Dengue determinants: Necessities and challenges for universal dengue vaccine development.

Dengue illness can range from mild illness to life-threatening haemorrhage. It is an Aedes-borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti-dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral-vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host-pathogen specific interaction, antibody-dependent enhancement, cross-reactive immunity among Flaviviruses, and host-susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.

Acceptability of a hypothetical dengue vaccine and the potential impact of dengue vaccination on personal vector control behavior: a qualitative study in Fortaleza, Brazil.

BACKGROUND: Dengue is the most rapidly spreading viral vector-borne disease in the world. Promising new dengue vaccines have contributed to a growing consensus that effective dengue control will require integrated strategies of vaccination and vector control. In this qualitative study, we explored the perspectives of residents of Fortaleza, Brazil on acceptability of a hypothetical safe and effective dengue vaccine, specific drivers of dengue vaccine acceptance or hesitance, and the expected impact of dengue vaccination on their personal vector control practices. METHODS: A total of 43 in-depth interviews were conducted from April to June 2022 with Fortaleza residents from a diverse range of educational and professional backgrounds, with and without recent personal experiences of symptomatic dengue infections. Data were analyzed using the principles of inductive grounded theory methodology. RESULTS: Our findings indicate that knowledge of dengue transmission, symptoms, and prevention methods was strong across respondents. Respondents described willingness to accept a hypothetical dengue vaccine for themselves and their children, while emphasizing that the vaccine must be demonstrably safe and effective. Respondents expressed diverse perspectives on how receiving a safe and effective dengue vaccine might influence their personal vector control behaviors, relating these behaviors to their perception of risk from other Aedes mosquito-carried infections and beliefs about the role of vector control in maintaining household cleanliness. CONCLUSIONS: Our study findings provide community-level perspectives on dengue vaccination and its potential impact on personal vector control behavior for policymakers and program managers in Fortaleza to consider as new dengue vaccines become available. With the introduction of any new dengue vaccine, community perspectives and emerging concerns that may drive vaccine hesitancy should be continuously sought out. Improved urban infrastructure and efforts to engage individuals and communities in vector control may be needed to optimize the impact of future dengue vaccinations and prevent rising cases of other arboviruses such as Zika and chikungunya.

Designing effective control of dengue with combined interventions.

Viruses transmitted by Aedes mosquitoes, such as dengue, Zika, and chikungunya, have expanding ranges and seem unabated by current vector control programs. Effective control of these pathogens likely requires integrated approaches. We evaluated dengue management options in an endemic setting that combine novel vector control and vaccination using an agent-based model for Yucatán, Mexico, fit to 37 y of data. Our intervention models are informed by targeted indoor residual spraying (TIRS) experiments; trial outcomes and World Health Organization (WHO) testing guidance for the only licensed dengue vaccine, CYD-TDV; and preliminary results for in-development vaccines. We evaluated several implementation options, including varying coverage levels; staggered introductions; and a one-time, large-scale vaccination campaign. We found that CYD-TDV and TIRS interfere: while the combination outperforms either alone, performance is lower than estimated from their separate benefits. The conventional model hypothesized for in-development vaccines, however, performs synergistically with TIRS, amplifying effectiveness well beyond their independent impacts. If the preliminary performance by either of the in-development vaccines is upheld, a one-time, large-scale campaign followed by routine vaccination alongside aggressive new vector control could enable short-term elimination, with nearly all cases avoided for a decade despite continuous dengue reintroductions. If elimination is impracticable due to resource limitations, less ambitious implementations of this combination still produce amplified, longer-lasting effectiveness over single-approach interventions.

Dengue vaccine acceptance and willingness to pay: a systematic review and meta-analysis.

