Guiding Principles for Evaluating Vaccines in Joint Health Technology Assessment in the European Union: Preparing for the EU's Regulation on HTA for Vaccines.

OBJECTIVES: The appraisal of vaccines in the European Union (EU) currently involves many different decision-making bodies and processes. The objective of this study was to help inform the development of standardized methodology and vaccine-specific processes for use in the EU Regulation on health technology assessment (HTA). METHODS: Literature reviews and expert consultation were conducted to identify current practices and gaps related to vaccine appraisals and to develop guiding principles for the joint clinical assessment of vaccines. RESULTS: We found that significant variation exists across the EU Member States in the decision-making processes when clinically evaluating vaccines. Three guiding principles consisting of 13 recommendations were developed to help inform the development of decision-making frameworks for the joint clinical assessment of vaccines in the EU: (1) Support the creation of appropriate terminology and measurements for clinical appraisals of vaccines; (2) Develop inclusive, timely, and transparent vaccine appraisal processes to support stronger evidence generation for vaccine decision-making and appraisal; and (3) Improve the collection and interoperability of real-world data, including robust surveillance, to foster evidence generation and support the standardization of vaccine clinical appraisals. CONCLUSIONS: Given the significance of vaccines for public health, there is an urgency to develop standardized and vaccine-specific methodologies and processes for use in the EU joint HTA framework. The proposed guiding principles could support the effective implementation of the EU Regulation on HTA for vaccines and have the potential to ensure consistent, transparent, and timely access to new vaccines in the EU.

The epidemiologic and economic burden of dengue in Singapore: A systematic review.

BACKGROUND: Despite its well-regarded vector control program, Singapore remains susceptible to dengue epidemics. To assist evaluation of dengue interventions, we aimed to synthesize current data on the epidemiologic and economic burden of dengue in Singapore. METHODOLOGY: We used multiple databases (PubMed, Embase, Cochrane, international/national repositories, surveillance) to search for published and gray literature (2000-2022). We included observational and cost studies, and two interventional studies, reporting Singapore-specific data on our co-primary outcomes, dengue incidence and dengue-related costs. Quality was assessed using the Newcastle-Ottawa Scale and an adapted cost-of-illness evaluation checklist. We performed a narrative synthesis and grouped studies according to reported outcomes and available stratified analyses. FINDINGS: In total, 333 reports (330 epidemiological, 3 economic) were included. Most published epidemiological studies (89%) and all economic studies were of good quality. All gray literature reports were from the Ministry of Health or National Environment Agency. Based predominantly on surveillance data, Singapore experienced multiple outbreaks in 2000-2021, attaining peak incidence rate in 2020 (621.1 cases/100,000 person-years). Stratified analyses revealed the highest incidence rates in DENV-2 and DENV-3 serotypes and the 15-44 age group. Among dengue cases, the risk of hospitalization has been highest in the ≥45-year-old age groups while the risks of dengue hemorrhagic fever and death have generally been low (both <1%) for the last decade. Our search yielded limited data on deaths by age, severity, and infection type (primary, secondary, post-secondary). Seroprevalence (dengue immunoglobulin G) increases with age but has remained <50% in the general population. Comprising 21-63% indirect costs, dengue-related total costs were higher in 2010-2020 (SGD 148 million) versus the preceding decade (SGD 58-110 million). CONCLUSION: Despite abundant passive surveillance data, more stratified and up-to-date data on the epidemiologic and economic burden of dengue are warranted in Singapore to continuously assess prevention and management strategies.

The macroeconomic impact of a dengue outbreak: Case studies from Thailand and Brazil.

BACKGROUND: Dengue is spreading in (sub)tropical areas, and half of the global population is at risk. The macroeconomic impact of dengue extends beyond healthcare costs. This study evaluated the impact of dengue on gross domestic product (GDP) based on approaches tailored to two dengue-endemic countries, Thailand and Brazil, from the tourism and workforce perspectives, respectively. FINDINGS: Because the tourism industry is a critical economic sector for Thailand, lost tourism revenues were estimated to analyze the impact of a dengue outbreak. An input-output model estimated that the direct effects (on international tourism) and indirect effects (on suppliers) of dengue on tourism reduced overall GDP by 1.43 billion US dollars (USD) (0.26%) in the outbreak year 2019. The induced effect (reduced employee income/spending) reduced Thailand's GDP by 375 million USD (0.07%). Overall, lost tourism revenues reduced Thailand's GDP by an estimated 1.81 billion USD (0.33%) in 2019 (3% of annual tourism revenue). An inoperability input-output model was used to analyze the effect of workforce absenteeism on GDP due to a dengue outbreak in Brazil. This model calculates the number of lost workdays associated with ambulatory and hospitalized dengue. Input was collected from state-level epidemiological and economic data for 2019. An estimated 22.4 million workdays were lost in the employed population; 39% associated with the informal sector. Lost workdays due to dengue reduced Brazil's GDP by 876 million USD (0.05%). CONCLUSIONS: The economic costs of dengue outbreaks far surpass the direct medical costs. Dengue reduces overall GDP and inflicts national economic losses. With a high proportion of the population lacking formal employment in both countries and low income being a barrier to seeking care, dengue also poses an equity challenge. A combination of public health measures, like vector control and vaccination, against dengue is recommended to mitigate the broader economic impact of dengue.

