#20: Modeling Zika virus tissue tropism in rhesus macaques to define the risk of donor derived transmission

Abstract Background Almost 115,000 people in the United States are currently on a transplant waitlist, which vastly exceeds the number of organ donors every year. This discrepancy emphasizes the need for retention of all possible donors. Those who have recently traveled to an area with an active outbreak of Zika virus (ZIKV) are often disqualified as a donor because immunosuppressed recipients would be at risk of a donor-derived ZIKV infection. Therefore, we define ZIKV tissue tropism and the risk of donor derived transmission. Methods We subcutaneously inoculated 15 Indian-origin rhesus macaques (RM) with a Puerto Rican isolate of ZIKV (PRVABC59). All RMs were inoculated in mid to early gestation.We inoculated during pregnancy because plasma viremia is typically prolonged in pregnancy and we wanted to model tissue tropism for donor derived transmission in the worst scenario of prolonged viremia. At 30, 65, and 105 days post-infection (dpi), the animals were euthanized and comprehensive necropsies were performed, which evaluated a minimum of 60 tissues per animal. ZIKV RNA was quantified in tissues via qRT-PCR. Results Plasma viremia duration was >10 days in 13 of 15 RMs. ZIKV RNA was most commonly detected in lymph nodes, with 19/45 lymph nodes that were vRNA positive in 5 RMs at 30 dpi. There were 15/45 vRNA positive lymph nodes at 60 dpi and 8/38 at 105 dpi. Reproductive and maternal fetal-interface (MFI) tissues were the second most commonly positive tissues. Twenty-five MFI tissues, including the amniotic/chorionic membrane, decidua, placenta, uterus, and placental bed, were positive, with 10/53 positive at 30 dpi, 14/24 positive at 60 dpi and 1/47 positive at 105 dpi. Other vRNA positive tissues included the primary bronchus, femoral vein, kidney, thyroid, lung, colon, mammary gland, pericardium, hand nerve, and sciatic nerve in 1–2 RMs at one of the three timepoints. Conclusions We found ZIKV RNA most frequently within lymph nodes. Lymph nodes are included in lung and small bowel transplants, indicating that these transplants could pose a risk of donor-derived ZIKV transmission. Virus detection within other commonly transplanted tissues, such as the kidney and blood vessels was much less common. We did not determine what fraction of vRNA comes from replication-competent virus in each tissue; some tissues with vRNA might not contain virions that could initiate new infections. Donor-derived Zika virus transmission from other commonly transplanted organs, such as liver, seems unlikely since no viral RNA was detected in this organ.

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#79: Modeling Zika Virus Tissue Tropism in Rhesus Macaques to Define the Risk of Donor-derived Transmission

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piaa170.012 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

pp. S4-S4

Author(s):

Taylor A Treadway ◽

Phoenix M Shepherd ◽

Christina M Newman ◽

Emma L Mohr ◽

Dawn M Dudley ◽

...

Keyword(s):

Lymph Nodes ◽

Zika Virus ◽

Rhesus Macaques ◽

Femoral Vein ◽

Virus Transmission ◽

Virus Detection ◽

The United States ◽

Tissue Tropism ◽

Plasma Viremia ◽

Chorionic Membrane

Abstract Background Almost 115,000 people in the United States are currently on a transplant waitlist, which vastly exceeds the number of organ donors every year. This discrepancy emphasizes the need for retention of all possible donors. Those who have recently traveled to an area with an active outbreak of Zika virus (ZIKV) are often disqualified as a donor because immunosuppressed recipients would be at risk of a donor-derived ZIKV infection. Therefore, we define ZIKV tissue tropism and the risk of donor-derived transmission. Methods We subcutaneously inoculated 15 Indian-origin rhesus macaques (RM) with a Puerto Rican isolate of ZIKV (PRVABC59). All RMs were inoculated in mid to early gestation. We inoculated during pregnancy because plasma viremia is typically prolonged in pregnancy and we wanted to model tissue tropism for donor-derived transmission in the worst scenario of prolonged viremia. At 30, 65, and 105 days post-infection (dpi), the animals were euthanized and comprehensive necropsies were performed, which evaluated a minimum of 60 tissues per animal. ZIKV RNA was quantified in tissues via qRT-PCR. Results Plasma viremia duration was >10 days in 13 of 15 RMs. ZIKV RNA was most commonly detected in lymph nodes, with 19/45 lymph nodes that were vRNA positive in 5 RMs at 30 dpi. There were 15/45 vRNA positive lymph nodes at 60 dpi and 8/38 at 105 dpi. Reproductive and maternal fetal-interface (MFI) tissues were the second most commonly positive tissues. Twenty-five MFI tissues, including the amniotic/chorionic membrane, decidua, placenta, uterus, and placental bed, were positive, with 10/53 positive at 30 dpi, 14/24 positive at 60 dpi and 1/47 positive at 105 dpi. Other vRNA positive tissues included the primary bronchus, femoral vein, kidney, thyroid, lung, colon, mammary gland, pericardium, hand nerve, and sciatic nerve in 1–2 RMs at one of the three timepoints. Conclusions We found ZIKV RNA most frequently within lymph nodes. Lymph nodes are included in lung and small bowel transplants, indicating that these transplants could pose a risk of donor-derived ZIKV transmission. Virus detection within other commonly transplanted tissues, such as the kidney and blood vessels was much less common. We did not determine what fraction of vRNA comes from replication-competent virus in each tissue; some tissues with vRNA might not contain virions that could initiate new infections. Donor-derived Zika virus transmission from other commonly transplanted organs, such as the liver, seems unlikely since no viral RNA was detected in this organ.

