Zika in Latin America Jimmy Whitworth Department of Infectious Disease Epidemiology WCFSJ October 2017 Improving health worldwide www.lshtm.ac.uk

Zika virus epidemic in latin America 2015-2017 75 countries have reported recent transmission, WHO estimates 478,000 cases in 2016; 31,000 in 2017 (Jan-Jun) Spread beyond Latin America: Florida & Texas, Singapore, SE Asia WHO declared PHEIC Feb-Nov 2016 complications: Guillain-Barre syndrome. Congenital Zika Syndrome (microcephaly). Over 1900 confirmed cases Risk estimates of CZS vary from 6% (USA) to 46% (Brazil) Risk estimates of microcephaly 3-4% (10-11% in first trimester)

Zika virus Flavivirus (like dengue, yellow fever, west nile) Main life cycle in Africa: Aedes mosquitos and monkeys, Humans are occasional hosts. Original African lineage, subsequent Asian lineage Asian lineage in latin America Primary vector in urban settings: Aedes aegypti Competent vector: Aedes albopictus (and other species) Other routes of transmission: Trans-placental (mother to child) Sexual Blood transfusion (also needlestick) Day-biting mosquito

Zika 1947-2007 First isolated 1947 from rhesus monkey, Zika forest, Uganda 14 human cases reported up to 2007 Red: isolated from humans Yellow: human antibodies Green: isolated from mosquitos Hayes E B. Emerg Infect Dis. 2009 Sep;15(9):1347-50

Zika timeline: global

Zika timeline: the Americas Why is this important? Zika epidemic like this never seen before Affects mothers and unborn children Olympics?

Clinical presentation Most infections have no symptoms (80%) Non-specific viral illness Lasts less than 1 week Itchy rash, headache, muscle and joint pains, red sore eyes, mild fever Similar presentation to dengue (flavivirus) and Chikungunya These are also circulating in Brazil Diagnostic tests unreliable Blood tests of exposure cross-react with dengue, yellow fever vaccine, malaria Blood tests of infection insensitive after first week or two How reliable are the numbers of cases reported?

Emergency Committee convened by the Director-General under the Emergency Committee convened by the Director-General under the International Health Regulations (2005) held 1 February 2016 “Recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern” WHO statement 14 April 2016:“Based on a growing body of research there is scientific consensus that Zika virus is a cause of microcephaly and other congenital anomalies and Guillain-Barre syndrome”

Association or causation? Microcephaly cases occurring in same place and at same time as zika cases. Association Zika could be causing microcephaly or it might be due to something completely different – eg pesticides, water contamination Causation: Zika infection at time of pregnancy consistent with defects observed (CMV, Rub, Tox) Specific characteristics in babies with confirmed zika infection Biological plausibility, zika kills brain cells Zika isolated from brains of affected babies This makes causation likely but does not prove it. Still room for other theories

29% of Brazilian municipalities reported at least one case in 2015 Spatial distribution of suspected notified cases of microcephaly by municipality Nov 739 (738 NE) Jan 3530 (3130 NE) May 7438 (5706 NE) Mid Aug 9015 (6330 NE) 1 29% of Brazilian municipalities reported at least one case in 2015 http://portalsaude.saude.gov.br/

Congenital infections “Congenital Zika syndrome”: wider than microcephaly alone. Similarities with rubella and other congenital infections Cases range in severity; some babies have neurological abnormalities with normal head circumference. Some babies born normal size but do not grow. Small heads Constant irritability and crying Spasms and seizures Eye and ear defects Swallowing defects What happens when the babies get older? ZIKV Infection in Pregnant Women in Rio de Janeiro — Preliminary Report A report from the follow up of a cohort of pregnant women with rash illness was published in the past week.  Preliminary findings suggest that ZIKV infection during pregnancy appears to be associated with serious outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS injury

Control measures Focus is on preventing transmission Vector control: breeding sites, personal protection, biological and genetic control of mosquitos Advice: pregnancy, sex, blood products There is no vaccine or specific antiviral treatment Symptomatic treatment only Vaccines under development but years until clinical deployment

Vaccines Prevent infection, do not cure infections Specific for each infection (like an artificial infection) Creates artificial immunity May need multiple doses to boost immunity Usually take many years to develop Cell studies, toxicity, animal studies Human studies – small numbers: safety and dose, then larger numbers to prove they are effective. Needs natural challenge from infection to prove it works!

