EPIDEMIC THE ZIKA. An Unprecedented Health Threat for Pregnant Women. Kristina Adams Waldorf, MD

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1 THE ZIKA EPIDEMIC the perfect s torm UW MEDICINE UNIVERSITY OF GOTHENBURG An Unprecedented Health Threat for Pregnant Women Kristina Adams Waldorf, MD Professor, Department of Obstetrics & Gynecology University of Washington, Seattle, WA, USA

2 DISCLOSURES None

3 ZIKA VIRUS: A GLOBAL PUBLIC HEALTH EMERGENCY February 2016: WHO declares Zika viral epidemic a public health emergency of international concern Clusters of Zika-associated microcephaly Rio Olympics were looming International research community responds In Jan 2016, ~50 total publications about Zika virus Now, ~50 publications per week

4 WHO LIFTED GLOBAL PUBLIC HEALTH EMERGENCY --It is a significant and enduring public health challenge, but it no longer represents an emergency. --If anything, this has been escalated in importance by becoming activities that will be continued longterm in the World Health Organization. --Zika is here to stay and WHO s response is here to stay in a very robust manner. WHO Zika Emergency Committee 30 countries reported birth defects linked to Zika virus 2,100 cases of confirmed microcephaly in Brazil alone

5 FIRST, GO TO YOUR HAPPY PLACE

6 CAN A VIRUS CAUSE MICROCEPHALY? McAdams and Adams Waldorf, Reproduction 2013;146:R151.

7 DISCOVERY OF ZIKA Zika Forest, Uganda First isolated 1947 in a rhesus monkey Zika forest, Uganda Transmitted by the bite of an Aedes aegypti mosquito Flavivirus related to Dengue, Yellow Fever, Chikungunya and Japanese Encephalitis Viruses Zika virus isolated from humans in Africa, Southeast Asia, Oceania, Americas Prior to 2007, only 14 cases of Zika documented in humans Simpson DI et al. Trans R Soc Trop Med Hyg 1964;58:335 8.

8 Mosquito-transmitted GLOBAL SPREAD OF ZIKA

9 2007: ZIKA OUTBREAK IN MICRONESIA Physicians on Yap Island reported outbreak of illness rash, pink eye, joint pain, unlike dengue Zika virus RNA in serum Yap: ~7,400 people About 16% of Yap island residents surveyed: 74% IgM antibody against Zika 38% reported an illness during outbreak period Duffy MR et al. NEJM 2009;360:2536.

10 EPIDEMIOLOGIC LINK WITH MICROCEPHALY IN BRAZIL Surge in cases of microcephaly in Brazil (~4,200 vs. 150 prior year) in tandem with Zika outbreak Zika isolated from amniotic fluid and placenta Cluster of microcephaly cases in 3 Northeastern States (Bahia, Paraíba and Pernambuco)

11 CASE REPORT: ZIKA IN THE FETAL BRAIN Fever at end of 1 st trimester in Brazil Patient moved back to Slovenia Ultrasound at 14 and 20 weeks was normal Ultrasound at weeks: Small brain (<2%) Fluid in brain Brain structures look blurred Zika virus genome in fetal brain Mlakar J. NEJM 2016;374:951-8.

12 THE USUAL MICROCEPHALY AND THE ZIKA BRAIN The usual microcephaly simply a small brain Zika microcephaly massive destruction and failure of normal brain development

13 CONGENITAL ZIKA VIRUS SYNDROME Microcephaly, Brain and Spinal Cord Injury Malformations of cortical development (Brain Disruption Sequence) Calcifications in cortex and subcortical white matter Ventriculomegaly Reduction in brain volume Hypoplasia of brainstem and cerebellum Thinning of the spinal cord and reduced ventral nerve roots Massive Ventriculomegaly Melo ASO et al. Ultrasound Obstet Gynecol 2016;47:6. O Leary DR et al. Pediatrics 2006;117:e537. de Fatima Vasco Aragao M, BMJ 2016;353:i1901. Van der Linden V et al, BMJ 2016;354:i3899.

