The future of dengue vaccines Date: 10/19/2002 Author: Halstead SB, Deen J

Type: Journal Articles

(Abstract) Every year, there are several hundred thousand cases of dengue haemorrhagic 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. Dengue vaccines must provide solid and longlasting protection against all four dengue viruses or, in dengue-endemic countries, there is the risk of sensitising 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. Evidence that dengue vaccines should succeed comes from encouraging experience with attenuated vaccines against related viruses such as yellow fever (YF) and Japanese encephalitis (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 200102. Scientific consultation on immunological correlates of protection induced by dengue vaccines report from a meeting held at the World Health Organization 17-18 November 2005 Date: 05/22/2007 Author: Hombach J, et al.

Type: Journal Articles

(Abstract) Several dengue vaccine candidates have been evaluated in early clinical phase, and some are scheduled for efficacy testing in population-based studies. Given the advancements in dengue vaccine development, there is an increased interest in identifying immunological correlates of protection for these vaccines in order to facilitate their evaluation, further refinement, production and registration. To this end, the WHO Initiative for Vaccine Research (IVR) convened a consultation on primary and secondary immunological correlates of protection induced by dengue vaccines. The meeting was held on the 17th and 18th of November, 2005 at WHO headquarters in Geneva. The consultation was a first dedicated review of the available data in support of establishing correlates. It is concluded that it is not yet possible to define one specific set of correlates, the consultation concluded in recommendations that should help to gather the missing evidence in conjunction with future vaccine trials.

Scientific consultation on cell mediated immunity (CMI) in dengue and dengue vaccine development

Date: 01/14/2009 Author: Thomas SJ, Hombach J, Barrett A

Type: Journal Articles

(Abstract) Dengue is a re-emerging arboviral disease of great public health importance. Limited understanding of protective immune responses against dengue has hampered advancement of dengue vaccine candidates. Demonstrating an immunological correlate of protection has been limited to associating quantitative neutralizing antibody titers with clinical outcomes following infection. There have been a number of studies investigating the role of cell mediated immunity (CMI) in natural infections and these have demonstrated roles in both virus clearance and potentiating disease. Vaccine developers have extended the exploratory study of CMI in natural infection to the study of dengue vaccine recipients.

Guidelines for clinical trials of dengue vaccine in endemic areas Date: 10/01/2009 Author: Hombach J

Type: Journal Articles

(Abstract) Guidelines for the clinical evaluation of dengue vaccines in endemic areas have recently been developed, building upon earlier recommendations published in 2002. This new document discusses the rationale and background of dengue vaccine trials and outlines dengue case definitions, proposed efficacy end points, requirements for trial sites, methods of measurement and proposed safety schedules. Demonstrated protective efficacy against each of the four dengue virus serotypes without safety concerns is the objective of any candidate tetravalent vaccine clinical trial. Accurate epidemiological data of dengue and other circulating flaviviruses over multiple transmission seasons are required to address factors such as background flavivirus immunity and subclinical infections that may confound serological results. Furthermore, bridging and post-licensure studies may be necessary to extend conclusions concerning vaccine characteristics, while co-administration trials are necessary in paediatrics. These guidelines are primarily aimed at national regulatory authorities, vaccine developers and research scientists and should be analysed, discussed and adjusted where necessary.

WHO Working Group on technical specifications for manufacture and evaluation of dengue vaccines, Geneva, Switzerland, 11-12 May 2009 Date: 12/06/2010 Author: Trent D, Shin J, Hombach J, Knezevic I, Minor P; WHO Working Group

Type: Journal Articles

(Abstract) In May 2009, a group of international experts on dengue, vaccine quality and clinical evaluation met together (i) to review disease, vaccine pipeline, quality issues in manufacturing, issues of environmental risk assessment, nonclinical and clinical evaluation of live recombinant dengue vaccines and (ii) to initiate revising WHO guidelines for the production and quality control of candidate tetravalent dengue vaccines (live). This report summarizes an exchange of views on scientific and technical issues related to the quality, safety and efficacy of candidate dengue vaccines. Recognizing live dengue vaccines are the major vaccines in the clinical pipeline, the Working Group agreed (i) to focus on live dengue vaccines in the revision of the WHO guidelines and (ii) to add new guidelines on nonclinical and clinical evaluation, and environmental risk assessment for live dengue vaccines in the revision.

