Wrapping Our Heads Around the Outbreak An Update on the Zika Virus P. Zach White, PharmD PGY1 Pharmacy Resident Mayo Eugenio Litta Children s Hospital Pharmacy Grand Rounds June 7, 2016 2015 MFMER slide-1
In the news WHO: World Health Organization CDC: Center for Disease Control 2015 MFMER slide-2
Objectives Discuss the epidemiology and prevalence of Zika virus (ZKV) Describe the fetal complications of ZKV List the challenges encountered when manufacturing a vaccine for ZKV 2015 MFMER slide-3
Zika Virus Timeline 1947 1952 Discovered in the Zika Forest of Uganda First human case detected 2007 First outbreak in Micronesia 2013 to 2015 Various outbreaks in French Polynesia and South Pacific May 2015 Feb 2016 Dec 2016 First identification in Brazil WHO declared ZKV a Public Health Emergency of International Concern WHO predicts first vector-borne cases in the United States WHO: World Health Organization ZKV: Zika virus Emerg Infect Dis. 2009 Sep;15(9):1347-50. PLoS Negl Trop Dis. 2014;8(1):e2636 Clin Microbiol Infect. 2014 Oct;20(10):O595-6 2015 MFMER slide-4
Background Flavivirus - same family as West Nile virus, dengue, tick-borne encephalitis & yellow fever Aedes aegypti mosquito Aggressive in daytime hours Dengue and chikungunya viruses In 2015, Brazil noticed 20-fold increase in microcephaly Higher incidence of Guillain-Barré syndrome reported by Brazil Ministry of Health Ultrasound Obstet Gynecol. 2016 Jan;47(1):6-7 Center for Disease Control and Prevention 2015 MFMER slide-5
Transmission Mosquitos Pregnancy Sexual contact Blood transfusions Saliva? Center for Disease Control and Prevention Oral Dis. 2016 May 27 2015 MFMER slide-6
Active Zika Virus Center for Disease Control and Prevention Accessed 27 May 2016 2015 MFMER slide-7
Zika Virus in the United States Total cases: 618 50 States Travel-associated cases: 618 Locally-acquired vector-borne cases: 0 Guillain-Barré syndrome: 1 Pregnant women: 195 Sexually transmitted: 11 Total cases: 1,114 U.S. Territories Travel-associated cases: 4 Locally-acquired vector-borne cases: 1,110 Guillain-Barré syndrome: 8 Pregnant women: 146 Minnesota: 17 Wisconsin: 2 Arizona: 3 Florida: 128 Iowa: 6 Center for Disease Control and Prevention Accessed 5 June 2016 2015 MFMER slide-8
Zika in the United States We conducted a single-center, retrospective chart review for all VLBW neonates from October 2011-March 2013 and April 2014-October 2015 and compared dexamethasone exposure specifics when prescribed for BPD prevention. The primary outcome was the difference in prescribing rates of dexamethasone for infants still intubated at day of life (DOL) 10. Secondary outcomes looked at mg/kg cumulative dexamethasone use, dexamethasone duration, DOL at time of dexamethasone initiation, and prescriber compliance to the order set. Center for Disease Control and Prevention Accessed 5 June 2016 2015 MFMER slide-9
Assessment Question All of the continental United States Zika cases have been travel-associated? A) True B) False 2015 MFMER slide-10
Maternal Signs and Symptoms 20% of infected patients are symptomatic Underdiagnosed or misdiagnosed as other viral illness Common symptoms include fever, rash, joint pain, conjunctivitis, myalgias, and headache Symptom duration of four to seven days Guillain-Barré symptoms may include bilateral extremity weakness & facial muscle weakness Complications requiring hospitalization are rare Zero fatalities to date Oral Dis. 2016 May 27 Clin Rev Allergy Immunol. 2016 May 28 2015 MFMER slide-11
Testing Laboratory diagnosis of serum or plasma Virus, viral RNA, viral-specific IgM ZKV present in blood up to 7 days after symptom onset Serum samples > 7 days can be tested for antibodies Viral RNA in urine up to 10 days after onset Identification and confirmation of ZKV-specific antibody is difficult High cross-reactivity with Flavivirus antibody assays IgM: immunoglobulin M N Engl J Med 2016; 374:1801-1803 2015 MFMER slide-12
Treatment Prevention Minimize mosquito bites during the first week of infection to prevent spread of the virus Prevent sexual transmission by using condoms for 8 weeks Supportive Get plenty of rest Drink fluids to prevent dehydration Acetaminophen to reduce fever and pain Avoid aspirin and other NSAIDs until dengue is ruled out to reduce bleeding risk NSAIDs: nonsteroidal anti-inflammatory drugs Center for Disease Control and Prevention 2015 MFMER slide-13
Mother and Baby Placental transfer of ZKV in all trimesters Major morphological changes occur in 1 st trimester CNS development in all stages Causes fetal microcephaly & severe brain defects Pregnant patients should see their doctor if symptomatic within 14 days of traveling Women should wait 8 weeks after exposure before trying to get pregnant No reports of ZKV transfer through breastmilk Benefits continue to outweigh the risks ZKV: Zika virus World Health Organization DOI: 10.1056/NEJMoa1602412 2015 MFMER slide-14
Fetal Complications Center for Disease Control and Prevention, National Center on Birth Defects and Development Disabilities 2015 MFMER slide-15
Secondary Complications Seizures Developmental delay Vision problems Hearing loss Movement and balance issues Feeding difficulties 2015 MFMER slide-16
Breaking and Entering Zika Virus AXL Receptors Infection of neural progenitors Neurotropism Microcephaly Cell Stem Cell Volume 18; 587-596 2015 MFMER slide-17
Zika-Induced Microcephaly Preliminary report in Rio De Janeiro 12 of 42 (29%) of ZKV-positive women had fetal abnormalities noticed on ultrasound Abnormalities included fetal death, placental insufficiency, fetal growth restriction and CNS injury Retrospective review of the French Polynesia outbreak in 2013-2014 66% of the general population was exposed to Zika Baseline prevalence of microcephaly: 2 cases per 10,000 Microcephaly from 1 st trimester exposure: 95 cases per 10,000 The Lancet, Volume 387, Issue 10033, 2125-32 DOI: 10.1056/NEJMoa1602412 2015 MFMER slide-18