14 CONGENITAL ZIKA VIRUS SYNDROME (continued) Stillbirth and neonatal death Fetal growth restriction Eye injury Neuroretinal atrophy Hearing loss Arthrogryposis Joint deformities Fixed postures in utero Severe Macular Neuroretinal Atrophy Ventura CV et al. Lancet 2016;387:228. Van der Linden V et al, BMJ 2016;354:i3899. Leal MC, Braz J Otorhinolaryngol 2016; S (16):

15 FETAL BRAIN DISRUPTION SEQUENCE

16 MICROCEPHALY AND ARTHROGRYPOSIS Well known to be induced by viruses, but also by toxins and insecticides Indicates cerebrospinal injury Courtesy of Dr. William Dobyns, Seattle Childrens Research Institute

17 RISK OF MICROCEPHALY IN PREGNANCY Polynesia ~8 cases of microcephaly per 270,000 pregnancies ~66% infection rate 0.9% risk Estimated risk in Brazil: % with 1 st trimester infection, but limited by: Difficulties in clinical confirmation of cases, with both underreporting and overreporting Evidence of fetal brain injury with infection in 2 nd and 3 rd trimesters late onset microcephaly Cauchemez S et al, Lancet Johansson MA et al, NEJM.

18 SEXUAL TRANSMISSION OF ZIKA VIRUS Zika virus detected in semen up to 181 days Reported sexual transmission of Zika: Male-to-female Male-to-male Female-to-male CDC and WHO now recommending men to avoid conception for 6 months after travel to an area with local Zika transmission

19 ZIKA THRIVES IN THE VAGINA Replication of Zika virus in the vagina of immunocompetent mice for up to 7 days Vaginal Zika virus infection in early pregnancy leads to fetal growth restriction and brain infection in mice Zika virus RNA detected in human vaginal fluids for 3 days and cervical mucus up to 11 days after symptom onset Yockey LJ et al, Cell Prisant N et al, Lancet Infect Dis 2016.

20 GUILLAIN-BARRE SYNDROME ASCENDING PARALYSIS Zika epidemic closely linked with spike in Guillain-Barre in each of 7 countries In a 3 month period in Venezuela, ~30,000 Zika infections reported and 680 Guillain-Barre cases (70 were expected) Population risk of Guillain-Barre increased ~2 to10-fold dossantos TM et al, NEJM.

21 FACTORS DRIVING INFECTION-ASSOCIATED FETAL INJURY Dose: How many mosquito bites? Inoculum per mosquito bite? Host inflammatory response at bite? Antibody-Dependent Enhancement: Prior exposure to a related flavivirus (like DENV) may boost viral load during subsequent ZIKV infection Host Factors: Immunocompromised host, placental susceptibility, nutrient deficiency, diminished integrity of blood-brain-barrier Viral Strain: Is the Brazilian ZIKV strain more virulent than the Ugandan strain?

22 CDC LEVEL 1 RESPONSE TO ZIKA CDC activated Level 1 response for their Emergency Operations Center, which it has only done four times for Hurricane Katrina, H1N1, Ebola, and now Zika the most complicated issue CDC has ever faced. Zika is a very challenging virus to fight, and the response is enormously complex. Dr. Tom Frieden, CDC Director

23 RESEARCH AREAS OF HIGH PRIORITY 1. Demonstrate cause and effect between Zika and fetal brain injury 2. Understand how Zika transmitted to fetus 3. 3 Understand how Zika affects developing nervous system and other organ systems 4. Characterize eye defects with fetal Zika infection 5. Pregnancy outcomes in women with Zika 6. 6 Studies to ascertain if Zika present in reproductive fluids (vaginal, semen) and how Zika enters the reproductive tract 7. 7 Vaccine development in pregnant women and children 8. Develop new diagnostic, vaccine and therapeutic strategies against Zika 8

24 FETAL BRAIN LESIONS AFTER ZIKA VIRUS INOCULATION OF A PREGNANT NONHUMAN PRIMATE IN LATE PREGNANCY

25 DIFFERENCES: MURINE VS. HUMAN PREGNANCY Different sensitivities to certain pathogens Maternal-fetal interface Physiology of labor Reproductive tract Gestation number Drug toxicity Placentation

26 PROGRAM OBJECTIVES Macaca nemestrina Pigtail macaque 11. Establish a causal relationship between ZIKV and fetal brain injury in a NHP model 22. Define how maternal ZIKV infection suppresses antiviral responses in mother, placenta and fetus 33. Determine immunologic correlates of ZIKV infection, which facilitate penetration of the blood-brain barrier and fetal injury 44. Determine mechanisms of fetal brain injury 55. Test new therapeutics for prevention of congenital ZIKV syndrome

27 HYPOTHESIS Subcutaneous inoculation of ZIKV into a pregnant pigtail macaque will induce injury and arrest growth of the fetal brain Aedes aegypti

28 METHODS Five subcutaneous inoculations of 10 7 PFU ZIKV at 119 days gestation (~28 weeks/early 3 rd tri.) ZIKV strain FSS13025, Cambodia 2010 Cesarean section and necropsy at 162 days gestation (10 days before due date ) Serial fetal ultrasound and MRI Comprehensive histopathology of fetus and dam, flow cytometry of fluids/tissues ZIKV assayed and quantified by qrt-pcr, RNA-Seq and IF

29 FETAL BRAIN GROWTH ARREST BIPARIETAL DIAMETER FEMUR LENGTH Marked change in trajectory of fetal brain growth (loss of 3 SD) versus continued growth of the femur. Adams Waldorf et al. Nature Medicine, in press. Conrad S. Am J Primatol 1995;36:15.

