scholarly journals Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques

2021 ◽  
Vol 15 (7) ◽  
pp. e0009641
Author(s):  
Chelsea M. Crooks ◽  
Andrea M. Weiler ◽  
Sierra L. Rybarczyk ◽  
Mason I. Bliss ◽  
Anna S. Jaeger ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Zika Virus ◽  
Rhesus Macaques ◽  
Maternal Plasma ◽  
Adverse Outcomes ◽  
Primate Model ◽  
Denv Serotypes ◽  
The Impact ◽  
Human Primate ◽  
Maternal Fetal Interface

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

scholarly journals Prior dengue immunity enhances Zika virus infection of the maternal-fetal interface in rhesus macaques

2021 ◽  
Author(s):  
C. M. Crooks ◽  
A. M. Weiler ◽  
S. L. Rybarczyk ◽  
M. I. Bliss ◽  
A. S. Jaeger ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
Maternal Plasma ◽  
Adverse Outcomes ◽  
Zikv Infection ◽  
Primate Model ◽  
Denv Serotypes ◽  
The Impact ◽  
Human Primate ◽  
Maternal Fetal Interface

ABSTRACTConcerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that prior DENV-2 exposure enhanced ZIKV infection of maternal-fetal interface tissues in macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

scholarly journals Comparative Pathogenesis of Asian and African-Lineage Zika Virus in Indian Rhesus Macaque’s and Development of a Non-Human Primate Model Suitable for the Evaluation of New Drugs and Vaccines

2018 ◽  
Author(s):  
Jonathan O. Rayner ◽  
Raj Kalkeri ◽  
Scott Goebel ◽  
Zhaohui Cai ◽  
Brian Green ◽  
...  
Keyword(s):  
Immune Response ◽  
Zika Virus ◽  
Rhesus Macaques ◽  
New Drugs ◽  
Primate Model ◽  
Robust Immune Response ◽  
African Lineage ◽  
Limit Of Quantitation ◽  
Asian Lineage ◽  
Human Primate

The establishment of a well characterized non-human primate model of Zika virus (ZIKV) infection is critical for the development of medical interventions. In this study, challenging Indian rhesus macaques (IRMs) with ZIKV strains of the Asian lineage resulted in dose dependent peak viral loads between days 2 and 5 post infection; and a robust immune response which protected the animals from homologous and heterologous re-challenge. In contrast, viremia in IRMs challenged with an African lineage strain was below the assays lower limit of quantitation and the immune response was insufficient to protect from re-challenge. These results corroborate previous observations but are contrary to reports using other African strains obviating the need for additional studies to elucidate the variables contributing to the disparities. Nonetheless, the utility of an Asian lineage ZIKV IRM model for countermeasures development was verified by vaccinating animals with a formalin inactivated reference vaccine and demonstrating sterilizing immunity against a subsequent subcutaneous challenge.

scholarly journals African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques

2021 ◽  
Author(s):  
Chelsea M. Crooks ◽  
Andrea M. Weiler ◽  
Sierra L. Rybarczyk ◽  
Mason Bliss ◽  
Anna S. Jaeger ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
High Titer ◽  
In Vivo Studies ◽  
Genetic Lineage ◽  
African Lineage ◽  
Asian Lineage ◽  
The Impact ◽  
Maternal Fetal Interface

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in-vitro and in-vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titer and caused more severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here we infected four pregnant rhesus macaques with a low-passage strain of African-lineage ZIKV and compared its pathogenesis to a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. Viral replication kinetics were not significantly different between the two experimental groups and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1-1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV vRNA was found in maternal-fetal interface tissues in the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015-16. In its most recent update, the WHO stated that improved understanding of African-lineage pathogenesis during pregnancy must be a priority. Recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational non-human primate model. We show African-lineage isolates replicate with similar kinetics to Asian-lineage isolates and can infect the placenta. However, there was no evidence of more severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for future epidemiological and translational in-vivo studies with African-lineage ZIKV.

scholarly journals African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques

2020 ◽  
Author(s):  
Chelsea M. Crooks ◽  
Andrea M. Weiler ◽  
Sierra L. Rybarczyk ◽  
Mason Bliss ◽  
Anna S. Jaeger ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
High Titer ◽  
In Vivo Studies ◽  
Genetic Lineage ◽  
African Lineage ◽  
Asian Lineage ◽  
The Impact ◽  
Maternal Fetal Interface