OBJECTIVE: Dengue is the most important human vector-borne disease in terms of disease burden. A first dengue vaccine has recently been licenced, and others are in advanced stages of development. However, to date, none of these vaccines has achieved balanced efficacy and safety for all dengue serotypes. The aim of this systematic review and meta-analysis was to assess the global acceptance and willingness to pay for unspecified dengue vaccines. METHODS: This systematic review and meta-analysis included cross-sectional and cohort studies that reported values for vaccine acceptance (percentage) and willingness to pay for currently available or hypothetical vaccines. These values were pooled using random-effects models for the acceptance, while weighted linear regression was chosen for willingness to pay. Heterogeneity between studies was assessed using prediction intervals (PIs), and a domain-based tool was used to assess the risk of bias. Subgroup and sensitivity analyses were performed where appropriate. This study was registered with PROSPERO (CRD42021255784). RESULTS: We included 19 studies from the Americas and Asia in the quantitative meta-analysis. The risk of bias was mainly related to the selection of participants and to the assumptions about the safety and efficacy of the vaccines. The percentage of vaccine acceptance was 88.3% (95% CI: 81.0%-93.0%), with some heterogeneity between studies (80% PI: 52.9%-98.1%). Willingness to pay was US$ 46.7 (95% CI: 25.9-67.5) per vaccine recipient. There were differences between continents, with higher acceptance in the Americas. CONCLUSIONS: We were able to obtain global estimates of vaccine acceptance and willingness to pay and identify the associated factors that influence these values. This knowledge is relevant for the planning of future vaccination strategies.

Designing vaccine candidates against dengue virus by in silico studies on structural and nonstructural domains.

One-third of the world's population is at risk of Dengue infection. Envelope domain 3 (EDIII) and nonstructural protein1 (NS1) proteins as the potent antigenicity regions for humoral immunity in addition to the bc loop region as a completely conserved region have been used for designing protective vaccines. We aimed to design vaccine candidates according to the bc loop, EDIII, and NS1 regions of Dengue serotype2 to be used as vaccine candidates for all serotypes of Dengue virus especially serotype 2. Firstly the bc loop region with EDII fragments at both ends as well as EDIII and NS1 regions were used which were linked with the GGGGS linker to the bc loop region. In two other strategies, the bc loop with EDII and NS1 fragments at both ends was used to increase its structural stability. Tertiary structure prediction and validation of vaccine constructs indicated that all vaccine constructs were modeled with high quality and stable structure during molecular dynamics simulation. B cell epitope mapping by Bepipred and ElliPro methods confirmed the existence of high potent epitopes in the bc loop, EDIII, and NS1 regions in both linear and conformational B cell epitopes. Furthermore, molecular docking for the bc loop region demonstrated that all designed vaccines have a higher affinity to interact with 1C19 monoclonal antibody than only the bc loop region or bc loop epitope in the protein EII. Our data of in silico studies indicated that the designed vaccines could effectively induce humoral immunity against four dengue serotypes.

Systematic review of dengue vaccine efficacy.

BACKGROUND: Dengue is an arbovirus that has rapidly spread worldwide, and the incidence of dengue has greatly increased in recent decades. The actual numbers of dengue cases are underreported, and many cases are not classified correctly. Recent estimates indicate that 390 million dengue infections occur per year (95% CI, 284-528 million), of which 96 million (67-136 million) are symptomatic infections of any severity. One of the goals of the World Health Organization is to reduce dengue mortality by 50% by the year 2020. The use of a vaccine can be an important strategy to achieve this goal. Vaccines for dengue are in various stages of development; in Brazil, only one commercial formulation is available (CYD-TDV), which was developed by Sanofi Pasteur. METHODS: To evaluate the efficacy of Dengue vaccine, a systematic review with a meta-analysis was conducted using randomized controlled clinical trials published between 2000 and 2017 that were identified in the MEDLINE databases via PubMed, LILACS, Cochrane Library, and EMBASE. The selection was performed by two reviewers independently, with disagreements resolved by a third reviewer. RESULTS: Seven clinical trials were included, with a total of 36,371 participants (66,511 person-years) between the ages of 2 and 45 years. The meta-analysis using the random-effects model estimated the efficacy of the vaccine at 44%, with a range from 25 to 59% and high heterogeneity (I2 = 80.1%). The serotype-stratified meta-analysis was homogeneous, except for serotype 2, with the heterogeneity of 64.5%. Most of the vaccinated individuals had previous immunity for at least one serotype, which generated safety concerns in individuals without previous immunity. CONCLUSIONS: Compared with other commercially available vaccines, the dengue vaccine showed poor efficacy.

