Vacina TAK-003 tetravalente para a prevenção de infecção pelo vírus da dengue / Quadrivalent TAK-003 vaccine for the prevention of dengue virus infection

INTRODUÇÃO: A dengue é uma arbovirose que cursa com uma doença febril aguda transmitida pelo mosquito Aedes Aegypti. Possui elevada prevalência em regiões tropicais e subtropicais, sendo a mais frequente dentre as arboviroses no contexto mundial. Em 2022, 2.803.096 casos de dengue foram notificados na Região das Américas, com uma taxa de incidência cumulativa de 282 casos por 100.000 habitantes, sendo observado no Brasil o maior número de casos (2.383.001). Classificada como Desastre Natural Biológico, a dengue tem potencial para produzir surtos com grande impacto na rede de atenção de saúde pública. A infecção pelo vírus gera uma doença descrita como dinâmica e sistêmica, que pode ser assintomática, ou se apresentar em sua forma mais benigna com remissão dos sintomas, como também pode raramente agravar-se e levar ao óbito. Medicamentos antivirais não estão disponíveis como forma de tratamento. As medidas de controle dos vetores são efetivas na redução do número de casos. Em 2015 foi autorizada a primeira vacina contra dengue (Dengvaxia®), contudo só deve ser administrada em indivíduos que já foram infectados anteriormente, pois os indivíduos não previamente infectados possuem um risco

Cost-effectiveness and budget impact analyses of dengue vaccination in Indonesia.

Despite the fact that the incidence and mortality rates due to dengue virus (DENV) infection in Indonesia are relatively high, dengue vaccination has not yet been introduced. This study aimed to analyse the cost-effectiveness and the budget impact of dengue vaccination in Indonesia by taking the potential of pre-vaccination screening into account. An age-structured decision tree model was developed to assess the cost-effectiveness value by applying a single cohort of 4,710,100 children that was followed-up in a 10-year time horizon within a 1-year analytical cycle. The budget impact was analysed in a 5-year period (2020-2024) by considering provinces' readiness to introduce dengue vaccine and their incidence rate of DENV infection in the last 10 years. Vaccination that was coupled with pre-vaccination screening would reduce dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) by 188,142, 148,089 and 426 cases, respectively. It would save treatment cost at $23,433,695 and $14,091,642 from the healthcare and payer perspective, respectively. The incremental cost-effectiveness ratios (ICERs) would be $5,733 and $5,791 per quality-adjusted-life-year (QALY) gained from both perspectives. The most influential parameters affecting the ICERs were probability of DENV infection, vaccine efficacy, under-reporting factor, vaccine price, case fatality rate and screening cost. It can be concluded that dengue vaccination and pre-vaccination screening would be cost-effective to be implemented in Indonesia. Nevertheless, it seems unaffordable to be implemented since the total required cost for the nationwide vaccination would be 94.44% of routine immunization budget.

An update on dengue vaccine development, challenges, and future perspectives.

INTRODUCTION: From both a public health and economic perspective, vaccination is arguably the most effective approach to combat endemic and pandemic infectious diseases. Dengue affects more than 100 countries in the tropical and subtropical world, with 100-400 million infections every year. In the wake of the recent setback faced by Dengvaxia, the only FDA-approved dengue vaccine, safer and more effective dengue vaccines candidates are moving along the clinical pipeline. AREA COVERED: This review provides an update of the latest outcomes of dengue vaccine clinical trials. In the light of recent progress made in our understanding of dengue pathogenesis and immune correlates of protection, novel vaccine strategies have emerged with promising second-generation dengue vaccine candidates. Finally, the authors discuss the dengue-specific challenges that remain to be addressed and overcome. EXPERT OPINION: The authors propose to explore various adjuvants and delivery systems that may help improve the design of safe, effective, and affordable vaccines against dengue. They also challenge the concept of a 'universal' dengue vaccine as increasing evidence support that DENV strains have evolved different virulence mechanisms.

A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain.

BACKGROUND: Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. METHODS: A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. RESULTS: Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5-9 days) and mean time of viremia was 6.8 days (range 3-9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted. CONCLUSIONS: We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing. CLINICAL TRIALS REGISTRATION: NCT02372175.

The potential impact of dengue vaccination with, and without, pre-vaccination screening.

