We will examine ZIKV tissue tropism and the duration of ZIKV RNA detection in maternal tissues at three time points following first trimester ZIKV infection: 30, 65 and 105 days post-infection. This specific study, ZIKV-020, will examine ZIKV tissue tropism and the duration of ZIKV RNA detection at 105 days post-infection. We will also examine ZIKV tissue tropism in fetal tissues at the same time points.
Pregnant Indian-origin rhesus macaques will be challenged subcutaneously at approximately day 45 of gestation with 10E4 PFU ZIKV Puerto Rico (PRVABC59). Plasma, urine and saliva viral loads will be measured frequently immediately following infection, then weekly until pregnancy termination. CSF viral loads will be measured twice during pregnancy. Amniotic fluid viral loads will be measured once. The dam will undergo necropsy at 105 days post-ZIKV infection and multiple tissues will be evaluated for ZIKV RNA and infectious virus. Fetal tissues will also be evaluated for ZIKV RNA and infectious virus.
- 664184 was challenged with 10E4 PFU ZIKV-Puerto Rico strain subcutaneously on 8.18.2017, at 46 days of gestation
- 416597 fetus of 664184
- 484880 was challenged with 10E4 PFU ZIKV-Puerto Rico strain subcutaneously on 5.30.17, at 43 days of gestation
- 424847 fetus of 484880
- 795784 was challenged with 10E4 PFU ZIKV-Puerto Rico strain subcutaneously on 7.11.17, at 41 days of gestation
- 499874 fetus of 795784
- 918724 was challenged with 10E4 PFU ZIKV-Puerto Rico strain subcutaneously on 7.28.17, at 50 days of gestation
- 527421 fetus of 918724
- 730267 was challenged with 10E4 PFU ZIKV-Puerto Rico strain subcutaneously on 10.20.2017, at 44 days of gestation
- 226691 fetus of 730267
Clinical and Assay Data
Viral RNA quantification
- Plasma viral loads Chart
- Pan urine viral loads Chart
- CSF viral loads Chart
- Infant viral loads during the fist week of life Chart
- Indirect ophthalmoscopy and slit lamp exam with Dr. Nork - The cornea appeared thinner than what he's seen in other macaques, but unsure what the normal thickness is for neonatal macaque of this age. No anterior segment dysgenesis was observed. There was a persistent hyaloidal artery present, also seen in the ZIKV-021 infant, likely a normal finding in neonatal macaques.
- Ocular coherence tomography with Carol Rasmussen - There were some areas in small retinal vessels that looked like there were microaneurysms, consistent with what they would expect from vaginal birth trauma, but this animal had a C-section. This was also seen in the ZIKV-021 infant, so it may be a normal finding. Image 1| Image 2
- Electroretinography and visual evoked potentials with Dr. Ver Hoeve - There was cone receptor activity in response to light, though at a lower level than they've seen in older macaques. This may be due to immaturity of the cone photoreceptors, so having age-matched controls will be key.Report of the traces recorded. Comparison traces from an adult cyno.
- 424847 - No hearing was able to evaluated due to unforeseen technical issues.
- December 15, 2016: One macaque is in breeding currently.
- 484880 is scheduled to be challenged on May 30, 2017 with 10E4 PFU ZIKV Puerto Rico (PRVABC59) via subcutaneous injection.
- May 30, 2017: 484880 was challenged with 10e4 PFU ZIKV PR at 43 days of gestation.
- June 2, 2017: The challenge was successful, 484880 has a positive plasma viral load at 1 DPI, quantification coming soon.
- 484880 reached peak plasma viremia at 4 days post infection with a plasma viral load of 1,430,000.0
- June 30, 2017: 795784, a pregnant dam, was added to the study and is scheduled to be challenged with 10E4 PFU ZIKV Puerto Rico on July 11, 2017 at 41 days of gestation.
- July 12, 2017: 795784 had a positive plasma viral load at 1 DPI, quantification coming soon.
