DVI Resources 
This occasional paper details various practical issues and some other complexities that will have to be considered when introducing a dengue vaccine, but as there is not (yet) a registered dengue vaccine, this overview must be considered as preliminary and tentative. Details relevant to the introduction of dengue vaccines will be clarified and become more specific as the vaccine candidates are further developed, so that more definitive recommendations can eventually be made.
This occasional paper outlines the complex challenges facing the laboratory diagnosis and surveillance of dengue, which in turn raise challenges facing efforts to estimate the burden and costs of the disease, and how these multiple challenges might affect the development, registration and eventual introduction of dengue vaccines. The Pediatric Dengue Vaccine Initiative (PDVI) recognizes these challenges, and has made efforts to address them in a systematic way as explained in this paper.
(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.
(Abstract) In this review, we consider the issues impacting conduct and design of dengue vaccine trials with reference to the recently published World Health Organization “Guidelines for Conduct of Clinical Trials of Dengue Vaccines in Endemic Areas.” We discuss logistic, scientific and ethical challenges concerning evaluation and introduction of dengue vaccines; these range from randomized trials that establish “proof of concept” of vaccine efficacy, to post-“proof of concept” trials, particularly demonstration projects likely to be required for licensure or for the introduction of an already licensed vaccine into public use. We clarify and define the meaning of “proof of concept” in the clinical trial context and the meaning of terms “phase 2b”, “phase 3b” and “demonstration project”, which are commonly used but have not been defined well in the clinical literature.
(Abstract) Dengue virus is the most common arboviral infection of humans in the tropical and subtropical regions of the world. This review briefly describes some of the challenges it presents. Dengue is an emerging disease; it is increasing in geographical distribution and severity, despite being significantly underreported. The existence of four closely related dengue virus serotypes contributes to difficulties in diagnosis and to original antigenic sin in the serological response to infection. The existence of multiple serotypes can result in more severe disease upon a second infection and complicates vaccine development.
At present there are no licensed vaccines to prevent dengue, and no effective anti-viral drugs are available for treatment. However, several different live, attenuated vaccines are in clinical trials. Major questions related to the development of dengue vaccines arise due to the existence of multiple serotypes and the tendency for second infections to provoke serious, life-threatening illness, observed in dengue endemic areas. Obstacles to vaccine development have included the need for a tetravalent product and the lack of an animal model for the disease, an in vitro correlate of protection, and a surrogate for vaccine efficacy.
(Abstract) The global spread of dengue fever within and beyond the usual tropical boundaries threatens a large percentage of the world's population, as human and environmental conditions for persistence and even spread are present in all continents. The disease casuses great human suffering, a sizable mortality from dengue haemorrhagic fever and its complications, and major costs. This situation has worsened in the recent past and may continue to do so in the future. Efforts to decrease transmission by vector control have failed, and no effective antiviral treatment is available or foreseeable on the immediate horizon. A safe and effective vaccine protective against all serotypes of dengue viruses is sorely needed.
[Abstract]
Background: Dengue fever is a virus infection that is spread by the Aedes aegypti mosquito and can cause severe disease especially in children. Dengue fever is a major problem in tropical and sub-tropical regions of the world.
Methodology/Principal Findings: We invited dengue experts from around the world to attend meetings to discuss dengue surveillance. We reviewed literature, heard detailed reports on surveillance programs, and shared expert opinions.
Results: Presentations by 22 countries were heard during the 2.5 day meetings. We describe the best methods of surveillance in general, the stakeholders in dengue surveillance, and the steps from mosquito bite to reporting of a dengue case to explore how best to carry out dengue surveillance. We also provide details and a comparison of the dengue surveillance programs by the presenting countries.
Conclusions/Significance: The experts provided recommendations for achieving the best possible data from dengue surveillance accepting the realities of the real world (e.g., limited funding and staff). Their recommendations included: (1)Every dengue endemic country should make reporting of dengue cases to the government mandatory; (2) electronic reporting systems should be developed and used; (3) at minimum dengue surveillance data should include incidence, hospitalization rates, deaths by age group; (4) additional studies should be completed to check the sensitivity of the system; (5) laboratories should share expertise and data; (6) tests that identify dengue virus should be used in patients with fever for four days or less and antibody tests should be used after day 4 to diagnose dengue; and (7) early detection and prediction of dengue outbreaks should be goals for national surveillance systems.
(Abstract) Dengue vaccines are now in late-stage development, and evaluation and robust estimates of dengue disease burden are needed to facilitate further development and introduction. In Cambodia, the national dengue case-definition only allows reporting of children less than 16 years of age, and little is known about dengue burden in rural areas and among older persons. To estimate the true burden of dengue in the largest province of Cambodia, Kampong Cham, we conducted community-based active dengue fever surveillance among the 0-to-19–year age group in rural villages and urban areas during 2006–2008. The large-scale active surveillance study for dengue fever in Cambodia found a higher disease incidence than reported to the national surveillance system, particularly in preschool children and that disease incidence was high in both rural and urban areas. It also confirmed the previously observed focal nature of dengue virus transmission.
(Abstract) Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ~50 million dengue infections and ~500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and
vaccines that are currently under development could also make an important contribution to dengue control in the future.