BACKGROUND: The World Health Organization defined a 'screen and vaccinate' strategy as its recommended policy for the licensed dengue vaccine (Dengvaxia, Sanofi Pasteur), so that only individuals with previous dengue infection are vaccinated. The objectives of the present study were to build upon a recently published analysis of the benefits and risks associated with dengue vaccination to evaluate the public health impact and cost-effectiveness of a screen and vaccinate strategy. METHODS: The current analysis was based on a previously reported transmission model and added, for the screening part, three rapid diagnostic tests with identical specificity (99%) but alternative sensitivities (50-70-90%) in the detection of prior dengue infection. The impact of a screen-and-vaccinate strategy considered nine settings representing different levels of transmission intensity. Outcomes (dengue-related hospitalizations, severe dengue, and symptomatic dengue) were assessed according to the level of transmission setting. The cost-effectiveness of vaccination in 10 endemic countries was also assessed. RESULTS: Although associated, in most cases, with a lower population impact than a 'no-screening' approach, a screen and vaccinate strategy is more effective in reducing the number of hospitalized and severe cases prevented per vaccination performed and generates positive health benefits for individuals screened and subsequently vaccinated. As a result, this intervention is cost-effective in all countries considered except for very low transmission settings. The overall population impact of a screen and vaccinate approach is also likely to be improved by the use of several rounds of screening (up to 48% reduction in dengue hospitalization over 10 years with 5 rounds). CONCLUSIONS: WHO recommended option of a screen and vaccinate policy is likely to have a positive impact both at the individual and population level across a wide range of transmission settings and has the potential to be as, if not more, cost-effective than a no screening strategy.

Updated recommendations of the International Dengue Initiative expert group for CYD-TDV vaccine implementation in Latin America.

Dengue disease represents a large and growing global threat to public health, causing a significant burden to health systems of endemic countries. For countries considering vaccination as part of their Integrated Management Strategy for Prevention and Control of Dengue, the World Health Organization currently recommends the first licensed dengue vaccine, CYD-TDV for: individuals aged 9 years or above from populations with high transmission rates, based on either seroprevalence criteria or pre-vaccination screening strategies, and for persons with confirmed prior exposure to infection in moderate to lower transmission settings. This paper describes the main conclusions of the Sixth Meeting of the International Dengue Initiative (IDI) held in June 2018, following release of a new product label by the manufacturer, updated WHO-SAGE recommendations, additional scientific evidence on vaccine performance, and reports of experiences by implementing countries. Considerations were made regarding the need for improving the quality of epidemiological and surveillance data in the region to help define the convenience of either of the two vaccination strategies recommended by WHO-SAGE. Extensive discussion was dedicated to the pros and cons of implementing either of such strategies in Latin America. Although, in general, a seroprevalence-based approach was preferred in high transmission settings, when cost-effectivity is favorable pre-vaccination screening is a convenient alternative. Cost-effectiveness evaluations can assist with the decisions by public health authorities of whether to introduce a vaccine. Where implemented, vaccine introduction should be part of a public health strategy that includes the participation of multiple sectors of society, incorporating input from scientific societies, ministries of heath, and civil society, while ensuring a robust communication program.

Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

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.

Bioethics of establishing a CHIM model for dengue vaccine development.

INTRODUCTION: Controlled human infection models (CHIM) have been used in vaccine development to up-select and down-select potential vaccine candidates and to provide proof of vaccine efficacy, and have also been used as a basis for licensure of vaccines for cholera and typhoid by regulatory agencies. CHIM IN DENGUE VACCINES DEVELOPMENT: Dengue fever results in ∼400 million infections a year and is of significant health concern especially in India. There are currently no antivirals for the disease and the only licensed vaccine for dengue is not widely used owing to safety concerns. Controlled dengue human challenge models (DHCM) are currently being used to assess the efficacy of vaccines in development for dengue. DENGUE CHIM IN INDIA: Conducting CHIM studies in India especially for evaluation of dengue vaccine candidates will be hugely beneficial as the disease is endemic to India and hence the effect of pre-exposure to the virus on vaccine safety and efficacy can be established. However, to date no CHIM studies have been conducted in India and there is a need to educate ethics committee members, policy makers and the public on the importance of such studies and what they entail.

Economic and epidemiological impact of dengue illness over 16 years from a public health system perspective in Brazil to inform future health policies including the adoption of a dengue vaccine.

