Zika Virus Vaccine Research Articles

Responding to a disease with resources from other diseases: Evidence from Zika vaccine research dynamics

AbstractResponding to health needs in one disease area might rely on being able to draw on research and funding oriented towards other disease areas. However, the tendency of medical research to cross-disease areas has received limited empirical consideration. An outbreak, in a disease area with little prior research or funding, means that any research response will necessarily be rich with cross-disease flows. This affords a setting that allows us to identify and examine the phenomenon over time. We estimate the extent to which the vaccine research community’s response to Zika virus drew on research and funding from other diseases. We find that a persistently low share of funding into Zika vaccine research was Zika-oriented. In contrast, a much higher share of knowledge inputs was oriented to Zika. The exercise serves to illustrate some general themes in priority setting for health research systems alongside some core features of vaccine innovation.

Onset and Progression of Infection Based on Viral Loads in Rhesus Macaques Exposed to Zika Virus

Outbreaks of Zika virus (ZIKV) have resulted in a call by global health advocates for increased surveillance and research with aggressive measures to combat ZIKV infections. There is no licensed ZIKV vaccine yet available, but a number of vaccine candidates are in development. Advancement of promising vaccine candidates to licensure may rely upon the development and use of well-characterized preclinical models developed based on the essential elements of an animal model as outlined in the U.S. FDA “Product Development Under the Animal Rule: Guidance for Industry”. Further, in the absence of adequate clinical cases to support a more traditional approval pathway based on clinical efficacy, regulatory approval could be based upon human safety data and use of a well-characterized animal model to evaluate vaccine efficacy. This report summarizes a statistical analysis that characterizes the progression of ZIKV infection in Rhesus macaques (RMs) with respect to viral load using available data on twenty-six (26) RMs from three (3) studies that were exposed to ZIKV and were not immunized with a ZIKV vaccine. Progression of infection was characterized by time to detection of viral RNA in serum (RT-qPCR) or time to positive viremia (plaque assay). Viral RNA was detected via RT-qPCR as early as day 1 post-infection and was undetectable for all animals by day 7. Viremia also was indicated by plaque assay as early as day 1 and was undetectable for all animals by day 5. Viral RNA was detected in all animals following exposure, while viremia was not observed in all animals. No significant differences in viral loads measured by either RT-qPCR or plaque assay were observed across sex, age, or study. Neither sex nor age were significant predictors of either time to detection of viral RNA or time to positive viremia following exposure to ZIKV. Progression of viral load, which is studied since infection is largely asymptomatic in both RMs and humans, is similar in RMs and humans with positive presentation ranging from 1 to 7 days post-infection and clearance by day 10. Overall, due to consistency of the model across sexes and ages and similarity to the infection profile in humans, it is concluded that the RM model of ZIKV infection is a well-characterized model for use for evaluation of ZIKV countermeasures.

Zika virus-like particle vaccine fusion loop mutation increases production yield but fails to protect AG129 mice against Zika virus challenge.

Zika virus (ZIKV) is a mosquito-borne flavivirus with maternal infection associated with preterm birth, congenital malformations, and fetal death, and adult infection associated with Guillain-Barré syndrome. Recent widespread endemic transmission of ZIKV and the potential for future outbreaks necessitate the development of an effective vaccine. We developed a ZIKV vaccine candidate based on virus-like-particles (VLPs) generated following transfection of mammalian HEK293T cells using a plasmid encoding the pre-membrane/membrane (prM/M) and envelope (E) structural protein genes. VLPs were collected from cell culture supernatant and purified by column chromatography with yields of approximately 1-2mg/L. To promote increased particle yields, a single amino acid change of phenylalanine to alanine was made in the E fusion loop at position 108 (F108A) of the lead VLP vaccine candidate. This mutation resulted in a modest 2-fold increase in F108A VLP production with no detectable prM processing by furin to a mature particle, in contrast to the lead candidate (parent). To evaluate immunogenicity and efficacy, AG129 mice were immunized with a dose titration of either the immature F108A or lead VLP (each alum adjuvanted). The resulting VLP-specific binding antibody (Ab) levels were comparable. However, geometric mean neutralizing Ab (nAb) titers using a recombinant ZIKV reporter were significantly lower with F108A immunization compared to lead. After virus challenge, all lead VLP-immunized groups showed a significant 3- to 4-Log10 reduction in mean ZIKV RNAemia levels compared with control mice immunized only with alum, but the RNAemia reduction of 0.5 Log10 for F108A groups was statistically similar to the control. Successful viral control by the lead VLP candidate following challenge supports further vaccine development for this candidate. Notably, nAb titer levels in the lead, but not F108A, VLP-immunized mice inversely correlated with RNAemia. Further evaluation of sera by an in vitro Ab-dependent enhancement assay demonstrated that the F108A VLP-induced immune sera had a significantly higher capacity to promote ZIKV infection in FcγR-expressing cells. These data indicate that a single amino acid change in the fusion loop resulted in increased VLP yields but that the immature F108A particles were significantly diminished in their capacity to induce nAbs and provide protection against ZIKV challenge.

