Systematic review of health economic evaluation studies of dengue vaccines

Objectives

To review the literature on economic evaluation of dengue vaccination to produce evidence to support a local cost-effectiveness study and to subsidize the decision to introduce a dengue vaccine in the Brazilian National Immunization Program. Methods: We systematically searched multiple databases (MEDLINE (via PubMed), EMBASE, SCOPUS, NHS Economic Evaluation Database (NHS EED), HTA Database (via Centre for Reviews and Dissemination – CRD) and LILACS), selecting full HEEs of dengue vaccine. Two independent reviewers screened articles for relevance and extracted the data. The methodology for the quality reporting was assessed using CHEERS checklist. We performed a qualitative narrative synthesis. Results: Thirteen studies conducted in Asian and Latin America countries were reviewed. All studies were favorable to the incorporation of the vaccine. However, the assumptions and values assumed for vaccine efficacy, safety and duration of protection, as well as the choice of the study population and the type of model used in the analyses, associated to an insufficient reporting of the methodological steps, affect the validity of the studies’ results. The quality reporting appraisal showed that the majority (8/13) of the studies reported less than 55% of the CHEERS checklists’ items. Conclusions: This systematic review shows that the economic evaluation of dengue vaccination did not adhere to key recommended general methods for economic evaluation. The presented cost-effectiveness results should not be transferred to other countries. It is recommended to conduct studies with local epidemiological and cost data, as well as assumptions about vaccination that reflect the results observed in clinical trials.     

Estimation of expected dengue seroprevalence from passive epidemiological surveillance systems in selected areas of Argentina: A proxy to evaluate the applicability of dengue vaccination

BackgroundCurrent recommendations about dengue vaccination by the World Health Organization depend on seroprevalence levels and serological status in populations and individuals. However, seroprevalence estimation may be difficult due to a diversity of factors. Thus, estimation through models using data from epidemiological surveillance systems could be an alternative procedure to achieve this goal.ObjectiveTo estimate the expected dengue seroprevalence in children of selected areas in Argentina, using a simple model based on data from passive epidemiological surveillance systems.MethodsA Markov model using a simulated cohort of individuals from age 0 to 9 years was developed. Parameters regarding the reported annual incidence of dengue, proportion of inapparent cases, and expansion factors for outpatient and hospitalized cases were considered as transition probabilities. The proportion of immune population at 9 years of age was taken as a proxy of the expected seroprevalence, considering this age as targeted for vaccination. The model was used to evaluate the expected seroprevalence in Misiones and Salta provinces and in Buenos Aires city, three settings showing different climatic favorability for dengue.ResultsThe estimates of the seroprevalence for the group of 9-year-old children for Misiones was 79% (95%CI:46–100%), and for Salta 22% (95%CI:14–30%), both located in northeastern and northwestern Argentina, respectively. Buenos Aires city, from central Argentina, showed a likely seroprevalence of 7% (95%CI: 3–11%). According to the deterministic sensitivity analyses, the parameter showing the highest influence on these results was the probability of inapparent cases.ConclusionsThis model allowed the estimation of dengue seroprevalence in settings where this information is not available. Particularly for Misiones, the expected seroprevalence was higher than 70% in a wide range of scenarios, thus in this province a vaccination strategy directed to seropositive children of >9 years should be analyzed, including further considerations as safety, cost-effectiveness, and budget impact.     

Potential impact of dengue vaccination: Insights from two large-scale phase III trials with a tetravalent dengue vaccine

BackgroundA tetravalent dengue vaccine demonstrated its protective efficacy in two phase III efficacy studies. Results from these studies were used to derive vaccination impact in the five Asian (Indonesia, Malaysia, Philippines, Thailand, Vietnam) and the five Latin American countries (Brazil, Colombia, Honduras, Mexico and Puerto Rico) participating in these trials.MethodsVaccination impact was investigated with an age-structured, host-vector, serotype-specific compartmental model. Parameters related to vaccine efficacy and levels of dengue transmission were estimated using data collected during the phase III efficacy studies. Several vaccination programs, including routine vaccination at different ages with and without large catch-up campaigns, were investigated.ResultsAll vaccination programs explored translated into significant reductions in dengue cases at the population level over the first 10 years following vaccine introduction and beyond. The most efficient age for vaccination varied according to transmission intensity and 9 years was close to the most efficient age across all settings. The combination of routine vaccination and large catch-up campaigns was found to enable a rapid reduction of dengue burden after vaccine introduction.ConclusionOur analysis suggests that dengue vaccination can significantly reduce the public health impact of dengue in countries where the disease is endemic.     

