Zika Virus Neutralizing Antibody Kinetics in Antenatally Exposed Infants

Abstract Background Zika virus (ZIKV) is associated with severe congenital abnormalities and laboratory diagnosis of antenatal infection is difficult. Here we evaluated ZIKV neutralizing antibody (Nab) kinetics in infants born to mothers with PCR-confirmed ZIKV infection during pregnancy. Methods Neonates (n=98) had serum specimens tested repeatedly for ZIKV Nab over the first two years of life using virus neutralization test (VNT). ZIKV neonatal infection was confirmed by RT-PCR in blood or urine and/or presence of ZIKV IgM antibodies, and results were correlated with infant clinical features. Results Postnatal laboratory evidence of ZIKV vertical transmission was obtained for 60.2% of children, while 32.7% exhibited clinical abnormalities. Congenital abnormalities were found in 37.3% of children with confirmed ZIKV infection and 31.0% of children without confirmed infection (p=0.734). All but one child displayed a physiologic decline in ZIKV Nab, reflecting maternal antibody decay, despite an early ZIKV-IgM response in 1/3 of infants. Conclusions Infants with antenatal ZIKV exposure do not develop ZIKV Nab despite an early IgM response. Therefore, ZIKV VNT in children is not useful for diagnosis of congenital infection. In light of these findings, it remains to be determined if children infected in utero are potentially susceptible to reinfection.

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Zika virus infection in asymptomatic persons in Myanmar, 2018

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1093/trstmh/trz134 ◽

2020 ◽

Vol 114 (6) ◽

pp. 440-447

Author(s):

Mya Myat Ngwe Tun ◽

Saw Wut Hmone ◽

Aung Min Soe ◽

Elizabeth Luvai ◽

Khine Mya Nwe ◽

...

Keyword(s):

Real Time ◽

Zika Virus ◽

Pacific Islands ◽

Neutralization Test ◽

Immunoglobulin M ◽

Enzyme Linked Immunosorbent Assay ◽

Rt Pcr ◽

Zikv Infection ◽

Healthy Persons ◽

Apparently Healthy

Abstract Background Zika virus (ZIKV) is a mosquito-borne flavivirus. Outbreaks of ZIKV infection have occurred in Africa, Southeast Asia, the Pacific Islands, the Americas and the Caribbean. Although most ZIKV infections are asymptomatic, cases of neurological manifestations have been described. The aim of the present study was to identify the prevalence of ZIKV infection among the asymptomatic persons in Myanmar in 2018. Methods A total of 284 serum samples from apparently healthy persons were collected from Yangon, Myanmar in 2018. They were analysed for ZIKV infection by immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA), IgG indirect ELISA, 50% focus reduction neutralization test, real-time reverse transcription polymerase chain reaction (RT-PCR) and conventional RT-PCR. Results Of the 284 apparently healthy persons, 31.3% were positive for the presence of IgM against ZIKV and 94.3% were positive for anti-flavivirus IgG. Among the ZIKV IgM-positive samples, we confirmed ZIKV infection in 15.8% of asymptomatic persons by neutralization test and real-time RT-PCR. Conclusions We conclude that ZIKV infection was increasing among asymptomatic persons in the same area in Myanmar during 2018 compared with 2017. It is highly recommended to strengthen the surveillance system for ZIKV to prevent possible outbreaks.

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Update on the Transmission of Zika Virus Through Breast Milk and Breastfeeding: A Systematic Review of the Evidence

Viruses ◽

10.3390/v13010123 ◽

2021 ◽

Vol 13 (1) ◽

pp. 123

Author(s):

Elizabeth Centeno-Tablante ◽

Melisa Medina-Rivera ◽

Julia L. Finkelstein ◽

Heather S. Herman ◽

Pura Rayco-Solon ◽

...

