Rémy Teyssou

From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine.

Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent dengue vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated vaccines (CYD-1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four dengue virus serotypes. The vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/III trials, and to anticipate and facilitate supply and access to vaccine in the countries where the dengue disease burden makes it an urgent public health priority. The vaccine has now been administered to more than 6000 children and adults from dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the vaccine. Preliminary results of an ongoing, proof-of-concept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful introduction of a dengue vaccine into immunization programs.

A Critical Assessment of Vector Control for Dengue Prevention

Recently, the Vaccines to Vaccinate (v2V) initiative was reconfigured into the Partnership for Dengue Control (PDC), a multi-sponsored and independent initiative. This redirection is consistent with the growing consensus among the dengue-prevention community that no single intervention will be sufficient to control dengue disease. The PDCs expectation is that when an effective dengue virus (DENV) vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. Although the concept of integrated intervention for dengue prevention is gaining increasingly broader acceptance, to date, no consensus has been reached regarding the details of how and what combination of approaches can be most effectively implemented to manage disease. To fill that gap, the PDC proposed a three step process: (1) a critical assessment of current vector control tools and those under development, (2) outlining a research agenda for determining, in a definitive way, what existing tools work best, and (3) determining how to combine the best vector control options, which have systematically been defined in this process, with DENV vaccines. To address the first step, the PDC convened a meeting of international experts during November 2013 in Washington, DC, to critically assess existing vector control interventions and tools under development. This report summarizes those deliberations.

Preparing for introduction of a dengue vaccine: Recommendations from the 1st Dengue v2V Asia-Pacific Meeting

Infection with dengue virus is a major public health problem in the Asia-Pacific region and throughout tropical and sub-tropical regions of the world. Vaccination represents a major opportunity to control dengue and several candidate vaccines are in development. Experts in dengue and in vaccine introduction gathered for a two day meeting during which they examined the challenges inherent to the introduction of a dengue vaccine into the national immunisation programmes of countries of the Asia-Pacific. The aim was to develop a series of recommendations to reduce the delay between vaccine licensure and vaccine introduction. Major recommendations arising from the meeting included: ascertaining and publicising the full burden and cost of dengue; changing the perception of dengue in non-endemic countries to help generate global support for dengue vaccination; ensuring high quality active surveillance systems and diagnostics; and identifying sustainable sources of funding, both to support vaccine introduction and to maintain the vaccination programme. The attendees at the meeting were in agreement that with the introduction of an effective vaccine, dengue is a disease that could be controlled, and that in order to ensure a vaccine is introduced as rapidly as possible, there is a need to start preparing now.

Dengue Shock Syndrome or Dehydration? The Importance of Considering Clinical Severity When Classifying Patients With Dengue

TO THE EDITOR—In a recent issue of Clinical Infectious Diseases, Lam et al reported the outcome of 1719 children admitted over a 10-year period and diagnosed with dengue shock syndrome (DSS) [1]. Patients were described as having had a severe clinical presentation resulting from plasma leakage and pulse pressure ≤20 mm Hg. The definition of DSS used was the 1997 World Health Organization (WHO) definition regarding pulse pressure and hematocrit determinations. However, other diagnostic procedures, such as laboratory tests for liver and renal function, coagulation, and acidbase determination, and the detection of serous effusion by imagery, were not completed in many patients. Finally, as stated by the authors, the main inclusion criterion was evidence of impaired perfusion “thought by the treating clinician to be due to vascular leakage and to require volume resuscitation.” In this series, most patients recovered within a few hours with a single infusion of saline and only 8 patients died, resulting in the lowest case-fatality rate in hospitalized dengue patients ever reported in Southeast Asia [2, 3]. Although the rapidity and quality of treatment are key factors in determining the chances of recovery, one can question the representativeness of this group of patients reported as having DSS. It is reasonable to suspect that many of these patients were not actually in shock, and that many patients with a straightforward dehydration associated with the febrile phase of the disease were included in a group of patients diagnosed with a severe plasma leakage. The issue is important when it comes to the inclusion of patients in clinical trials [4]. Describing the clinical forms of dengue is difficult because of the diversity and overlapping nature of the clinical manifestations. The frequency of any given category of patients in a cohort may be confounded by selection bias, and by the misuse of medical terms such as “hemorrhage” in patients who do not have clinically significant bleeding, or “shock” in patients with transient hypotension. Based on our clinical experience of severe dengue in adults [5] and field epidemic experiences in Martinique and in Cape Verde, the 2009 WHO guideline that includes warning signs may be of value for the triage of patients by field clinicians. However, many patients with warning signs do not develop severe disease. Specifically, hypotensive patients who improve dramatically within a few hours with an infusion of saline represent a significant category of intermediate severity that do not deserve to be classified in the same group as that of patients in shock [6]. To meet the requirements of representativeness, consistency, and comparability, the description of the severe forms of dengue should include an assessment using an