INTRODUCTION: Dengue is a serious global health problem endemic in Brazil. Consequently, our aim was to measure the costs and disease burden of symptomatic dengue infections in Brazil from the perspective of the Brazilian Public Health System (SUS) between 2000 and 2015, using Brazilian public health system databases. Specific age group incidence estimates were used to calculate the disability-adjusted life years (DALYs) to gain a better understanding of the disease burden. Areas covered: SUS spent almost USD159 million and USD10 million to treat dengue and severe dengue, respectively, between 2000 and 2015. This is principally hospitalization costs, with the majority of patients self-treated at home with minor symptoms. The average notification rate for dengue was 273 per 100,000 inhabitants and three per 100,000 for severe dengue, with annual DALYs estimates ranging between 72.35 and 6,824.45 during the 16 years. Expert commentary: The epidemiological and morbidity burden associated with dengue is substantial in Brazil, with costs affected by the fact that most patients self-treat at home with these costs not included in SUS. The Brazilian government urgently needs to proactively evaluate the real costs and clinical benefits of any potential dengue vaccination program by the National Immunization Program to guide future decision-making.

Assessment of benefits and risks associated with dengue vaccination at the individual and population levels: a dynamic modeling approach.

BACKGROUND: A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination. RESEARCH DESIGN AND METHODS: Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study. The model was used to assess vaccination outcomes for a range of transmission settings over 5-30 years, with or without indirect protection. MAIN OUTCOME MEASURES: Symptomatic dengue cases, dengue hospitalizations, and severe dengue cases. RESULTS: The model is consistent with previous results indicating a transitory period at increased risk for dengue-seronegative vaccine recipients (setting-dependent duration) and long-term benefits for dengue-seropositive recipients. At the population level, benefits to seropositive individuals over 10 years outweighed the risk to those seronegative in moderate to high transmission settings (≥50% seropositivity at age 9), especially in high transmission settings (no excess hospitalizations in dengue-seronegative for ≥80% seropositivity at age 9). Results were more favorable when longer time horizons or indirect protection were considered. CONCLUSIONS: Results indicate a public health benefit associated with dengue vaccination especially in high-transmission settings, even with the initial excess risks to dengue-seronegative patients which diminish over time.

Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.

Cost-effectiveness of dengue vaccination in ten endemic countries.

Following publication of results from two phase-3 clinical trials in 10 countries or territories, endemic countries began licensing the first dengue vaccine in 2015. Using a published mathematical model, we evaluated the cost-effectiveness of dengue vaccination in populations similar to those at the trial sites in those same Latin American and Asian countries. Our main scenarios (30-year horizon, 80% coverage) entailed 3-dose routine vaccinations costing US$20/dose beginning at age 9, potentially supplemented by catch-up programs of 4- or 8-year cohorts. We obtained illness costs per case, dengue mortality, vaccine wastage, and vaccine administration costs from the literature. We estimated that routine vaccination would reduce yearly direct and indirect illness cost per capita by 22% (from US$10.51 to US$8.17) in the Latin American countries and by 23% (from US$5.78 to US$4.44) in the Asian countries. Using a health system perspective, the incremental cost-effectiveness ratio (ICER) averaged US$4,216/disability-adjusted life year (DALY) averted in the five Latin American countries (range: US$666/DALY in Puerto Rico to US$5,865/DALY in Mexico). In the five Asian countries, the ICER averaged US$3,751/DALY (range: US$1,935/DALY in Malaysia to US$5,101/DALY in the Philippines). From a health system perspective, the vaccine proved to be highly cost effective (ICER under one times the per capita GDP) in seven countries and cost effective (ICER 1-3 times the per capita GDP) in the remaining three countries. From a societal perspective, routine vaccination proved cost-saving in three countries. Including catch-up campaigns gave similar ICERs. Thus, this vaccine could have a favorable economic value in sites similar to those in the trials.

Resource Use and Costs of Dengue: Analysis of Data from Phase III Efficacy Studies of a Tetravalent Dengue Vaccine.

A tetravalent dengue vaccine (CYD-TDV) has recently been approved in 12 countries in southeast Asia and Latin America for individuals aged 9-45 years or 9-60 years (age indication approvals vary by country) living in endemic areas. Data on utilization of medical and nonmedical resources as well as time lost from school and work were collected during the active phase of two phase III efficacy studies performed in 10 countries in the Asia-Pacific region and Latin America (NCT01373281; NCT01374516). We compared dengue-related resource utilization and costs among vaccinated and nonvaccinated participants. Country-specific unit costs were derived from available literature. There were 901 virologically confirmed dengue episodes among participants aged ≥ 9 years (N = 25,826): corresponding to 373 episodes in the CYD-TDV group (N = 17,230) and 528 episodes in the control group (N = 8,596). Fewer episodes in the CYD-TDV group resulted in hospitalization than in the control group (7.0% versus 13.3%; P = 0.002), but both had a similar average length of stay of 4 days. Overall, a two-thirds reduction in resource consumption and missed school/work days was observed in the CYD-TDV group relative to the control group. The estimated direct and indirect cost (2014 I$) associated with dengue episodes per participant in the CYD-TDV group was 73% lower than in the control group (I$6.72 versus I$25.08); representing a saving of I$I8.36 (95% confidence interval [CI]:17.05-19.78) per participant with vaccination. This is the first study providing information on dengue costs among vaccinated individuals and direct confirmation that vaccination has the potential to reduce dengue illness costs.