Next generation dengue vaccines: a review of candidates in preclinical development

Dengue represents a major public health problem of growing global importance. In the absence of specific dengue therapeutics, strategies for disease control have increasingly focused on the development of dengue vaccines. While a licensed dengue vaccine is not yet available, several vaccine candidates are currently being evaluated in clinical trials and are described in detail in accompanying articles. In addition, there are a large variety of candidates in preclinical development, which are based on diverse technologies, ensuring a continued influx of innovation into the development pipeline. Potentially, some of the current preclinical candidates may become next generation dengue vaccines with superior product profiles. This review provides an overview of the various technological approaches to dengue vaccine development and specifically focuses on candidates in preclinical development.     

A multi-country study of dengue vaccination strategies with Dengvaxia and a future vaccine candidate in three dengue-endemic countries: Vietnam,Thailand, and Colombia

BackgroundThe dengue vaccination era began when Dengvaxia (CYD-TDV) became available in 2016. In addition, several second-generation vaccine candidates are currently in phase 3 trials, suggesting that a broader availability of dengue vaccines may be possible in the near future. Advancing on the recent WHO-SAGE recommendations for the safe and effective use of CYD-TDV at the regional level on average, this study investigates the vaccination impacts and cost-effectiveness of CYD-TDV and of a hypothetical new vaccine candidate (NVC) in a country-specific manner for three endemic countries: Vietnam, Thailand, and Colombia.MethodsThe vaccination impacts of CYD-TDV and NVC were derived by fitting the empirical seroprevalence rates of 9 year olds into an individual-based meta-population transmission model, previously used for the WHO-SAGE working group. The disability-adjusted life years were estimated by applying country-specific parametric values. The cost-effectiveness analyses of four intervention strategies in combination with routine and catch-up campaigns were compared for both vaccines to inform decision makers regarding the most suitable immunization program in each of the three countries.Results and conclusionBoth CYD-TDV and NVC could be cost-effective at the DALY threshold cost of $2000 depending upon vaccination costs. With CYD-TDV, targeting 9 year olds in routine vaccination programs and 10–29 year olds as a one-off catch-up campaign was the most cost-effective strategy in all three countries. With NVC, while the most cost-effective strategy was to vaccinate 9–29 and 9–18 year olds in Vietnam and Thailand respectively, vaccinating younger age cohorts between 1 and 5 years old in Colombia was more cost-effective than other strategies. Given that three countries will soon face decisions regarding whether and how to incorporate CYD-TDV or future dengue vaccines into their budget-constrained national immunization programs, the current study outcomes can be used to help decision makers understand the expected impacts and cost-effectiveness of such vaccines.     

Effectiveness of a single-dose mass dengue vaccination in Cebu,Philippines: A case-control study

