Introduction Of Dengue Vaccine Research Articles

Seroprevalence of dengue virus infection in Pune City in India, 2019: A decadal change

BackgroundThe burden of dengue infection needs to be monitored along with tracking of the changes in dengue virus (DENV) transmission intensity for vaccine introduction decisions. MethodsThe seroprevalence of dengue was investigated in Pune City in India, in early 2019 using 1654 sera from apparently healthy human participants enrolled randomly through multistage cluster sampling. We used 797 retrospective human sera from late 2009 for comparison. All sera were assessed for the presence of dengue-specific IgG antibodies. A subset (n = 230) was tested for serotype-specific plaque reduction-neutralizing antibodies against all four serotypes. ResultsThe dengue IgG seroprevalence of 62.9% (95% CI 59.4–66.1) in 2009 increased to 88.4% (95% CI 86.8–89.8) in 2019. Age-stratified dengue seroprevalence revealed a gradual increase in IgG seropositivity from 70.1% in 0–9 years to 85.0% in 10–19 years. The annual probability of dengue infection estimated as a force of infection was 4.1 (95% CI 3.8–4.5) in 2009, which increased to 10.9 (95% CI 10.2–11.6) in 2019. Analysis of dengue serotype-specific neutralizing antibodies revealed DENV-3 as the dominant serotype. The age of exposure to at least one dengue serotype was reduced in 2019 over 2009. ConclusionsThere was a significant increase in the intensity of dengue virus transmission in Pune City over the decade. Since over 85% of the participants above nine years of age had exposure to DENV by 2019, dengue vaccine introduction can be considered. Moreover, such repeated serosurveys in different regions might inform about the readiness of the population for dengue vaccination.

Dengue virus seroprevalence study in Bangphae district, Ratchaburi, Thailand: A cohort study in 2012-2015.

BackgroundTo determine the seroprevalence and transmission dynamics of dengue virus (DENV), age-stratified longitudinal serological surveys were conducted in Bangphae district, Ratchaburi province, Thailand, for 3 years between April 2012 and April 2015.MethodologyThe surveys enrolled 2012 healthy children and adults between 1 and 55 years-of-age, and a longitudinal serosurvey of six repeated bleeds of the same cohort of individuals was conducted every 8 months for the first 2 years (M0, M8, M16) and every half a year (M24, M30, M36) for the rest of the study period. All samples were tested using in-house indirect sandwich dengue IgG ELISA to determine DENV antibody titer, and 640 paired samples which showed rising of DENV IgG titers in paired serum were further tested using in-house neutralization assay, Plaque Reduction Neutralization Test (PRNT50).Principal findingsWhen compared against the gold standard based on the results of PRNT50, sensitivity and specificity of indirect ELISA were found to be both about 85%. The overall DENV IgG positivity determined by ELISA was 74.3% in 2012 and increased to 79.4% by the final sample collection in 2015. In our study sample, more than 98% of subjects older than 25 years were found to be seropositive. Among 518 IgG negative subjects at enrollment, the seroconversion rates were measured in paired bleeds; the rates (between successive visits, approximately 6 months) ranged between 4.8% (between M16 and M24) and 14.7% (between M0 and M8). The dominant serotype of primary DENV infection cases based on seroconversion was identified from the PRNT results and it was DENV-2.ConclusionsOur study documented high levels of seroprevalence and rate of transmission. Given the importance of the serostatus and disease burden in consideration for dengue vaccine introduction, our data could be used in decision-making on implementation of various dengue control and preventive measures.

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.