Vacuna tetravalente CYD-TDV contra el Dengue / Quadrivalent vaccine CYD-TDV against Dengue

CONTEXTO CLÍNICO: El dengue es una enfermedad viral transmitida por la picadura del mosquito Aedes aegypti, vector de la enfermedad. El virus pertenece a la familia Flaviviridae, y existen cuatro variantes: los serotipos DEN1, DEN2, DEN3 y DEN4. El número de casos de dengue notificados anualmente a la Organización Mundial de la Salud há aumentado de 0,4 a 1,3 millones entre 1996-2005, llegando a 2,2 millones en el 2010 y 3,2 millones en el 2015. La Organización Mundial de la Salud (OMS) estima que alrededor de 50 a 100 millones de casos sintomáticos en los últimos años, predominantemente en Asia, seguida por América Latina y África. Los casos de infección que presentan síntomas probablemente representen alrededor del 25% de todas las infecciones por el virus. La incidencia reportada promedio entre 1995 y 2009 en Argentina fue de 1,6 casos por cada 100.000 habitantes, mientras que en países como Brasil, Paraguay y Bolivia es de 196, 107, y 108 casos cada 100.000 habitantes, respectivamente. TECNOLOGÍA: La vacuna CYD-TDV (Dengvaxia®) es una vacuna recombinante a virus atenuado de los cuatro serotipos virales (DEN1, DEN2, DEN3, DEN4) insertados en el esqueleto de la vacuna de la fiebre amarilla. Es um producto liofilizado para ser reconstituido antes de la inyección y aplicado en una dosis de 0,5 ml em por vía subcutánea. Se indica a pacientes de 9 a 60 años y debe administrarse en tres dosis a los 0, 6 y 12 meses. La vacuna está contraindicada en individuos con un historial de reacción alérgica a cualquier componente de la vacuna de dengue; individuos con inmunodeficiencia celular congénita o adquirida; personas con infección por VIH sintomática o con infección asintomática por VIH cuando se acompanha de evidencia de deterioro de la función inmune; mujeres embarazadas o mujeres en lactancia; además la aplicación debería ser pospuesta en personas con síndrome febril. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de la vacuna tetravalente CYD-TDV contra el dengue. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron dos RS, una GPC, una evaluación económica, y cuatro informes de políticas de cobertura. CONCLUSIONES: Evidencia de alta calidad demuestra que la vacuna tetravalente contra el dengue (CYD-TDV) es efectiva para prevenir la enfermedad sintomática, al comparar la incidencia de la misma en indivíduos vacunados versus no vacunados. El análisis de efectividad por subgrupos, demuestra que la misma es mayor en aquellos pacientes que han sido previamente sensibilizados de manera natural. Una guía de la Organización Mundial de la Salud (OMS) recomienda su aplicación en poblaciones que presentan una seroprevalencia mayor al 70%. En aquellas poblaciones con una seroprevalencia entre el 50 y 70%, refiere que su uso también sería aceptable, pero el impacto del programa sería menor. No recomienda su aplicación en poblaciones con una seroprevalencia menor al 50%. No se cuenta con información acerca de la seroprevalencia en Argentina, pero se estima que sería muy baja, en base a estudios de incidencia.

A novel immunization approach for dengue infection based on conserved T cell epitopes formulated in calcium phosphate nanoparticles.