ABSTRACTFollowing the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The isolates responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in-vitro and in-vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titer and caused more severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here we infected four pregnant rhesus macaques with a low-passage strain of African-lineage ZIKV and compared its pathogenesis to a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-infected controls. Viral replication kinetics were not significantly different between the two experimental groups and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery in either group. However, a significantly higher burden of ZIKV vRNA was found in maternal-fetal interface tissues in the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV isolates of any genetic lineage pose a threat to women and their infants.IMPORTANCEZIKV was first identified over 70 years ago in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015-16. In its most recent update, the WHO stated that improved understanding of African-lineage pathogenesis during pregnancy must be a priority. Recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational non-human primate model. We show African-lineage isolates replicate with similar kinetics to Asian-lineage isolates and are capable of infecting the placenta. However, there was no evidence of more severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to women and their infants and the need for future epidemiological and translational in-vivo studies with African-lineage ZIKV.

scholarly journals Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 584
Author(s):  
Natalia Nunez ◽  
Louis Réot ◽  
Elisabeth Menu
Keyword(s):  
Immune System ◽  
Mode Of Delivery ◽  
Microbial Colonization ◽  
Therapeutic Interventions ◽  
Primate Model ◽  
Neonatal Immune System ◽  
Gastrointestinal Colonization ◽  
The Impact ◽  
Human Primate

Interactions between the immune system and the microbiome play a crucial role on the human health. These interactions start in the prenatal period and are critical for the maturation of the immune system in newborns and infants. Several factors influence the composition of the infant’s microbiota and subsequently the development of the immune system. They include maternal infection, antibiotic treatment, environmental exposure, mode of delivery, breastfeeding, and food introduction. In this review, we focus on the ontogeny of the immune system and its association to microbial colonization from conception to food diversification. In this context, we give an overview of the mother–fetus interactions during pregnancy, the impact of the time of birth and the mode of delivery, the neonate gastrointestinal colonization and the role of breastfeeding, weaning, and food diversification. We further review the impact of the vaccination on the infant’s microbiota and the reciprocal case. Finally, we discuss several potential therapeutic interventions that might help to improve the newborn and infant’s health and their responses to vaccination. Throughout the review, we underline the main scientific questions that are left to be answered and how the non-human primate model could help enlighten the path.

scholarly journals The Impact of Chronic Marijuana Exposure on Fetal Development in a Non-Human Primate Model

2022 ◽  
Vol 226 (1) ◽  
pp. S150
Author(s):  
Rahul J. D'Mello ◽  
Victoria H. Roberts ◽  
Xiaojie Wang ◽  
Juanito D. Terrobias ◽  
Jamie O. Lo
Keyword(s):  
Fetal Development ◽  
Primate Model ◽  
The Impact ◽  
Human Primate

scholarly journals Selective intra-arterial brain cooling improves long-term outcomes in a non-human primate model of embolic stroke: Efficacy depending on reperfusion status

2020 ◽  
Vol 40 (7) ◽  
pp. 1415-1426 ◽  
Author(s):  
Di Wu ◽  
Jian Chen ◽  
Mohammed Hussain ◽  
Longfei Wu ◽  
Jingfei Shi ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Motor Dysfunction ◽  
Neurological Deficits ◽  
Brain Cooling ◽  
Long Term Outcomes ◽  
Primate Model ◽  
Tissue Plasminogen ◽  
Human Primate ◽  
Arterial Thrombolysis

Nearly all stroke neuroprotection modalities, including selective intra-arterial cooling (SI-AC), have failed to be translated from bench to bed side. Potentially overlooked reasons may be biological gaps, inadequate attention to reperfusion states and mismatched attention to neurological benefits. To advance stroke translation, we describe a novel thrombus-based stroke model in adult rhesus macaques. Intra-arterial thrombolysis with tissue plasminogen activator leads to three clinically relevant outcomes – complete, partial, and no recanalization based on digital subtraction angiography. We also find reperfusion as a prerequisite for SI-AC-induced benefits, in which models with complete or partial reperfusion exhibit significantly reduced infarct volumes, mitigated neurological deficits, improved upper limb motor dysfunction in both acute and chronic stages; however, no further neuroprotection is observed in those without reperfusion. In summary, we discover reperfusion as a crucial regulator of SI-AC-induced neuroprotection and provide insights of long-term functional benefits in behavior and imaging levels. Our findings could be important not only for the translational prerequisite and potential molecular targets, but also for this thrombus-thrombolysis model in monkeys as a powerful tool for further translational stroke studies.

scholarly journals Low seroprevalence of Zika virus infection among adults in Southern Taiwan

