Emerging Concepts in Dengue Pathogenesis and Host Innate Immune Response

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Cover image for research topic "Emerging Concepts in Dengue Pathogenesis and Host Innate Immune Response"
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22 October 2020
Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine
Rahul Shukla
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Navin Khanna
Cross-reactive, prM and fusion-loop Abs facilitate immature DENV entry through Fcγ receptor and mediate enhanced DENV replication by following the intrinsic ADE pathway. (Left half) DENV attaches to a host cell surface and is endocytosed followed by virus-endosomal membrane fusion leading to the release of viral genome. Post-release, viral RNA is translated and the viral genome is replicated. Virus assembly occurs on the surface of the endoplasmic reticulum, and immature viral particles mature into their infectious form in the Golgi network. These mature viruses are then released from the cell and ready to infect other cells. (Right half) Cross-reactive Abs bind with immature non-infectious particles turning into infectious virus-Ab immune complexes (V-Ab IC) which then bind with the Fc receptor bearing cells. This assembly down-regulates the DENV-specific pattern recognition receptor (PRRs) signaling, inhibits type I interferon (IFNα/β) release and activates production of Interleukin-10 (IL-10) which causes up-regulation of Suppressor of Cytokine Signaling (SOCS) family. Henceforth, controlled mature DENV production is lost, resulting into manifold increase in wide-range of immature viruses which leads to the extrinsic-ADE pathway by infecting other cells via binding with cross-reactive Abs (Figure is adapted from Halstead et al., 2010 under Copyright license, # 4852311472038 and generated in Biorender.com).

In 2019, the United States Food and Drug Administration accorded restricted approval to Sanofi Pasteur's Dengvaxia, a live attenuated vaccine (LAV) for dengue fever, a mosquito-borne viral disease, caused by four antigenically distinct dengue virus serotypes (DENV 1-4). The reason for this limited approval is the concern that this vaccine sensitized some of the dengue-naïve recipients to severe dengue fever. Recent knowledge about the nature of the immune response elicited by DENV viruses suggests that all LAVs have inherent capacity to predominantly elicit antibodies (Abs) against the pre-membrane (prM) and fusion loop epitope (FLE) of DENV. These antibodies are generally cross-reactive among DENV serotypes carrying a higher risk of promoting Antibody-Dependent Enhancement (ADE). ADE is a phenomenon in which suboptimal neutralizing or non-neutralizing cross-reactive antibodies bind to virus and facilitate Fcγ receptor mediated enhanced entry into host cells, followed by its replication, and thus increasing the cellular viral load. On the other hand, antibody responses directed against the host-cell receptor binding domain of DENV envelope domain-III (EDIII), exhibit a higher degree of type-specificity with lower potential of ADE. The challenges associated with whole DENV-based vaccine strategies necessitate re-focusing our attention toward the designed dengue vaccine candidates, capable of inducing predominantly type-specific immune responses. If the designed vaccines elicited predominantly EDIII-directed serotype specific antibodies in the absence of prM and FLE antibodies, this could avoid the ADE phenomenon largely associated with the prM and FLE antibodies. The generation of type-specific antibodies to each of the four DENV serotypes by the designed vaccines could avoid the immune evasion mechanisms of DENVs. For the enhanced vaccine safety, all dengue vaccine candidates should be assessed for the extent of type-specific (minimal ADE) vs. cross-reactive (ADE promoting) neutralizing antibodies. The type-specific EDIII antibodies may be more directly related to protection from disease in the absence of ADE promoted by the cross-reactive antibodies.

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Emerging Arboviruses in the Americas: Epidemiology, Public Health Impact, and Future Preparedness
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