The Molecular Specificity of the Human Antibody Response to Dengue Virus Infections.

Dengue viruses (DENV) are mosquito-borne positive sense RNA viruses in the family Flaviviridae. The four serotypes of DENV (DENV1, DENV2, DENV3, DENV4) are widely distributed and it is estimated over a third of the world's population is at risk of infection [4]. While the majority of infections are asymptomatic, DENV infection can cause a spectrum of disease, from mild flu-like symptoms, to the more severe DENV hemorrhagic fever and shock syndrome [24]. Over the past 20 years, there have been intense efforts to develop a tetravalent live-attenuated DENV vaccine [36]. The process of vaccine development has been largely empirical, because effective live attenuated vaccines have been developed for other flaviviruses like yellow fever and Japanese encephalitis viruses. However, recent results from phase III live attenuated DENV vaccine efficacy trials are mixed with evidence for efficacy in some populations but not others [20]. In light of unexpected results from DENV vaccine trials, in this chapter we will review recent discoveries about the human antibody response to natural DENV infection and discuss the relevance of this work to understanding vaccine performance.

[Dengue vaccines. A reality for Argentina?]. / Las vacunas contra el dengue ¿Una realidad para la Argentina?

Dengue outbreaks have occurred yearly in Argentina since 1998. A number of candidate vaccines have been tested in endemic countries. The most advanced one was licensed in three countries of Latin America for children over 9 years of age. In the present article the benefits and drawbacks of these vaccines as well as the challenges for the implementation of a vaccination strategy in Argentina are discussed. Furthermore, a risk stratification strategy with new criteria and a multidisciplinary vision is suggested as a possible path for the assessment of the pertinence of a vaccination program in areas showing the highest risk of dengue transmission and/or for people at the greatest risk of developing severe dengue. It is also suggested that the definition regarding the status of endemicity should take into account the local realities. Finally, this paper proposes a broad discussion on the evidences, the expected impact and instrumental aspects that would be involved in the incorporation of a dengue vaccine, marketed or in development, into the national immunization program, and especially which subpopulation should be targeted for the immunization strategy to be cost-effective.

[Observations on the dengue vaccination strategy in Argentina]. / Observaciones sobre la estrategia de vacunación contra el dengue en Argentina.

A new dengue vaccine has recently been licensed in Argentina, with the Argentine government planning to acquire it in order to develop a vaccination strategy. As the disease is gradually following a path to endemicity in some regions of the country, the incorporation of these vaccines will have the potential to tackle the growing incidence of the disease and to reduce the disease burden. However, the establishment of the vaccination programme may also be susceptible of threats related to the epidemiological shift of the disease. Selecting a specific age group for the vaccine may result in a change in the peak incidence to other age groups more susceptible to severe forms of the disease, such as children or the elderly. Furthermore, the perception of protection following vaccine introduction in one jurisdiction may reduce adherence to vector control activities, increasing the risk of virus introduction and transmission in other areas not prioritised by the vaccination strategy, and the risk of other arboviral diseases such as Zika and chikungunya fever. These and other potential limitations to be considered prior to the implementation of vaccination programmes are discussed in this article, with a series of recommendations on how to address these concerns. These recommendations can help decision makers and public health practitioners at this early stage of the vaccination programme development.

