Dengue and Zika virus infections are enhanced by live attenuated dengue vaccine but not by recombinant DSV4 vaccine candidate in mouse models

Abstract

Background A tetravalent live attenuated dengue vaccine, Dengvaxia, sensitised naïve recipients to severe dengue illness upon a subsequent natural dengue infection and is suspected to be due to antibody-dependent enhancement (ADE). ADE has also been implicated in the severe neurological outcomes of Zika virus (ZIKV) infection. It has become evident that cross-reactive antibodies targeting the viral pre-membrane protein and fusion-loop epitope are ADE-competent. A pre-clinical tetravalent dengue sub-unit vaccine candidate, DSV4, eliminates these ADE-competent epitopes. Methods We compared protective efficacy and ADE-competence of murine polyclonal antibodies induced by DSV4, Dengvaxia and an ‘in house’ tetravalent mixture of all four laboratory DENV strains, TV DENV, using established mouse models. Findings DSV4-induced antibodies, known to be predominantly type-specific, provided significant protection against lethal DENV challenge, but did not promote ADE of either DENV or ZIKV infection in vivo . Antibodies elicited by Dengvaxia and TV DENV, which are predominantly cross-reactive, not only failed to offer protection against lethal DENV challenge, but also promoted ADE of both DENV and ZIKV infection in vivo . Interpretation Protective efficacy against DENV infection may be linked to the induction of neutralising antibodies which are type-specific rather than cross-reactive. Whole virus-based dengue vaccines may be associated with ADE risk, despite their potent virus-neutralising capacity. Vaccines designed to eliminate ADE-competent epitopes may help eliminate/minimise ADE risk. Funding This study was supported partly by ICGEB, India, the National Biopharma Mission, DBT, Government of India, Sun Pharmaceutical Industries Limited, India, and NIAID, NIH, USA.

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

“…However, unlike the ICs made with 3H5 mAb, the ICs generated with 4G2 mAb revealed potent lethality in the denguesensitive AG129 mouse, without enhancing serum viremia. This finding is further affirmed with a recent report published in EBioMedicine by Shukla et al (2020). The investigators showed that both Dengue and Zika virus infections are enhanced by live attenuated dengue vaccine that majorly elicits FL and prM crossreactive antibodies but not by a recombinant tetravalent Dengue Subunit Vaccine candidate, capable of inducing predominantly EDIII directed type-specific antibodies in the absence of antibodies to FL and prM epitopes in murine models.…”

“…Moreover, enhanced ZIKV infection were observed in several organs of Stat2 −/− mice inoculated with anti-Dengvaxia and anti-TV DENV sera. However, DSV4-induced anti-serum neither cross-neutralized ZIKV in vitro nor promoted ADE in vivo (Shukla et al, 2020). The pre-immunity against ZIKV is also a serious concern for developing the dengue vaccine.…”

“…The in vivo ADE assay is based on mice with genetic defects in the innate immune signaling pathway. Typically, an antibody whose ADE potential is to be evaluated, is either introduced into the mouse by passive transfer, followed by challenge with a sublethal dose of a mouse adapted DENV strain or pre-incubated with the mouse-adapted DENV strain to generate ICs, which are then injected into the mouse, followed by survival monitoring, as well as analysis of vascular leakage and cytokine production (Watanabe et al, 2015;Shukla et al, 2020).…”

Impact of prior Dengue immunity on Zika vaccine protection in rhesus macaques and mice

“…These data suggest that suboptimal vaccine protection is a more likely explanation for incidences of breakthrough viremia. It is important to note that other studies have detected elevated ZIKV viral loads after challenge in both plasma and tissues, following passive transfer of anti-DENV immune sera from humans or previously DENV immunized BALB/c mice into both STAT2 -/- and CD11c- Ifnar1 -/- mouse models [ 23 ]. These data attest that the specific mouse strain used, due to differences in pathogenesis, viral tropism, and susceptibility, may affect the magnitude of ZIKV disease enhancement observed.…”

Ross River Virus Immune Evasion Strategies and the Relevance to Post-viral Fatigue, and Myalgic Encephalomyelitis Onset

“…Subsequent studies conducted over the 1970s−80s established in vitro ADE for the global pathogen Dengue virus (DEN), as well as identified the role for Fc-Receptor (Fc-R) engagement in ADE via studies with other flaviviruses (27)(28)(29). By the 1990s, ADE was recognized as a factor in severe DEN disease (Haemorrhagic Fever, Shock Syndrome), on subsequent infection with a DEN serotype different to the original case (30), which has also frustrated attempts to develop a DEN vaccine (31). Many virus families have been observed as displaying enhanced in vitro growth post-infection due to ADE, but the impact in vivo and on disease manifestation are not currently well-understood (32)(33)(34).…”