Data Collection and Reporting There are two objects of medical education: To heal the sick, and to advance the science Charles H. Mayo 2015 MFMER slide-19
United States Zika Registry Created by the CDC to better understand ZKV Collaboration with state, tribal, local and territorial health departments Aim is to collect information about pregnancy and infant outcomes Data will be used to: Update recommendations Plan for services Reduce incidence of ZKV during pregnancy CDC: Center for Disease Control ZKV: Zika virus 2015 MFMER slide-20
United States Zika Registry Registry inclusion Pregnant women with laboratory evidence of ZKV with or without symptoms Prenatally or perinatally exposed infants born to these women Infants with laboratory evidence of congenital ZKV regardless of symptoms and their mothers Includes positive or inconclusive tests ZKV: Zika virus Center for Disease Control and Prevention Accessed 1 June 2016 2015 MFMER slide-21
Obstetrics Providers Pediatric Providers Identify suspected pregnancy exposure Identify suspected congenital infant exposure Collect pertinent information Collect pertinent information Note adverse effects (i.e. spontaneous abortion or termination of pregnancy) Note adverse effects (i.e. perinatal or infant deaths, microcephaly, developmental delay) Report to appropriate health department Center for Disease Control and Prevention Accessed 1 June 2016 2015 MFMER slide-22
Reporting the Data Laboratory-confirmed cases State, tribal, local, or territorial health department Suspected cases Consult the CDC Zika Pregnancy Hotline (770) 488-7100 or ZikaPregnancy@cdc.gov CDC will then inform the health department CDC: Center for Disease Control 2015 MFMER slide-23
Assessment Question Which of the following statements is true? A) Common symptoms of ZKV include joint pain, conjunctivitis, and myalgia B) Breastfeeding should be discouraged in a mother with confirmed ZKV C) Laboratory-confirmed ZKV cases should be reported directly to the CDC D) Treatment includes antipyretics (i.e. NSAIDs) NSAIDs: nonsteroidal anti-inflammatory drugs 2015 MFMER slide-24
Ideal Qualities of Any Vaccine Developed, produced and delivered in large volumes Low processing costs Safe and efficient distribution Short development and delivery times Safe and effective BioPharm Intl. 21 (1) s1 s6 (2008) 2015 MFMER slide-25
Bioprocessing Basics Upstream Downstream Cell isolation Clarification of virus Inactivation Concentration Media preparation Preservative stabilizer Formulation Contaminant removal Antigen Growth Sterile filtration Fill and finish Cell harvest Ray et al. BioPharm International Supplements; Oct 2011 2015 MFMER slide-26
New Vaccine Manufacturing Challenges No history or experience with patient response Promising animal models do not often correlate to effectiveness in humans New, specific biological assay required to validate activity of virus and assure quality control Contaminant removal must be documented Adventitious agents must be removed or inactivated Increased production costs for manufacturers BioPharm Intl. 21 (1) s1 s6 (2008) Nat Biotechnol. 2006 Nov;24(11):1377-83. 2015 MFMER slide-27
Zika Vaccine Challenges Knowledge of the disease is lacking 25 PubMed articles published between 1952-2009 225 PubMed articles published between January May Lack of reliable animal models Lack of reliable biological assays Complex human response to flaviviruses One infection or vaccination against one flavivirus can enhance a secondary severe infection N Engl J Med 2016; 374:1801-1803 2015 MFMER slide-28
Zika Vaccine Research Approaches 1) DNA-based vaccine Similar to investigational flavivirus vaccine for West Nile Safe and effective in Phase I trial 2) Genetically engineered vesicular stomatitis virus (VSV) vaccine Same approach used for investigational Ebola vaccine Planning stages 3) Whole-particle, inactivated Zika vaccine Similar approach used for Japanese encephalitis and dengue viruses National Institute of Allergy and Infectious Diseases 2015 MFMER slide-29
Approaches, continued 4) Live-attenuated vaccine Promising Phase III trials shown in Brazil for similar dengue virus Advantages Closely mimics natural infection Strong antibody response Lifelong immunity in 1-2 doses Easier to create for viruses Viruses mutate Disadvantages Revert back to virulent form and cause disease Shouldn t administer in immunosuppressed patients Refrigeration to keep potency National Institute of Allergy and Infectious Diseases 2015 MFMER slide-30
Assessment Question Which of the following are challenges of manufacturing a ZKV vaccine? A) Lack of knowledge about the disease state B) A complex human response to flaviviruses C) Underdiagnosed disease state D) All of the above 2015 MFMER slide-31
Sources of Information Center for Disease Control website Bulletin of the World Health Organization Per protocol for public health emergencies of international concern Primary literature not yet approved for publication Unrestricted use, distribution and reproduction Ask Mayo Expert PubMed 2015 MFMER slide-32
Conclusion All ZKV cases in the continental U.S. have been travel-associated ZVK has been linked to increase incidence of microcephaly in newborns Expecting mothers should avoid areas with ZKV outbreaks Healthcare providers should utilize the Zika Registry Multiple challenges need to be overcome before a Zika vaccine is made available 2015 MFMER slide-33
Questions and Discussion White.Phillip@mayo.edu 2015 MFMER slide-34