InVivoMAb anti-Zika virus E protein DIII-LR

Catalog #BE0431

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The ZV-67 monoclonal antibody reacts with Zika virus envelope (E) protein at the lateral ridge of domain III (DIII-LR), and it is reported to neutralize infections of American, African, and Asian strains of Zika virus (ZIKV). Biologically, ZIKV is a positive-stranded RNA virus that is transmitted through Aedes aegypti (the yellow fever mosquito). ZIKV gets transmitted through sexual contact as well, and ZIKV infections during pregnancy have been linked to developmental defects in newborns e.g., congenital zika syndrome (CZS), which is characterized by neuropathogenesis and microcephaly in unborn babies, eye abnormalities, arthrogryposis, etc., In adults also, the ZIKV infections lead to serious neurological complications. ZIKV’s genome for seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) and the ZIKV enveloped virion consists of three structural proteins - capsid (C), membrane (M), and envelope (E). In experimental studies, the E protein of ZIKV is often targeted with the ZV-67 monoclonal antibody which was generated by immunizing a lethal mouse model with ZIKV (MR-766), ZIKV (H/PF/2013), and the recombinant E protein DIII domain. This antibody specifically binds to the immunoglobulin-like segment DIII lateral ridge (DIII-LR) of the ZIKV E protein, which is responsible for viral assembly, attachment, entry, and fusion. In ELISA and Western blot, the ZV-67 monoclonal antibody has been reported to specifically detect the recombinant ZIKV E protein DIII and ZIKV E protein reporter virus particles (RVPs) in transfected cells. Several in vitro investigations have reported the neutralization potential of the ZV-67 monoclonal antibody against ZIKV H/PF/2013, ZIKV/KOR/SNU/2016, ZIKV/PRVABC59, African strains (MR-766, Uganda 1947, and Dakar 41519, Senegal 1982), American stain (Paraiba 2015, Brazil strain), Zika virus MR766 mutants, and ZIKV E protein-RVPs. In animal studies, in vivo administration of the ZV-67 monoclonal antibody provided significant protection against ZIKV Dakar 41519 infection in young mice and against ZIKV Asian strain GZ01 infection in pregnant mice. The ZV-67 monoclonal antibody does not show any cross-reactivity with Japanese encephalitis (JEV) or Dengue virus (DENV).


Isotype Mouse IgG2c, κ
Recommended Isotype Control(s) InVivoMAb mouse IgG2c isotype control, anti-dengue virus
Recommended Dilution Buffer InVivoPure pH 7.0 Dilution Buffer
Immunogen ZIKV (MR-766), ZIKV (H/PF/2013) and ZIKV E protein (DIII)
Reported Applications in vivo inhibition of ZIKV infection
in vitro neutralization of ZIKV
Flow cytometry
Western blot
Focus forming assay (FFA)
Focus reduction neutralization test (FRNT)
Plaque reduction neutralization test (PRNT)
Formulation PBS, pH 7.0
Contains no stabilizers or preservatives
Endotoxin <2EU/mg (<0.002EU/μg)
Determined by LAL gel clotting assay
Purity >95%
Determined by SDS-PAGE
Sterility 0.2 µm filtration
Production Purified from cell culture supernatant in an animal-free facility
Purification Protein A
Molecular Weight 150 kDa
Storage The antibody solution should be stored at the stock concentration at 4°C. Do not freeze.
in vitro neutralization of ZIKV
Kikawa C, Cartwright-Acar CH, Stuart JB, Contreras M, Levoir LM, Evans MJ, Bloom JD, Goo L. (2023). "The effect of single mutations in Zika virus envelope on escape from broadly neutralizing antibodies" J Virol 10.1128/jvi.01414-23. PubMed

The wide endemic range of mosquito-vectored flaviviruses-such as Zika virus and dengue virus serotypes 1-4-places hundreds of millions of people at risk of infection every year. Despite this, there are no widely available vaccines, and treatment of severe cases is limited to supportive care. An avenue toward development of more widely applicable vaccines and targeted therapies is the characterization of monoclonal antibodies that broadly neutralize all these viruses. Here, we measure how single amino acid mutations in viral envelope protein affect neutralizing antibodies with both broad and narrow specificities. We find that broadly neutralizing antibodies with potential as vaccine prototypes or biological therapeutics are quantifiably more difficult to escape than narrow, virus-specific neutralizing antibodies.