Novel microparticulate Zika vaccine induces a significant immune response in a preclinical murine model after intramuscular administration

Despite the detrimental effects associated with Zika infection, there are no approved treatments or vaccines available. To address the need for a safe and effective vaccine for Zika, we formulated poly(lactic-co-glycolic) acid (PLGA) polymeric vaccine microparticles (MP) encapsulating the inactivated Zika virus, along with adjuvant MP encapsulating Alhydrogel® and MPL-A®. We characterized the vaccine MP for size, surface charge, morphology, encapsulation efficiency, and antigen integrity. Further, we evaluated immunogenicity and cytotoxicity of vaccine MP in vitro in murine dendritic cells. Vaccine MP with adjuvants induced significantly higher production of nitric oxide, a marker of innate immunity, when compared to the untreated cells. In addition, vaccine MP with or without adjuvants induced increased autophagy in murine dendritic cells when compared to inactivated Zika virus, which is critical in antigen presentation. Next, we evaluated in vivo efficacy of vaccine MP with and without adjuvants in a preclinical murine model by measuring the immune response after intramuscular administration. Vaccine MP with adjuvants induced significant IgG, Ig2a, and IgG1 titers as compared to the control group of untreated mice. Thus, this study provided the ‘proof-of-concept’ for a microparticulate Zika vaccine.

Important arboviral diseases in returning travelers: dengue, chikungunya and zika

Arboviral infections are an important differential diagnosis in returning travelers with fever, muscle or joint pain and rash. Arboviruses have spread widely around the globe in the last decades. The most common arboviral infections in returning travelers from tropical and subtropical areas are dengue, chikungunya and zika. Their most important vectors, Aedes (Stegomyia) mosquito species, have adapted to the urban environment, which enabled arboviruses to establish urban transmission cycles. Population growth, urbanization, globalization, modern means of transportation and global warming are speeding up their spread.Laboratory confirmation of an arboviral infection can generally be obtained by direct virus detection (PCR, antigen test) in the first week of illness; from the second week of illness serology can be used. Treatment is mostly symptomatic.Dengue fever is the most common cause of fever in returning travelers from South-East Asia. Patients have to be educated about and observed for warning signs of severe dengue that can rarely develop around day 5 of the disease and is marked by a rise in hematocrit.Chikungunya mostly occurs in epidemics and is characterized by severe and often long-lasting arthritis.Preconceptional screening for zika virus infection is not recommended. Instead, travelers should delay conception for up to three months after returning from a zika endemic area.Dengue, chikungunya and zika vaccine development has been hampered by difficulties, for example antibody-dependent-enhancement or the unpredictability of outbreaks, and up to now no vaccines for travelers have been licensed. Yet several promising vaccine candidates are currently under development.

Nucleic Acid Vaccine Platform for DENGUE and ZIKA Flaviviruses.

Dengue virus and Zika virus are mosquito-borne, single-stranded, positive-sense RNA viruses that belong to the Flaviviridae family. Both the viruses are closely related and have similarities with other flaviviruses. Dengue virus (DENV) causes a severe febrile illness with fever, joint pain, and rash leading to a life-threatening condition in severe cases. While Zika virus (ZIKV) primarily causes mild fever, it can be passed from a pregnant mother to her fetus, resulting in severe birth defect microcephaly and even causing a rare autoimmune disease—Guillain–Barre syndrome. To date, there are no approved DENV and ZIKA vaccines available, except a Dengue vaccine (Dengvaxia, Sanofi Pasteur Inc., Lyon, France) recently approved to be used only for 9–16 years of age groups living in endemic areas and having a previous record of confirmed dengue infection. There are several potential vaccine candidates in the clinical trials based on multiple vaccine platforms, such as live attenuated, subunit, nucleic acid, and viral vector-based vaccines. In the current review, we have focused exclusively on the nucleic acid vaccine platform and discussed the progress of all the DNA/RNA vaccine candidates under preclinical and clinical studies for DENV and ZIKA viruses. Additionally, we have described a brief history of the emergence of these flaviviruses, major structural similarities between them, prominent vaccine targets, and the mechanism of virus entry and infection.