- July 28, 2017: 918724 was challenged with 10e4 PFU ZIKV PR at 50 days of gestation.
- August 15, 2017: The fetus of animal 918724 developed hydrops as demonstrated by subcutaneous edema and pericardial effusion on ultrasound a week ago, so a parvovirus PCR was tested on maternal blood and it was negative. On August 22, the hydrops looked as if it had resolved on ultrasound.
- August 18, 2017: 664184 was challenged with 10e4 PFU ZIKV PR at 46 days of gestation.
- September 19, 2017: 484880 underwent a C-section and an infant male macaque, 424847, was born. No apparent birth defects were noted on physical exam. This infant will undergo neurobehavioral, hearing, vision and brain imaging assessments during its first week of life. The Dam 484880 underwent a comprehensive necropsy following the C-section.
- September 27: 424847 underwent a comprehensive necropsy.
- October 20, 2017: 730267 was challenged with 10e4 PFU ZIKV PR at 44 days of gestation.
- Infant 499874
- November 2, 2017: 795784 underwent a C-section and an infant male macaque 499874 was born. The C-section was unremarkable. The infant had respiratory distress and required positive pressure ventilation for 60 min after birth, with desaturations down to 65% without the support. He did ok with blow by oxygen after that but still really needs that with desats to 70s when the blowby is removed. The vet staff tried lasix to remove extra fluid, a dose of steroids, and a chest x-ray. He will probably go into his incubator with an oxygen tube flowing inside.
- November 3, 2017: The infant appeared to be progressing well and was able to maintain oxygen saturation for longer periods of time. Respiratory rate remains elevated. No apparent respiratory distresses was observed during the neurobehavioral assessments. Neurobehavioral assessments showed the expected maturational gains in motor, attentional, temperamental, and activity domains. Muscle tone in upper and lower extremities was rated lower than would be expected. He showed an exaggerated Moro response.
- November 6, 2017: Infant 499874 continued to experience temperature regulations problems over the weekend and dehydration. Infant was able to be stabilized. Neurobehavioral assessments showed the expected maturational gains in motor, attentional, temperamental, and activity domains. The Moro reflex and auditory startle responses were exaggerated. A few minor asymmetries were noted in muscle tone and vestibular function.
- November 7, 2017: Infant 499874 underwent an ocular exam today and had difficulties recovering from the anesthesia and took longer than normal to recover from sedation. He required positive pressure ventilation and was given an IV. The infant did recover from sedation and was stabilized in an oxygen chamber. The infant remains under close clinical supervision. Images from the exam are found here.
- November 8, 2017: Infant 499874 is stable, but with a slightly elevated temperature. It was noted that the infants should be able to thermoregulate by now even though he was anesthetized, and that neonates of the same age are able to recover more quickly after being anesthetized for longer periods, for more sophisticated procedures. We are currently planning on euthanizing after the sedation for the MRI imaging on the 9th.
- November 9, 2017: Infant 499874 underwent a comprehensive necropsy. Lung abnormalities were noted with medial and caudal lobes that multi focally failed to deflate and were moderately harden and solid. Bacterial cultures taken from the lung came back positive. Amniotic fluid and placenta bacterial results were negative Results from bacterial cultures and histology are still being interpreted.
- November 9, 2017: 918724 underwent a C-section and an infant female 527421 was born. The C-section was unremarkable and no apparent birth defects were noted during the physical exam. This infant underwent neurobehavioral, hearing, vision and brain imaging assessments during its first week of life without any major complications. The Dam 918724 underwent a comprehensive necropsy following the C-section.
- November 13, 2017: 664184 miscarried. Comprehensive necropsies were preformed on both dam and fetus 416597 this occurred on day 133 day of gestation, 87 days post ZIKV infection.
- November 17, 2017: 527421underwent a comprehensive necropsy. No gross abnormalities were noted.