Dengue virus serological prevalence and seroconversion rates in children and adults in Medellin, Colombia: implications for vaccine introduction

Dengue is an important public health problem worldwide. A vaccine has recently been licensed in some countries of Latin America and Asia. Recommendations for dengue vaccine introduction include endemicity and a high serological prevalence of dengue in the territories considering its introduction. A community-based survey was conducted to estimate dengue seroprevalence and age-specific seroconversion rates in a community in Medellin, Colombia, using a dengue serological test (IgG indirect ELISA). Residents were selected at random and were first screened for dengue infection; they were then followed over 2.5 years. A total of 3684 individuals aged between 1 and 65 years participated in at least one survey. The overall dengue seroprevalence was 61%, and only 3.3% of seropositive subjects self-reported a past history of dengue. Among dengue virus (DENV)-naïve subjects with more than two visits (n=1002), the overall seroconversion rate was 8.7% (95% confidence interval 7.3-10.4) per 1000 person-months, over the study period. Overall, the mean age of DENV prevalent subjects was significantly higher than the mean age of seroconverted subjects. Specifically, DENV seropositivity over 70% was observed in participants over 21 years old. Serotype-specific plaque-reduction neutralization tests (PRNT) revealed that all four dengue serotypes were circulating, with DENV4 being most prevalent. These laboratory-based findings could inform dengue vaccine decisions, as they provide age-specific seroprevalence and seroconversion data, evidencing permanent and ongoing dengue transmission in the study area. This study provides evidence for the existing rates of secondary and heterotypic responses, presenting a challenge that must be addressed adequately by the new vaccine candidates.

Willingness to pay for a dengue vaccine and its associated determinants in Indonesia: A community-based, cross-sectional survey in Aceh

Vaccination strategies are being considered as a part of dengue prevention programs in endemic countries. To accelerate the introduction of dengue vaccine into the public sector program and private markets, understanding the private economic benefits of a dengue vaccine is therefore essential. The aim of this study was to assess the willingness to pay (WTP) for a dengue vaccine among community members in Indonesia and its associated explanatory variables. A community-based, cross-sectional survey was conducted in nine regencies of Aceh province, Indonesia, from November 2014 to March 2015. A pre-tested validated questionnaire was used to facilitate the interviews. To assess the explanatory variables influencing participants’ WTP for a dengue vaccine, a linear regression analysis was employed. We interviewed 677 healthy community members; 476 participants (87.5% of the total) were included in the final analysis. An average individual was willing to pay around US-$ 4 (mean: US-$ 4.04; median: US-$ 3.97) for a dengue vaccine. Our final multivariate model revealed that working as a civil servant, living in the city, and having good knowledge on dengue viruses, a good attitude towards dengue, and good preventive practice against dengue virus infection were associated with a higher WTP (P<0.05). Our model suggests that marketing efforts should be directed to community members who are working in the suburbs especially as farmers. In addition, the results of our study underscore the need for low-cost quality vaccines, public sector subsidies for vaccinations, and intensifying efforts to further educate and encourage households regarding other dengue preventive measures, using trusted individuals as facilitators.

Modifiable determinants of attitude towards dengue vaccination among healthy inhabitants of Aceh, Indonesia: Findings from a community-based survey.

To explore and understand the attitude towards dengue vaccination and its modifiable determinants among inhabitants of Aceh (northern Sumatra Island, Indonesia), the region that was most severely affected by the earthquake and tsunami of 26 December 2004. A community-based, cross-sectional study was conducted among 535 healthy inhabitants in nine regencies (Kabupaten or Kotamadya) of Aceh that were selected randomly from November 2014 to March 2015. A set of validated, pre-tested, structured questionnaires was used to guide the interviews. The questionnaires covered a range of explanatory variables and one outcome variable (attitude to dengue vaccination). Multi-step logistic regression analysis and Spearman's rank correlation were used to test the role of explanatory variables for the outcome variable. More than 70% of the participants had a poor attitude towards dengue vaccination. Modifiable determinants associated with poor attitude to dengue vaccination were low education level, working as farmers and traditional market traders, low socioeconomic status and poor knowledge, attitude and practice regarding dengue fever (P<0.05). The KAP domain scores were correlated strongly with attitude to dengue vaccination, rs=0.25, rs=0.67 and rs=0.20, respectively (P<0.001). Multivariate analysis found that independent predictors associated with attitude towards dengue vaccination among study participants were only sex and attitude towards dengue fever (P<0.001). This study reveals that low KAP regarding dengue fever, low education level and low socioeconomic status are associated with a poor attitude towards dengue vaccination. Therefore, inhabitants of suburbs who are working as farmers or traditional market traders with low socioeconomic status are the most appropriate target group for a dengue vaccine introduction program.