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Readiness for an Increase in Congenital Zika Virus Infections in the United States: Geographic Distance to Pediatric Subspecialist Care

Disaster Medicine and Public Health Preparedness ◽

10.1017/dmp.2018.77 ◽

2018 ◽

Vol 13 (03) ◽

pp. 476-486 ◽

Cited By ~ 1

Author(s):

Jeanne Bertolli ◽

Joseph Holbrook ◽

Nina D. Dutton ◽

Bryant Jones ◽

Nicole F. Dowling ◽

...

Keyword(s):

United States ◽

Zika Virus ◽

Full Range ◽

Geographic Distance ◽

Virus Transmission ◽

The United States ◽

Travel Distance ◽

Mosquito Vector ◽

Children's Hospital ◽

Children’S Hospital

ABSTRACTObjectiveThe study’s purpose was to investigate readiness for an increase in the congenital Zika infection (CZI) by describing the distribution of pediatric subspecialists needed for the care of children with CZI.MethodsWe applied county-level subspecialist counts to US maps, overlaying the geocoded locations of children’s hospitals to assess the correlation of hospital and subspecialist locations. We calculated travel distance from census tract centroids to the nearest in-state children’s hospital by state (with/without > 100 reported adult Zika virus cases) and by regions corresponding to the likely local Zika virus transmission area and to the full range of the mosquito vector. Travel distance percentiles reflect the population of children < 5 years old.ResultsOverall, 95% of pediatric subspecialists across the United States are located in the same county or neighboring county as a children’s hospital. In the states where Zika virus transmission is likely, 25% of children must travel more than 50 miles for subspecialty care; in one state, 50% of children must travel > 100 miles.ConclusionThe travel distance to pediatric subspecialty care varies widely by state and is likely to be an access barrier in some areas, particularly states bordering the Gulf of Mexico, which may have increasing numbers of CZI cases. (Disaster Med Public Health Preparedness. 2019;13:476-486)

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Infection via mosquito bite alters Zika virus tissue tropism and replication kinetics in rhesus macaques

Nature Communications ◽

10.1038/s41467-017-02222-8 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 52

Author(s):

Dawn M. Dudley ◽

Christina M. Newman ◽

Joseph Lalli ◽

Laurel M. Stewart ◽

Michelle R. Koenig ◽

...

Keyword(s):

Zika Virus ◽

Rhesus Macaques ◽

Tissue Tropism ◽

Mosquito Bite

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Long-term protection of rhesus macaques from Zika virus reinfection

10.1101/712281 ◽

2019 ◽

Cited By ~ 2

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.

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Effects of In-Utero Zika Virus Transmission on the Development of Gait in Infant Rhesus Macaques

American Journal of Occupational Therapy ◽

10.5014/ajot.2020.74s1-po2132 ◽

2020 ◽

Vol 74 (4_Supplement_1) ◽

pp. 7411505107p1

Author(s):

Sabrina Kabakov ◽

Sarah Navin ◽

Natalie Dulaney ◽

Kathryn Bach ◽

Karla Ausderau

Keyword(s):

Zika Virus ◽

Rhesus Macaques ◽

Virus Transmission ◽

In Utero ◽

Infant Rhesus

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Travel Volume to the United States from Countries and U.S. Territories with Local Zika Virus Transmission

PLoS Currents ◽

10.1371/currents.outbreaks.ac6d0f8c9c35e88825c1a1147697531c ◽

2016 ◽

Cited By ~ 5

Author(s):

Bradley Nelson ◽

Stephanie Morrison ◽

Heather Joseph ◽

Abbey Wojno ◽

R. Ryan Lash ◽

...

Keyword(s):

United States ◽

Zika Virus ◽

Virus Transmission ◽

The United States

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx162.129 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S55-S55 ◽

Cited By ~ 4

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

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Oropharyngeal mucosal transmission of Zika virus in rhesus macaques

10.1101/107128 ◽

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.

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Genetic characterization of the Zika virus epidemic in the US Virgin Islands

10.1101/113100 ◽

2017 ◽

Cited By ~ 3

Author(s):

Allison Black ◽

Barney Potter ◽

Gytis Dudas ◽

Leora Feldstein ◽

Nathan D Grubaugh ◽

...

Keyword(s):

Zika Virus ◽

Draft Genome ◽

Virus Transmission ◽

The United States ◽

Virgin Islands ◽

Public Health Response ◽

Us Virgin Islands ◽

Department Of Health ◽

Health Response ◽

The Us

AbstractHere we release draft genome sequences of Zika virus (ZIKV) that were sequenced from PCR-positive diagnostic specimens collected by the United States Virgin Islands Department of Health (USVI DoH) as part of their ongoing response to the ZIKV outbreak. We will use these sequences to conduct a genomic epidemiological study of ZIKV transmission in the USVI. We are releasing these genomes in the hope that they are useful for those individuals involved in the public health response to ZIKV and to other groups working to understand Zika virus transmission and evolution.

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