Development of Sanofi Pasteur tetravalent dengue vaccine Date: 09/16/2010 Author: Guy B, Saville M, Lang J

Type: Journal Articles

(Abstract) The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of 4 recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the TV dengue vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D and does not infect mosquitoes by the oral route. TV dengue vaccine reactogenicity, viraemia induction and antibody responses were investigated in three Phase I trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. Results showed that the majority of adverse events were mild to moderate and transient in nature. Viraemia was transient and low, and was not increased after initial dengue TV administration, even in the case of incomplete responses. Finally, the challenges inherent to the development of such TV dengue vaccines will also be discussed in the last part of this review. In conclusion, preclinical and clinical results support the favorable immunogenicity and short-term safety of the dengue TV vaccine. An extensive clinical development program for dengue TV is underway including completion of the enrollment of 4,000 4-11 years old children in an efficacy trial in Thailand, in an area of high dengue incidence. Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.

Update on dengue: epidemiology, virus evolution, antiviral drugs, and vaccine development Date: 05/01/2010 Author: Wilder-Smith A, Ooi EE, Vasudevan SG, Gubler DJ

Type: Journal Articles

(Abstract) Dengue virus is the most widespread geographically of the arboviruses and a major public health threat in the tropics and subtropics. Scientific advances in recent years have provided new insights about the pathogenesis of more severe disease and novel approaches into the development of antiviral compounds and dengue vaccines. The efforts to find specific dengue inhibitors are intensifying and the tools to evaluate the efficacy of new drugs are now in place for rapid translation into trials in humans. Furthermore, several dengue vaccine candidates are in development, of which the chimeric dengue/yellow fever vaccine has now entered phase 3 trials. Until the availability of a licensed vaccine, disease surveillance and vector population control remain the mainstay of dengue prevention.

Dengue Date: 11/10/2007 Author: Halstead SB

Type: Journal Articles

(Abstract) The four dengue viruses are transmitted in tropical countries that circle the globe. All can cause syndromes that are self-limited or severe. The common severe syndrome--dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS)--is characterised by sudden vascular permeability generated by cytokines released when T cells attack dengue-infected cells. Here, I review and discuss data on clinical diagnosis and pathophysiology of vascular permeability and coagulopathy, parenteral treatment of DHF/DSS, and new laboratory tests.

Dengue haemorrhagic fever--a public health problem and a field for research Date: 01/01/1980 Author: Halstead SB

Type: Journal Articles

(Abstract) Dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS) is an enigmatic and growing public health problem which is confined at present to countries of South-East Asia. Epidemiological studies in South-East Asia clearly link DHF/DSS to individuals who have had a previous dengue infection or who have acquired maternal dengue antibody. There is an urgent need for a comprehensive identification of "risk factors" in DHF/DSS. This research could be approached by undertaking comparative prospective epidemiological studies in dengue-endemic areas with and without DHF/DSS.

Dengue surveillance in preparation for field vaccine trials Date: 10/01/2009 Author: Letson GW

Type: Journal Articles

(Abstract) Preparations for dengue vaccine trials as well as vaccine introduction strategies require laboratory-based surveillance on an international and coordinated level. The Pediatric Dengue Vaccine Initiative (PDVI) has developed an international consortium of field sites in Latin America and Asia. These sites conduct community-based and enhanced passive laboratorybased surveillance of dengue fever. Through this consortium, PDVI is facilitating harmonized laboratory-based surveillance processes, so that disease incidence can be compared between different regions and countries. Prevention of dengue fever is the most suitable primary end point for a proof-of-concept dengue vaccine trial. However, such trials may provide insufficient information for stratified analysis of outcomes according to varied risk factors and virus serotype. Consequently large community-based demonstration trials may be necessary.

