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

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.

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

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009641 ◽

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.

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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

10.20944/preprints201804.0096.v1 ◽

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.

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

Journal of Virology ◽

10.1128/jvi.02220-20 ◽

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.

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Impact of prior Dengue immunity on Zika vaccine protection in rhesus macaques and mice

PLoS Pathogens ◽

10.1371/journal.ppat.1009673 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009673

Author(s):

Rafael A. Larocca ◽

Peter Abbink ◽

John D. Ventura ◽

Abishek Chandrashekar ◽

Noe Mercado ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Passive Transfer ◽

Zikv Infection ◽

Vaccine Protection ◽

Denv Serotypes ◽

Immunization Strategies ◽

Specific Igg ◽

The Impact

Pre-existing immunity to flaviviruses can influence the outcome of subsequent flavivirus infections. Therefore, it is critical to determine whether baseline DENV immunity may influence subsequent ZIKV infection and the protective efficacy of ZIKV vaccines. In this study, we investigated the impact of pre-existing DENV immunity induced by vaccination on ZIKV infection and the protective efficacy of an inactivated ZIKV vaccine. Rhesus macaques and mice inoculated with a live attenuated DENV vaccine developed neutralizing antibodies (NAbs) to multiple DENV serotypes but no cross-reactive NAbs responses to ZIKV. Animals with baseline DENV NAbs did not exhibit enhanced ZIKV infection and showed no overall reduction in ZIKV vaccine protection. Moreover, passive transfer of purified DENV-specific IgG from convalescent human donors did not augment ZIKV infection in STAT2 -/- and BALB/c mice. In summary, these results suggest that baseline DENV immunity induced by vaccination does not significantly enhance ZIKV infection or impair the protective efficacy of candidate ZIKV vaccines in these models. These data can help inform immunization strategies in regions of the world with multiple circulating pathogenic flaviviruses.

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Highly Efficient Maternal-Fetal Zika Virus Transmission in Pregnant Rhesus Macaques

10.1101/106674 ◽

2017 ◽

Author(s):

Sydney M. Nguyen ◽

Kathleen M. Antony ◽

Dawn M. Dudley ◽

Sarah Kohn ◽

Heather A. Simmons ◽

...

Keyword(s):

Vertical Transmission ◽

Zika Virus ◽

Rhesus Macaques ◽

Therapeutic Interventions ◽

Fetal Anomalies ◽

Fetal Head ◽

Fetal Outcomes ◽

Zikv Infection ◽

Primate Model ◽

In Pregnancy

AbstractInfection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.Author summaryMaternal ZIKV infection in pregnancy is associated with severe fetal anomalies, including microcephaly. It has been shown that infection manifests differently in pregnancy than in the non-pregnant state, with prolonged maternal viremia. ZIKV is spread by mosquitos and through sexual contact and since its first detection in early 2015, has become endemic to the Americas. While much has been learned from studying infected human pregnancies, there are still many questions concerning transmission of ZIKV from mother to fetus. Investigating ZIKV infection in non-human primates could help answer these questions due to similarities in the immune system, and the tissues separating the fetus from the mother during pregnancy. Our study serves to model ZIKV transmission in early and late pregnancy, as well as study the effects of this infection on the fetus and mother at these different times in pregnancy. The data collected provides an important insight on ZIKV in pregnancy where the pregnancies have been monitored throughout the entire infection period until term, and suggests that vertical transmission may be very efficient, although severe fetal outcomes are uncommon.

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

10.1101/2020.11.30.405670 ◽

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.

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

Vaccines ◽

10.3390/vaccines9060584 ◽

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.

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Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

Viruses ◽

10.3390/v13081427 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1427

Author(s):

Paula Sobral da Silva ◽

Sophie Eickmann ◽

Ricardo Ximenes ◽

Celina Martelli ◽

Elizabeth Brickley ◽

...

Keyword(s):

Neurological Examination ◽

Zika Virus ◽

Control Group ◽

P Value ◽

Zikv Infection ◽

Clinical Neurological Examination ◽

Cognitive Delay ◽

Increased Risk ◽

Neurodevelopmental Impairment ◽

The Impact

The relation of Zika virus (ZIKV) with microcephaly is well established. However, knowledge is lacking on later developmental outcomes in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly. The objective of this analysis is to investigate the impact of prenatal exposure to ZIKV on neuropsychomotor development in children without microcephaly. We evaluated 274 children including 235 ZIKV exposed and 39 controls using the Bayley-III Scales of Infant and Toddler Development (BSIDIII) and neurological examination. We observed a difference in cognition with a borderline p-value (p = 0.052): 9.4% of exposed children and none of the unexposed control group had mild to moderate delays. The prevalence of delays in the language and motor domains did not differ significantly between ZIKV-exposed and unexposed children (language: 12.3% versus 12.8%; motor: 4.7% versus 2.6%). Notably, neurological examination results were predictive of neurodevelopmental delays in the BSIDIII assessments for exposed children: 46.7% of children with abnormalities on clinical neurological examination presented with delay in contrast to 17.8% among exposed children without apparent neurological abnormalities (p = 0.001). Overall, our findings suggest that relative to their unexposed peers, ZIKV-exposed children without microcephaly are not at considerably increased risk of neurodevelopmental impairment in the first 42 months of life, although a small group of children demonstrated higher frequencies of cognitive delay. It is important to highlight that in the group of exposed children, an abnormal neuroclinical examination may be a predictor of developmental delay. The article contributes to practical guidance and advances our knowledge about congenital Zika.

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From Mosquito Bites to Sexual Transmission: Evaluating Mouse Models of Zika Virus Infection

Viruses ◽

10.3390/v13112244 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2244

Author(s):

Elizabeth Balint ◽

Amelia Montemarano ◽

Emily Feng ◽

Ali A. Ashkar

Keyword(s):

Mouse Models ◽

Zika Virus ◽

Reproductive Tract ◽

Sexual Transmission ◽

Zikv Infection ◽

Sexually Transmitted ◽

Advantages And Disadvantages ◽

Effective Use ◽

The Impact ◽

Male To Female

Following the recent outbreak of Zika virus (ZIKV) infections in Latin America, ZIKV has emerged as a global health threat due to its ability to induce neurological disease in both adults and the developing fetus. ZIKV is largely mosquito-borne and is now endemic in many parts of Africa, Asia, and South America. However, several reports have demonstrated persistent ZIKV infection of the male reproductive tract and evidence of male-to-female sexual transmission of ZIKV. Sexual transmission may broaden the reach of ZIKV infections beyond its current geographical limits, presenting a significant threat worldwide. Several mouse models of ZIKV infection have been developed to investigate ZIKV pathogenesis and develop effective vaccines and therapeutics. However, the majority of these models focus on mosquito-borne infection, while few have considered the impact of sexual transmission on immunity and pathogenesis. This review will examine the advantages and disadvantages of current models of mosquito-borne and sexually transmitted ZIKV and provide recommendations for the effective use of ZIKV mouse models.

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