIIV3 in senior members of large national managed health care company in the U.S.

Factors associated with the uptake of newly introduced childhood vaccinations in Ethiopia: the cases of rotavirus and pneumococcal conjugate vaccines.

BACKGROUND: Childhood immunization programmes have made substantial contributions to lowering the burden of disease among children in developing countries, however a large proportion of children still remain unimmunized. This study aimed to explore the determinants of rotavirus vaccine (RVV) and pneumococcal conjugate vaccine (PCV) uptake in Ethiopia. METHODS: The 2016 Ethiopian demographic and health survey dataset was used in this analysis. A total of 2004 children aged 12-23 months were included in the analysis. A multivariable logistic regression model was employed to identify the determinants of uptake of the complete schedules of RVV (two doses) and PCV (three doses). Crude and adjusted odds ratios with 95% confidence intervals (CIs) were calculated. RESULTS: The uptakes of the complete schedules of RVV and PCV among children aged 12-23 months were 56 and 49.1%, respectively. The likelihood of immunization with the complete schedule of RVV was significantly lower among children from the relatively poor Afar region in Ethiopia (AOR 0.16; 95%-CI 0.04-0.61). Similarly, children living in not only the Afar region (AOR 0.10; 95%-CI 0.03-0.38), but also the Gambela region (AOR 0.25; 95%-CI 0.08-0.83), were less likely to be vaccinated with PCV. On the other hand, children from more wealthy households had higher odds of vaccination with RVV (AOR 1.69; 95%-CI 1.04-2.75). Also attending antenatal care (ANC) was found to be significantly associated with uptake of the complete schedule of RVV and PCV. CONCLUSIONS: The uptake of RVV and PCV is suboptimal in Ethiopia. The uptake of the vaccines were found to be associated with region, ANC use and wealth status.

Respiratory syncytial virus subunit vaccines based on the viral envelope glycoproteins intended for pregnant women and the elderly.

Introduction: Respiratory syncytial virus (RSV) causes high morbidity and mortality rates among infants, young children, and the elderly worldwide. Unfortunately, a safe and effective vaccine is still unavailable. In 1966, a formalin-inactivated RSV vaccine failed and resulted in the death of two young children. This failure shifted research toward the development of subunit-based vaccines for pregnant women (to passively vaccinate infants) and the elderly. Among these subunit-based vaccines, the viral envelope glycoproteins show great potential as antigens. Areas covered: In this review, progress in the development of safe and effective subunit RSV vaccines based on the viral envelope glycoproteins and intended for pregnant women and the elderly, are reviewed and discussed. Studies published in the period 2012-2018 were included. Expert opinion: Researchers are close to bringing safe and effective subunit-based RSV vaccines to the market using the viral envelope glycoproteins as antigens. However, it remains a major challenge to elicit protective immunity, with a formulation that has sufficient (storage) stability. These issues may be overcome by using the RSV fusion protein in its pre-fusion conformation, and by formulating this protein as a dry powder. It may further be convenient to administer this powder via the pulmonary route.