Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Oct 22:10:572681.
doi: 10.3389/fcimb.2020.572681. eCollection 2020.

Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine

Rahul Shukla  1 , Viswanathan Ramasamy  1 , Rajgokul K Shanmugam  1 , Richa Ahuja  1 , Navin Khanna  1
Affiliations
Review

Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine

Rahul Shukla et al. Front Cell Infect Microbiol. .

Abstract

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.

Keywords: Dengvaxia; antibody-dependent enhancement (ADE); dengue; dengue vaccine; dengue virus (DENV); live attenuated vaccine; virus-like particle.

PubMed Disclaimer

Figures

Figure 1
Figure 1
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., under Copyright license, # 4852311472038 and generated in Biorender.com).
Figure 2
Figure 2
Type-specific (TS) monoclonal antibody (mAb) does not cause ADE in the mouse model whereas cross-reactive (CR) mAb does. The sublethal dose of D2 S221 was inoculated as fully- and sub-neutralized immune complexes (“Fully-nICs” and “Sub-nICs,” respectively) made with either cross-reactive (4G2) or type-specific (3H5) mAbs. Investigators (Watanabe et al., 2015) found 100% mortality and elevated levels of different ADE related parameters in the small intestine (Vascular leakage, inflammatory cytokines, and viral load) in both fully and sub-neutralized ICs made with 4G2. On the contrary, fully neutralized TS-ICs exhibited full protection accompanied by very low virus load. TS sub-neutralizing ICs showed a very minimal level of mortality accompanied by low virus load. ND, data not available (The illustrative figure created with Biorender.com).
Figure 3
Figure 3
Comparison of conventional DENV vaccine strategy vs. Designer DENV vaccine candidate immune responses. Conventional DENV vaccine generally have the mixture of live-attenuated all four DENV serotypes, whereas, ongoing pre-clinical designer DENV vaccine candidate (s) has single entity expressing all four DENV component. The whole DENV-based vaccine inherently poses to induce imbalance immune responses with high load of cross-reactive Abs against all four DENV serotype, suggests to explore designer DENV vaccine strategy, which may induce non-enhancing type-specific neutralizing immune response in human (Figure designed with Biorender.com).
Figure 4
Figure 4
Design of DSV4. Top panel shows schematic diagram of all four DENV, encircled parts represent envelope domain III (EDIII) component of all four viruses. These EDIIIs components were linked with hexa-glycine linkers, fused to n-terminus of Hepatitis-B surface antigen (HBsAg) and further cloned in the background of four copies of HBsAg. The cloned expression cassette including DENV-EDIIIs, was integrated into the yeast expression host, Pichia pastoris, and DSV4 antigen was purified from the recombinant host for further immunological studies. The figure approach is adapted from Ramasamy et al. (2018) and created with Biorender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abbink P., Larocca R. A., Dejnirattisai W., Peterson R., Nkolola J. P., Borducchi E. N., et al. . (2018). Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys. Nat. Med. 24, 721–723. 10.1038/s41591-018-0056-0 - DOI - PMC - PubMed
    1. Arredondo-García J. L., Hadinegoro S. R., Reynales H., Chua M. N., Rivera Medina D. M., Chotpitayasunondh T., et al. . (2018). Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America. Clin. Microbiol. Infect. 24, 755–763. 10.1016/j.cmi.2018.01.018 - DOI - PubMed
    1. Barba-Spaeth G., Dejnirattisai W., Rouvinski A., Vaney M. C., Medits I., Sharma A., et al. . (2016). Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature 536, 48–53. 10.1038/nature18938 - DOI - PubMed
    1. Bardina S. V., Bunduc P., Tripathi S., Duehr J., Frere J. J., Brown J. A., et al. . (2017). Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science 356, 175–180. 10.1126/science.aal4365 - DOI - PMC - PubMed
    1. Beatty P. R., Puerta-Guardo H., Killingbeck S. S., Glasner D. R., Hopkins K., Harris E. (2015). Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci. Transl. Med. 7:304ra141. 10.1126/scitranslmed.aaa3787 - DOI - PubMed