Focus forming assay (FFA)
Reynoso GV, Gordon DN, Kalia A, Aguilar CC, Malo CS, Aleshnick M, Dowd KA, Cherry CR, Shannon JP, Vrba SM, Holmes AC, Alippe Y, Maciejewski S, Asano K, Diamond MS, Pierson TC, Hickman HD. (2023). "Zika virus spreads through infection of lymph node-resident macrophages" Cell Rep 10.1016/j.celrep.2023.112126. PubMed

To disseminate through the body, Zika virus (ZIKV) is thought to exploit the mobility of myeloid cells, in particular monocytes and dendritic cells. However, the timing and mechanisms underlying shuttling of the virus by immune cells remains unclear. To understand the early steps in ZIKV transit from the skin, at different time points, we spatially mapped ZIKV infection in lymph nodes (LNs), an intermediary site en route to the blood. Contrary to prevailing hypotheses, migratory immune cells are not required for the virus to reach the LNs or blood. Instead, ZIKV rapidly infects a subset of sessile CD169+ macrophages in the LNs, which release the virus to infect downstream LNs. Infection of CD169+ macrophages alone is sufficient to initiate viremia. Overall, our experiments indicate that macrophages that reside in the LNs contribute to initial ZIKV spread. These studies enhance our understanding of ZIKV dissemination and identify another anatomical site for potential antiviral intervention.

Bollman B, Nunna N, Bahl K, Hsiao CJ, Bennett H, Butler S, Foreman B, Burgomaster KE, Aleshnick M, Kong WP, Fisher BE, Ruckwardt TJ, Morabito KM, Graham BS, Dowd KA, Pierson TC, Carfi A. (2023). "An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection" NPJ Vaccines 10.1038/s41541-023-00656-4. PubMed

Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20th of the dose and provided complete protection from ZIKV challenge in non-human primates. In-depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation.

Georgiev GI, Malonis RJ, Wirchnianski AS, Wessel AW, Jung HS, Cahill SM, Nyakatura EK, Vergnolle O, Dowd KA, Cowburn D, Pierson TC, Diamond MS, Lai JR. (2022). "Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo" Cell Chem Biol 10.1016/j.chembiol.2022.02.004. PubMed

Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop "resurfaced" (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV.

in vitro neutralization of ZIKV
Kim SI, Kim S, Shim JM, Lee HJ, Chang SY, Park S, Min JY, Park WB, Oh MD, Kim S, Chung J. (2021). "Neutralization of Zika virus by E protein domain III-Specific human monoclonal antibody" Biochem Biophys Res Commun 10.1016/j.bbrc.2021.01.075. PubMed

Zika virus (ZIKV) infection in both infants and adults is associated with neurological complications including, but not limited to, microcephaly and Guillain-Barre syndrome. Antibody therapy can be effective against virus infection. We isolated ZIKV envelope domain III-specific neutralizing antibodies (nAbs) from two convalescent patients with ZIKV infection. One antibody, 2F-8, exhibited potent in vitro neutralizing activity against Asian and American strains of ZIKV. To prevent FcγR-mediated antibody-dependent enhancement, we prepared IgG1 with LALA variation. A single dose of 2F-8 in the context of IgG1 or IgG1-LALA prior to or post lethal ZIKV challenge conferred complete protection in mice.

in vitro neutralization of ZIKV
Zhao H, Xu L, Bombardi R, Nargi R, Deng Z, Errico JM, Nelson CA, Dowd KA, Pierson TC, Crowe JE, Diamond MS, Fremont DH. (2020). "Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge" J Exp Med 10.1084/jem.20191792. PubMed

We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a domain II residue (R204K) that potentially modulates exposure of the distally located, partially cryptic epitope. The V-J reverted germline configuration of ZIKV-116 preferentially binds to and neutralizes an Asian ZIKV strain, suggesting that this epitope may optimally induce related B cell clonotypes. Overall, these studies provide a structural and molecular mechanism for a cross-reactive mAb that uniquely neutralizes ZIKV and DENV1.

