Dengue and Zika Virus Infections Are Enhanced by Live Attenuated Dengue Vaccine but Not by Recombinant DSV4 Vaccine Candidate in Mouse Models

Abstract

Background: Dengue is caused by four antigenically distinct serotypes of dengue viruses, DENV-1, -2, -3 and -4. A tetravalent live attenuated dengue vaccine, Dengvaxia, sensitised naive recipients to severe dengue illness upon a subsequent natural dengue infection that 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 have made a head-to-head comparison of the putative 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 of DENV and ZIKV ADE. Findings: DSV4-induced antibodies neutralised DENVs, but not ZIKV, and did not promote ADE of either DENV or ZIKV in vivo, whereas antibodies elicited by Dengvaxia and TV DENV, not only neutralised DENVs and ZIKV potently, but also promoted ADE of both DENV and ZIKV in vivo. Further, unlike DSV4-induced antibodies, Dengvaxia- and TV DENV-induced antibodies significantly enhanced ZIKV load in several tissues. Interpretation: 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, Department of Biotechnology, Government of India (Grant No. BT/NBM0011/01/17), Sun Pharmaceutical Industries Limited, India, and the National Institute of Allergy and Infectious Diseases, NIH, USA (R21AI144844) Declaration of Interests: All authors declare that the research was conducted in the interest of advancing knowledge for dengue vaccine development and in the absence of any explicit commercial or financial interests that could be construed as a potential conflict of interest. HB, SK and AAL are employees of Sun Pharmaceutical Industries Limited. Ethics Approval Statement: Animal experiments were strictly compliant with the ‘Committee for the Purpose of Control and Supervision of Experiments on Animals’ guidelines issued by the Government of India. Experiments using C57BL/6 Stat2-/- mice (IACUC Approved Protocol # LA11-00147) were carried out at Icahn School of Medicine at Mount Sinai, and complied with the US federal regulations and the guidelines of the National Research Council Guide for the Care and Use of Laboratory Animals.