Forming and updating vaccination beliefs: does the continued effect of misinformation depend on what we think we know?

People may cling to false facts even in the face of updated and correct information. The present study confronted misconceptions about the measles, mumps and rubella vaccine and a novel, fictitious Zika vaccine. Two experiments are reported, examining misconceptions as motivated by a poor risk understanding (Experiment 1, N = 130) or the exposure to conspiracy theories (Experiment 2, N = 130). Each experiment featured a Misinformation condition, wherein participants were presented with fictitious stories containing some misinformation (Experiment 1) and rumours focused on conspiracy theories (Experiment 2) that were later retracted by public health experts and a No misinformation condition, containing no reference to misinformation and rumours. Across experiments, participants were more hesitant towards vaccines when exposed to stories including vaccine misinformation. Notwithstanding, our results suggest a positive impact of a trusted source communicating the scientific consensus about vaccines. Zika virus represents a particular case showing how missing information can easily evolve into misinformation. Implications for effective dissemination of information are discussed.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10339-022-01093-2.

Self-Assembling Nanovaccine Confers Complete Protection Against Zika Virus Without Causing Antibody-Dependent Enhancement.

The Zika virus (ZIKV) epidemic poses a substantial threat to the public, and the development of safe and effective vaccines is a demanding challenge. In this study, we constructed a kind of self-assembling nanovaccine which confers complete protection against ZIKV infection. The ZIKV envelop protein domain III (zEDIII) was presented on recombinant human heavy chain ferritin (rHF) to form the zEDIII-rHF nanoparticle. Immunization of mice with zEDIII-rHF nanoparticle in the absence of an adjuvant induced robust humoral and cellular immune responses. zEDIII-rHF vaccination conferred complete protection against lethal infection with ZIKV and eliminated pathological symptoms in the brain. Importantly, the zEDIII-rHF nanovaccine induced immune response did not cross-react with dengue virus-2, overcoming the antibody-dependent enhancement (ADE) problem that is a safety concern for ZIKV vaccine development. Our constructed zEDIII-rHF nanovaccine, with superior protective performance and avoidance of ADE, provides an effective and safe vaccine candidate against ZIKV.

Measles-based Zika vaccine induces long-term immunity and requires NS1 antibodies to protect the female reproductive tract

Zika virus (ZIKV) can cause devastating effects in the unborn fetus of pregnant women. To develop a candidate vaccine that can protect human fetuses, we generated a panel of live measles vaccine (MV) vectors expressing ZIKV-E and -NS1. Our MV-based ZIKV-E vaccine, MV-E2, protected mice from the non-lethal Zika Asian strain (PRVABC59) and the lethal African strain (MR766) challenge. Despite 100% survival of the MV-E2 mice, however, complete viral clearance was not achieved in the brain and reproductive tract of the lethally challenged mice. We then tested MV-based vaccines that expressed E and NS1 together or separately in two different vaccines. We observed complete clearance of ZIKV from the female reproductive tract and complete fetal protection in the lethal African challenge model in animals that received the dual antigen vaccines. Additionally, MV-E2 and MV-NS1, when administered together, induced durable plasma cell responses. Our findings suggest that NS1 antibodies are required to enhance the protection of ZIKV-E antibodies in the female reproductive tract.

Design of a multi-epitope Zika virus vaccine candidate – an in-silico study

Zika virus (ZIKV), an RNA virus, rapidly spreads Aedes mosquito-borne sickness. Currently, there are neither effective vaccines nor therapeutics available to prevent or treat ZIKV infection. In this study, to address these unmet medical needs, we aimed to design B- and T-cell candidate multi-epitope-based subunit against ZIKV using an in silico approach. In this study we applied immunoinformatics, molecular docking, and dynamic simulation assessments targeting the most immunogenic proteins; the capsid (C), envelope (E) proteins and the non-stuctural protein (NS1), described in our previous study, and which predicted immunodominant B and T cell epitopes. The final non-allergenic and highly antigenic multi-epitope was constituted of immunogenic screened-epitopes (3 CTL and 3 HTL) and the β-defensin as an adjuvant that have been linked using EAAAK, AAY, and GPGPG linkers, respectively. The final construct containing 143 amino acids was characterized for its allergenicity, antigenicity, and physiochemical properties; and found to be safe and immunogenic with a good prediction of solubility. The existence of IFN-γ epitopes asserts the capacity to trigger strong immune responses. Subsequently, the molecular docking among vaccine and immune receptors (TLR2/TLR4) was revealed with a good binding affinity with and stable molecular interactions. Molecular dynamics simulation confirmed the stability of the complexes. Finally, the construct was subjected to in silico cloning demonstrating the efficiently of its expression in E.coli. However, this study needs the experimental validation to demonstrate vaccine safety and efficacy. Communicated by Ramaswamy H. Sarma

