Challenges for the formulation of a universal vaccine against dengue

Abstract

Dengue is rapidly becoming a disease of an escalating global public health concern. The disease is a vector-borne disease, transmitted by the bite of an Aedes spp. mosquito. Dynamic clinical manifestations, ranging from asymptomatic, flu-like febrile illness, dengue fever (DF) to dengue hemorrhagic fever (DHF) with or without dengue shock syndrome (DSS), make the disease one of the most challenging to diagnose and treat. DF is a self-limited illness, while DHF/DSS, characterized by plasma leakage resulting from an increased vascular permeability, can have severe consequences, including death. The pathogenesis of dengue virus infection remains poorly understood, mainly due to the lack of a suitable animal model that can recapitulate the cardinal features of human dengue diseases. Currently, there is no specific treatment or antiviral therapy available for dengue virus infection and supportive care with vigilant monitoring is the principle course of treatment. Since vector control programs have been largely unsuccessful in preventing outbreaks, vaccination seems to be the most viable option for prevention. There are four dengue viral serotypes and each one of them is capable of causing severe dengue. Although immunity induced by infection by one serotype is effective in protection against the homologous viral serotype, it only has a transient protective effect against infection with the other three serotypes. The meager cross protective immunity generated wanes over time and may even induce a harmful effect at the time of subsequent secondary infection. Thus, it is imperative to have a vaccine that can elicit equal and long-lasting immunity to all four serotypes simultaneously. Numerous tetravalent vaccines are currently either in the pipeline for clinical trials or under development. For those frontrunner tetravalent vaccines in clinical trials, despite good safety and immunogenicity profiles registered, issues such as imbalanced immune responses between serotypes and questions with regard to whether the optimum formulation have been identified remain unresolved. This review centers on these issues and offers strategies that may improve the tetravalent vaccine formulation.

Vaccine-Mediated Immunity Against Dengue and the Potential for Long-Term Protection Against Disease

“…The 50% plaque-reduction neutralizing test (PRNT 50 ) assay used to measure antiviral immunity in the CYD-TDV Phase IIb trial has come into question since it was performed in Vero cells (16) and some have proposed that DENV strains should be grown in other cell types or that primary DENV strains isolated directly from acutely infected DENV patients be used in the analysis (17). It may not be feasible to perform standardized neutralization assays under GLP compliance using direct DENV isolates from human serum but these questions nevertheless further illustrate the point that despite the publication of a WHO guidance document (18), there is still little consensus among the scientific community on how neutralizing titers to DENV should be performed or which DENV strains should be used in this crucial analysis of antiviral immunity.…”

Dengue virus NS1 protein interacts with the ribosomal protein RPL18: This interaction is required for viral translation and replication in Huh-7 cells

“…Despite multiple studies conducted by several research groups to produce a vaccine or an effective antiviral treatment, so far neither is available (Chokephaibulkit and Perng, 2013). Dengue virus (DENV), a member of the Flaviviridae family and Flavivirus genus is a single-stranded RNA virus with positive polarity, which encodes for ten viral proteins, three structural, capsid (C), membrane (M) and envelope (E) proteins and seven nonstructural NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5.…”

Caracterización epidemiológica del dengue en la Unidad de Terapia Intensiva Adultos. Hospital Central "Dr. Emilio Cubas" del Instituto de Previsión Social, Paraguay

“…La infección por un serotipo induce inmunidad de por vida contra el serotipo viral homólogo, pero solo tiene un efecto protector transitorio contra los demás tres serotipos (3,4).…”