BackgroundDengue fever is an important public health problem in the Philippines. In April 2016, the Department of Health launched a three-dose school based dengue vaccination program of nine- to fourteen-year-old children in three regions with the highest number of dengue cases using CYD-TDV (Dengvaxia, Sanofi Pasteur). In July 2017, a community-based dengue vaccination program was implemented in Cebu province. The program was discontinued in December 2017 amidst public controversy, after the first dose had been administered. We assessed the effectiveness of a single dose of CYD-TDV against hospitalized virologically confirmed dengue (VCD).MethodsWe conducted a case-control study in Cebu province following the dengue mass vaccination. Children who were nine to fourteen years of age during the mass vaccination and subsequently admitted to any of four participating public hospitals with suspected dengue were enrolled in the study as cases. Blood for RT-PCR and clinical and socio-demographic information were obtained. To estimate the level of vaccine protection, vaccination status was compared between children with hospitalized virologically confirmed dengue and controls of the same six-year age-group as the cases, matched on sex, neighborhood and time of occurrence of cases.FindingsWe enrolled 490 cases and 980 controls. Receipt of one dose of CYD-TDV was associated with 26% (95 % CI, −2 to 47%; p = 0 0675) overall protection against hospitalized virologically confirmed dengue and 51% (95 % CI, 23 to 68; p = 0 0016) protection against dengue with warning signs.InterpretationA single dose of CYD-TDV given to nine to fourteen-year-old children through a community-based mass vaccination program conferred protection against dengue with warning signs and severe dengue but we were unable to conclude on protection against milder illness.     

Cost-utility analysis comparing meropenem with imipenem plus cilastatin in the treatment of severe infections in intensive care

This study compared the cost-effectiveness of meropenem with that of imipenem plus cilastatin in the treatment of severe infections in hospital intensive care in the UK. A Markov model was constructed to model lifetime costs and quality-adjusted life years (QALYs) of using meropenem and imipenem plus cilastatin for the treatment of severe infections in intensive care. Estimates of effectiveness, utility weights and costs were obtained from the published literature. Probabilistic sensitivity analysis was conducted to assess the robustness of the results. Estimated treatment costs for the patient cohort were £14,938 with meropenem and £15,585 with imipenem plus cilastatin. QALYs gained were 7,495 with meropenem and 7,413 with imipenem plus cilastatin. Probabilistic sensitivity analysis showed meropenem to be significantly less costly (–£636.47, 95% CI –£132.33 to–£1,140.62) and more effective (0.084, 95% CI 0.023 to 0.144). Meropenem thus appears significantly more effective and less expensive than imipenem plus cilastatin and should therefore be considered the dominant treatment strategy.     

贵州省农村癫痫项目点防治管理的成本-效用分析

目的 了解贵州省内农村癫痫项目覆盖地区参与管理治疗和自行治疗的癫痫患者在治疗后,费用和生存质量改善方面的情况,为管理治疗癫痫的后期成本投入提供科学依据。方法 采用QOLIE-31量表收集2组癫痫患者的生存质量情况,并计算改善的QALY值,依据卫生经济学的分析方法,计算其成本效用。结果 经比较,项目组与非项目组的各项指标均无统计学差异,具有较好的比较性。项目组平均QALY为30.14,非项目组为17.62,QALY的改善主要集中在中青年癫痫患者;项目组平均改善1个QALY需要20 903.8元,非项目组为24 201.4元,项目组人均成本效用比为34.10,而非项目组为136.73。结论 农村癫痫防治管理项目在提高农村癫痫患者的生存质量方面具有经济优势,作为一项惠民政策,应该逐步推广综合干预模式,为其他农村综合防治项目提供参考。     

Laboratory surveillance of dengue in Argentina, 1995-2001

Local transmission of dengue fever virus in Argentina is increased by the presence of Aedes aegypti mosquitoes and dengue outbreaks in neighboring countries. From 1995 to 2001, a laboratory-based active surveillance program detected 922 dengue cases. Indigenous transmission involving dengue-1 and -2 serotypes was confirmed only in subtropical areas in northern Argentina.     

Cost-utility analysis of cariprazine compared to risperidone among patients with negative symptoms of schizophrenia

Objectives

The aim was to assess the cost-effectiveness of cariprazine compared to second-generation antipsychotics in the treatment of schizophrenia for patients with negative symptoms in Hungary.