Low Immune Cross-Reactivity between West Nile Virus and a Zika Virus Vaccine Based on Modified Vaccinia Virus Ankara.

Zika virus (ZIKV) is a mosquito-borne flavivirus whose infection in pregnant women is associated with a spectrum of birth defects, which are together referred as Congenital Zika Syndrome. In addition, ZIKV can also induce Guillain–Barré syndrome, which is an autoimmune disease with neurological symptoms. The recent description of the first local infections of ZIKV in the European continent together with the expansion of one of its potential vectors, the Asian tiger mosquito (Aedes albopictus), invite us to be prepared for future outbreaks of ZIKV in this geographical region. However, the antigenic similarities of ZIKV with other flaviviruses can lead to an immune cross-reactivity with other circulating flaviviruses inducing, in some cases, flavivirus-disease exacerbation by antibody-dependent enhancement (ADE) of infection, which is a major concern for ZIKV vaccine development. Until now, West Nile virus (WNV) is the main medically relevant flavivirus circulating in the Mediterranean Basin. Therefore, anticipating the potential scenario of emergency vaccination against ZIKV in areas of Europe where WNV is endemic, in this investigation, we have evaluated the cross-reactivity between WNV and our previously developed ZIKV vaccine candidate based on modified vaccinia virus Ankara (MVA) vector expressing ZIKV structural proteins (MVA-ZIKV). To this end, mice were first immunized with MVA-ZIKV, subsequently challenged with WNV, and then, the ZIKV- and WNV-specific immune responses and protection against WNV were evaluated. Our results indicate low cross-reactivity between the MVA-ZIKV vaccine candidate and WNV and absence of ADE, supporting the safety of this ZIKV vaccine candidate in areas where the circulation of WNV is endemic.

Peculiarities of Zika Immunity and Vaccine Development: Lessons from Dengue and the Contribution from Controlled Human Infection Model.

The Zika virus (ZIKV) was first isolated from a rhesus macaque in the Zika forest of Uganda in 1947. Isolated cases were reported until 2007, when the first major outbreaks of Zika infection were reported from the Island of Yap in Micronesia and from French Polynesia in 2013. In 2015, ZIKV started to circulate in Latin America, and in 2016, ZIKV was considered by WHO to be a Public Health Emergency of International Concern due to cases of Congenital Zika Syndrome (CZS), a ZIKV-associated complication never observed before. After a peak of cases in 2016, the infection incidence dropped dramatically but still causes concern because of the associated microcephaly cases, especially in regions where the dengue virus (DENV) is endemic and co-circulates with ZIKV. A vaccine could be an important tool to mitigate CZS in endemic countries. However, the immunological relationship between ZIKV and other flaviviruses, especially DENV, and the low numbers of ZIKV infections are potential challenges for developing and testing a vaccine against ZIKV. Here, we discuss ZIKV vaccine development with the perspective of the immunological concerns implicated by DENV-ZIKV cross-reactivity and the use of a controlled human infection model (CHIM) as a tool to accelerate vaccine development.

Efficacy of an inactivated Zika vaccine against virus infection during pregnancy in mice and marmosets

Zika virus (ZIKV) is a mosquito-borne arbovirus that can cause severe congenital birth defects. The utmost goal of ZIKV vaccines is to prevent both maternal-fetal infection and congenital Zika syndrome. A Zika purified inactivated virus (ZPIV) was previously shown to be protective in non-pregnant mice and rhesus macaques. In this study, we further examined the efficacy of ZPIV against ZIKV infection during pregnancy in immunocompetent C57BL6 mice and common marmoset monkeys (Callithrix jacchus). We showed that, in C57BL/6 mice, ZPIV significantly reduced ZIKV-induced fetal malformations. Protection of fetuses was positively correlated with virus-neutralizing antibody levels. In marmosets, the vaccine prevented vertical transmission of ZIKV and elicited neutralizing antibodies that remained above a previously determined threshold of protection for up to 18 months. These proof-of-concept studies demonstrate ZPIV’s protective efficacy is both potent and durable and has the potential to prevent the harmful consequence of ZIKV infection during pregnancy.