Keyword(s):

Breast Milk ◽

Zika Virus ◽

Mother To Child Transmission ◽

Inclusion Criteria ◽

Rt Pcr ◽

Child Transmission ◽

Zikv Infection ◽

Milk Samples ◽

Clinical Complications ◽

Mother To Child

We systematically searched regional and international databases and screened 1658 non-duplicate records describing women with suspected or confirmed ZIKV infection, intending to breastfeed or give breast milk to an infant to examine the potential of mother-to-child transmission of Zika virus (ZIKV) through breast milk or breastfeeding-related practices. Fourteen studies met our inclusion criteria and inform this analysis. These studies reported on 97 mother–children pairs who provided breast milk for ZIKV assessment. Seventeen breast milk samples from different women were found positive for ZIKV via RT-PCR, and ZIKV replication was found in cell cultures from five out of seven breast milk samples from different women. Only three out of six infants who had ZIKV infection were breastfed, no evidence of clinical complications was found to be associated with ZIKV RNA in breast milk. This review updates our previous report by including 12 new articles, in which we found no evidence of ZIKV mother-to-child transmission through breast milk intake or breastfeeding. As the certainty of the present evidence is low, additional studies are still warranted to determine if ZIKV can be transmitted through breastfeeding.

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

Viruses ◽

10.3390/v13091807 ◽

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.

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Distinct cellular immune signatures in acute Zika virus infection are associated with high or low persisting neutralizing antibody titers

10.1101/2021.05.27.446054 ◽

2021 ◽

Author(s):

Elizabeth E. McCarthy ◽

Pamela M. Odorizzi ◽

Emma Lutz ◽

Carolyn P. Smullin ◽

Iliana Tenvooren ◽

...

Keyword(s):

Zika Virus ◽

Neutralizing Antibodies ◽

Viral Infections ◽

Immune Cell ◽

Acute Infection ◽

Neutralizing Antibody ◽

Natural Immunity ◽

Zikv Infection ◽

Antibody Titers ◽

Cellular Immune

Although the formation of a durable neutralizing antibody response after an acute viral infection is a key component of protective immunity, little is known about why some individuals generate high versus low neutralizing antibody titers to infection or vaccination. Infection with Zika virus (ZIKV) during pregnancy can cause devastating fetal outcomes, and efforts to understand natural immunity to this infection are essential for optimizing vaccine design. In this study, we leveraged the high-dimensional single-cell profiling capacity of mass cytometry (CyTOF) to deeply characterize the cellular immune response to acute and convalescent ZIKV infection in a cohort of blood donors in Puerto Rico incidentally found to be viremic during the 2015-2016 epidemic in the Americas. During acute ZIKV infection, we identified widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated innate immune subsets, as well as activated follicular helper CD4+ T cells and proliferating CD27-IgD- B cells, during acute infection were associated with high titers of ZIKV neutralizing antibodies at 6 months post-infection. On the other hand, low titers of ZIKV neutralizing antibodies were associated with immune features that suggested a cytotoxic-skewed immune "set-point." Our study offers insight into the cellular coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials for ZIKV and other acute viral infections aimed at inducing high titers of neutralizing antibodies.

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Clinical and Epidemiological Features of Acute Zika Virus Infections in León, Nicaragua

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1191 ◽

2021 ◽

Author(s):

Natalie M. Bowman ◽

Filemón Bucardo ◽

Matthew H. Collins ◽

Yaoska Reyes ◽

Edwing Centeno Cuadra ◽

...