Una nueva vacuna contra el dengue ha sido recientemente aprobada en Argentina, y el gobierno argentino se encuentra planificando su adquisición para desarrollar una estrategia de vacunación. Mientras la enfermedad se está dirigiendo gradualmente hacia la endemicidad en algunas regiones del país, la incorporación de estas vacunas tendrá el potencial de atacar la creciente incidencia de la enfermedad y de reducir su carga. Sin embargo, el establecimiento de un programa de vacunación puede también ser susceptible de amenazas relacionadas con el cambio epidemiológico de la enfermedad. La selección de un grupo de edad específico para la vacunación puede resultar en un cambio en el pico de la incidencia hacia otros grupos de edad más vulnerables a las formas graves de la enfermedad, como los niños o los ancianos. Además, la percepción de protección luego de la introducción de la vacuna en una jurisdicción puede reducir la adherencia a las actividades de control del vector, incrementando el riesgo de introducción y transmisión del virus en otras áreas no priorizadas por la estrategia de vacunación, y aumentando el riesgo de otras arbovirosis como las fiebres Zika y chikungunya. Estas y otras potenciales limitaciones para ser consideradas antes de la implementación de los programas de vacunación son discutidas en este artículo, en conjunto con una serie de recomendaciones sobre cómo abordar estas preocupaciones. Estas recomendaciones pueden resultar de utilidad para los tomadores de decisión y actores sanitarios, en esta etapa temprana del desarrollo de un programa de vacunación.

[Clinical Update on Diagnosis, Treatment and Prevention of Dengue]. / Atualização Clínica sobre Diagnóstico, Tratamento e Prevenção da Dengue.

Dengue is a vector-borne disease that has a significant impact on global public health. The vector mosquito belongs to the genus Aedes. Two species play a key role in human transmission: Ae. aegypti, which has adapted to the urban environment of highly populated areas in tropical and subtropical countries, leading to a dramatic increase in dengue cases over the years, and Ae. albopictus, which poses a potential threat to temperate climate countries due to its ability to adapt to colder climates. The disease is widespread across the world, posing a risk to nearly half of the world's population. Although most cases are asymptomatic, dengue causes a burden on healthcare systems and mainly affects the younger population. The disease is also spreading to temperate climate countries, thus becoming a global threat. Vector control measures and vaccine development have been the main prevention strategies, as there is still no effective treatment for the disease.

A dengue é uma doença transmitida por um vetor hematófago (mosquito) que possui um impacto significativo na saúde pública mundial. O mosquito transmissor pertence ao género Aedes. São duas as espécies responsáveis pela transmissão humana: o Ae. aegypti, que se adaptou ao ambiente urbano de áreas altamente populosas de países tropicais e subtropicais, resultando num aumento dramático dos casos de dengue ao longo dos anos; e o Ae. Albopictus, que representa uma potencial ameaça para os países de clima temperado pela sua capacidade de adaptação aos climas mais frios. A doença está presente em grande parte do mundo, colocando cerca de metade da população do planeta em risco. Embora a maioria dos casos seja assintomática, a dengue causa uma sobrecarga nos sistemas de saúde e impacta principalmente os jovens. A doença também tem vindo a alastrar-se a países de clima temperado, tornando-se uma ameaça global. As medidas de controlo vetorial e o desenvolvimento de vacinas têm sido as principais estratégias de prevenção, uma vez que não existe ainda um tratamento eficaz para a doença.

[After the COVID-19 pandemic-Which new vaccinations for adults are available or coming soon?] / Nach der COVID-19-Pandemie ­ welche neuen Impfungen im Erwachsenenalter sind schon oder bald verfügbar?