Generation of CpG-Recoded Zika Virus Vaccine Candidates.

Experimental increase of cytosine-phosphate-guanine (CpG) dinucleotides in an RNA virus genome impairs infection. Beneficially, this weak infection may lead to robust antiviral host immunity providing a cutting-edge approach for vaccines. For example, we have recently demonstrated that recoded Zika virus variants with the increased CpG content showed considerable attenuated infection phenotypes and protection against lethal challenge in mice. Here, we describe the workflow for the design and generation of CpG-recoded Zika virus vaccine candidates. The workflow can be adapted for other viruses.

MRNA Vaccine Protects against Zika Virus.

Zika virus (ZIKV), a mosquito-borne flavivirus, has recently triggered global concern due to severe health complications. In 2015, a large ZIKV outbreak occurred in the Americas and established a link between ZIKV and microcephaly in newborn babies, spontaneous abortion, persistent viremia, and Guillain–Barré syndrome. While antivirals are being developed and prevention strategies focus on vector control, a safe and effective Zika vaccine remains unavailable. Messenger RNA (mRNA) vaccine technology has arisen as a flexible, simplified, and fast vaccine production platform. Here, we report on an mRNA vaccine candidate that encodes the pre-membrane and envelope (prM–E) glycoproteins of ZIKV strain Brazil SPH2015 and is encapsulated in lipid nanoparticles (LNPs). Our ZIKV prM–E mRNA-LNP vaccine candidate induced antibody responses that protected in AG129 mice deficient in interferon (IFN) alpha/beta/gamma (IFN-α/β/γ) receptors. Notably, a single administration of ZIKV prM–E mRNA-LNP protected against a lethal dose of ZIKV, while a two-dose strategy induced strong protective immunity. E-specific double-positive IFN-γ and TNF-α T-cells were induced in BALB/c mice after immunizations with a two-dose strategy. With the success of mRNA vaccine technology in facing the coronavirus (COVID-19) pandemic, our data support the development of prM–E RNActive® as a promising mRNA vaccine against Zika to counter future epidemics.

Single dose of chimeric dengue-2/Zika vaccine candidate protects mice and non-human primates against Zika virus

The development of a safe and effective Zika virus (ZIKV) vaccine has become a global health priority since the widespread epidemic in 2015-2016. Based on previous experience in using the well-characterized and clinically proven dengue virus serotype-2 (DENV-2) PDK-53 vaccine backbone for live-attenuated chimeric flavivirus vaccine development, we developed chimeric DENV-2/ZIKV vaccine candidates optimized for growth and genetic stability in Vero cells. These vaccine candidates retain all previously characterized attenuation phenotypes of the PDK-53 vaccine virus, including attenuation of neurovirulence for 1-day-old CD-1 mice, absence of virulence in interferon receptor-deficient mice, and lack of transmissibility in the main mosquito vectors. A single DENV-2/ZIKV dose provides protection against ZIKV challenge in mice and rhesus macaques. Overall, these data indicate that the ZIKV live-attenuated vaccine candidates are safe, immunogenic and effective at preventing ZIKV infection in multiple animal models, warranting continued development.

Efficient Control of Zika Virus Infection Induced by a Non-Replicating Adenovector Encoding Zika Virus NS1/NS2 Antigens Fused to the MHC Class II-Associated Invariant Chain.

It is generally believed that a successful Zika virus (ZIKV) vaccine should induce neutralizing antibodies against the ZIKV envelope (E) protein to efficiently halt viral infection. However, E-specific neutralizing antibodies have been implicated in a phenomenon called antibody-dependent enhancement, which represents an ongoing concern in the flavivirus-vaccinology field. In this report, we investigated the vaccination potential of replication-deficient adenoviral vectors encoding the ZIKV non-structural proteins 1 and 2 (NS1/NS2) and employed the strategy of linking the antigens to the MHC-II associated invariant chain (li) to improve immunogenicity and by inference, the level of protection. We demonstrated that li-linkage enhanced the production of anti-NS1 antibodies and induced an accelerated and prolonged polyfunctional CD8 T cell response in mice, which ultimately resulted in a high degree of protection against ZIKV infection of the CNS.