Economic evaluation and budget impact analysis of dengue vaccination following pre-vaccination serological screening in India

ObjectivesTo evaluate the budget impact and cost-effectiveness of dengue vaccination following pre-vaccination serological screening in India.MethodsWe used a static cohort model (combination of decision tree and Markov model) to compare dengue disease and cost burden with and without dengue vaccination program with serological screening for a hypothetical cohort of 10-year-old adolescents. Budget impact was expressed in terms of total budget required for implementation of vaccination programme. Program impact was expressed in terms of disability-adjusted life-years (DALYs) averted. Cost effectiveness was expressed as costs per DALY averted. All costs are expressed in 2018 US dollars. Sensitivity analysis was performed for ICERs in different vaccination scenarios.ResultsThe total budget for implementation of dengue vaccination programme is approximately around US$ 530 million (INR 3620 crores). Our model results suggest dengue vaccination result in a net gain of almost 86,000 DALYS. We found the Dengue vaccine to be a cost-effective intervention with an ICER of $3364 (INR 2,30,098) which is less than three-times GDP per capita of India ($6047; INR 413,601). One-way sensitivity analysis shows that the ICER is most affected by the overall incidence of dengue infections followed by vaccine price. Probabilistic sensitivity analysis shows that ICER for dengue vaccination varied from $1182 (INR 80,837) to $6367 (INR 435,439).ConclusionOur study shows that dengue vaccine with pre-vaccination serological screening programme is a cost-effective intervention with the conservative estimates.     

Development of dengue DNA vaccines

Vaccination with plasmid DNA against infectious pathogens including dengue is an active area of investigation. By design, DNA vaccines are able to elicit both antibody responses and cellular immune responses capable of mediating long-term protection. Great technical improvements have been made in dengue DNA vaccine constructs and trials are underway to study these in the clinic. The scope of this review is to highlight the rich history of this vaccine platform and the work in dengue DNA vaccines accomplished by scientists at the Naval Medical Research Center. This work resulted in the only dengue DNA vaccine tested in a clinical trial to date. Additional advancements paving the road ahead in dengue DNA vaccine development are also discussed.     

莆田口岸登革热流行风险分析

目的通过分析评估莆田口岸登革热流行的风险,明确登革热流行的风险点和防控的关键环节,指导一线防控工作,确保口岸卫生安全。方法采用人工小时法调查伊蚊成蚊密度,入户调查积水容器,统计阳性容器进行幼蚊密度指数监测;抽取易感人群血样检测登革热抗体水平,调查收集当地出入境人员往来及周边国家疫情动态、现场考察监测点周边生活卫生及自然地理状况等,依据《口岸及出入境交通工具医学媒介生物监测风险评估技术方案》对莆田口岸登革热流行风险进行评估。结果莆田口岸属亚热带海洋性气候,夏秋雨水多,气候适宜伊蚊的生长繁殖;环境卫生较差,居民喜种花养花也有利于蚊虫孳生。2012年、2013年莆田市涵江区布雷图指数分别为29．48、36．00均超过安全系数,是登革热不安全地区。2013年莆田口岸秀屿港区伊蚊成蚊密度2．21只/人工小时超过口岸医学媒介控制标准。2012—2013年共检出405份易感人群血清,仅1例登革热抗体阳性。结论莆田口岸登革热发生的可能性为C级,即可能发生;危害性为2级,即危害较小;登革热流行风险等级结果为中等危险度风险,应强化口岸登革热防控工作,严防登革热疫情输入造成流行。     

Generation and preclinical immunogenicity study of dengue type 2 virus-like particles derived from stably transfected mosquito cells

Recent phase IIb/III trials of a tetravalent live attenuated vaccine candidate revealed a need for improvement in the stimulation of protective immunity against diseases caused by dengue type 2 virus (DENV-2). Our attempts to develop particulate antigens for possibly supplementing live attenuated virus preparation involve generation and purification of recombinant DENV-2 virus-like particles (VLPs) derived from stably (prM+E)-expressing mosquito cells. Two VLP preparations generated with either negligible or enhanced prM cleavage exhibited different proportions of spherical particles and tubular particles of variable lengths. In BALB/c mice, VLPs were moderately immunogenic, requiring adjuvants for the induction of strong virus neutralizing antibody responses. VLPs with enhanced prM cleavage induced higher levels of neutralizing antibody than those without, but the stimulatory activity of both VLPs was similar in the presence of adjuvants. Comparison of EDIII-binding antibodies in mice following two adjuvanted doses of these VLPs revealed subtle differences in the stimulation of anti-EDIII binding antibodies. In cynomolgus macaques, VLPs with enhanced prM cleavage augmented strongly neutralizing antibody and EDIII-binding antibody responses in live attenuated virus-primed recipients, suggesting that these DENV-2 VLPs may be useful as the boosting antigen in prime-boost immunization. As the levels of neutralizing antibody induced in macaques with the prime-boost immunization were comparable to those infected with wild type virus, this virus-prime VLP-boost regimen may provide an immunization platform in which a need for robust neutralizing antibody response in the protection against DENV-2-associated illnesses could be tested.     