The accumulation of respiratory infections in the winter months repeatedly highlights the relevance of prevention through vaccination, even beyond a pandemic. Current developments in this field are therefore highly relevant, particularly for older people who are more susceptible to infections due to immune senescence and comorbidities. The Standing Committee on Vaccination (STIKO) has responded accordingly by recommending the 20-valent pneumococcal conjugate vaccine PCV20 for standard and indication vaccination of adults. Furthermore, new vaccines against respiratory syncytial virus (RSV) infections are available for which the STIKO has not yet issued a recommendation. The development of other more effective and more immunogenic vac2cines is being driven in particular by new technologies, such as mRNA or vector vaccines. Various higher valent pneumococcal vaccine candidates and, for example, universal influenza vaccines are also already in development.

Dengue havoc: overview and eco-friendly strategies to forestall the current epidemic.

Dengue fever is a mosquito-borne viral illness that affects over 100 nations around the world, including Africa, America, the Eastern Mediterranean, Southeast Asia, and the Western Pacific. Those who get infected by virus for the second time are at greater risk of having persistent dengue symptoms. Dengue fever has yet to be treated with a long-lasting vaccination or medication. Because of their ease of use, mosquito repellents have become popular as a dengue prevention technique. However, this has resulted in environmental degradation and harm, as well as bioaccumulation and biomagnification of hazardous residues in the ecosystem. Synthetic pesticides have caused a plethora of serious problems that were not foreseen when they were originally introduced. The harm caused by the allopathic medications/synthetic pesticides/chemical mosquito repellents has paved the door to employment of eco-friendly/green approaches in order to reduce dengue cases while protecting the integrity of the nearby environment too. Since the cases of dengue have become rampant these days, hence, starting the medication obtained from green approaches as soon as the disease is detected is advisable. In the present paper, we recommend environmentally friendly dengue management strategies, which, when combined with a reasonable number of vector control approaches, may help to avoid the dengue havoc as well as help in maintaining the integrity of the ecosystem.

Preparedness for the Dengue Epidemic: Vaccine as a Viable Approach.

Dengue fever is one of the significant fatal mosquito-borne viral diseases and is considered to be a worldwide problem. Aedes mosquito is responsible for transmitting various serotypes of dengue viruses to humans. Dengue incidence has developed prominently throughout the world in the last ten years. The exact number of dengue cases is underestimated, whereas plenty of cases are misdiagnosed as alternative febrile sicknesses. There is an estimation that about 390 million dengue cases occur annually. Dengue fever encompasses a wide range of clinical presentations, usually with undefinable clinical progression and outcome. The diagnosis of dengue depends on serology tests, molecular diagnostic methods, and antigen detection tests. The therapeutic approach relies completely on supplemental drugs, which is far from the real approach. Vaccines for dengue disease are in various stages of development. The commercial formulation Dengvaxia (CYD-TDV) is accessible and developed by Sanofi Pasteur. The vaccine candidate Dengvaxia was inefficient in liberating a stabilized immune reaction toward different serotypes (1-4) of dengue fever. Numerous promising vaccine candidates are now being developed in preclinical and clinical stages even though different serotypes of DENV exist that worsen the situation for a vaccine to be equally effective for all serotypes. Thus, the development of an efficient dengue fever vaccine candidate requires time. Effective dengue fever management can be a multidisciplinary challenge, involving international cooperation from diverse perspectives and expertise to resolve this global concern.

Dengue: current state one year before WHO 2010-2020 goals.

BACKGROUND: Dengue is a possibly life-threatening human mosquito-borne viral infection widely spread in peridomestic (sub)tropical climates. The global incidence has expanded rapidly in the last decades, with 40% of the world's population currently at risk. To date, no anti-viral treatment other than supportive care exists. In 2015, the first and only dengue-vaccine, CYD-TDV, received marketing authorization. OBJECTIVES: To present the current understanding of dengue in terms of epidemiology, transmission, pathogenesis, disease management and prevention. To illustrate the knowledge gaps that remain to be filled in order to control dengue and achieve the WHO 2010-2020 goals. METHODS: An updated systematic review (2009-2019) was carried out. The databases Pubmed, Embase and The Cochrane Library were searched along with WHO and CDC guidelines. RESULTS: In total, 39 articles were included. Contemporary climatic and economic factors significantly contributed to the emergence of epidemic dengue. Unfortunately, CYD-TDV failed to meet safety and efficacy demands. New vaccination approaches are in the pipeline along with innovative vector-control strategies. Current anti-viral drug research focuses on repurposing drugs in addition to specific anti-dengue strategies that interfere with viral replication. CONCLUSION: The lack of understanding dengue pathogenesis and immunology has hampered the development of an effective vaccine. Recent research has provided new insights into the therapeutic and prophylactic approach. Implementation of complementary methods to control disease burden are required considering the socio-economic impact of this rapidly emerging global disease.