Hide and Seek: The Interplay Between Zika Virus and the Host Immune Response.

Zika virus (ZIKV) received worldwide attention over the past decade when outbreaks of the disease were found to be associated with severe neurological syndromes and congenital abnormalities. Unlike most other flaviviruses, ZIKV can spread through sexual and transplacental transmission, adding to the complexity of Zika pathogenesis and clinical outcomes. In addition, the spread of ZIKV in flavivirus-endemic regions, and the high degree of structural and sequence homology between Zika and its close cousin Dengue have raised questions on the interplay between ZIKV and the pre-existing immunity to other flaviviruses and the potential immunopathogenesis. The Zika epidemic peaked in 2016 and has affected over 80 countries worldwide. The re-emergence of large-scale outbreaks in the future is certainly a possibility. To date, there has been no approved antiviral or vaccine against the ZIKV. Therefore, continuing Zika research and developing an effective antiviral and vaccine is essential to prepare the world for a future Zika epidemic. For this purpose, an in-depth understanding of ZIKV interaction with many different pathways in the human host and how it exploits the host immune response is required. For successful infection, the virus has developed elaborate mechanisms to escape the host response, including blocking host interferon response and shutdown of certain host cell translation. This review provides a summary on the key host factors that facilitate ZIKV entry and replication and the mechanisms by which ZIKV antagonizes antiviral innate immune response and involvement of adaptive immune response leading to immunopathology. We also discuss how ZIKV modulates the host immune response during sexual transmission and pregnancy to induce infection, how the cross-reactive immunity from other flaviviruses impacts ZIKV infection, and provide an update on the current status of ZIKV vaccine development.

A CRISPR Activation Screen Identifies an Atypical Rho GTPase That Enhances Zika Viral Entry.

Zika virus (ZIKV) is a re-emerging flavivirus that has caused large-scale epidemics. Infection during pregnancy can lead to neurologic developmental abnormalities in children. There is no approved vaccine or therapy for ZIKV. To uncover cellular pathways required for ZIKV that can be therapeutically targeted, we transcriptionally upregulated all known human coding genes with an engineered CRISPR–Cas9 activation complex in human fibroblasts deficient in interferon (IFN) signaling. We identified Ras homolog family member V (RhoV) and WW domain-containing transcription regulator 1 (WWTR1) as proviral factors, and found them to play important roles during early ZIKV infection in A549 cells. We then focused on RhoV, a Rho GTPase with atypical terminal sequences and membrane association, and validated its proviral effects on ZIKV infection and virion production in SNB-19 cells. We found that RhoV promotes infection of some flaviviruses and acts at the step of viral entry. Furthermore, RhoV proviral effects depend on the complete GTPase cycle. By depleting Rho GTPases and related proteins, we identified RhoB and Pak1 as additional proviral factors. Taken together, these results highlight the positive role of RhoV in ZIKV infection and confirm CRISPR activation as a relevant method to identify novel host–pathogen interactions.

Enemy of My Enemy: A Novel Insect-Specific Flavivirus Offers a Promising Platform for a Zika Virus Vaccine.

Vaccination remains critical for viral disease outbreak prevention and control, but conventional vaccine development typically involves trade-offs between safety and immunogenicity. We used a recently discovered insect-specific flavivirus as a vector in order to develop an exceptionally safe, flavivirus vaccine candidate with single-dose efficacy. To evaluate the safety and efficacy of this platform, we created a chimeric Zika virus (ZIKV) vaccine candidate, designated Aripo/Zika virus (ARPV/ZIKV). ZIKV has caused immense economic and public health impacts throughout the Americas and remains a significant public health threat. ARPV/ZIKV vaccination showed exceptional safety due to ARPV/ZIKV’s inherent vertebrate host-restriction. ARPV/ZIKV showed no evidence of replication or translation in vitro and showed no hematological, histological or pathogenic effects in vivo. A single-dose immunization with ARPV/ZIKV induced rapid and robust neutralizing antibody and cellular responses, which offered complete protection against ZIKV-induced morbidity, mortality and in utero transmission in immune-competent and -compromised murine models. Splenocytes derived from vaccinated mice demonstrated significant CD4+ and CD8+ responses and significant cytokine production post-antigen exposure. Altogether, our results further support that chimeric insect-specific flaviviruses are a promising strategy to restrict flavivirus emergence via vaccine development.