Introducing dengue vaccine: Implications for diagnosis in dengue vaccinated subjects

Diagnosis of dengue virus infections is complicated by preference for different diagnostic tests in different post onset days of illness and the presence of multiple serotypes leading to secondary and tertiary infections. The sensitivity of the most commonly employed diagnostic assays such as anti dengue IgM capture (MAC) ELISA and non structural protein (NS) 1 capture ELISA are lower in secondary and subsequent infections. Introduction of dengue vaccine in endemic regions will affect the way how dengue is diagnosed in vaccinated subjects. This viewpoint article discusses implications of introduction of dengue vaccine on the diagnosis of dengue infections in vaccinated subjects and the strategies that are needed to tackle the issue.

Dengue disease surveillance: improving data for dengue control.

Dengue disease surveillance: improving data for dengue control.

The introduction of dengue vaccine may temporarily cause large spikes in prevalence.

A dengue vaccine is expected to be available within a few years. Once vaccine is available, policy-makers will need to develop suitable policies to allocate the vaccine. Mathematical models of dengue transmission predict complex temporal patterns in prevalence, driven by seasonal oscillations in mosquito abundance. In particular, vaccine introduction may induce a transient period immediately after vaccine introduction where prevalence can spike higher than in the pre-vaccination period. These spikes in prevalence could lead to doubts about the vaccination programme among the public and even among decision-makers, possibly impeding the vaccination programme. Using simple dengue transmission models, we found that large transient spikes in prevalence are robust phenomena that occur when vaccine coverage and vaccine efficacy are not either both very high or both very low. Despite the presence of transient spikes in prevalence, the models predict that vaccination does always reduce the total number of infections in the 15 years after vaccine introduction. We conclude that policy-makers should prepare for spikes in prevalence after vaccine introduction to mitigate the burden of these spikes and to accurately measure the effectiveness of the vaccine programme.

Dengue: challenges for policy makers and vaccine developers.

Because of the increasing incidence, geographic expansion and economic burden of dengue transmission, dengue poses major challenges to policy makers. A vaccine against dengue is urgently needed, but vaccine development has been hampered by the lack of an appropriate animal model, poor understanding of correlates of successful human immunity, the fear of immune enhancement, and viral interference in tetravalent combinations. The most suitable target epitopes for vaccines, as well as the role of nonstructural proteins remain elusive. The chimeric yellow fever bone-based live attenuated dengue vaccine is furthest in development, but initial efficacy results have been disappointing. Lessons learnt from this failure will affect the design of future trials, and increase the urgency to identify the best epitope and immune correlates. Dengue vaccine introduction will not be the only strategy to combat dengue, but needs to be “packaged” with novel vector control approaches, with community-based interventions to reduce the number of breeding sites, and reducing the case fatality rate by improving case management.

Preparing for Dengue Vaccine Introduction: Recommendations from the 1st Dengue v2V International Meeting

groundwork for the accelerated introduction of effective dengue vaccines to endemic countries following regulatory approval. The aim of the initiative is to further our understanding of disease burden; raise awareness of the benefits of vaccination among regulatory agencies, national health authorities, and public health agencies; provide recommendations to national health authorities for vaccine

Will Dengue Vaccines Be Used in the Public Sector and if so, How? Findings from an 8-country Survey of Policymakers and Opinion Leaders