Vaccination coverage and adherence to a dengue vaccination program in the state of Paraná, Brazil.

The success of vaccination programs depends on the level of acceptance of the vaccine to achieve high vaccine coverage rates (VCR). Vaccine hesitancy is a challenge, especially concerning new vaccines. Dengue vaccine, Dengvaxia®, was licensed in Brazil in 2015 and implemented, in a pioneering publicly-funded initiative in the state of Paraná, between 2016 and 2018. The vaccination program took place in five phases in the 30 municipalities most affected by dengue in the state, targeting individuals from nine to 44 years-old in two cities and from 15 to 27 years-old in the other 28 municipalities, totaling a target population of 500,000 individuals. A cross-sectional descriptive study was carried out to assess VCR and adherence to the dengue vaccine in this program. VCR, dropout ratio (DR), and compliance with the vaccination schedule (CVS) were analyzed by sex, age group, and municipality size. A total of 302,603 individuals (60.5%) received ≥ 1 dose, 44.2% received ≥ 2 doses, and 28.6% 3 doses. The DR was 52.8%. Among individuals who started vaccination, 40.6% achieved CVS. The highest VCR, highest CVS, and lowest DR occurred in the age group from 9 to 14 years old and from 28 to 44 years old and in smaller municipalities. A greater proportion of men started vaccination (male 64.0%; female 57.1%) however, the DR was higher in men (male 55.4%; female 49.9%), and a higher percentage of women completed the vaccination schedule according to the recommendations (CVS male 37.8%; female 43.6%). Differences were noted in the CVS according to the initial phase of the program (first phase 50.8%; second phase 18.8%). The heterogeneity in vaccine uptake and compliance according to sex, age, and municipality size suggests the need for differentiated strategies to address challenges with new and multiple-dose vaccines.

Transcutaneous Administration of Dengue Vaccines.

In the present study, we evaluated the immunological responses induced by dengue vaccines under experimental conditions after delivery via a transcutaneous (TC) route. Vaccines against type 2 Dengue virus particles (DENV2 New Guinea C (NGC) strain) combined with enterotoxigenic Escherichia coli (ETEC) heat-labile toxin (LT) were administered to BALB/c mice in a three-dose immunization regimen via the TC route. As a control for the parenteral administration route, other mouse groups were immunized with the same vaccine formulation via the intradermic (ID) route. Our results showed that mice vaccinated either via the TC or ID routes developed similar protective immunity, as measured after lethal challenges with the DENV2 NGC strain. Notably, the vaccine delivered through the TC route induced lower serum antibody (IgG) responses with regard to ID-immunized mice, particularly after the third dose. The protective immunity elicited in TC-immunized mice was attributed to different antigen-specific antibody properties, such as epitope specificity and IgG subclass responses, and cellular immune responses, as determined by cytokine secretion profiles. Altogether, the results of the present study demonstrate the immunogenicity and protective properties of a dengue vaccine delivered through the TC route and offer perspectives for future clinical applications.

Dengue vaccine: a key for prevention.

