scholarly journals Long-term protection of rhesus macaques from Zika virus reinfection

2019 ◽  
Author(s):  
Gage K. Moreno ◽  
Christina M. Newman ◽  
Michelle R. Koenig ◽  
Mariel S. Mohns ◽  
Andrea M. Weiler ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Minimal Length ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

AbstractBy 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 (CZS). Guillain-Barré syndrome (GBS) 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 two years after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies (nAbs) that protect from detectable plasma viremia following rechallenge and persist for at least 27 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity.Author SummaryZIKV 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 drop in ZIKV cases since the 2015-16 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. While pre-existing 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 two years prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. While this work establishes a new minimal length of protective immunity, additional studies are necessary to define the maximum length of protective immunity following ZIKV infection.

scholarly journals Long-Term Protection of Rhesus Macaques from Zika Virus Reinfection

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Gage K. Moreno ◽  
Christina M. Newman ◽  
Michelle R. Koenig ◽  
Mariel S. Mohns ◽  
Andrea M. Weiler ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Minimal Length ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

ABSTRACT 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.

scholarly journals Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Carol L. Vinton ◽  
Samuel J. Magaziner ◽  
Kimberly A. Dowd ◽  
Shelly J. Robertson ◽  
Emerito Amaro-Carambot ◽  
...  
Keyword(s):  
Immune Responses ◽  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Zikv Infection ◽  
Adaptive Immune ◽  
Immunodeficiency Virus

ABSTRACT Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1- to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIV-positive (SIV+) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV+ RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV+ RMs. IMPORTANCE Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIV-infected individuals influence ZIKV infection.

scholarly journals Vesicular Stomatitis Virus and DNA Vaccines Expressing Zika Virus Nonstructural Protein 1 Induce Substantial but Not Sterilizing Protection against Zika Virus Infection

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Anzhong Li ◽  
Miaoge Xue ◽  
Zayed Attia ◽  
Jingyou Yu ◽  
Mijia Lu ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Nonstructural Protein ◽  
Ns1 Protein ◽  
Zikv Infection ◽  
Partial Protection ◽  
Nonstructural Protein 1 ◽  
Vesicular Stomatitis

ABSTRACT The nonstructural protein 1 (NS1) of several flaviviruses, including West Nile, dengue, and yellow fever viruses, is capable of inducing variable degrees of protection against flavivirus infection in animal models. However, the immunogenicity of NS1 protein of Zika virus (ZIKV) is less understood. Here, we determined the efficacy of ZIKV NS1-based vaccine candidates using two delivery platforms, methyltransferase-defective recombinant vesicular stomatitis virus (mtdVSV) and a DNA vaccine. We first show that expression of ZIKV NS1 could be significantly enhanced by optimizing the signal peptide. A single dose of mtdVSV-NS1-based vaccine or two doses of DNA vaccine induced high levels of NS1-specfic antibody and T cell immune responses but provided only partial protection against ZIKV viremia in BALB/c mice. In Ifnar1−/− mice, neither NS1-based vaccine provided protection against a lethal high dose (105 PFU) ZIKV challenge, but mtdVSV-NS1-based vaccine prevented deaths from a low dose (103 PFU) challenge, though they experienced viremia and body weight loss. We conclude that ZIKV NS1 alone conferred substantial, but not complete, protection against ZIKV infection. Nevertheless, these results highlight the value of ZIKV NS1 for vaccine development. IMPORTANCE Most Zika virus (ZIKV) vaccine research has focused on the E or prM-E proteins and the induction of high levels of neutralizing antibodies. However, these ZIKV neutralizing antibodies cross-react with other flaviviruses, which may aggravate the disease via an antibody-dependent enhancement (ADE) mechanism. ZIKV NS1 protein may be an alternative antigen for vaccine development, since antibodies to NS1 do not bind to the virion, thereby eliminating the risk of ADE. Here, we show that recombinant VSV and DNA vaccines expressing NS1, alone, confer partial protection against ZIKV infection in both immunocompetent and immunodeficient mice, highlighting the value of NS1 as a potential vaccine candidate.

scholarly journals Galidesivir, a Direct-Acting Antiviral Drug, Abrogates Viremia in Rhesus Macaques Challenged with Zika Virus