Review of dengue virus and the development of a vaccine Date: 03/01/2011 Author: Murrell S, Wu SC, Butler M

Type: Journal Articles

(Abstract) Dengue viral infection has become an increasing global health concern with over two-fifths of the world's population at risk of infection. It is the most rapidly spreading vector borne disease, attributed to changing demographics, urbanization, environment, and global travel. It continues to be a threat in over 100 tropical and sub-tropical countries, affecting predominantly children. Dengue also carries a hefty financial burden on the health care systems in affected areas, as those infected seek care for their symptoms. The search for a suitable vaccine for dengue has been ongoing for the last sixty years, yet any effective treatment or vaccine remains elusive. A vaccine must be protective for all four serotypes of dengue and be cost-effective. Many approaches to developing candidate vaccines have been employed. The candidates include live attenuated tetravalent vaccines, chimeric tetravalent vaccines based on attenuated dengue virus or Yellow Fever 17D, and recombinant DNA vaccines based on flavivirus and non-flavivirus vectors. This review outlines the challenges involved in dengue vaccine development and presents the current stages of proposed vaccine candidate development.

Dengue vaccines: progress and challenges Date: 06/01/2011 Author: Coller BA, Clements DE

Type: Journal Articles

(Abstract) With several dengue vaccine candidates progressing through clinical trials, several options for controlling this disease appear feasible. This would represent a major achievement

and reflect decades of research and development activities. The challenges associated with the limited understanding of protective responses and those factors which determine disease severity remain, but with prospective studies ongoing in various dengue endemic areas and the initiation of dengue vaccine efficacy trials, immune responses are being evaluated in the context of protection and severe disease and these studies are highly likely to provide additional insights.

Dengue and dengue hemorrhagic fever in the Americas: lessons and challenges Date: 05/01/2003 Author: Guzman MG, Kouri G

Type: Journal Articles

(Abstract) The incidence of dengue and dengue hemorrhagic fever (DF/DHF) has increased significantly over the last decades. Yearly, an estimated 50-100 million cases of DF and about 250,000-500,000 cases of DHF occur worldwide. The epidemiological situation in Latin America now resembles that in Southeast Asia. Here, the main clinical, epidemiological and virological observations in the American region are presented and compared with those previously reported from Southeast Asia.

The growing burden of dengue in Latin America Date: 10/01/2009 Author: Tapia-Conyer R, Mndez-Galvn JF, Gallardo-Rincn H

Type: Journal Articles

(Abstract) The re-emergence and subsequent failure to control dengue in Latin America provides a compelling illustration of the clinical, political and socio-economic challenges to eradicating dengue across the world. Insufficient political commitment, inadequate financial resources and increased urbanisation have contributed to the re-emergence and dramatic increase in dengue fever and dengue haemorrhagic fever in all 19 Latin American countries previously certified as free of Aedes aegypti. Successful introduction of a dengue vaccine will require an educational programme that clearly communicates the cost-effectiveness and desirability of this interventional measure.

Global Spread and Persistence of Dengue Date: 04/22/2008 Author: Kyle JL, Harris E

Type: Journal Articles

(Abstract) Dengue viruses have evolved rapidly as they have spread worldwide, and genotypes associated with increased virulence have expanded from South and Southeast Asia into the Pacific and the Americas. This review explores the human, mosquito, and viral factors that contribute to the global spread and persistence of dengue, as well as the interaction between the three spheres, in the context of ecological and climate changes. What is known, as well as gaps in knowledge, is emphasized in light of future prospects for control and prevention of this pandemic disease.

Cost-effectiveness of a pediatric dengue vaccine Date: 09/03/2003 Author: Shepard DS, et al.

Type: Journal Articles

(Abstract) To ascertain the economic feasibility of a pediatric tetravalent dengue vaccine, we developed and calibrated a cost-effectiveness model of vaccinating children at 15 months in Southeast (SE) Asia using a societal perspective.We assumed that full immunization would require two doses at prices of US$ 0.50 and US$ 10 per dose in the public and private sectors, respectively. The gross cost per 1000 population (of all ages) of the vaccination program would be US$ 154. Due to projected savings in dengue treatment, the net cost per capita would be only US$ 17 (89% below the gross cost). The cost per disability adjusted life year (DALY) saved by a pediatric vaccine would be US$ 50, making the potential vaccine highly cost-effective. Eventually, vaccination may be able to replace environmental control as a strategy for dengue prevention and be cost saving.