Focus reduction neutralization test (FRNT), ELISA
Maciejewski S, Ruckwardt TJ, Morabito KM, Foreman BM, Burgomaster KE, Gordon DN, Pelc RS, DeMaso CR, Ko SY, Fisher BE, Yang ES, Nair D, Foulds KE, Todd JP, Kong WP, Roy V, Aleshnick M, Speer SD, Bourne N, Barrett AD, Nason MC, Roederer M, Gaudinski MR, Chen GL, Dowd KA, Ledgerwood JE, Alter G, Mascola JR, Graham BS, Pierson TC. (2020). "Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality" Sci Transl Med 10.1126/scitranslmed.aaw9066. PubMed

The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.

in vitro neutralization of ZIKV
Zhou W, Woodson M, Sherman MB, Neelakanta G, Sultana H. (2019). "Exosomes mediate Zika virus transmission through SMPD3 neutral Sphingomyelinase in cortical neurons" Emerg Microbes Infect 10.1080/22221751.2019.1578188. PubMed

The harmful effects of ZIKA virus (ZIKV) infection are reflected by severe neurological manifestations such as microcephaly in neonates and other complications associated with Guillain-Barré syndrome in adults. The transmission dynamics of ZIKV in or between neurons, or within the developing brains of the foetuses are not fully understood. Using primary cultures of murine cortical neurons, we show that ZIKV uses exosomes as mediators of viral transmission between neurons. Cryo-electron microscopy showed heterogeneous population of neuronal exosomes with a size range of 30-200 nm. Increased production of exosomes from neuronal cells was noted upon ZIKV infection. Neuronal exosomes contained both ZIKV viral RNA and protein(s) that were highly infectious to naïve cells. RNaseA and neutralizing antibodies treatment studies suggest the presence of viral RNA/proteins inside exosomes. Exosomes derived from time- and dose-dependent incubations showed increasing viral loads suggesting higher packaging and delivery of ZIKV RNA and proteins. Furthermore, we noted that ZIKV induced both activity and gene expression of neutral Sphingomyelinase (nSMase)-2/SMPD3, an important molecule that regulates production and release of exosomes. Silencing of SMPD3 in neurons resulted in reduced viral burden and transmission through exosomes. Treatment with SMPD3 specific inhibitor GW4869, significantly reduced ZIKV loads in both cortical neurons and in exosomes derived from these neuronal cells. Taken together, our results suggest that ZIKV modulates SMPD3 activity in cortical neurons for its infection and transmission through exosomes perhaps leading to severe neuronal death that may result in neurological manifestations such as microcephaly in the developing embryonic brains.

Gao Y, Tai W, Wang N, Li X, Jiang S, Debnath AK, Du L, Chen S. (2019). "Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors" Viruses 10.3390/v11111019. PubMed

Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.

Plaque reduction neutralization tests (PRNT), ELISA
Setoh YX, Amarilla AA, Peng NYG, Griffiths RE, Carrera J, Freney ME, Nakayama E, Ogawa S, Watterson D, Modhiran N, Nanyonga FE, Torres FJ, Slonchak A, Periasamy P, Prow NA, Tang B, Harrison J, Hobson-Peters J, Cuddihy T, Cooper-White J, Hall RA, Young PR, Mackenzie JM, Wolvetang E, Bloom JD, Suhrbier A, Khromykh AA. (2019). "Determinants of Zika virus host tropism uncovered by deep mutational scanning" Nat Microbiol 10.1038/s41564-019-0399-4. PubMed