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S55-S55 ◽  
Author(s):  
So-Yon Lim ◽  
Christa Osuna ◽  
Jessica Lakritz ◽  
Elsa Chen ◽  
Gyeol Yoon ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
Antiviral Drug ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Multiple Endpoints ◽  
Direct Acting Antiviral ◽  
Dosing Strategies ◽  
Complete Blood Counts ◽  
High Level

Abstract Background Zika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infection in humans is associated with serious neurological and reproductive complications. No antiviral or protective vaccine is yet available. Galidesivir an adenosine analog is a potent viral RNA-dependent RNA polymerase inhibitor with demonstrated broad-spectrum antiviral activity. Methods We have conducted four pre-clinical studies in rhesus macaques to assess the safety, antiviral efficacy and dosing strategies of galidesivir against ZIKV infection. Collectively, we have challenged 70 rhesus macaques by various routes using 1x105 TCID50of a Puerto Rican ZIKV isolate. We have evaluated galidesivir therapy administered via IM injection as early as 90 minutes and up to 72 hours after subcutaneous (SC) ZIKV challenge, and as late as 5 days after intravaginal (IVAG) challenge. In these studies, we evaluated the efficacy of a range of loading and maintence doses of galidesivir. The highest dose evaluated has been a loading dose of 100mg/kg BID followed by a maintenance dose of 25mg/kg BID for nine days. We followed multiple endpoints, including ZIKV RNA levels in plasma, urine, saliva, and cerebrospinal fluid. Immune activation, complete blood counts, chemistries and galidesivir pharmacokinetics were also monitored. Results Galidesivir was well-tolerated in all studies. All untreated controls developed high-level plasma viremia, and had readily detectable ZIKV RNA in CSF, saliva and urine post-infection. Animals treated in the first 24 hours after SC ZIKV challenge did not develop plasma viremia and were either negative or had significantly reduced ZIKV RNA in bodily fluids. Animals treated with galidesivir later (up to 72 hours) were partially protected; they had detectable plasma ZIKV RNA, but the onset was delayed and/or magnitude significantly reduced compared with controls. Animals infected IVAG were protected by galidesivir treatment up until day 5 after infection, with no blood viremia and significant reductions in ZIKV RNA in the CSF as compared with controls. Conclusion Galidesivir dosing in rhesus macaques was well-tolerated and offered significant protection against ZIKV infection. These results warrant continued study and clinical evaluation. Disclosures R. Taylor, BioCryst Pharmaceuticals: Employee, Salary; S. MacLennan, BioCryst: Employee, Salary; M. Leonard, BioCryst: Employee, Salary; E. Giuliano, BioCryst: Employee, Salary; A. Mathis, BioCryst Pharmaceuticals: Employee, Salary; E. Berger, BioCryst: Employee, Salary; Y. Babu, BioCryst: Employee, Salary; W. Sheridan, BioCryst Pharmaceuticals: Employee, Salary

scholarly journals Oropharyngeal mucosal transmission of Zika virus in rhesus macaques

2017 ◽  
Author(s):  
Christina M. Newman ◽  
Dawn M. Dudley ◽  
Matthew T. Aliota ◽  
Andrea M. Weiler ◽  
Gabrielle L. Barry ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
Infected Individual ◽  
Transmission Risk ◽  
High Dose ◽  
Plasma Viremia ◽  
Oral Secretions ◽  
Zikv Infection ◽  
Mucosal Transmission ◽  
Mucosal Route

AbstractZika virus (ZIKV) is present in urine, saliva, tears, and breast milk, but the transmission risk associated with these body fluids is currently unknown. We evaluated the risk of ZIKV transmission through mucosal contact in rhesus macaques. Application of high-dose ZIKV directly to the tonsils of 3 rhesus macaques resulted in detectable plasma viremia in all animals by 2 days post-exposure; virus replication kinetics were similar to those observed in animals infected subcutaneously. Three additional macaques inoculated subcutaneously with ZIKV served as saliva donors to assess the transmission risk from contact with oral secretions from an infected individual. Seven naive animals repeatedly exposed to donor saliva via the conjunctivae, tonsils, or nostrils did not become infected. Our results suggest that there is a risk of ZIKV transmission via the mucosal route, but that the risk posed by oral secretions from individuals with a typical course of ZIKV infection is low.

scholarly journals Zika virus-specific IgM elicited during pregnancy exhibits ultrapotent neutralization

