Complexity of Human Antibody Response to Dengue Virus: Implication for Vaccine Development

Abstract

The four serotypes of dengue virus (DENV) are the leading cause of arboviral diseases in humans. Decades of efforts have made remarkable progress in dengue vaccine development. Despite the first dengue vaccine (dengvaxia from Sanofi Pasteur), a live-attenuated tetravalent chimeric yellow fever-dengue vaccine, has been licensed by several countries since 2016, its overall moderate efficacy (56.5–60.8%) in the presence of neutralizing antibodies during the Phase 2b and 3 trials, lower efficacy among dengue naïve compared with dengue experienced individuals, and increased risk of hospitalization among young children during the follow-up highlight the need for a better understanding of humoral responses after natural DENV infection. Recent studies of more than 300 human monoclonal antibodies (mAbs) against DENV have led to the discovery of several novel epitopes on the envelope protein recognized by potent neutralizing mAbs. This information together with in-depth studies on polyclonal sera and B-cells following natural DENV infection has tremendous implications for better immunogen design for a safe and effective dengue vaccine. This review outlines the progress in our understanding of mouse mAbs, human mAbs, and polyclonal sera against DENV envelope and precursor membrane proteins, two surface proteins involved in vaccine development, following natural infection; analyses of these discoveries have provided valuable insight into new strategies involving molecular technology to induce more potent neutralizing antibodies and less enhancing antibodies for next-generation dengue vaccine development.

The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement

“…It is well appreciated that a second dengue virus infection with a different serotype can result in a hemorrhagic fever. In addition, a dengue-virus vaccine was reported to increase hospitalizations of vaccinees after their first dengue-virus exposure (Flipse and Smit, 2015;Tsai et al, 2017). In both cases, the underlying mechanism is presumed to be enhanced Fc-receptor-mediated internalization of virions bound to antibodies.…”

Nanosensors based on LSPR are able to serologically differentiate dengue from Zika infections

“…In such scenario, nanostructured sensors become an attractive alternative due to their potential sensitivity and specificity aspects. The choice for the DENV E protein as the sensor's probing component is based on the fact that after an infection the majority of all antibody species produced against DENV recognize epitopes that are distributed on the virus' surface proteins, either E or M, whereas a lesser proportion of these antibodies recognizes the NS1 non-structural protein 36 . Overall, serotype cross-reactive anti-E antibodies constitute the bulk of antibody responses elicited on a DENV-infected patient, followed by invariably smaller amounts of anti-(pr)M and anti-NS1 36,37 .…”

“…The choice for the DENV E protein as the sensor's probing component is based on the fact that after an infection the majority of all antibody species produced against DENV recognize epitopes that are distributed on the virus' surface proteins, either E or M, whereas a lesser proportion of these antibodies recognizes the NS1 non-structural protein 36 . Overall, serotype cross-reactive anti-E antibodies constitute the bulk of antibody responses elicited on a DENV-infected patient, followed by invariably smaller amounts of anti-(pr)M and anti-NS1 36,37 . Conversely, any anti-DENV vaccine design must certainly include the E protein, as it is the main target of neutralizing antibodies which, despite some recent scrutiny, are still viewed as important correlates of immunological protection against the infection 36,[38][39][40] .…”

Position Paper on Road Map for RNA Virus Research in India

“…Vaccine challenges: The problems of live-attenuated vaccines for dengue is highlighted by the recent adverse events reported with the only vaccine that is licensed for human use (Tsai et al, 2017 ). The problem of inaccurate prediction of circulating strains and logistical difficulties in vaccine manufacturing is a challenge for flu vaccines.…”