Dengue virus (DV) is the etiologic agent of dengue fever, the most significant mosquito-borne viral disease in humans. Most DV vaccine approaches are focused on generating antibody mediated responses; one such DV vaccine is approved for use in humans but its efficacy is limited. While it is clear that T cell responses play important role in DV infection and subsequent disease manifestations, fewer studies are aimed at developing vaccines that induce robust T cells responses. Potent T cell based vaccines require 2 critical components: the identification of specific T cell stimulating MHC associated peptides, and an optimized vaccine delivery vehicle capable of simultaneously delivering the antigens and any required adjuvants. We have previously identified and characterized DV specific HLA-A2 and -A24 binding DV serotypes conserved epitopes, and the feasibility of an epitope based vaccine for DV infection. In this study, we build on those previous studies and describe an investigational DV vaccine using T cell epitopes incorporated into a calcium phosphate nanoparticle (CaPNP) delivery system. This study presents a comprehensive analysis of functional immunogenicity of DV CaPNP/multipeptide formulations in vitro and in vivo and demonstrates the CaPNP/multipeptide vaccine is capable of inducing T cell responses against all 4 serotypes of DV. This synthetic vaccine is also cost effective, straightforward to manufacture, and stable at room temperature in a lyophilized form. This formulation may serve as an effective candidate DV vaccine that protects against all 4 serotypes as either a prophylactic or therapeutic vaccine.

An economic evaluation of vector control in the age of a dengue vaccine.

INTRODUCTION: Dengue is a rapidly emerging vector-borne Neglected Tropical Disease, with a 30-fold increase in the number of cases reported since 1960. The economic cost of the illness is measured in the billions of dollars annually. Environmental change and unplanned urbanization are conspiring to raise the health and economic cost even further beyond the reach of health systems and households. The health-sector response has depended in large part on control of the Aedes aegypti and Ae. albopictus (mosquito) vectors. The cost-effectiveness of the first-ever dengue vaccine remains to be evaluated in the field. In this paper, we examine how it might affect the cost-effectiveness of sustained vector control. METHODS: We employ a dynamic Markov model of the effects of vector control on dengue in both vectors and humans over a 15-year period, in six countries: Brazil, Columbia, Malaysia, Mexico, the Philippines, and Thailand. We evaluate the cost (direct medical costs and control programme costs) and cost-effectiveness of sustained vector control, outbreak response and/or medical case management, in the presence of a (hypothetical) highly targeted and low cost immunization strategy using a (non-hypothetical) medium-efficacy vaccine. RESULTS: Sustained vector control using existing technologies would cost little more than outbreak response, given the associated costs of medical case management. If sustained use of existing or upcoming technologies (of similar price) reduce vector populations by 70-90%, the cost per disability-adjusted life year averted is 2013 US$ 679-1331 (best estimates) relative to no intervention. Sustained vector control could be highly cost-effective even with less effective technologies (50-70% reduction in vector populations) and in the presence of a highly targeted and low cost immunization strategy using a medium-efficacy vaccine. DISCUSSION: Economic evaluation of the first-ever dengue vaccine is ongoing. However, even under very optimistic assumptions about a highly targeted and low cost immunization strategy, our results suggest that sustained vector control will continue to play an important role in mitigating the impact of environmental change and urbanization on human health. If additional benefits for the control of other Aedes borne diseases, such as Chikungunya, yellow fever and Zika fever are taken into account, the investment case is even stronger. High-burden endemic countries should proceed to map populations to be covered by sustained vector control.

Cost-Effectiveness of Dengue Vaccination Programs in Brazil.

AbstractThe first approved dengue vaccine, CYD-TDV, a chimeric, live-attenuated, tetravalent dengue virus vaccine, was recently licensed in 13 countries, including Brazil. In light of recent vaccine approval, we modeled the cost-effectiveness of potential vaccination policies mathematically based on data from recent vaccine efficacy trials that indicated that vaccine efficacy was lower in seronegative individuals than in seropositive individuals. In our analysis, we investigated several vaccination programs, including routine vaccination, with various vaccine coverage levels and those with and without large catch-up campaigns. As it is unclear whether the vaccine protects against infection or just against disease, our model incorporated both direct and indirect effects of vaccination. We found that in the presence of vaccine-induced indirect protection, the cost-effectiveness of dengue vaccination decreased with increasing vaccine coverage levels because the marginal returns of herd immunity decreases with vaccine coverage. All routine dengue vaccination programs that we considered were cost-effective, reducing dengue incidence significantly. Specifically, a routine dengue vaccination of 9-year-olds would be cost-effective when the cost of vaccination per individual is less than $262. Furthermore, the combination of routine vaccination and large catch-up campaigns resulted in a greater reduction of dengue burden (by up to 93%) than routine vaccination alone, making it a cost-effective intervention as long as the cost per course of vaccination is $255 or less. Our results show that dengue vaccination would be cost-effective in Brazil even with a relatively low vaccine efficacy in seronegative individuals.