Arboviruses cycle between, and replicate in, both invertebrate and vertebrate hosts, which for Zika virus (ZIKV) involves Aedes mosquitoes and primates1. The viral determinants required for replication in such obligate hosts are under strong purifying selection during natural virus evolution, making it challenging to resolve which determinants are optimal for viral fitness in each host. Herein we describe a deep mutational scanning (DMS) strategy2-5 whereby a viral cDNA library was constructed containing all codon substitutions in the C-terminal 204 amino acids of ZIKV envelope protein (E). The cDNA library was transfected into C6/36 (Aedes) and Vero (primate) cells, with subsequent deep sequencing and computational analyses of recovered viruses showing that substitutions K316Q and S461G, or Q350L and T397S, conferred substantial replicative advantages in mosquito and primate cells, respectively. A 316Q/461G virus was constructed and shown to be replication-defective in mammalian cells due to severely compromised virus particle formation and secretion. The 316Q/461G virus was also highly attenuated in human brain organoids, and illustrated utility as a vaccine in mice. This approach can thus imitate evolutionary selection in a matter of days and identify amino acids key to the regulation of virus replication in specific host environments.

in vivo inhibition of ZIKV infection
Li C, Wang Q, Jiang Y, Ye Q, Xu D, Gao F, Xu JW, Wang R, Zhu X, Shi L, Yu L, Zhang F, Guo W, Zhang L, Qin CF, Xu Z. (2018). "Disruption of glial cell development by Zika virus contributes to severe microcephalic newborn mice" Cell Discov 10.1038/s41421-018-0042-1. PubMed

The causal link between Zika virus (ZIKV) infection and microcephaly has raised alarm worldwide. Microglial hyperplasia, reactive gliosis, and myelination delay have been reported in ZIKV-infected microcephalic fetuses. However, whether and how ZIKV infection affects glial cell development remain unclear. Here we show that ZIKV infection of embryos at the later stage of development causes severe microcephaly after birth. ZIKV infects the glial progenitors during brain development. Specifically, ZIKV infection disturbs the proliferation and differentiation of the oligodendrocyte progenitor cells and leads to the abolishment of oligodendrocyte development. More importantly, a single intraperitoneal injection of pregnant mice with a human monoclonal neutralizing antibody provides full protection against ZIKV infection and its associated damages in the developing fetuses. Our results not only provide more insights into the pathogenesis of ZIKV infection, but also present a new model for the preclinical test of prophylactic and therapeutic agents against ZIKV infection.

in vivo inhibition of ZIKV infection
Li C, Gao F, Yu L, Wang R, Jiang Y, Shi X, Yin C, Tang X, Zhang F, Xu Z, Zhang L. (2018). "A Single Injection of Human Neutralizing Antibody Protects against Zika Virus Infection and Microcephaly in Developing Mouse Embryos" Cell Rep 10.1016/j.celrep.2018.04.005. PubMed

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is generally benign in humans. However, an emergent strain of ZIKV has become widespread, causing severe pre- and post-natal neurological defects. There is now an urgent need for prophylactic and therapeutic agents. To address this, we investigated six human monoclonal antibodies with ZIKV epitope specificity and neutralizing activity in mouse models of ZIKV infection and microcephaly. A single intraperitoneal injection of these antibodies conveyed distinct levels of adult and in utero protection from ZIKV infection, which closely mirrored their respective in vitro neutralizing activities. One antibody, ZK2B10, showed the most potent neutralization activity, completely protected uninfected mice, and markedly reduced tissue pathology in infected mice. Thus, ZK2B10 is a promising candidate for the development of antibody-based interventions and informs the rational design of ZIKV vaccine.

in vitro neutralization of ZIKV, Western Blot
Goo L, DeMaso CR, Pelc RS, Ledgerwood JE, Graham BS, Kuhn RJ, Pierson TC. (2018). "The Zika virus envelope protein glycan loop regulates virion antigenicity" Virology 10.1016/j.virol.2017.12.032. PubMed

Because antibodies are an important component of flavivirus immunity, understanding the antigenic structure of flaviviruses is critical. Compared to dengue virus (DENV), the loop containing the single N-linked glycosylation site on Zika virus (ZIKV) envelope (E) proteins extends further towards the DII fusion loop (DII-FL) on neighboring E proteins within E dimers on mature viruses. Although ZIKV is poorly neutralized by DII-FL antibodies, we demonstrated significantly increased neutralization sensitivity of ZIKV particles incorporating the DENV glycan loop. Increased neutralization sensitivity was independent of E protein glycosylation: ZIKV lacking E protein glycans remained poorly neutralized, whereas ZIKV loop chimeras with or without an E protein glycan were potently neutralized. ZIKV particles lacking the E protein glycan were capable of infecting Raji cells expressing the lectin DC-SIGNR, suggesting the prM glycan of partially mature particles can facilitate entry. Our study provides insight into the determinants of ZIKV E protein function and antigenicity.