BackgroundA face-to-face survey of 158 policymakers and other influential professionals was conducted in eight dengue-endemic countries in Asia (India, Sri Lanka, Thailand, Vietnam) and Latin America (Brazil, Colombia, Mexico, Nicaragua) to provide an indication of the potential demand for dengue vaccination in endemic countries, and to anticipate their research and other requirements in order to make decisions about the introduction of dengue vaccines. The study took place in anticipation of the licensure of the first dengue vaccine in the next several years.Methods/Principal FindingsSemi-structured interviews were conducted on an individual or small group basis with government health officials, research scientists, medical association officers, vaccine producers, local-level health authorities, and others considered to have a role in influencing decisions about dengue control and vaccines. Most informants across countries considered dengue a priority disease and expressed interest in the public sector use of dengue vaccines, with a major driver being the political pressure from the public and the medical community to control the disease. There was interest in a vaccine that protects children as young as possible and that can fit into existing childhood immunization schedules. Dengue vaccination in most countries surveyed will likely be targeted to high-risk areas and begin with routine immunization of infants and young children, followed by catch-up campaigns for older age groups, as funding permits. Key data requirements for decision-making were additional local dengue surveillance data, vaccine cost-effectiveness estimates, post-marketing safety surveillance data and, in some countries vaccine safety and immunogenicity data in the local population.Conclusions/SignificanceThe lookout for the public sector use of dengue vaccines in the eight countries appears quite favorable. Major determinants of whether and when countries will introduce dengue vaccines include whether WHO recommends the vaccines, their price, the availability of external financing for lower income countries, and whether they can be incorporated into countries' routine immunization schedules.

Roadmap for successful dengue vaccine introduction

Worldwide dengue epidemics continue to increase; climate change, growing urbanization and migration patterns predict our scenario. These epidemiological and sociological conditions impose an overwhelming economic burden and use of health services due to dengue's high morbidity in all socioeconomically strata. Up to now, the most commonly used control strategy against dengue has been vector control, which has proven limited effectiveness. Thanks to R&D efforts a safe and effective dengue vaccine could become available in the near future. In this paramount, the countries develop preparedness plans for the introduction of a dengue vaccine that ought to include:-Determination of the real dengue burden of disease, by strengthening information systems and developing specific epidemiological studies.-Development of a vaccine introduction strategy: defining specific target populations, strengthening vaccine delivery platform, and training.-Adjustment of the regulatory requirements, to allow proper and timely licensing of the new vaccine.-Implementation of econometric studies to estimate costs involved in the vaccine introduction and cost-effectiveness analysis.-Strengthening dengue prevention and control programs.-Ensuring budgetary resources.-Preparation of health promotion and social dissemination strategy to ensure an adequate uptake of the vaccine. The development of a preparedness plan requires the leadership and active participation of all interested parties: public health agencies, academic bodies, research groups, regulatory authority and operational organizations focusing on five strategic areas:-Epidemiological information and burden of disease.-Vaccine introduction strategy and operative elements.-Legal and regulatory issues.Economic and financial issues.-Social communication and health promotion. Science, technology and human creativity, have come together to provide a public health innovation with great impact, to prevent a worldwide high burden disease; it is imperative for governments and society to ensure that this new tool, be incorporated in the national immunization programs and therefore reaching dengue control.

Cost of production of live attenuated dengue vaccines: A case study of the Instituto Butantan, Sao Paulo, Brazil

BackgroundA vaccine to prevent dengue disease is urgently needed. Fortunately, a few tetravalent candidate vaccines are in the later stages of development and show promise. But, if the cost of these candidates is too high, their beneficial potential will not be realized. The price of a vaccine is one of the most important factors affecting its ultimate application in developing countries. In recent years, new vaccines such as those for human papilloma virus and pneumococcal disease (conjugate vaccine) have been introduced with prices in developed countries exceeding $50 per dose. These prices are above the level affordable by developing countries. In contrast, other vaccines such as those against Japanese encephalitis (SA14-14-2 strain vaccine) and meningitis type A have prices in developing countries below one dollar per dose, and it is expected that their introduction and use will proceed more rapidly. Because dengue disease is caused by four related viruses, vaccines must be able to protect against all four. Although there are several live attenuated dengue vaccine candidates under clinical evaluation, there remains uncertainty about the cost of production of these tetravalent vaccines, and this uncertainty is an impediment to rapid progress in planning for the introduction and distribution of dengue vaccines once they are licensed. MethodWe have undertaken a detailed economic analysis, using standard industrial methodologies and applying generally accepted accounting practices, of the cost of production of a live attenuated vaccine, originally developed at the US National Institutes of Health (National Institute of Allergy and Infectious Diseases), to be produced at the Instituto Butantan in Sao Paulo, Brazil. We determined direct costs of materials, direct costs of personnel and labor, indirect costs, and depreciation. These were analyzed assuming a steady-state production of 60 million doses per year. ResultsAlthough this study does not seek to compute the price of the final licensed vaccine, the cost of production estimate produced here leads to the conclusion that the vaccine can be made available at a price that most ministries of health in developing countries could afford. This conclusion provides strong encouragement for supporting the development of the vaccine so that, if it proves to be safe and effective, licensure can be achieved soon and the burden of dengue disease can be reduced.

