The number of cases of severe dengue disease continues to grow in endemic areas of southeast Asia, Central and South America, and other subtropical regions. Children bear the greatest burden of disease, and the development of an effective vaccine remains a global public health priority. A tetravalent vaccine is urgently needed and must be effective against all four dengue virus serotypes, be cost-effective and provide long-term protection. In this Review we discuss the unique immunological concerns in dengue virus vaccine development and the current prospects for the development of an acceptable vaccine, a goal that is likely to be reached in the near future.

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Prospects for a dengue virus vaccine.

Dengue viral infections are one of the most important mosquito borne diseases in the world. They may be asymptomatic or may give rise to undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF), or dengue shock syndrome. Annually, 100 million cases of dengue fever and half a million cases of DHF occur worldwide. Ninety percent of DHF subjects are children less than 15 years of age. At present, dengue is endemic in 112 countries in the world. No vaccine is available for preventing this disease. Early recognition and prompt initiation of appropriate treatment are vital if disease related morbidity and mortality are to be limited. This review outlines aspects of the epidemiology of dengue infections, the dengue virus and its mosquito vector, clinical features and pathogenesis of dengue infections, and the management and control of these infections.

https://pmj.bmj.com/content/postgradmedj/80/948/588.full.pdf

Dengue viral infections

Background. Infection with any 1 of the 4 dengue viruses (DVs) can produce several illnesses, ranging from a mild febrile illness to classic dengue fever (DF) to dengue hemorrhagic fever (DHF), a potentially life-threatening disease. Most DHF cases occur after sequential heterotypic DV infections. The role of preexisting humoral immunity in modifying severity of dengue disease is not well understood. Methods. We conducted a prospective cohort study of children in a region where dengue disease is hyperendemic and examined the role of preexisting neutralizing anti-DV antibodies (Abs) in modifying secondary dengue-3 virus (D3V), dengue-2 virus (D2V), and dengue-1 virus (D1V) infections. Results. In secondary D3V infection, higher levels of preexisting neutralizing Ab directed against D3V (reference virus strain and patient’s virus isolate) were associated with lower viremia levels and milder disease. Preexisting neutralizing Ab levels against D2V were not associated with severity of secondary D2V infection. The levels of preexisting neutralizing Ab against the infecting virus isolates were not associated with viremia levels in secondary D2V or D1V infections. Conclusions. Cross-reactive memory humoral immune responses appear to be beneficial in symptomatic secondary D3V infection, but not in secondary D2V or D1V infection. These results may have important implications for the development of live attenuated tetravalent dengue vaccines. Dengue is an emerging arboviral disease caused by infection with 1 of the dengue viruses (DVs), a group of 4 antigenically related mosquito-borne flaviviruses (D1V, D2V, D3V, and D4V) [1]. Infection with any 1 of the 4 DV serotypes can produce a spectrum of clinical illness, ranging from an asymptomatic or mild febrile illness to

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Relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand.

Dengue viruses (DENVs) cause the most common arthropod-borne viral disease in man with 50-100 million infections per year. Because of the lack of a vaccine and antiviral drugs, the sole measure of control is limiting the Aedes mosquito vectors. DENV infection can be asymptomatic or a self-limited, acute febrile disease ranging in severity. The classical form of dengue fever (DF) is characterized by high fever, headache, stomach ache, rash, myalgia, and arthralgia. Severe dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) are accompanied by thrombocytopenia, vascular leakage, and hypotension. DSS, which can be fatal, is characterized by systemic shock. Despite intensive research, the underlying mechanisms causing severe dengue is still not well understood partly due to the lack of appropriate animal models of infection and disease. However, even though it is clear that both viral and host factors play important roles in the course of infection, a fundamental knowledge gap still remains to be filled regarding host cell tropism, crucial host immune response mechanisms, and viral markers for virulence.

https://www.tandfonline.com/doi/pdf/10.3402/iee.v3i0.19839

Dengue viruses - an overview.

The flavivirus E glycoprotein, the primary antigen that induces protective immunity, is essential for membrane fusion and mediates binding to cellular receptors. Human flavivirus infections stimulate virus species-specific as well as flavivirus cross-reactive immune responses. Flavivirus cross-reactive antibodies in human sera create a serious problem for serodiagnosis, especially for secondary flavivirus infections, due to the difficulty of differentiating primary from secondary cross-reactive serum antibodies. The presence of subneutralizing levels of flavivirus cross-reactive serum antibodies may result in a dramatic increase in the severity of secondary flavivirus infections via antibody-dependent enhancement. An understanding of flavivirus E-glycoprotein cross-reactive epitopes is therefore critical for improving public health responses to these serious diseases. We identified six E-glycoprotein residues that are incorporated into three distinct flavivirus cross-reactive epitopes. Two of these epitopes which are recognized by distinct monoclonal antibodies contain overlapping continuous residues located within the highly conserved fusion peptide. The third epitope consists of discontinuous residues that are structurally related to the strictly conserved tryptophan at dengue virus serotype 2 E-glycoprotein position 231.

https://jvi.asm.org/content/jvi/78/24/13975.full.pdf

Localization and Characterization of Flavivirus Envelope Glycoprotein Cross-Reactive Epitopes

Dengue fever, caused by four serotypes of a mosquito-borne virus, is a growing problem in tropical countries. Currently, there is no treatment or vaccine. We evaluated safety and immunogenicity of two doses, given six months apart, of seven formulations of dengue tetravalent live-attenuated vaccine (containing different concentrations of the component viruses) versus placebo in 59 flavivirus-seronegative Thai adults. The first dose was the more reactogenic. Most volunteers experienced clinically moderate fever, headache, myalgia, eye pain or rash 7-11 days after injection, generally lasting three days or less. Modest decreases in platelets and neutrophils were observed. After one dose, 58% of dengue recipients seroconverted (neutralizing antibody level > or = 1:10) against > or = 3 serotypes; 35% seroconverted against all four. After the second dose, seroconversion was 76% and 71%, respectively. All subjects seroconverted to serotype 3 after one dose. Serotype 4 elicited the lowest primary response but the highest increase in seroconversion after the second dose.

Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: role of serotype concentration, ratio, and multiple doses.

Achara Jagsudee

Papers

Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: role of serotype concentration, ratio, and multiple doses.