ELISA, Flow Cytometry
Hasan SS, Miller A, Sapparapu G, Fernandez E, Klose T, Long F, Fokine A, Porta JC, Jiang W, Diamond MS, Crowe JE, Kuhn RJ, Rossmann MG. (2017). "A human antibody against Zika virus crosslinks the E protein to prevent infection" Nat Commun 10.1038/ncomms14722. PubMed

The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. Neutralizing antibodies present a possible therapeutic approach to prevent and control ZIKV infection. Here we present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117. The antibody had been shown to prevent fetal infection and demise in mice. The structure shows that ZIKV-117 Fabs cross-link the monomers within the surface E glycoprotein dimers as well as between neighbouring dimers, thus preventing the reorganization of E protein monomers into fusogenic trimers in the acidic environment of endosomes.

Flow Cytometry
Rogers TF, Goodwin EC, Briney B, Sok D, Beutler N, Strubel A, Nedellec R, Le K, Brown ME, Burton DR, Walker LM. (2017). "Zika virus activates de novo and cross-reactive memory B cell responses in dengue-experienced donors" Sci Immunol 10.1126/sciimmunol.aan6809. PubMed

Zika virus (ZIKV) shares a high degree of homology with dengue virus (DENV), suggesting that preexisting immunity to DENV could affect immune responses to ZIKV. We have tracked the evolution of ZIKV-induced B cell responses in three DENV-experienced donors. The acute antibody (plasmablast) responses were characterized by relatively high somatic hypermutation and a bias toward DENV binding and neutralization, implying the early activation of DENV clones. A DENV-naïve donor in contrast showed a classical primary plasmablast response. Five months after infection, the DENV-experienced donors developed potent type-specific ZIKV neutralizing antibody responses in addition to DENV cross-reactive responses. Because cross-reactive responses were poorly neutralizing and associated with enhanced ZIKV infection in vitro, preexisting DENV immunity could negatively affect protective antibody responses to ZIKV. The observed effects are epitope-dependent, suggesting that a ZIKV vaccine should be carefully designed for DENV-seropositive populations.

in vivo inhibition of ZIKV infection, in vitro neutralization of ZIKV, ELISA
Zhao H, Fernandez E, Dowd KA, Speer SD, Platt DJ, Gorman MJ, Govero J, Nelson CA, Pierson TC, Diamond MS, Fremont DH. (2016). "Structural Basis of Zika Virus-Specific Antibody Protection" Cell 10.1016/j.cell.2016.07.020. PubMed

Zika virus (ZIKV) infection during pregnancy has emerged as a global public health problem because of its ability to cause severe congenital disease. Here, we developed six mouse monoclonal antibodies (mAbs) against ZIKV including four (ZV-48, ZV-54, ZV-64, and ZV-67) that were ZIKV specific and neutralized infection of African, Asian, and American strains to varying degrees. X-ray crystallographic and competition binding analyses of Fab fragments and scFvs defined three spatially distinct epitopes in DIII of the envelope protein corresponding to the lateral ridge (ZV-54 and ZV-67), C-C' loop (ZV-48 and ZV-64), and ABDE sheet (ZV-2) regions. In vivo passive transfer studies revealed protective activity of DIII-lateral ridge specific neutralizing mAbs in a mouse model of ZIKV infection. Our results suggest that DIII is targeted by multiple type-specific antibodies with distinct neutralizing activity, which provides a path for developing prophylactic antibodies for use in pregnancy or designing epitope-specific vaccines against ZIKV.