30 FETAL BRAIN LESIONS BY MRI Adams Waldorf et al. Nature Medicine, in press

31 GROWTH ARREST OF WHITE MATTER No change in white matter volume over last 3 weeks Gray matter volume continued to increase Persistence of large posterior ventricular CSF spaces (normally contract)

32 HISTOPATHOLOGY OF FETAL BRAIN Marked deficiency of white matter posteriorly in comparison to controls White matter gliosis, many apoptotic figures Increased density of GFAP + astrocytes and CD163 + microglial cells Axonal spheroids Enrichment of astrocytes in fetal brain (flow cytometry) Adams Waldorf et al. Nature Medicine, in press

33 ZIKV RNA IN PLACENTA, FETAL BRAIN, LIVER Dam (mother) seropositive for ZIKV-IgG 14 days post-inoculation, fetus seropositive at birth By qrt-pcr, ZIKV RNA in: placenta fetal brain, eyes, testes maternal brain, eyes, kidney RNA-Seq of dam and fetal brain complete coverage of viral reads spanning ZIKV FSS13025 genome Adams Waldorf et al. Nature Medicine, in press

34 CONCLUSIONS First case of fetal brain injury in a nonhuman primate after maternal ZIKV infection Consistent with congenital ZIKV syndrome: Arrested fetal brain growth White matter injury ZIKV RNA in multiple fetal organs Pigtail macaque may have utility for testing novel therapeutics to prevent ZIKV vertical transmission

35 INTERNATIONAL SPREAD OF ZIKA >2 billion people in areas at risk for Zika ~2 million pregnancies at risk Bogoch I et al. Lancet 2016;387:336. Messina JP et al.

36 ZIKA VIRUS VACCINE Good news! - ZIKV strains are similar and people develop natural immunity after infection Bad news! - Antibody dependent enhancement - vaccination against ZIKV may worse a subsequent related flaviviral infection - NIH/Dr. Fauci Naked-DNA vaccine strategy - Fast, easy to make, but may not be strong enough. - Technically challenging to produce A LOT of vaccine

37 IMMUNE SYSTEM PATHWAYS MIGHT BE DRUG TARGETS Cytoplasm RIG-I MDA5 LGP2 MAVS IRF-3 NF-κB Adapted from Suthar et al., 2013 Nucleus Immune system effector genes

38 PROPHYLACTIC THERAPY Small molecule compounds that can activate the body s antiviral response (e.g. RIG-I agonist) to the Zika virus, but also many other viruses Neutralizing antibody to ZIKV intravenous antibody infusion before the trip to Costa Rica? Sapparapu G et al. Nature 2016 doi: /nature20564

39 OUR TEAM University of Washington Kristina Adams Waldorf Michael Gale, Jr Jennifer Stencel-Baerenwald Jennifer Tisoncik-Go Michael Davis Elyse Dewey Marian Fairgrieve Rich Green Katharina Esser-Nobis Justin Roby Michael Gough Jason Ogle Chris English Audrey Baldessari Wonsok Lee Richard Grant LaRene Kuller Acknowledgments Neonatology Sandra Juul Colin Studholme Pratikh Parikh Neurology Gwenn Garden Stephanie Hopkins Diagnostic Imaging Sciences Center Todd Richards Chris Gatenby Radiology Manjiri Dighe Jeff Thiel Dennis Shaw Lakshmi Rajagopal Erica Boldenow Jay Vornhagen Blair Armistead Sean Merillat Claire Gendrin Adrian Piliponsky William Dobyns Neurological Surgery and Pathology Robert Hevner Raj Kapur

40 OUR TEAM Kristina Adams Waldorf Acknowledgments Lara Brandão: Robert Tesh: Ann Powers: Neuroradiologist, Clinica Felippe Mattoso, Grupo Fleury, Rio de Janeiro, Brazil University of Texas Medical Branch at Galveston/ World Reference Center for Emerging Viruses and Arbovirus Centers for Disease Control Funding Sources Grant #s R01AI100989, AI104002, AI083019, AI104002, HD007233, AI07509, P51OD010425