Policymakers’ views on dengue fever/dengue haemorrhagic fever and the need for dengue vaccines in four southeast Asian countries

A survey of policymakers and other influential professionals in four southeast Asian countries (Cambodia, Indonesia, Philippines and Vietnam) was conducted to determine policymakers’ views on the public health importance of dengue fever and dengue haemorrhagic fever (DHF), the need for a vaccine and the determinants influencing its potential introduction. The survey, which involved face-to-face interviews with policymakers, health programme managers, researchers, opinion leaders and other key informants, revealed an almost uniformly high level of concern about dengue fever/DHF and a high perceived need for a dengue vaccine. Several characteristics of the disease contribute to this high sense of priority, including its geographic spread, occurrence in outbreaks, the recurrent risk of infection each dengue season, its severity and the difficulty in diagnosis and management, its urban predominance, its burden on hospitals, and its economic toll on governments and families. Research felt to be key to future decision-making regarding dengue vaccine introduction include: disease surveillance studies, in-country vaccine trials or pilot projects, and studies on the economic burden of dengue and the cost-effectiveness of dengue vaccines. The results suggest favourable conditions for public and private sector markets for dengue vaccines and the need for creative financing strategies to ensure their accessibility to poor children in dengue-endemic countries.

The future of dengue vaccines

Every year there are several hundred thousand acres of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) resulting in thousands of deaths. The only method currently available to prevent dengue infections is the control of Aedes aegypti the mosquito vector. This approach has proved expensive and mostly unworkable. Serial infection occurs in most areas of the world where multiple dengue viruses circulate. A small percentage of second dengue infections result in DHF/DSS. Dengue vaccines must provide solid and long-lasting protection against all four dengue viruses or in dengue-endemic countries there is the risk of sensitizing recipients to severe disease. Many candidate dengue vaccines are moving towards clinical trials in human beings. These vaccines include several based on the formation of live-attenuated chimeric viruses. Yellow fever (YF) Japanese encephalitis (JE) and the four dengue viruses are all small single-strand positive-sense ribonucleic acid flaviviruses with similar genetic organization and replication strategies. Evidence that dengue vaccines should succeed comes from encouraging experience with attenuated vaccines against related viruses such as YF and JE and from a recent successful phase 1 trial of a chimera of these two viruses. This progress is timely because global dengue morbidity achieved an all time high during 2001-02. Thomas Monath and colleagues developed a live-attenuated chimeric vaccine against JE virus by replacing the premembrane (prM) and envelope (E) genes of the YF 17D vaccine with the corresponding genes from SA 14-14-2 an attenuated JE virus strain to produce YF-JE chimera. No unusual side-effects were seen in the phase 1 study and high titers of neutralizing antibodies to JE virus were found 3-4 weeks after inoculation of doses of 100000 and 1000. plaque-forming units. Similar methodology has been used to make chimera vaccines with YF virus for all four dengue viruses. Hence to ensure the introduction of safe and effective dengue vaccines for the worlds children ways must be found to accelerate phase 3 trials of tetravalent dengue vaccines in suitable people. Only testing in man can answer questions of safety and efficacy. A parallel effort is needed to understand protective mechanisms in dengue-infections especially those mediated by antibodies. The largest constraint to the solution of these problems is adequate funding which is now being addressed by a new international consortium. (authors)