Epidemiology and costs of dengue in Thailand: A systematic literature review.

BACKGROUND: Dengue is the fastest-spreading vector-borne viral disease worldwide. In Thailand, dengue is endemic and is associated with a high socioeconomic burden. A systematic literature review was conducted to assess and describe the epidemiological and economic burden of dengue in Thailand. METHODS: Epidemiological and economic studies published in English and Thai between 2011-2019 and 2009-2019, respectively, were searched in MEDLINE, Embase, and Evidence-Based Medicines reviews databases. Reports published by the National Ministry of Public Health (MoPH) and other grey literature sources were also reviewed. Identified studies were screened according to predefined inclusion and exclusion criteria. Extracted data were descriptively summarised and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 155 publications were included in the review (39 journal articles and 116 grey literature). Overall, dengue incidence varied yearly, with the highest rates per 100,000 population in 2013 (dengue fever (DF) 136.6, dengue haemorrhagic fever (DHF) 100.9, dengue shock syndrome (DSS) 3.58) and 2015 (DF 133.1, DHF 87.4, DSS 2.14). Peak incidence coincided with the monsoon season, and annual mortality was highest for DSS, particularly in the age group 15-24-year-olds. The highest dengue incidence rates were reported in children (10-14-year-olds) and young adults (15-24-year-olds), irrespective of dengue case definition. Economic and societal burdens are extensive, with the average cost per case ranging from USD 41 to USD 261, total cost per year estimated at USD 440.3 million, and an average of 7.6 workdays lost for DHF and 6.6 days for DF. CONCLUSIONS: The epidemiological, economic, and societal burden of dengue in Thailand is high and underreported due to gaps in national surveillance data. The use of expansion factors (EFs) is recommended to understand the true incidence of dengue and cost-benefit of control measures. Furthermore, as dengue is often self-managed and underreported, lost school and workdays result in substantial underestimation of the true economic and societal burden of dengue. The implementation of integrated strategies, including vaccination, is critical to reduce the disease burden and may help alleviate health disparities and equity challenges posed by dengue.

Epidemiology (2012-2019) and costs (2009-2019) of dengue in Malaysia: a systematic literature review.

OBJECTIVES: A systematic literature review was conducted to assess the epidemiology and economic burden of dengue in Malaysia. METHODS: Embase, MEDLINE, Evidence-Based Reviews databases, and gray literature sources were searched for English and Malay studies and surveillance reports on the epidemiology (between 2012 and 2019) and costs (between 2009 and 2019) of dengue in Malaysia. Independent screening of titles/abstracts, followed by full texts was performed using prespecified criteria. RESULTS: A total of 198 publications were included (55 peer-reviewed and 143 gray literature). Dengue incidence has been increasing in recent years, with 130,101 cases (dengue fever 129,578 cases; dengue hemorrhagic fever 523 cases) reported in 2019, which is the highest since 2012. All dengue virus serotypes co-circulated between 2004 and 2017, and major outbreaks occurred in a cyclical pattern, often associated with a change in the predominant circulating serotype. Economic impacts are substantial, including the societal impact of lost work (7.2-8.8 days) and school days (3.2-4.1 days) due to dengue. CONCLUSION: The rising incidence and high cost of dengue, coupled with overlapping diseases, will likely result in further pressures on the healthcare system. To appropriately mitigate and control dengue, it is critical to implement integrated strategies, including vaccination, to reduce the burden of dengue.

Fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway attentuates microglial activation in vivo and in vitro.

Several neurodegenerative disorders are associated with evidence of inflammation, one feature of which is increased activation of microglia, the most likely cellular source of inflammatory cytokines like interleukin-1beta. It is now recognized that interaction of microglia with other cells contributes to maintenance of microglia in a quiescent state and the complementary distribution of the chemokine, fractalkine (CX(3)CL1) on neurons and its receptor (CX(3)CR1) on microglia, suggests that this interaction may play a role in modulating microglial activation. Here we demonstrate that both soluble and membrane-bound fractalkine attenuate lipopolysaccharide-induced microglial activation in vitro. We also show that fractalkine expression is reduced in the brain of aged rats and this is accompanied by an age-related increase in microglial activation. Treatment of aged rats with fractalkine attenuates the age-related increase in microglial activation and the evidence indicates that fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway is required to maintain microglia in a quiescent state both in vivo and in vitro.