2021 ◽  
Author(s):  
Tulika Singh ◽  
Kwan-Ki Hwang ◽  
Andrew S. Miller ◽  
Rebecca L. Jones ◽  
Cesar A. Lopez ◽  
...  
Keyword(s):  
Zika Virus ◽  
Binding Sites ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Igg Antibodies ◽  
Zikv Infection ◽  
Unique Role ◽  
Infected Pregnant Woman ◽  
Neurodevelopmental Deficits

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM responses contribute to ZIKV immunity in pregnancy, mediating neutralization up to three months post symptoms. From a ZIKV-infected pregnant woman, we established a B cell line secreting a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets a novel envelope dimer epitope within Domain II. The arrangement of this epitope on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not achievable by IgG antibodies. DH1017.IgM protected against lethal ZIKV challenge in mice. Our findings identify a unique role of antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunoprophylactic, particularly during pregnancy.

scholarly journals Differential Type 1 IFN Gene Expression in CD14+ Placenta Cells Elicited by Zika Virus Infection During Pregnancy

2021 ◽  
Vol 1 ◽  
Author(s):  
Nicole N. Haese ◽  
Hannah Smith ◽  
Kosiso Onwuzu ◽  
Craig N. Kreklywich ◽  
Jessica L. Smith ◽  
...  
Keyword(s):  
Zika Virus ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Fetal Brain ◽  
Bioinformatic Analysis ◽  
Interferon Response ◽  
Zikv Infection ◽  
Expression Of Genes ◽  
Congenital Zika Syndrome

Zika virus (ZIKV) is an arthropod-borne Flavivirus that can also be transmitted vertically from infected mother to fetus. Infection of the fetus during pregnancy can lead to congenital malformations and severely impact fetal brain development causing a myriad of diseases now labeled Congenital Zika Syndrome (CZS). The mechanisms by which ZIKV crosses the placenta into the fetal circulation and the extent of ZIKV-induced changes remain unclear. We have previously shown that ZIKV infection of pregnant rhesus macaques results in abnormal oxygen transport across the placenta which may promote uterine vasculitis and placental villous damage. Changes in immune cell frequencies and activation status were also detected, as were distinct changes in the proportions of CD14+ cell subsets with an altered ratio of classical to non-classical CD14+ monocyte cells in both the maternal decidua and placental villous from ZIKV-infected animals compare to uninfected controls. In the current study, we performed single cell RNA sequencing on CD14+ cells isolated from the decidua of animals that were ZIKV infected at 31, 51, or 115 days of gestation (where term is ~168 days) compared to pregnant, time-matched uninfected controls. Bioinformatic analysis identified unique transcriptional phenotypes between CD14+ cells of infected and uninfected animals suggesting a distinct and sustained difference in transcriptomes between infected and uninfected CD14+ cells derived from the decidua. The timing of ZIKV infection had no effect on the CD14+ cell transcriptional profiles. Interestingly, ZIKV infection caused changes in expression of genes in pathways related to cellular stress and metabolism as well as immune response activation. Type 1 interferon response genes (ISGs) were among those that were differentially expressed following infection and these included members of the ISG12 family, IFI27 and IFI6. These ISGs have been recently described as effectors of the IFN response to flaviviruses. Supplementing our animal findings, in CD14+ cells isolated from human placenta, ZIKV infection similarly induced the expression of IFI27 and IFI6. Overall, our results showed that ZIKV infection during pregnancy induces the stable expression of antiviral genes within CD14+ cells of the placenta, which may provide an immune shield to protect the placenta from further infection and damage.

SARS-CoV-2 Biology Insights, Part IV.Antibody-Dependent Enhancement (ADE) and the tricky “Herd Immunity”: narrative review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Whooping Cough ◽  
Common Knowledge ◽  
Herd Immunity ◽  
Life Quality ◽  
Host Cells ◽  
System P