Keyword(s):

Risk Factors ◽

Sore Throat ◽

Zika Virus ◽

Clinical Symptoms ◽

Laboratory Data ◽

Maculopapular Rash ◽

Laboratory Diagnosis ◽

Zikv Infection ◽

Serological Tests ◽

Laboratory Findings

The American Zika virus (ZIKV) epidemic has highlighted the need to gain a better understanding of this emerging virus. The goal of this study was to describe the clinical symptoms, laboratory findings, and risk factors for symptomatic ZIKV infection in an area with ongoing transmission of other arboviral infections. We recruited patients at least 2 years of age seeking care at public health centers in León, Nicaragua, between January 2016 and August 2017, for fever, maculopapular rash, and/or nonsuppurative conjunctivitis with a duration of less than 1 week. A laboratory diagnosis of ZIKV was established using a combination of molecular and serological tests. Clinical and laboratory findings and potential risk factors were compared between participants with and without acute ZIKV infection. Fifty-eight (26%) of the 225 participants included in the analysis were found to have acute ZIKV infection. Pregnancy and reports of previous arboviral infection were associated with a higher risk of ZIKV infection. Rash, conjunctivitis, sore throat, and lower absolute neutrophil counts were associated with acute ZIKV infection. The clinical characteristics and risk factors identified were consistent with those identified by previous studies; however, we found sore throat to be a feature of ZIKV infection. We also found that neutrophil counts were lower in ZIKV-infected subjects. These clinical symptoms and laboratory data may help clinicians suspect ZIKV infection during future outbreaks.

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Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: From systematic review to living systematic review

F1000Research ◽

10.12688/f1000research.13704.1 ◽

2018 ◽

Vol 7 ◽

pp. 196 ◽

Cited By ~ 14

Author(s):

Michel Jacques Counotte ◽

Dianne Egli-Gany ◽

Maurane Riesen ◽

Million Abraha ◽

Teegwendé Valérie Porgo ◽

...

Keyword(s):

Systematic Review ◽

Zika Virus ◽

Congenital Abnormalities ◽

Causal Link ◽

The Body ◽

Guillain Barre Syndrome ◽

Sufficient Evidence ◽

Zikv Infection ◽

Guillain Barré Syndrome ◽

Guillain Barré

Background. The Zika virus (ZIKV) outbreak in the Americas has caused international concern due to neurological sequelae linked to the infection, such as microcephaly and Guillain-Barré syndrome (GBS). The World Health Organization stated that there is “sufficient evidence to conclude that Zika virus is a cause of congenital abnormalities and is a trigger of GBS”. This conclusion was based on a systematic review of the evidence published until 30.05.2016. Since then, the body of evidence has grown substantially, leading to this update of that systematic review with new evidence published from 30.05.2016 – 18.01.2017, update 1. Methods. We review evidence on the causal link between ZIKV infection and adverse congenital outcomes and the causal link between ZIKV infection and GBS or immune-mediated thrombocytopaenia purpura. We also describe the transition of the review into a living systematic review, a review that is continually updated. Results. Between 30.05.2016 and 18.01.2017, we identified 2413 publications, of which 101 publications were included. The evidence added in this update confirms the conclusion of a causal association between ZIKV and adverse congenital outcomes. New findings expand the evidence base in the dimensions of biological plausibility, strength of association, animal experiments and specificity. For GBS, the body of evidence has grown during the search period for update 1, but only for dimensions that were already populated in the previous version. There is still a limited understanding of the biological pathways that potentially cause the occurrence of autoimmune disease following ZIKV infection. Conclusions. This systematic review confirms previous conclusions that ZIKV is a cause of congenital abnormalities, including microcephaly, and is a trigger of GBS. The transition to living systematic review techniques and methodology provides a proof of concept for the use of these methods to synthesise evidence about an emerging pathogen such as ZIKV.

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Zika virus is transmitted in neural progenitor cells via cell-to-cell spread and infection is inhibited by the autophagy inducer trehalose

Journal of Virology ◽

10.1128/jvi.02024-20 ◽

2020 ◽

pp. JVI.02024-20

Author(s):

Alex E Clark ◽

Zhe Zhu ◽

Florian Krach ◽

Jeremy N Rich ◽

Gene W. Yeo ◽

...

