Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus

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214

While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV

Section: Methodsmentioning

confidence: 99%

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

Grifoni

Pham

Sidney

et al. 2017

154

214

“…When administered as prophylaxis, neutralizing mouse MAbs targeting the lateral ridge of E domain III (77) or human MAbs targeting interdimer and intradimer epitopes in the E domain II (ZIKV-117 and Z20, respectively) (80) or separate epitopes in domains I, II, and III (Z3L1 and Z23) (81) all protected vulnerable mice from lethal ZIKV infection. Analogously, a cross-reactive human MAb targeting the envelope dimer epitope of dengue virus (EDE1 C10) (79) and an Fc mutant form of a ZIKV-specific human MAb (ZKA64) targeting E domain III, which cannot bind FcyRs or C1q (78), also protected mice from lethal ZIKV infection. Although MAb prophylaxis protected against ZIKV-induced morbidity and mortality, viremia, although reduced, remained detectable (77).…”

mentioning

confidence: 99%

“…Studies designed to evaluate the utility of therapeutic murine and human MAbs for the prevention and treatment of ZIKV-induced disease have been an intense area of investigation. For example, mice deficient in type I IFN signaling by treatment with anti-IFNAR1 MAb (14) or by genetic deletion of type I, or type I and type II, IFN receptor subunits (14,15,24) have been used to evaluate the protective capacity of human and mouse anti-ZIKV MAbs (77)(78)(79)(80)(81). When administered as prophylaxis, neutralizing mouse MAbs targeting the lateral ridge of E domain III (77) or human MAbs targeting interdimer and intradimer epitopes in the E domain II (ZIKV-117 and Z20, respectively) (80) or separate epitopes in domains I, II, and III (Z3L1 and Z23) (81) all protected vulnerable mice from lethal ZIKV infection.…”

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confidence: 99%

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Morrison

Diamond

2017

236

239

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.

“…Maturation of virus particles occurs during virus egress via the secretory pathway, where furin in the Golgi apparatus cleaves prM, releasing the pr peptide as the virus reaches neutral pH upon exit from the cell (14). The E protein is the major target for neutralizing antibodies, and monoclonal antibodies against all 3 E protein domain (DI, DII, and DIII) target epitopes have been found (15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

Development of Virus-Like-Particle Vaccine and Reporter Assay for Zika Virus

Garg

Sedano

Plata

et al. 2017

Recent worldwide outbreaks of Zika virus (ZIKV) infection and the lack of an approved vaccine raise serious concerns regarding preparedness to combat this emerging virus. We used a virus-like particle (VLP)-based approach to develop a vaccine and a microneutralization assay for ZIKV. A synthetic capsid-premembrane-envelope (CprM-E) gene construct of ZIKV was used to generate reporter virus particles (RVPs) that package a green fluorescent protein (GFP) reporter-expressing West Nile virus (WNV) replicon. The assay was adapted to a 96-well format, similar to the plaque reduction neutralization test (PRNT), and showed high reproducibility with specific detection of ZIKV neutralizing antibodies. Furthermore, C-prM-E and prM-E VLPs were tested as vaccine candidates in mice and compared to DNA vaccination. While the ZIKV prM-E construct alone was sufficient for generating VLPs, efficient VLP production from the C-prM-E construct could be achieved in the presence of the WNV NS2B-3 protease, which cleaves C from prM, allowing virus release. Immunization studies in mice showed that VLPs generated higher neutralizing antibody titers than those with the DNA vaccines, with C-prM-E VLPs giving slightly higher titers than those with prM-E VLPs. The superiority of C-prM-E VLPs suggests that inclusion of capsid may have benefits for ZIKV and other flaviviral VLP vaccines. To facilitate the VLP platform, we generated a stable cell line expressing high levels of ZIKV prM-E proteins that constitutively produce VLPs as well as a cell line expressing ZIKV C-prM-E proteins for RVP production. While several vaccine platforms have been proposed for ZIKV, this study describes a safe, effective, and economical VLP-based vaccine against ZIKV.IMPORTANCE To address the growing Zika virus epidemic, we undertook this study with two objectives: first, to develop a safe, effective, and economical vaccine for ZIKV, and second, to develop a rapid and versatile assay to detect the anti-ZIKV immune response. We generated a cell line stably expressing ZIKV prM-E that produces large amounts of VLPs in the supernatant and a ZIKV C-prM-E cell line that produces reporter virus particles upon transfection with a GFP replicon plasmid. The prM-E VLPs induced a strong neutralizing antibody response in mice that was better when the capsid was included. VLP-based vaccines showed significantly better neutralizing antibody responses than those with their DNA counterparts. The RVP-based microneutralization assay worked similarly to the PRNT assay, with a rapid GFP readout in a 96-well format. Our VLP-based platform provides a source for a ZIKV vaccine and diagnosis that can rapidly be adapted to current outbreaks.KEYWORDS C-prM-E, diagnostics, microneutralization, neutralization, PRNT, reporter, reporter virus particles, vaccine, Zika, prM-E S ince the identification of Zika virus (ZIKV) from a rhesus monkey in Uganda in 1947 (1, 2) until 2010, the virus predominantly circulated between Aedes mosquitoes and nonhuman primates. Periodic episodes were inde...