BACKGROUND It is common knowledge that vaccination has improved our life quality and expectancy since it succeeded in achieving almost eradication of several diseases including chickenpox (varicella), diphtheria, hepatitis A and B, measles, meningococcal, mumps, pneumococcal, polio, rotavirus, rubella, tetanus and whooping cough (pertussis) Vaccination success is based on vaccine induction of neutralizing antibodies that help fight the infection (e.g. by a virus), preventing the disease. Conversely, Antibody-dependent enhancement (ADE) of a viral infection occurs when anti-viral antibodies facilitate viral entry into host cells and enhance viral infection in these cells. ADE has been previously studied in Dengue and HIV viruses and explains why a second infection with Dengue can be lethal. As already reviewed in Part I and Part II, SARS-Cov-2 shares with HIV not only 4 sequences in the Spike protein but also the capacity to attack the immune system. OBJECTIVE As HIV presents ADE, we wondered whether this was also the case regarding SARS-CoV-2. METHODS A literature review was done through Google. RESULTS SARS-CoV-2 presents ADE. As SARS, which does not have the 4 HIV-like inserts, has the same property, ADE would not be driven by the HIV-like spike sequences. CONCLUSIONS ADE can explain the failure of herd immunity-based strategies and will also probably hamper anti-SARS-CoV-2 vaccine development. As reviewed in Part I, there fortunately are promising therapeutic strategies for COVID-19, which should be further developed. In the meantime, complementary countermeasures to protect mainly the youth from this infection are presented to be discussed in Part V Viewpoint.

scholarly journals Association between Genetic Variants in NOS2 and TNF Genes with Congenital Zika Syndrome and Severe Microcephaly

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 325
Author(s):  
Julia A. Gomes ◽  
Eduarda Sgarioni ◽  
Juliano A. Boquett ◽  
Ana Cláudia P. Terças-Trettel ◽  
Juliana H. da Silva ◽  
...  
Keyword(s):  
Risk Factors ◽  
Zika Virus ◽  
Genetic Variants ◽  
Educational Level ◽  
Congenital Anomalies ◽  
Family Income ◽  
First Trimester ◽  
In Utero ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in VEGFA, PTGS2, NOS3, TNF, and NOS2 genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (p < 0.001) and had mothers with lower educational level (p < 0.001) and family income (p < 0.001). We found higher risk of CZS due the allele rs2297518[A] of NOS2 (OR = 2.28, CI 95% 1.17–4.50, p = 0.015). T allele and TT/CT genotypes of the TNF rs1799724 and haplotypes associated with higher expression of TNF were more prevalent in children with CZS and severe microcephaly (p = 0.029, p = 0.041 and p = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in NOS2 and TNF genes affect the risk of CZS and severe microcephaly.

scholarly journals Embryonic Stage of Congenital Zika Virus Infection Determines Fetal and Postnatal Outcomes in Mice

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1807
Author(s):  
Eri Nakayama ◽  
Yasuhiro Kawai ◽  
Satoshi Taniguchi ◽  
Jessamine E. Hazlewood ◽  
Ken-ichi Shibasaki ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Neonatal Death ◽  
Motor Behavior ◽  
Wide Spectrum ◽  
Fetal Loss ◽  
Congenital Infection ◽  
Sensory Function ◽  
Zikv Infection ◽  
Wide Range

Zika virus (ZIKV) infection during pregnancy causes a wide spectrum of congenital abnormalities and postnatal developmental sequelae such as fetal loss, intrauterine growth restriction (IUGR), microcephaly, or motor and neurodevelopmental disorders. Here, we investigated whether a mouse pregnancy model recapitulated a wide range of symptoms after congenital ZIKV infection, and whether the embryonic age of congenital infection changed the fetal or postnatal outcomes. Infection with ZIKV strain PRVABC59 from embryonic day 6.5 (E6.5) to E8.5, corresponding to the mid-first trimester in humans, caused fetal death, fetal resorption, or severe IUGR, whereas infection from E9.5 to E14.5, corresponding to the late-first to second trimester in humans, caused stillbirth, neonatal death, microcephaly, and postnatal growth deficiency. Furthermore, 4-week-old offspring born to dams infected at E12.5 showed abnormalities in neuropsychiatric state, motor behavior, autonomic function, or reflex and sensory function. Thus, our model recapitulated the multiple symptoms seen in human cases, and the embryonic age of congenital infection was one of the determinant factors of offspring outcomes in mice. Furthermore, maternal neutralizing antibodies protected the offspring from neonatal death after congenital infection at E9.5, suggesting that neonatal death in our model could serve as criteria for screening of vaccine candidates.

Sign in / Sign up

Export Citation Format

Share Document