Keyword(s):

Viral Replication ◽

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Neutralizing Antibody ◽

Neural Progenitor ◽

Health Concern ◽

Free Virus ◽

Zikv Infection ◽

Infected Cells

Zika virus (ZIKV) is a mosquito-borne human pathogen that causes congenital Zika syndrome and neurological symptoms in some adults. There are currently no approved treatments or vaccines for ZIKV, and exploration of therapies targeting host processes could avoid viral development of drug resistance. The purpose of our study was to determine if the non-toxic and widely used disaccharide trehalose, which showed antiviral activity against Human Cytomegalovirus (HCMV) in our previous work, could restrict ZIKV infection in clinically relevant neural progenitor cells (NPCs). Trehalose is known to induce autophagy, the degradation and recycling of cellular components. Whether autophagy is proviral or antiviral for ZIKV is controversial and depends on cell type and specific conditions used to activate or inhibit autophagy. We show here that trehalose treatment of NPCs infected with recent ZIKV isolates from Panama and Puerto Rico significantly reduces viral replication and spread. In addition, we demonstrate that ZIKV infection in NPCs spreads primarily cell-to-cell as an expanding infectious center, and NPCs are infected via contact with infected cells far more efficiently than by cell-free virus. Importantly, ZIKV was able to spread in NPCs in the presence of neutralizing antibody.Importance Zika virus causes birth defects and can lead to neurological disease in adults. While infection rates are currently low, ZIKV remains a public health concern with no treatment or vaccine available. Targeting a cellular pathway to inhibit viral replication is a potential treatment strategy that avoids development of antiviral resistance. We demonstrate in this study that the non-toxic autophagy-inducing disaccharide trehalose reduces spread and output of ZIKV in infected neural progenitor cells (NPCs), the major cells infected in the fetus. We show that ZIKV spreads cell-to-cell in NPCs as an infectious center and that NPCs are more permissive to infection by contact with infected cells than by cell-free virus. We find that neutralizing antibody does not prevent the spread of the infection in NPCs. These results are significant in demonstrating anti-ZIKV activity of trehalose and in clarifying the primary means of Zika virus spread in clinically relevant target cells.

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Animal Models of Zika Virus Infection during Pregnancy

Viruses ◽

10.3390/v10110598 ◽

2018 ◽

Vol 10 (11) ◽

pp. 598 ◽

Cited By ~ 29

Author(s):

Elizabeth Caine ◽

Brett Jagger ◽

Michael Diamond

Keyword(s):

Animal Models ◽

Virus Infection ◽

Zika Virus ◽

Reproductive Tract ◽

Congenital Abnormalities ◽

Tissue Tropism ◽

Zikv Infection ◽

In Vivo Models ◽

Sexually Transmitted

Zika virus (ZIKV) emerged suddenly in the Americas in 2015 and was associated with a widespread outbreak of microcephaly and other severe congenital abnormalities in infants born to mothers infected during pregnancy. Vertical transmission of ZIKV in humans was confirmed when viral RNA was detected in fetal and placental tissues, and this outcome has been recapitulated experimentally in animals. Unlike other flaviviruses, ZIKV is both arthropod- and sexually-transmitted, and has a broad tissue tropism in humans, including multiple tissues of the reproductive tract. The threats posed by ZIKV have prompted the development of multiple in vivo models to better understand the pathogenesis of ZIKV, particularly during pregnancy. Here, we review the progress on animal models of ZIKV infection during pregnancy. These studies have generated a foundation of insights into the biology of ZIKV, and provide a means for evaluating vaccines and therapeutics.

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The proportion of asymptomatic infections and spectrum of disease among pregnant women infected by Zika virus: systematic monitoring in French Guiana, 2016

Eurosurveillance ◽

10.2807/1560-7917.es.2017.22.44.17-00102 ◽

2017 ◽

Vol 22 (44) ◽

Cited By ~ 23

Author(s):

Claude Flamand ◽

Camille Fritzell ◽

Séverine Matheus ◽

Maryvonne Dueymes ◽

Gabriel Carles ◽

...

