Humoral Immune Responses of Dengue Fever Patients Using Epitope-Specific Serotype-2 Virus-Like Particle Antigens

Abstract

Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing.

Clinical profile of dengue fever infection in King Abdul Aziz University Hospital Saudi Arabia

“…Although there are promising vaccine candidates in development, further studies are required for a greater understanding of the humoral immune responses to DENV infection and disease pathogenesis [20].…”

“…All the patients survived during 2005, but 4.55%, 25%, and 2.7% of patients died during 2006-2008. Therefore, the highest mortality rate (25%) occurred during 2007, when 25% of patients had Hb levels < 5g/dL, and 50% had severe thrombocytopenia (11)(12)(13)(14)(15)(16)(17)(18)(19)(20),000 platelets/μL). Consequently, 25% of patients required blood and platelet transfusions.…”

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…Additionally, it is important to note that unlike the murine antibody response to DENV, EDIII-reactive antibodies represent only a minor fraction of the human antibody repertoire (33,58,59) -consequently, the above observations may be limited to the mouse model. Nevertheless, human EDIII-specific antibodies are potently neutralizing (59) and may still contribute significantly to protection (60). Whether human PDK53 immune serum exhibits similar variability in neutralizing activity against different strains of DENV2 remains to be investigated.…”

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

“…For flaviviruses, this approach has provided insights into how antibodies engage the many surfaces of the virion (53,62,63,223). Second, several groups have developed molecular and biochemical approaches to identify epitopes recognized by NAbs within sera (57,(224)(225)(226)(227)(228).…”