Immunogenicity and efficacy of chimeric dengue vaccine (DENVax) formulations in interferon-deficient AG129 mice

Formulations of chimeric dengue vaccine (DENVax) viruses containing the pre-membrane (prM) and envelope (E) genes of serotypes 1-4 expressed in the context of the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity and efficacy in interferon receptor knock-out mice (AG129). Monovalent formulations were safe and elicited robust neutralizing antibody responses to the homologous virus and only limited cross-reactivity to other serotypes. A single dose of monovalent DENVax-1, -2, or -3 vaccine provided eighty or greater percent protection against both wild-type (wt) DENV-1 (Mochizuki strain) and DENV-2 (New Guinea C strain) challenge viruses. A single dose of monovalent DENVax-4 also provided complete protection against wt DENV-1 challenge and significantly increased the survival times after challenge with wt DENV-2. In studies using tetravalent mixtures, DENVax ratios were identified that: (i) caused limited viremia, (ii) induced serotype-specific neutralizing antibodies to all four DENV serotypes with different hierarchies, and (iii) conferred full protection against clinical signs of disease following challenge with either wt DENV-1 or DENV-2 viruses. Overall, these data highlight the immunogenic profile of DENVax, a novel candidate tetravalent dengue vaccine and the advantage of sharing a common attenuated genomic backbone among the DENVax monovalent vaccines that confer protection against homologous or heterologous virus challenge.     

气象因素对登革热传播影响的研究进展

目的 系统回顾气象对登革热疫情的影响模式,评估各种气象因素在登革热传播中的作用。方法 以登革热（dengue）、气候(climate)、传播(transmission)等关键词进行组合检索,检索中国知网、百度学术、谷歌学术和SCI - HUB文库近20年的相关文献并进行整理。结果 温度、降水、相对湿度是影响登革热疫情的最主要因素,大多呈非线性关系,但具体影响具有时空异质性;且多数研究围绕温度展开,说明温度对其传播起到关键作用。结论 不同气象因素对登革热影响差异明显,针对具体地区进行登革热气象因素分析具有重要意义,可为风险评估和策略制订提供科学依据。     

2019年珠海市登革病毒传播影响因素分析

目的 根据2019年珠海市登革病毒(DENV)的流行病学数据统计分析、DENV包膜蛋白(E)基因序列测定、登革抗体水平回顾分析及蚊媒密度监测,分析珠海市登革病毒传播的影响因素.方法 收集2019年登革热流行病学资料开展统计学分析;采集登革热临床诊断病例的血清标本,提取RNA,用RT-PCR方法检测,阳性标本针对E基因测...     

Cost-utility analysis of vaccination against HPV in Israel

Using WHO-CHOICE methodology, we calculated cost-utility ratios for various interventions (PAP smear, HPV-DNA testing, VIA and vaccination against HPV) at various frequencies to reduce the burden of cervical cancer and condyloma (in the case of the HPV vaccination) in Israel, which has a low prevalence of cervical cancer. Assuming non-waning efficacy, HPV vaccinations will become cost-effective, very cost-effective and cost saving when the cost per dose falls below $96.85, $50.42 and $27.20, respectively. Attempts should be made to raise compliancy with PAP smears from the current opportunistic 12.2-20.0% per annum either before and/or after the vaccination is introduced.