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Early Embryonic Loss Following Intravaginal Zika Virus Challenge in Rhesus Macaques.

ABSTRACT: Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) and is primarily transmitted by Aedes species mosquitoes; however, ZIKV can also be sexually transmitted. During the initial epidemic and in places where ZIKV is now considered endemic, it is difficult to disentangle the risks and contributions of sexual versus vector-borne transmission to adverse pregnancy outcomes. To examine the potential impact of sexual transmission of ZIKV on pregnancy outcome, we challenged three rhesus macaques (Macaca mulatta) three times intravaginally with 1 x 10⁷ PFU of a low passage, African lineage ZIKV isolate (ZIKV-DAK) in the first trimester (~30 days gestational age). Samples were collected from all animals initially on days 3 through 10 post challenge, followed by twice, and then once weekly sample collection; ultrasound examinations were performed every 3-4 days then weekly as pregnancies progressed. All three dams had ZIKV RNA detectable in plasma on day 3 post-ZIKV challenge. At approximately 45 days gestation (17-18 days post-challenge), two of the three dams were found with nonviable embryos by ultrasound. Viral RNA was detected in recovered tissues and at the maternal-fetal interface (MFI) in both cases. The remaining viable pregnancy proceeded to near term (~155 days gestational age) and ZIKV RNA was detected at the MFI but not in fetal tissues. These results suggest that sexual transmission of ZIKV may represent an underappreciated risk of pregnancy loss during early gestation.

SUBMITTER: Newman CM

PROVIDER: S-EPMC8165274 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Early Embryonic Loss Following Intravaginal Zika Virus Challenge in Rhesus Macaques.

Newman Christina M CM Tarantal Alice F AF Martinez Michele L ML Simmons Heather A HA Morgan Terry K TK Zeng Xiankun X Rosinski Jenna R JR Bliss Mason I MI Bohm Ellie K EK Dudley Dawn M DM Aliota Matthew T MT Friedrich Thomas C TC Miller Christopher J CJ O'Connor David H DH

Frontiers in immunology 20210517

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) and is primarily transmitted by <i>Aedes</i> species mosquitoes; however, ZIKV can also be sexually transmitted. During the initial epidemic and in places where ZIKV is now considered endemic, it is difficult to disentangle the risks and contributions of sexual versus vector-borne transmission to adverse pregnancy outcomes. To examine the potential impact of sexual transmission of ZIKV on pregnancy outcome, we challenged three rhesus maca ...[more]

PMID: 34079560

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Project description:BackgroundZika virus (ZIKV; Flaviviridae, Flavivirus) was declared a public health emergency of international concern by the World Health Organization (WHO) in February 2016, because of the evidence linking infection with ZIKV to neurological complications, such as Guillain-Barre Syndrome in adults and congenital birth defects including microcephaly in the developing fetus. Because development of a ZIKV vaccine is a top research priority and because the genetic and antigenic variability of many RNA viruses limits the effectiveness of vaccines, assessing whether immunity elicited against one ZIKV strain is sufficient to confer broad protection against all ZIKV strains is critical. Recently, in vitro studies demonstrated that ZIKV likely circulates as a single serotype. Here, we demonstrate that immunity elicited by African lineage ZIKV protects rhesus macaques against subsequent infection with Asian lineage ZIKV.Methodology/principal findingsUsing our recently developed rhesus macaque model of ZIKV infection, we report that the prototypical ZIKV strain MR766 productively infects macaques, and that immunity elicited by MR766 protects macaques against heterologous Asian ZIKV. Furthermore, using next generation deep sequencing, we found in vivo restoration of a putative N-linked glycosylation site upon replication in macaques that is absent in numerous MR766 strains that are widely being used by the research community. This reversion highlights the importance of carefully examining the sequence composition of all viral stocks as well as understanding how passage history may alter a virus from its original form.Conclusions/significanceAn effective ZIKV vaccine is needed to prevent infection-associated fetal abnormalities. Macaques whose immune responses were primed by infection with East African ZIKV were completely protected from detectable viremia when subsequently rechallenged with heterologous Asian ZIKV. Therefore, these data suggest that immunogen selection is unlikely to adversely affect the breadth of vaccine protection, i.e., any Asian ZIKV immunogen that protects against homologous challenge will likely confer protection against all other Asian ZIKV strains.

Project description:BackgroundZika virus (ZIKV), a mosquito-borne flavivirus, is a re-emerging virus that constitutes a public health threat due to its recent global spread, recurrent outbreaks, and infections that are associated with neurological abnormalities in developing fetuses and Guillain-Barré syndrome in adults. To date, there are no approved vaccines against ZIKV infection. Various preclinical and clinical development programs are currently ongoing in an effort to bring forward a vaccine for ZIKV.Methodology/principle findingsWe have developed a ZIKV vaccine candidate based on Virus-Like-Particles (VLPs) produced in HEK293 mammalian cells using the prM (a precursor to M protein) and envelope (E) structural protein genes from ZIKV. Transient transfection of cells via plasmid and electroporation produced VLPs which were subsequently purified by column chromatography yielding approximately 2mg/L. Initially, immunogenicity and efficacy were evaluated in AG129 mice using a dose titration of VLP with and without Alhydrogel 2% (alum) adjuvant. We found that VLP with and without alum elicited ZIKV-specific serum neutralizing antibodies (nAbs) and that titers correlated with protection. A follow-up immunogenicity and efficacy study in rhesus macaques was performed using VLP formulated with alum. Multiple neutralization assay methods were performed on immune sera including a plaque reduction neutralization test, a microneutralization assay, and a Zika virus Renilla luciferase neutralization assay. All of these assays indicate that following immunization, VLP induces high titer nAbs which correlate with protection against ZIKV challenge.Conclusions/significanceThese studies confirm that ZIKV VLPs could be efficiently generated and purified. Upon VLP immunization, in both mice and NHPs, nAb was induced that correlate with protection against ZIKV challenge. These studies support translational efforts in developing a ZIKV VLP vaccine for evaluation in human clinical trials.

Project description:By the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome, as well as Guillain-Barré syndrome, in ZIKV-infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity; however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV 22 to 28 months after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies that protect from detectable plasma viremia following rechallenge and persist for at least 22 to 28 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity.IMPORTANCE ZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the decrease in ZIKV cases since the 2015-2016 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. Although preexisting herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV 22 to 28 months prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. This study establishes a new minimal length of protective immunity.

Dataset Information

Early Embryonic Loss Following Intravaginal Zika Virus Challenge in Rhesus Macaques.

Publications

Early Embryonic Loss Following Intravaginal Zika Virus Challenge in Rhesus Macaques.

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