INTRODUCTION: Dengue infection is the most important mosquito-borne viral disease in the world. Most mosquito control methods currently available for public health use are not very efficacious. Dengue vaccine is required to control dengue diseases in the future through the use of a safe and effective vaccine. AREAS COVERED: This review covered dengue vaccine development and candidate dengue vaccines in the clinical trial pipeline including licensed dengue vaccine. EXPERT OPINION: Dengue has become an intractable global health problem. Vector control has achieved only limited success in reducing the transmission of dengue. A dengue vaccine is needed as part of an integrated approach to dengue prevention and control since dengue poses a heavy economic cost to the health system and society. Because dengue is a unique and complex disease developing a dengue vaccine has proven equally complex. However, there is an advanced pipeline of vaccine research currently in clinical and preclinical studies including live-attenuated vaccine candidates as well as virus-vectored and virus-like particle-based vaccines.

Comparison of purified psoralen-inactivated and formalin-inactivated dengue vaccines in mice and nonhuman primates.

Dengue fever, caused by dengue viruses (DENV 1-4) is a leading cause of illness and death in the tropics and subtropics. Therefore, an effective vaccine is urgently needed. Currently, the only available licensed dengue vaccine is a chimeric live attenuated vaccine that shows varying efficacy depending on serotype, age and baseline DENV serostatus. Accordingly, a dengue vaccine that is effective in seronegative adults, children of all ages and in immunocompromised individuals is still needed. We are currently researching the use of psoralen to develop an inactivated tetravalent dengue vaccine. Unlike traditional formalin inactivation, psoralen inactivates pathogens at the nucleic acid level, potentially preserving envelope protein epitopes important for protective anti-dengue immune responses. We prepared highly purified monovalent vaccine lots of formalin- and psoralen-inactivated DENV 1-4, using Capto DeVirS and Capto Core 700 resin based column chromatography. Tetravalent psoralen-inactivated vaccines (PsIV) and formalin-inactivated vaccines (FIV) were prepared by combining the four monovalent vaccines. Mice were immunized with either a low or high dose of PsIV or FIV to evaluate the immunogenicity of monovalent as well as tetravalent formulations of each inactivation method. In general, the monovalent and tetravalent PsIVs elicited equivalent or higher titers of neutralizing antibodies to DENV than the FIV dengue vaccines and this response was dose dependent. The immunogenicity of tetravalent dengue PsIVs and FIVs were also evaluated in nonhuman primates (NHPs). Consistent with what was observed in mice, significantly higher neutralizing antibody titers for each dengue serotype were observed in the NHPs vaccinated with the tetravalent dengue PsIV compared to those vaccinated with the tetravalent dengue FIV, indicative of the importance of envelope protein epitope preservation during psoralen inactivation of DENV.

A Dengue Vaccine: Will It be Accepted and Is It Feasible? Lessons from Barranquilla, Colombia, and Merida, Venezuela.

With one vaccine on the market and others in clinical trials, policy makers in dengue endemic regions face the decision of whether to introduce a dengue vaccine in their communities. The World Health Organization (WHO) recommends that individualized assessments be conducted before any vaccine introduction to evaluate disease burden and the strength of current vaccination programs. This study seeks to aid in that decision-making process by examining the acceptability and feasibility of dengue vaccine introduction in Barranquilla, Colombia, and Merida, Venezuela. Surveys were administered February-June of 2018 for three groups: patients (n = 351), health professionals (n = 197), and government officials (n = 26). In Barranquilla, most respondents reported dengue to be a moderate-severe problem, that a dengue vaccine would be useful in their communities, and that their current vaccination programs could handle the addition of a new vaccine. In Venezuela, respondents were less likely to view dengue as a major concern and listed multiple barriers to not just dengue vaccine introduction, but to providing current vaccines as well. Further work is needed in Colombia to more objectively assess the country's readiness as a whole for a future dengue vaccine. As political and social unrest continues in Venezuela, however, future initiatives should focus on trust and capacity building. This study can serve as a framework for future assessments of the acceptability and feasibility of a dengue vaccine in both targeted areas and on larger scales.

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.