Keyword(s):

Pregnant Women ◽

Zika Virus ◽

French Guiana ◽

Rt Pcr ◽

Zikv Infection ◽

Younger Women ◽

Adjusted Risk ◽

Adjusted Risk Ratio ◽

Asymptomatic Infections

Zika virus (ZIKV) infection has been associated with complications during pregnancy. Although the presence of symptoms might be a risk factor for complication, the proportion of ZIKV-infected pregnant women with symptoms remains unknown. Following the emergence of ZIKV in French Guiana, all pregnancies in the territory were monitored by RT-PCR and/or detection of ZIKV antibodies. Follow-up data collected during pregnancy monitoring interviews were analysed from 1 February to 1 June 2016. We enrolled 3,050 pregnant women aged 14–48 years and 573 (19%) had laboratory-confirmed ZIKV infection. Rash, arthralgia, myalgia and conjunctival hyperaemia were more frequently observed in ZIKV-positive women; 23% of them (95% confidence interval (CI): 20–27) had at least one symptom compatible with ZIKV infection. Women 30 years and older were significantly more likely to have symptoms than younger women (28% vs 20%). The proportion of symptomatic infections varied from 17% in the remote interior to 35% in the urbanised population near the coast (adjusted risk ratio: 1.6; 95% CI: 1.4–1.9.). These estimates put findings on cohorts of symptomatic ZIKV-positive pregnant women into the wider context of an epidemic with mainly asymptomatic infections. The proportion of symptomatic ZIKV infections appears to vary substantially between populations.

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Congenital abnormalities associated with Zika virus infection–Dengue as potential co-factor? A systematic review

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008984 ◽

2021 ◽

Vol 15 (1) ◽

pp. e0008984

Author(s):

Stephanie Petzold ◽

Nisreen Agbaria ◽

Andreas Deckert ◽

Peter Dambach ◽

Volker Winkler ◽

...

Keyword(s):

Systematic Review ◽

Virus Infection ◽

Dengue Virus ◽

Protective Effect ◽

Zika Virus ◽

Congenital Abnormalities ◽

Denv Infection ◽

Current Evidence ◽

Geographic Variability ◽

Zikv Infection

Zika virus (ZIKV) emerged in Brazil during 2013–2014 causing an epidemic of previously unknown congenital abnormalities. The frequency of severe congenital abnormalities after maternal ZIKV infection revealed an unexplained geographic variability, especially between the Northeast and the rest of Brazil. Several reasons for this variability have been discussed. Prior immunity against DENV, that affects ZIKV seems to be the most likely explanation. Here we summarise the current evidence regarding the prominent co-factor to potentially explain the geographic variability. This systematic review followed the PRISMA guidelines. The search was conducted up to May 15th, 2020, focussing on immunological interactions from Zika virus with previous Dengue virus infections as potential teratogenic effect for the foetus. Eight out of 339 screened studies reported on the association between ZIKV, prior Dengue virus infection and microcephaly, mostly focusing on antibody-dependent enhancement (ADE) as potential pathomechanism. Prior DENV infection was associated with enhancement for ZIKV infection and increased neurovirulence in one included in vitro study only. Interestingly, the seven in vivo studies exhibited a heterogeneous picture with three studies showing a protective effect of prior DENV infections and others no effect at all. According to several studies, socio-economic factors are associated with increased risk for microcephaly. Very few studies addressed the question of unexplained variability of infection-related microcephaly. Many studies focussed on ADE as mechanism without measuring microcephaly as endpoint. Interestingly, three of the included studies reported a protective effect of prior DENV infection against microcephaly. This systematic review strengthens the hypothesis that immune priming after recent DENV infection is the crucial factor for determining protection or enhancement activity. It is of high importance that the currently ongoing prospective studies include a harmonized assessment of the potential candidate co-factors.

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