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yu-Wen Chien ◽  
Tzu-Chuan Ho ◽  
Pei-Wen Huang ◽  
Nai-Ying Ko ◽  
Wen-Chien Ko ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Migrant Workers ◽  
Zika Virus ◽  
Southeast Asian ◽  
Asian Countries ◽  
Zikv Infection ◽  
Serological Tests ◽  
Cross Sectional ◽  
Denv Serotypes ◽  
Southeast Asian Countries

Abstract Background We recently conducted a serosurvey of newly arrived workers in Taiwan from four Southeast Asian countries which revealed that 1% of the migrant workers had laboratory-confirmed recent Zika virus (ZIKV) infection. Taiwan, where Aedes mosquitoes are prevalent, has a close relationship with Southeast Asian countries. Up to now, 21 imported cases of ZIKV infection have been reported in Taiwan, but there has been no confirmed indigenous case. The aim of this serosurvey was to assess whether there was unrecognized ZIKV infections in Taiwan. Methods A total of 212 serum samples collected in a cross-sectional seroepidemiologic study conducted during the end of the 2015 dengue epidemic in Tainan, Taiwan, were analyzed. Anti-ZIKV IgM and IgG were tested using commercial enzyme-linked immunosorbent assays (ELISAs). Plaque reduction neutralization tests (PRNTs) for ZIKV and four dengue virus (DENV) serotypes were performed for samples with positive anti-ZIKV antibodies. A confirmed case of ZIKV infection was defined by ZIKV PRNT90 titer ratio ≥ 4 compared to four DENV serotypes. Results The mean age of the 212 participants was 54.0 years (standard deviation 13.7 years), and female was predominant (67.0%). Anti-ZIKV IgM and IgG were detected in 0 (0%) and 9 (4.2%) of the 212 participants, respectively. For the 9 samples with anti-ZIKV IgG, only 1 sample had 4 times higher ZIKV PRNT90 titers compared to PRNT90 titers against four dengue virus serotypes; this individual denied having traveled abroad. Conclusions The results suggest that undetected indigenous ZIKV transmission might have occurred in Taiwan. The findings also suggest that the threat of epidemic transmission of ZIKV in Taiwan does exist due to extremely low-level of herd immunity. Our study also indicates that serological tests for ZIKV-specific IgG remain a big challenge due to cross-reactivity, even in dengue non-endemic countries.

scholarly journals Immunogenicity and Efficacy of Flagellin-Envelope Fusion Dengue Vaccines in Mice and Monkeys

2015 ◽  
Vol 22 (5) ◽  
pp. 516-525 ◽  
Author(s):  
Ge Liu ◽  
Langzhou Song ◽  
David W. C. Beasley ◽  
Robert Putnak ◽  
Jason Parent ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Antigen ◽  
Rhesus Macaques ◽  
Geometric Mean ◽  
Vaccine Antigen ◽  
Placebo Control ◽  
Vaccine Platform ◽  
Post Dose ◽  
Primate Model ◽  
Denv Serotypes

ABSTRACTThe envelope (E) protein of flaviviruses includes three domains, EI, EII, and EIII, and is the major protective antigen. Because EIII is rich in type-specific and subcomplex-specific neutralizing epitopes and is easy to express, it is particularly attractive as a recombinant vaccine antigen. VaxInnate has developed a vaccine platform that genetically links vaccine antigens to bacterial flagellin, a Toll-like receptor 5 ligand. Here we report that tetravalent dengue vaccines (TDVs) consisting of four constructs, each containing two copies of EIII fused to flagellin (R3.2x format), elicited robust and long-lived neutralizing antibodies (geometric mean titers of 200 to 3,000), as measured with a 50% focus reduction neutralization test (FRNT50). In an immunogenicity study, rhesus macaques (n= 2) immunized subcutaneously with 10 μg or 90 μg of TDV three or four times, at 4- to 6-week intervals, developed neutralizing antibodies to four dengue virus (DENV) serotypes (mean post-dose 3 FRNT50titers of 102 to 601). In an efficacy study, rhesus macaques (n= 4) were immunized intramuscularly with 16 μg or 48 μg of TDV or a placebo control three times, at 1-month intervals. The animals that received 48-μg doses of TDV developed neutralizing antibodies against the four serotypes (geometric mean titers of 49 to 258) and exhibited reduced viremia after DENV-2 challenge, with a group mean viremia duration of 1.25 days and 2 of 4 animals being completely protected, compared to the placebo-treated animals, which all developed viremia, with a mean duration of 4 days. In conclusion, flagellin-EIII fusion vaccines are immunogenic and partially protective in a nonhuman primate model.

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