Zika vaccine 2015 – nothing! But work on related flaviviruses: dengue, West Nile Existing animal models, immune assays, vaccine designs 13 weeks to first in-human trial Now most advanced vaccine in intervention trial (2400 people) US, Peru, Brazil, Costa Rica, Panama, Mexico Few cases now, so hard to test. Need natural transmission causing real cases to prove vaccine works.

What has happened during this outbreak? With no vaccine and limited vector control measures epidemic will stay in latin America until it exhausts the pool of susceptibles: estimated that epidemic will be over within 3 years Confirmed cases in Brazil 2015 – 141,000 2016 – 478,000 2017 – 31,000 (Jan-Jun) In Salvador (NE Brazil) 60% have evidence of zika exposure, also 75% dengue and 5% chikungunya Epidemic has infected up to 2 million child-bearing women 10 s of thousands of babies could be affected How has birth rate been affected by outbreak? What is the risk at different stages of pregnancy? Challenge for society and health services in Americas: Support and linkage to care Babies and their families

Epidemic of scientific papers As numbers of cases of zika exploded so did the numbers of zika scientific papers Are they important? Studies on cells, animals, models, people Number of people – the more the better Type of study: case report, case series, case-control, cohort, controlled trial Journal, or press release? Peer reviewed?

What will happen next? Zika still present, but much reduced. Mostly affecting populations at northern (Mexico) and southern (Uruguay, Argentina, Chile, southern Brazil) margins, If reported numbers are reliable, epidemic is now over until enough children are born to sustain a new outbreak: probably over 10 years until next major epidemic It may move on. WHERE? Vector competence and density all of tropics and subtropics potentially at risk Potential distribution of Ae aegypti

Guillain-Barré Syndrome Increase in neurological and auto-immune conditions reported: mainly Guillain-Barré syndrome Rapid onset muscle weakness, starts in hands & feet and spreads Immune damage to peripheral nerves Rare complication of gastrointestinal or respiratory infections, also seen with dengue Can be life-threatening if affects breathing muscles Lasts about 1 week, most make full recovery Supportive care, ventilation Risk 0.24 cases/1000 infections (French Polynesia 2013/14) Consistent with risk after campylobacter GBS reported after zika in 14 countries Guillain-Barré syndrome (GBS) is an autoimmune condition in which the individual’s immune system inappropriately attacks components of their peripheral nerves. This results in muscle weakness in the legs and/or arms, which can spread to other parts of the body. GBS occurs worldwide but is a rare condition with an overall incidence of 0.4 to 4.0 per 100,000 people per year (WHO factsheet, 2016). People of all ages can be affected, but it is more common in adults and males. It is believed that GBS occurs when antibodies produced in response to an infection cross-react with peripheral nerve components, through molecular mimicry. Less commonly, GBS may be triggered by immunisation, surgery, trauma or bone marrow transplantation.

Why did zika emerge? Several non-exclusive hypotheses: Zika has evolved for enhanced mosquito transmission (seen in Chikungunya) Asian Zika has adapted for higher viraemia in humans (vertical transmission, neuropathology) Introduction into a naïve population susceptible to infection Previous exposure to Dengue may exacerbate Zika disease (some evidence, 43% amino acids identical) Human genetic predisposition in latin America Shan et al., An Infectious cDNA Clone of Zika Virus to Study Viral Virulence, Mosquito Transmission, and Antiviral Inhibitors, Cell Host & Microbe (2016 in press), http://dx.doi.org/10.1016/j.chom.2016.05.004