Economic impact of dengue fever/dengue hemorrhagic fever in Thailand at the family and population levels Date: 06/01/2005 Author: Clark DV, et al.

Type: Journal Articles

(Abstract) Dengue fever and dengue hemorrhagic fever constitute a substantial health burden on the population in Thailand. In this study, the impact of symptomatic dengue virus infection on the families of patients hospitalized at the Kamphaeng Phet Provincial Hospital with laboratoryconfirmed dengue in 2001 was assessed, and the disability-adjusted life years (DALYs) lost for fatal and non-fatal cases of dengue were calculated using population level data for Thailand. When we accounted for the direct cost of hospitalization, indirect costs due to loss of productivity, and the average number of persons infected per family, we observed a financial loss of approximately US$61 per family, which is more than the average monthly income in Thailand. This figure is of the same order of magnitude as the impact of several diseases currently given priority in southeast Asia, such as the tropical cluster (trypanosomiasis, Chagas

disease, schistosomiasis, leishmaniasis, lymphatic filariasis, and onchocerciasis), malaria, meningitis, and hepatitis. These results indicate that dengue prevention, control, and research should be considered equally important as that of diseases currently given priority.

Cost of dengue and other febrile illnesses to households in rural Cambodia: a prospective community-based case-control study Date: 05/27/2009 Author: Huy R, et al.

Type: Journal Articles

(Abstract) The average annual reported dengue incidence in Cambodia is 3.3/1,000 among children <15 years of age (20022007). To estimate the economic burden of dengue, accurate cost-of-illness data are essential. We conducted a prospective, community-based, matched casecontrol study to assess the cost and impact of an episode of dengue fever and other febrile illness on households in rural Cambodia. In Cambodia, dengue and other febrile illnesses pose a financial burden to households. A possible reason for a lower rate of hospitalization among children from poor households could be the burden of higher illness-related costs and debts.

Cost and disease burden of Dengue in Cambodia Date: 08/31/2010 Author: Beaut J, Vong S

Type: Journal Articles

(Abstract) Dengue is endemic in Cambodia (pop. estimates 14.4 million), a country with poor health and economic indicators. Disease burden estimates help decision makers in setting priorities. Using recent estimates of dengue incidence in Cambodia, we estimated the cost of dengue and its burden using disability adjusted life years (DALYs). Our analysis confirmed the high societal and individual family burden of dengue. Total costs represented between 0.03 and 0.17% of Gross Domestic Product. Health seeking behavior has a major impact on costs. The more accurate estimate used in this study will better allow decision makers to account for dengue costs particularly among the poor when balancing the benefits of introducing a potentially effective dengue vaccine. Health Economics of Dengue: A Systematic Literature Review and Expert Panels Assessment Date: 03/01/2011 Author: Beatty ME, et al.

Type:

Journal Articles

(Abstract) Dengue vaccines are currently in development and policymakers need appropriate economic studies to determine their potential financial and public health impact. We searched five databases (PubMed, EMBASE, LILAC, EconLit, and WHOLIS) to identify health economics studies of dengue. Forty-three manuscripts were identified that provided primary data: 32 report economic burden of dengue and nine are comparative economic analyses assessing various interventions. The remaining two were a willingness-to-pay study and a policymaker survey. An expert panel reviewed the existing dengue economic literature and recommended future research to fill information gaps. Although dengue is an important vectorborne disease, the economic literature is relatively sparse and results have often been conflicting because of use of inconsistent assumptions. Health economic research specific to dengue is urgently needed to ensure informed decision making on the various options for controlling and preventing this disease.

Economic Value of Dengue Vaccine in Thailand Date: 05/01/2011 Author: Lee BY, et al.

Type: Journal Articles

(Abstract) With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (costeffectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual ( 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A 50% efficacious vaccine was highly cost-effective [< 1 per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3 per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving.